ALBERT

Description: Introduction: Patients with portal vein thrombosis (PVT) are frequently referred to hematology for hypercoagulable evaluation. The prevalence of identifiable thrombophilic conditions in patients with PVT is not well reported and the clinical impact of thrombophilia testing is unknown. Methods: We conducted a retrospective review of patients at a single tertiary care center. Patients were identified who had a documented PVT with or without concurrent thrombosis in additional splanchnic vessels, followed between 1/1/2000 and 5/1/2019 with at least 3-month follow-up available. Exclusion criteria included liver transplantation within 6 months of PVT and inadequate documentation. Changes in clinical management were determined by chart review and determination of documented change in choice, dose, or duration of anticoagulant, future thromboprophylaxis, or counseling of asymptomatic family members as documented in the medical chart. Results: Baseline characteristics of the entire cohort are summarized in Table 1. Five-hundred and forty-four unique patients were identified. Most patients had an isolated PVT (55.3%). The most common concurrent vessel thrombosed was the superior mesenteric vein (36.9%). Cirrhosis was the most common predisposing provoking condition, followed by recent abdominal surgery and inflammatory bowel disease. Of note, 106 patients (19.4%) had no identifiable underlying provoking factor. Two-hundred ninety-one patients (53.5%) had at least one hypercoagulable laboratory test performed, with a median number of 8 tests (Table 2). PAI-1 polymorphism was the most common positive thrombophilia test, followed by MTHFR mutation and an elevated homocysteine. Of note, these three test abnormalities have not been consistently linked to increased thrombotic potential. Identification of a JAK2 mutation was noted in 16.7% of patients tested and was detected in 37% of patients without a predisposing provoking factor prior to testing. No patients harbored a mutated CALR and MPL. In patients without a predisposing provoking factor who had thrombophilia testing performed (n=98), thrombophilia testing was positive in 59 patients (60.2%). Of note, 39 patients (40.0%) of these patients had a negative thrombophilia evaluation. In patients with thrombophilia testing (n=291), only 41 (14.1%) patients had a test result which impacted management. By far the most common positive-management altering test was JAK2 mutational testing, with 33 patients receiving further workup including a bone marrow biopsy and/or treatment of an underlying MPN as a result of testing. One patient who was diagnosed with paroxysmal nocturnal hemoglobinuria (PNH) received treatment with eculizumab. Two patients with antiphospholipid antibody syndrome were specifically administered coumadin as a result of testing. One patient with Factor V Leiden was anticoagulated for a longer duration, two received thromboprophylaxis during subsequent high-risk situations (which may have been done regardless of Factor V Leiden mutation), and one had screening performed on an asymptomatic family member. One patient with MTHFR mutation and elevated homocysteine received folate supplementation. Conclusions: These results demonstrate that nearly all hypercoagulable laboratory testing in patients with PVT is not of clinical utility. The most notable exception is JAK2 mutational testing, which appears to be an essential component in the workup of PVT without an obvious provoking factor both because of its relatively high frequency of occurrence and its significant impact on clinical management. In addition, while PNH and APLS are rarely positive in thrombophilia evaluation of PVT, they likely merit evaluation in appropriate clinical settings given their potential to meaningfully impact management. Extensive thrombophilia testing does not appear to reliably impact management. Disclosures Kremyanskaya: Incyte, Celgene, Constellation, Protagonist.: Research Funding; La Jolla: Consultancy.

Description: Introduction: Hypomethylating agents (HMAs) are used as induction therapy for patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. HMA therapy is frequently initiated in the hospital and some patients remain hospitalized through the initiation of cycle 2 (C2). Clinicians are often faced with the decision to administer C2 while the patient is still hospitalized, however, there is a paucity of prognostic information to guide treatment decisions in this common scenario. Methods: We conducted a retrospective review of patients diagnosed with treatment naïve, de novo and secondary AML who were ineligible for induction chemotherapy (at the discretion of the treating physician based on advanced age, comorbidities, or other reasons) at a single, tertiary, referral center. Patients were included if they received induction therapy with an HMA, including azacitidine and decitabine between 7/1/2008 and 7/1/2018. Exclusion criteria included receipt of intensive induction chemotherapy and inadequate electronic medical documentation. Patients were divided into four groups: patients who were discharged after completion of C1 and received C2 as an outpatient (discharged after C1), patients who received C1 and C2 during the same hospitalization (C1-C2 continuous hospitalization), those who received one total cycle (C1 only), and patients who received C1 as an outpatient (C1 outpatient). The groups were analyzed separately for the primary outcome of overall survival (OS), calculated by Kaplan Meier analysis. Results: Out of 105 patients identified who received an HMA, 100 patients were identified who met inclusion/exclusion criteria and their baseline characteristics are shown in Table 1. Most patients had de novo AML (39.0%), although 33.0% and 19.0% of patients had AML secondary to myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN), respectively. Additionally, 8 patients (8.0%) had therapy related AML. The majority of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or 2 at induction. Patients who received C1 as an outpatient had a significantly better performance status than those who did not (p= 0.033) Decitabine was the most common HMA (57.0%) administered and was most often on 5-day schedule. Eight patients (8.0%) were continually hospitalized until C2, 5 because of active medical issues (most often fevers requiring intravenous antibiotics), 2 had physical debility precluding discharge home, and 1 was receiving intrathecal chemotherapy twice weekly for central nervous system involvement of AML. The median OS was 15.6 months (95% CI 2.66-28.6) in patients who received C1 outpatient, 10 months (95% CI 6.67-13.43) in patients discharged after C1, 4 months (95% CI 2.40-6.40) in the C1-C2 continuous hospitalization group, and 1 month (95% CI 0.61-1.30) in those who only received C1 as shown in Figure 1. Patients discharged after C1 had a significantly longer OS compared to the C1-C2 continuous hospitalization group (p=0.003). There was a trend (p=0.054) towards worse survival in patients who received C1 only compared to patients hospitalized continually from C1-C2. Conclusions: Continued hospitalization from C1 to C2 of HMA therapy led to an extremely poor median survival of 4 months in this cohort, compared to 10 months in patients who were able to be discharged after C1 and receive C2 as an outpatient. Patients who only received a single cycle of HMA did not have a significantly different survival as compared to patients who were continually hospitalized from C1 to C2. While this is a small retrospective series, these data suggest that AML patients still requiring hospitalization at time of C2 of HMA therapy should be re-evaluated for alternative therapeutic approaches including hospice given poorer outcomes. Although this grouping selects for patients who are sicker and unable to leave the hospital, there is apparent lack of significant benefit of continued HMA therapy in the majority of patients while inpatient. The impact on hospital length of stay, unnecessary utilization of healthcare resources, and patient's quality of life should also be considered in these cases. Prospective identification of these patients with a poorer prognosis could lead to better alternatives for therapeutic approaches. Disclosures Kremyanskaya: Incyte, Celgene, Constellation, Protagonist.: Research Funding; La Jolla: Consultancy. Navada:Onconova Therapeutics Inc: Research Funding. Mascarenhas:Merus: Research Funding; Pharmaessentia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Promedior: Research Funding; Roche: Consultancy, Research Funding; Janssen: Research Funding; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Background: PRM-151 (PRM) is a recombinant form of pentraxin-2, an endogenous human protein that acts at sites of tissue damage, inducing macrophage differentiation to prevent and reverse fibrosis. 27 patients with primary myelofibrosis (MF), post-essential thrombocythemia MF, or post-polycythemia vera MF and Grade 2 or 3 bone marrow (BM) fibrosis enrolled in the first stage of a 2-stage adaptive trial in which PRM-151 10 mg/kg IV was administered for 24 weeks in four different arms: PRM-151 QW (n=8), PRM-151 Q4W (n=7), PRM-151 QW + ruxolitinib (RUX) (n=6), or PRM-151 Q4W + RUX (n=6). At 24 weeks, reductions in BM fibrosis, improvements in hemoglobin (Hgb) and platelets (PLT), decreases in symptoms (MPN-SAF Total Symptom Score [TSS]), and modest reductions in spleen size by palpation were observed in all arms, with a favorable safety profile (Verstovsek, ASH 2014, Abstract 713). Patients experiencing clinical benefit were allowed to continue beyond 24 weeks. We now report efficacy and safety in 13 patients who have completed at least 72 weeks of treatment. Bone marrow fibrosis status by morphologic WHO grading and computer-assisted image analysis (CIA) are available up to 48 weeks in some patients, as assessed by central hematopathologist reviewers blinded to patient, treatment, and timepoint. BM data through 72 weeks is pending. WHO response was defined as ≥1 grade reduction in MF grade at any time and CIA response was defined as a decrease in the % fibrosis compared to baseline with a negative slope 〉 1. (Pozdnyakova, EHA 2015, Abstract P677). Baseline Demographics (N=13): Median age 60 (51-76); 46% DIPSS Int-1, 54% DIPSS Int-2; 62% PMF, 15% post-ET MF, 23% post-PV MF; 46% grade 3 BM fibrosis, Hgb 〈 100 g/L in 38%, PLT 〈 100 x 109/L in 69% and 12 weeks. (Figure 4) Safety (N=13): Most common adverse events (AEs) regardless of relatedness were fatigue (4), nausea (3), fever (3), cough (2), diarrhea (2), tooth infection (2), headache (2), upper respiratory infection (2), hyperglycemia (2), and hyperuricemia (2). There were 13 possibly or probably related adverse events in 3 patients from beginning of study through 71 weeks, 11 Grade 1, 1 Grade 2 and 1 Grade 3, with no event occurring in 〉 1 patient. There were no related serious AEs in these patients. Conclusion: In 13 patients completing at least 72 weeks, PRM-151 treatment was well tolerated, and improvements in Hgb, PLT, symptoms and spleen appeared to increase with longer treatment duration. Disclosures Mesa: Novartis Pharmaceuticals Corporation: Consultancy; NS Pharma: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Genentech: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding; Pfizer: Research Funding. Foltz:Promedior: Research Funding. Gupta:Incyte Corporation: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Promedior: Research Funding. Mascarenhas:Kalobios: Research Funding; Roche: Research Funding; Promedior: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding. Ritchie:Incyte: Speakers Bureau; Celgene: Speakers Bureau. Hoffman:All Cells, LLC: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Promedior: Research Funding. Silver:Promedior: Research Funding. Pozdnyakova:Promedior: Consultancy. Hasserjian:Promedior: Consultancy. Trehu:Promedior: Employment, Equity Ownership. Salama:Promedior: Consultancy. Gotlib:Allakos, Inc.: Consultancy.

Description: Hematopoietic stem cells located in spleens (SP) of patients with myelofibrosis (MF) have functional properties that differ from those present in peripheral blood (PB) (Wang et al, JCI,122: 3888, 2012 ). We hypothesized that the spleen might be a source of malignant stem cells in MF which ultimately lead to disease progression and leukemic transformation. To investigate the genetic diversity of MF SP cells, cytogenetic analyses of SP and peripheral blood (PB )/bone marrow (BM) cells from 13 MF patients were performed. Nine of 13 patients (69%) had concordant normal (n=5) and abnormal (n=4) cytogenetic and FISH analyses when comparing SP and PB/BM cells. Four (30%) patients had discordant results with specific chromosomal abnormalities present in either SP or PB cells. One patient had 3 cytogenetic abnormalities associated with an unfavorable prognosis: (1;7), del(12p), and i(17q) in SP cells that were not observed in PB cells. A second patient who had progressed to acute leukemia had pentasomy 21 in 45% of SP cells but not in PB cells and had del (20q) in PB cells but not SP cells, suggesting that del (20q) had arisen in the BM while pentasomy 21 had originated in the SP . In a third patent 20% of PB cells had +8 while only 1.6% of SP cells had +8, indicating that the +8 clone originated in the BM. Studies of BM and PB of the 4 th patient showed a normal karyotype in 2008 and 2011 while 2% of SP cells in 2011, at the time of progression to MF, possessed del 20q while the BM remained normal. In 2014, when the patient developed an accelerated phase of MF, 85% of BM cells possessed del (20q), indicating that del(20q) originated in the SP and migrated to the BM. We next hybridized SP DNA from 12 of the 13 patients to the Agilent 400k platform [355515 (CGH) + 59646 (SNP)] and performed CGH and SNP analysis. These studies revealed that all 12 patients had additional gains and losses of chromosomal regions as well as uniparental disomy (UPD) in SP cells. Two groups of acquired genomic changes were observed in SP cells: 1) four acquired regions were present in over 60% of pts and 2) three regions of acquired changes were observed in 25- 33% of patients. Irrespective of the patient’s karyotype, gains of 4 chromosomal regions: 1p13.2 (RHOC), 12q24.31 (NCOR2), 13q34 (RASA3) and 17q12 (TAF15) were detected in 83%, 83%, 75% and 67%, of patient’s SP cells, respectively. All four genes are known to be involved in leukemogenesis. Gains of these 4 chromosomal regions have not been observed in normal controls or PB CD34+ cells from 437 patients with MPNs including MF (Klampfl et al, Blood 167, 2011, Rumi et al Am J Hematol 974, 2011). Gains of an additional three regions, 18q21.31 (NEDD4L), 16q23.2 (WWOX) and 17q21.31 (WNT3) were detected in the SP cells of 25-33% of patients. These genes have also been implicated in leukemogenesis. The greater the complexity of the karyotype of the SP cells the greater the number of copy number genomic changes (up to 92) were observed. Although SNP analyses demonstrated 28 acquired UPD regions in 12 patients 9p13-p24 was the most common occurring in 25% of patients. SNP analyses also demonstrated triplication of 9q and quadruplication of 9p, suggesting that UPD of the entire chromosome 9 in SP cells can be associated with disease progression. Transplantation of SP CD34+ cells with a normal karyotype or with one chromosomal abnormality into NOD/SCID/IL2Rγ(null) mice resulted in a modest degree of donor cell chimerism (0.2%-4%), while transplantation of SP CD34+ cells with UPD of 9p, the entire chromosome 9 UPD, del20q originating in SP cells, complex karyotypes and gains of 4 chromosomal regions (1p,13, 12q24, 13q34 and 17q12 ) resulted in a higher degree of donor cell chimerism (18%-25%) indicating the association of these genetic events with altered stem cell function. Our findings indicate that some chromosomal abnormalities are acquired in MPNs initially in the SP sometimes occurring years prior to their appearance in the BM/PB. Other abnormalities, such as del(20q) may originate in either the BM or SP. All MF SP cells were characterized by additional diverse cytogenomic changes involving at least four regions, containing genes associated with leukemogenesis, leading to recurrent copy number gains in 67% to 83% of MF patients. We hypothesize that the SP provides a microenvironment in a subpopulation of MF patients which is associated with increased genomic diversity resulting in disease progression and leukemic transformation. Disclosures Mascarenhas: Incyte Corporation: Consultancy.

Description: Background The outcomes of older adults with acute lymphoblastic leukemia (ALL) remain poor when compared to younger ALL patients [PMID 19897583, 28419558, 22409379, 10653870]. Asparaginase (Asp) induces death of human lymphoblasts, and effective asparagine depletion is associated with improved outcomes in ALL. PEG-Asparaginase (PEG-Asp), which has a longer half-life than Asp, is a key component of the intensive chemotherapeutic regimens utilized for treatment of pediatric and younger adult ALL [PMID 29450465]. Frequently, older patients with Ph-negative ALL are not offered PEG-Asp containing pediatric chemotherapy regimen because of concerns related to tolerability and safety in this population [PMID 28355969]. Methods The Adult Leukemia Program at Mount Sinai Hospital developed an age-based, dose-adjusted, CALGB 10403 based intensive chemotherapy regimen for adults (≥40 years) with a diagnosis of Ph-negative ALL. For patients up to 60 years, prednisone (PRD) dose was reduced from 60 to 40 mg/m2/day from D1 to D28, and PEG-Asp reduced from 2500 to 1000 units/m2 (D4). For patients aged 61 years and above, PRD was further reduced to 25 mg/m2/day, and PEG-Asp to 1000 units/m2 on D4. In CD20+ ALL, rituximab x 8 doses were added to the regimen. CNS-prophylaxis consisted of intrathecal methotrexate at D1, D8 and D29 during induction, and during subsequent courses of chemotherapy based on the CALGB 10403 protocol. A PEG-Asp oriented supportive care plan was developed to prevent and treat Asp-related adverse effects. After the administration of PEG-Asp, Antithrombin III (ATIII) and fibrinogen levels were monitored on the same day, twice a week, for at least two weeks. If ATIII levels were 〈 70% and/or fibrinogen levels 〈 120 mg/dL, levels were corrected with the administration of ATIII concentrate and/or cryoprecipitate, respectively. Results Twelve patients with a median age of 58 years (45 - 76) were evaluable, and three patients were ≥ 70 years. Nine patients had B-cell ALL and three T-cell ALL. Three patients had a white blood cell count 〉 30 x103/µL at diagnosis. An ECOG status ≤ 2 at diagnosis was described in all patients, and all of them had multiple complex cytogenetic and molecular abnormalities. Ten patients had significant co-morbidities at diagnosis, including diabetes, hypertension, previous history of cancer, coronary artery disease, obesity, alcohol related chronic pancreatitis, and chronic diarrhea. Nine out of the twelve patients (75%) attained a bone marrow morphological complete remission (CR) at the end of induction (EOI), three of them with detectable minimal residual disease (MRD) that became undetectable after completing course II. Of the three patients who had ≥5% bone marrow blasts at EOI, one attained a CR with undetectable MRD at the end of course IA and another when switched to blinatumomab, and the third one died of progressive disease. No patient experienced early death. Five patients underwent allogeneic hematopoietic stem cell transplantation (HCT) while in CR (age range 46 to 60 years) and four remain in CR at last follow up (median 489 days, range 181 - 841), and one died of relapsed disease 67 days post-HCT. The other six patients who are receiving chemotherapy are alive and in remission at last follow up (median 272 days, range 52 - 639). The common adverse effects associated with PEG-Asp administration in this older group of patients were asymptomatic hypofibrinogenemia and depleted ATIII levels requiring supplementation (n=8), severe hyperbilirubinemia (n=1), and non-life-threatening venous thrombosis (n=1). Severe allergic reaction, clinical pancreatitis and cognitive impairment were not observed. Conclusion This age-based dose-adjusted PEG-Asp containing regimen was associated with an encouraging CR rate and a tolerable and manageable adverse event profile in this older patient population with significant co-morbidities. Treatment related mortality was 0%. Ten of 12 patients are currently in sustained remission, either with chemotherapy alone or following allogeneic HCT (median follow up 422 days, range 52 to 841 days). Treatment optimization for older patients with ALL utilizing an intensified, age-adjusted PEG-Asp containing induction and consolidation therapy regimen is associated with favorable outcomes and provides an effective bridge to potentially curative therapies such as HCT. Further prospective evaluation is under way. Table. Table. Disclosures Kremyanskaya: Incyte: Research Funding. Mascarenhas:Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Promedior: Research Funding; Janssen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding.

Description: MF is a myeloproliferative neoplasm characterized by abnormal megakaryocytes and elevated proinflammatory cytokines which results in bone marrow fibrosis, progressive hepatosplenomegaly due to extramedullary hematopoiesis, and debilitating constitutional symptoms. Current treatments, including ruxolitinib (the only approved drug for MF), provide symptomatic relief but have limited effects on the underlying disease. Effective therapies with potential MF disease course modification and second line therapies are urgently needed. CPI-0610 has been evaluated in 3 Phase 1 studies in 〉 140 patients with lymphoma, multiple myeloma and acute leukemias/myelodysplastic syndrome/MF. Although CPI-0610 was tested at doses as high as 400 mg PO QD, the maximum tolerated dose was 225 mg PO QD for 2 weeks on, 1 week off. Clear anti-tumor activity was observed in patients with lymphomas, particularly ABC-DLBCL (Blum et al. TAT conference 2018). Preclinical data on CPI-0610 demonstrated downregulation of pro-inflammatory cytokines through its effects on NF-κB pathway as well as inhibition of megakaryocyte differentiation. Both of these features are thought to be important in the pathogenesis of MF. In addition, a recent preclinical publication using a mouse model of MF, suggests that BET inhibition reduces inflammatory cytokine production, platelet counts, spleen volume and bone marrow fibrosis, the effects of which were further magnified when combined with ruxolitinib (Kleppe et al. 2018). Taken together, these data suggest that BET inhibitors such as CPI-0610, administered with and without ruxolitinib, have the potential to affect the underlying MF disease and supports further clinical evaluation of CPI-0610 in patients with MF. Therefore, we have embarked on a Phase 2 trial of CPI-0610 as monotherapy or in combination with ruxolitinib. This Phase 2 study aims to evaluate CPI-0610 as a monotherapy and in combination with ruxolitinib in patients with MF who are not eligible to receive a JAK inhibitor or have had an inadequate response to ruxolitinib. The primary objectives are to evaluate spleen volume response by imaging after 24 weeks of therapy and to evaluate the effect on transfusion independence rate. Other key secondary objectives are to evaluate the change in patient reported outcomes and the duration of splenic response. Exploratory objectives include characterizing the effects of treatment on the bone marrow and blood biomarkers. The Phase 2 study has a 2-stage design to enroll up to 35 patients in each arm (monotherapy and combination therapy) if ≥2 responses are observed during stage 1. The study is registered at ClinicalTrials.gov NCT02158858. Disclosures Kremyanskaya: Incyte: Research Funding. Hoffman:Formation Biologics: Research Funding; Summer Road: Research Funding; Incyte: Research Funding; Merus: Research Funding; Janssen: Research Funding. Mascarenhas:CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Promedior: Research Funding; Merck: Research Funding; Janssen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Verstovsek:Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees. Mertz:Constellation Pharma: Employment. Garner:Constellation Pharma: Employment. Senderowicz:Constellation Pharma: Employment.

Description: Interferon (IFN-α) is effective therapy for polycythemia vera (PV) patients, but it is frequently interrupted because of adverse events. To permit the long-term use of IFN, we propose combining low doses of IFN with Nutlin-3, an antagonist of MDM2, which is also capable of promoting PV CD34+ cell apoptosis. Combination treatment with subtherapeutic doses of Peg IFN-α 2a and Nutlin-3 inhibited PV CD34+ cell proliferation by 50% while inhibiting normal CD34+ cells by 30%. Combination treatment with Nutlin-3 and Peg IFN-α 2a inhibited PV colony formation by 55%-90% while inhibiting normal colony formation by 22%-30%. The combination of these agents also decreased the proportion of JAK2V617F-positive hematopoietic progenitor cells in 6 PV patients studied. Treatment with low doses of Peg IFN-α 2a combined with Nutlin-3 increased phospho-p53 and p21 protein levels in PV CD34+ cells and increased the degree of apoptosis. These 2 reagents affect the tumor suppressor p53 through different pathways with Peg IFN-α 2a activating p38 MAP kinase and STAT1, leading to increased p53 transcription, whereas Nutlin-3 prevents the degradation of p53. These data suggest that treatment with low doses of both Nutlin-3 combined with Peg IFN-α 2a can target PV hematopoietic progenitor cells, eliminating the numbers of malignant hematopoietic progenitor cells.

Description: PRM-151 (PRM) is a recombinant form of Pentraxin-2, an endogenous human protein that acts at sites of tissue damage, inducing macrophage differentiation to prevent and reverse fibrosis. PRM has broad anti-fibrotic activity in multiple preclinical models of established fibrotic diseases and no dose limiting toxicities in phase 1 trials. Myelofibrosis (MF: primary (PMF), post-essential thrombocythemia (post-ET MF), and post polycythemia vera (Post PV MF)) is a myeloid malignancy characterized by progressive bone marrow (BM) fibrosis with resultant anemia, abnormal platelet and leukocyte counts, extramedullary hematopoiesis, and a well-defined symptom complex. This study investigated the potential of PRM in MF to reduce BM fibrosis and to improve key disease features including abnormal blood counts, symptoms, and splenomegaly. MF patients (pts) with Dynamic International Prognostic Scoring System (DIPSS) intermediate-1, intermediate-2, or high-risk disease and grade ≥ 2 BM fibrosis, either on no current therapy or on a stable dose of ruxolitinib (RUX) for ≥ 12 weeks and no improvement in spleen for ≥ 4 weeks, were eligible for stage 1 of this open-label adaptive trial. Assignment to one of the 4 treatment arms was per investigator and pt choice: PRM 10 mg/kg IV 1-hour infusion days 1, 3, 5, then weekly (QW) or every 4 weeks (Q4W), alone or with RUX, for 24 weeks. Primary endpoint was overall response rate by IWG-MRT (symptoms by MPN-SAF Total Symptom Score (TSS), spleen by palpation) and/or decrease in BM fibrosis by ≥ 1 grade with otherwise stable disease. BM biopsies were obtained at baseline, 3 and 6 months, and were evaluated centrally by two blinded hematopathologists. Pts with clinical benefit were allowed to continue treatment in an extension. At least one response in any arm was required for that regimen to be evaluated in Stage 2. Twenty seven pts were enrolled: 8 PRM QW, 7 PRM Q4W, 6 PRM QW + RUX, 6 PRM Q4W + RUX. Median age 67 years (52-85); 70% DIPSS Int-2 or High Risk; 52% PMF, 15% post-ET MF, 33% post-PV MF; 63% grade 3 BM fibrosis, Hemoglobin (Hgb) 〈 100 g/L in 56% and 〈 85 g/L in 26%, platelet count (PLT)〈 100 x 109/L in 52% and 〈 25 x 109/L in 30%; 22% were JAK inhibitor-naive and 52% had received a prior JAK inhibitor (not including ongoing RUX). Twenty pts completed 24 weeks of therapy; 18 continued extension treatment. PRM-151 was well-tolerated alone and with RUX; most adverse events (AEs) were Grade 1/2 and unrelated, with 3 Grade 3 possibly related AEs and 5 possibly related serious AEs. Nine of 26 evaluable pts responded, for an overall response rate (ORR) of 35%, with 4 IWG symptom clinical improvements (CI) and 6 BM fibrosis responses (Table 1), with ≥ 1 response in each arm. One pt had a CI and BM response. Reduction in BM fibrosis was associated with normal erythroid microarchitecture, normal or decreased myeloid:erythroid ratio, and fewer paratrabecular megakaryocytes, all potential surrogates of improved bone marrow microenvironment. IWG stable disease was observed in 77% of pts, with trends of clinical benefit in Hgb, PLT, peripheral blood blasts, spleen, and symptoms (Table 2). In 14 patients (54%), all parameters were stable or improved. Conclusion: PRM-151 was well-tolerated in patients with advanced MF, with no evidence of drug-related myelosuppression and encouraging trends in both clinical and histologic aspects of the disease. Reduction in BM fibrosis, stable to improved hematologic parameters, symptom responses, and stable to reduced spleen size support further development of PRM-151 in MF. Table 1 Two additional subjects had decrease in bone marrow fibrosis but progressive disease. Number of Patients BM Fibrosis Grade at Last Study Timepoint 3 2 1 BM Fibrosis Grade at Baseline 3 8 3 1 2 1 4 2 Abstract 713. Table 2 Outcome Parameter Denominator (n) Clinical Benefit Pts with Improvement (n/%) ORR (primary endpoint) All evaluable pts (26) IWG-MRT CI AND/OR reduction in BM fibrosis by ≥ 1 grade 9 (35%) Hgb Hgb 〈 100 g/L (15) ≥10 g/L increase from baseline AND no transfusions or 50% reduction in transfusions if transfusion dependent 6 (40%) PLT PLT 〈 100 x 109/L (13) 〉 100 x 109/L AND increase of ≥20 x 109/L ; increase of ≥20 x 109/L if baseline 〈 50, AND/OR increase of ≥ 10 x 109/L with discontinuation of transfusions 8 (62%) Blasts ≥ 1% peripheral blasts (14) No peripheral blasts 3 (21%) Symptoms All evaluable pts (26) ≥ 25% reduction in TSS ≥ 12 weeks 10 (38%) Spleen Palpable spleen (19) ≥ 25% decrease ≥ 4 weeks AND any decrease ≥ 12 weeks 5 (26%) Disclosures Verstovsek: Incyte: Research Funding; Astrazeneca: Research Funding; Lilly Oncology: Research Funding; Roche: Research Funding; Geron: Research Funding; NS Pharma: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Seattle Genetics: Research Funding; Promedior: Research Funding; Cell Therapeutics: Research Funding. Mesa:Incyte, CTI, NS pharma, Gilead, Celgene: Research Funding; Promedior: Research Funding. Foltz:Janssen: Consultancy; Promedior: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Gupta:Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Promedior: Research Funding. Mascarenhas:Novartis Pharmaceuticals Corporation: Research Funding; Incyte Corporation: Consultancy, Research Funding; Promedior: Research Funding. Ritchie:Celgene, Incyte: Speakers Bureau; Promedior: Research Funding. Hoffman:Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; All Cells LLC: Consultancy, Membership on an entity's Board of Directors or advisory committees; Promedior: Research Funding. Pozdnyakova:Sanofi: Consultancy; Incyte: Consultancy; Promedior: Consultancy. Hasserjian:Sanofi: Consultancy; Incyte: Consultancy; Promedior: Consultancy. Trehu:Promedior: Employment, Equity Ownership. Kantarjian:ARIAD, Pfizer, Amgen: Research Funding. Gotlib:Novartis: Research Funding, Travel Reimbursement, Travel Reimbursement Other; Sanofi: Research Funding; Gilead: Research Funding; Incyte: Consultancy, Honoraria, Research Funding, Travel Reimbursement Other; Promedior: Research Funding.