Post ASH speaker abstracts 2018

MPN (not CML)

Abstracts to support presentations from Claire Harrison and Austin Kulasekararaj

Personalized Prognostic Predictions for Patients with Myeloproliferative Neoplasms through Integration of Comprehensive Genomic and Clinical Information

Result Type: Paper
Number: 491
Presenter: Jacob Grinfeld
Program: Oral and Poster Abstracts
Session: 635. Myeloproliferative Syndromes: Basic Science: Molecular events occurring within the myeloproliferative neoplasms

Jacob Grinfeld, MBChB, BSc, MRCP, FRCPath1*, Jyoti Nangalia, MBBChir, MA, MRCP, FRCPath, PhD2*, E Joanna Baxter, PhD1*, Anna L. Godfrey, BMBCh, PhD, MRCP, FRCPath3*, Paola Guglielmelli, MD, PhD4, Rob Cantrill, PhD5*, David Wedge, PhD6*, Nicos Angelopoulos, PhD7*, Gunes Gundem, PhD8*, Charlie Massie, PhD9*, Elli Papaemmanuil, PhD10, Cathy MacLean, BSc, MSc, MBA1*, Julia Cook, BSc1*, Francesca Lauren Nice, PhD, MSc1*, Christen Lykkegaard Andersen, PhD11,12*, Hans Carl Hasselbalch, MD, Professor, DMSc13, Mary Frances McMullin, MB, Bch BAO, MD, FRCPath14, Alessandro M. Vannucchi, MD15, Claire N. Harrison, BMBCh, DM16, Moritz Gerstung, PhD5*, Peter J Campbell, MD, PhD7* and Anthony R Green, PhD 1

1Department of Haematology, University of Cambridge, Cambridge, United Kingdom
2Wellcome Trust Sanger Institute, Hinxton, United Kingdom
3Department of Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
4CRIMM, Center Research and Innovation of Myeloproliferative Neoplasms, University of Florence, AOU Careggi, Florence, Italy
5European Bioinformatics Institute, Hinxton, United Kingdom
6Big Data Institute, University of Oxford, Oxford, United Kingdom
7Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom
8Memorial Sloan-Kettering Cancer Center, New York, NY
9Early detection programme, CRUK Cambridge Centre, University of Cambridge, Cambridge, United Kingdom
10Center for Molecular Oncology and Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
11Department of Haematology, Roskilde University Hospital, Roskilde, Denmark
12Department of Public Health, Copenhagen University, Copenhagen, Denmark
13Department of Hematology, Roskilde Hospital, Roskilde, Denmark
14Centre for Medical Education, Queen’s University Belfast, Belfast, GBR
15Center for Research and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliero-Universitaria Careggi, University of Florence, Florence, Italy
16Department of Haematology, Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom


The vast majority of Philadelphia-negative myeloproliferative neoplasms share a narrow set of phenotypic driver mutations affecting the erythropoietin/thrombopoietin signalling pathways. Despite this, there is significant heterogeneity in disease phenotype at diagnosis, as well as in patient outcome with respect to thrombosis, disease progression and survival. Current risk stratification models are useful for predicting outcome and guiding treatment in those patients with MF. However, there remains significant heterogeneity within risk subgroups, and no models are available for identifying poor risk patients with chronic phase disease.

We sequenced the full coding regions of 68 genes and genome-wide single nucleotide polymorphisms in 2041 patients (1326 essential thrombocytosis (ET), 355 polycythemia vera (PV) and 311 primary/post-ET/post-PV myelofibrosis (MF), 49 with other MPN diagnoses) to characterize the associations between somatic mutations, copy number variant profiles, germline predisposition, order of mutation acquisition, clinical phenotype and patient outcome.

Mutations in established myeloid driver genes other than JAK2CALR or MPL were identified in 827 patients (41%). The presence and number of additional mutations correlated with both MPN phenotype and age at diagnosis. Non-canonical JAK2 and MPL mutations were found in 51 patients, of whom 17 had “triple-negative” disease. Novel protein truncating mutations in PPM1D and MLL3 were identified in 54 (2.6%) and 25 patients (1.2%) respectively. Chromosomal events, predominantly uniparental disomy of chromosome 9p (9p UPD), were seen in only 8% of those with ET, compared to 45% and 55% of those with MF and PV respectively. The JAK2 46/1 haplotype correlated with the presence of JAK2V617F, 9pUPD, increased JAK2 clone size and a PV phenotype. In addition, a range of other genetic and non-genetic factors were found to significantly correlate with phenotype at presentation.

Mutation timing was assessed to characterize the patterns of tumor evolution. Many genes were specifically acquired either early or late in disease. The sequence of mutation acquisition was also linked to phenotype. In JAK2-mutated patients, JAK2 was the earliest detected event (and/or was present in the dominant clone) in 80% of cases of PV and MF, but was preceded by other mutations in the majority of patients with ET. DNMT3A and SF3B1mutations preceding JAK2 mutations were almost exclusively seen in ET, while EZH2 and ASXL1 mutations post-JAK2 were commonly a feature of MF.

There were 422 different combinations of mutational/chromosomal events observed in this study, of which only 37 were recurrent in at least 5 cases. Bayesian network analysis and clustering using Bayesian Dirichlet processes were used to identify distinct patterns and genetic groups within MPNs. Two groups in particular were enriched in MF (as well as MDS) patients and were associated with adverse outcomes. Mutations in TP53 in association with chromosome 17p aberrations and/or 5q- were a distinct group associated with an increased risk of AML transformation in both chronic phase and MF patients.

We then developed a unifying predictive model for all MPN patients. In order to take into account the striking degree of heterogeneity in genetic events, clinical characteristics and potential clinical outcomes, we developed a multi-state random effects Cox proportional hazards model. This allowed integration of a total of 63 clinical and genomic variables in order to generate individualised patient predictions for survival and disease transformation for all MPN patients. The model generated accurate predictions on the training cohort, and performed well on internal cross-validation and on application to an external validation cohort. In patients with MF, the model was more accurate for predictions of event-free survival than DIPSS or IPSS (concordance 81% v 69% v 77% respectively). We have devised an online calculator that can generate personalised outcome predictions for individual patients (and impute missing information where unavailable). This could be used to guide the management of chronic phase and MF patients and improve stratification within clinical trials.

Together our results demonstrate the utility of combining genomic data with clinical parameters to refine disease classification and improve prognostication.

MIPSS70: Mutation-Enhanced Prognostic System for Transplant Age Patients with Primary Myelofibrosis

Result Type: Paper
Number: 200
Presenter: Alessandro Vannucchi
Program: Oral and Poster Abstracts
Session: 634. Myeloproliferative Syndromes: Clinical: Biologic-Clinical Correlative Studies in MPNs, Including Transplant

Alessandro M. Vannucchi, MD1, Paola Guglielmelli, MD, PhD1, Terra L. Lasho, PhD2, Giada Rotunno, MSc, PhD1*, Carmela Mannarelli, MSc, PhD1*, Annalisa Pacilli, PhD1*, Animesh Pardanani, MBBS PhD2, Elisa Rumi, MD3*, Vittorio Rosti, MD4, Curtis A. Hanson, MD2, Francesco Mannelli5*, Rhett P. Ketterling, MD6*, Naseema Gangat, MBBS2, Alessandro Rambaldi, MD, Prof7, Francesco Passamonti, MD8*, Giovanni Barosi, MD4, Tiziano Barbui, MD9* and Ayalew Tefferi, MD2*

1CRIMM, Center Research and Innovation of Myeloproliferative Neoplasms, University of Florence, AOU Careggi, Florence, Italy
2Divisions of Hematology and Laboratory Medicine, Mayo Clinic, Rochester, MN
3Departments of Hematology Oncology & Molecular Medicine, Fondazione IRCCS Policlinico San Matteo & University of Pavia, Pavia, Italy
4Center for the Study of Myelofibrosis, Foundation IRCCS Policlinico San Matteo, Pavia, Italy
5Center for Research and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliero-Universitaria Careggi, University of Florence, Florence, Italy
6Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
7Hematology and Bone Marrow Transplant Unit, University of Milan, ASST Papa Giovanni XXIII, Bergamo, Italy
8Division of Hematology, Ospedale di Circolo – Fondazione Macchi Università degli Studi dell’Insubria – Varese Viale Borri 57 – 21100 Varese – Italia, Varese, Italy
9Research Foundation, Ospedali Riuniti di Bergamo, Bergamo, Italy


Background: The International Prognostic Scoring System (IPSS) (Blood 2009;113:2895), the dynamic(D) IPSS (Blood 2010;115:1703) and the DIPSS-plus (JCO 2011;29:392) are commonly used to predict survival among patients (pts) with Primary Myelofibrosis (PMF). These scores were developed using populations of PMF pts that differ from the 2 categories outlined in the 2016 WHO criteria, i.e. prefibrotic and overt PMF (Blood 2016; 127:2391); indeed, IPSS performed suboptimally when applied to the two PMF variants (Blood 2017; 129:3227). The prognostic relevance of fibrosis grade and mutation profile, including both driver (JAK2/CALR/MPL) and other myeloid malignancies-associated genes (Blood 2017; 129:3227), has been shown. Furthermore, high molecular risk category (HMR), including pts with any one mutated genes of ASXL1, SRSF2, EZH2, IDH1/2 (Leukemia 2013; 27:1861), and unfavorable karyotype (JCO 2011;29:392)both provided IPSS/DIPSS-independent prognostic information for overall survival (OS) and leukemia-free survival (LFS). The aim of current study was to develop an updated prognostic score that included molecular (MIPSS70) and, when available, cytogenetic information (MIPSS70-plus), specifically directed to pts with pre-PMF and overt-PMF 70yr old and younger that are potential candidates to stem cell transplantation (SCT).

Methods: Previously published methods were used to sequence JAK2, MPL, CALR, EZH2, ASXL1, IDH1/2 and SRSF2. Survival was calculated from date of diagnosis (AGIMM cohort) or date of first referral (Mayo cohort). A Cox model with a stepwise selection procedure was used to select covariates significant for OS. The prognostic model was developed based on the magnitude of the hazard ratios (HR) in the training cohort.

Results: Development of MIPSS70. The learning cohort included 490 pts aged <70y (225 Pre-PMF, 265 overt-PMF) from 6 Italian institutions (AGIMM group). During a median FU of 5.8y (6.8y pre-PMF, 5.22y overt PMF), 25.3% of pre-PMF and 50.2% of overt-PMF pts died and 63 (9.8% pre-PMF, 15.5% overt PMF) progressed to leukemia. Mutation frequency was: JAK2V617F 58%, CALR 26% (76% type1/like, 24% type2/like), MPL 5%, ASXL1 23%, SRSF27%, EZH2 6%, IDH1/2 2.7%; 30.8% were HMR-positive with 8% of pts presenting >2 HMR mutated genes. A HR-weighted score was assigned to variables maintaining significance in multivariable analysis: 2.0 points to leukocytes >25x109/L, platelets <100x109/L, >2 HMR mutations; 1.0 point to hemoglobin <100g/L, circulating blasts ≥2%, constitutional symptoms, fibrosis grade >2, absence of CALR type1/like, HMR category. Accordingly, 3 risk categories were delineated (Fig 1A): Low (score 0-1); Intermediate (score 2-4); and High (score >5) with 10-y survival of 83%, 39% and 12%, respectively. MIPSS70 yielded a better prediction of OS in a ROC analysis (MIPSS70 AUC = 0.760 vs. IPSS AUC = 0.710). Significantly different (p<0.0001) LFS was also predicted by the 3 risk categories. The aforementioned observations were validated in an external cohort of 223 patients from Mayo Clinic (details to follow at time of presentation). Finally, we showed that MIPSS70 efficiently resolved patients aged >70y in both cohorts.

Development of MIPSS70-plus. The learning cohort included 209 cytogenetically-annotated pts, aged ≤70y, from Mayo Clinic. Unfavorable vs favorable karyotype was added to the multivariable model that included all 8 MIPSS70 variables. Unfavorable karyotype (HR 2.6), presence of one (HR 1.7) or ≥2 (HR 2.3) HMR mutations, absence of type1/like CALR (HR 2.2), constitutional symptoms (HR 2.4), circulating blasts ≥2% (HR 1.7) and hemoglobin <10 g/dL (HR 1.5) remained significant. Based on HR-weighted scoring of these 6 variables, 4 risk categories were established and effectively predicted OS (Figure 1B) and LFS. These observations were validated in a separate cohort of 260 pts from the AGIMM group (details to follow at time of presentation). The MIPP70-plus was also effective in pts aged >70y.

Conclusions. The new MIPSS70 and MIPSS70-plus scores include modern disease-associated, risk variables pertinent to both pre-PMF and overt-PMF according to the 2016 WHO classification, and are intended to facilitate decision-making for patients 70yr old and younger who are potential candidates to SCT.

Hydroxycarbamide Plus Aspirin Vs Aspirin Alone in Intermediate Risk Essential Thrombocythemia: Results of the PT-1 International, Prospective, Randomized Clinical Trial

Result Type: Paper
Number: 319
Presenter: Anna Godfrey
Program: Oral and Poster Abstracts
Session: 634. Myeloproliferative Syndromes: Clinical: Phase III and Long-Term Outcome Studies in MPNs

Anna L. Godfrey, BMBCh, PhD, MRCP, FRCPath1*, Peter J Campbell, MD, PhD2*, Cathy MacLean, BSc, MSc, MBA3*, Georgina Buck, BSc, MSc4*, Clare L. East, BSc3*, Julia Cook, BSc3*, Julie Temple, BSc3*, Bridget S. Wilkins, MD, FRCPath5*, Keith Wheatley, DPhil6*, Jyoti Nangalia, MBBChir, MA, MRCP, FRCPath, PhD2*, Jacob Grinfeld, MBChB, BSc, MRCP, FRCPath3*, Mary Frances Frances McMullin, MB, Bch BAO, MD, FRCPath7, Cecily Forsyth, MB BS8*, Jean-Jacques Kiladjian, MD, PhD9, Anthony R. Green, FRCP, FRCPath, FMed Sci10 and Claire N. Harrison, BMBCh, DM11

1Department of Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
2Wellcome Trust Sanger Institute, Hinxton, United Kingdom
3Department of Haematology, University of Cambridge, Cambridge, United Kingdom
4Nuffield Department of Population Health, Richard Doll Building, Clinical Trials Service Unit, University of Oxford, Oxford, United Kingdom
5Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom
6Institute of Cancer and Genomic Sciences, Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, United Kingdom
7Centre for Medical Education, Queen’s University Belfast, Belfast, GBR
8Gosford Hospital, Gosford, Australia
9Centre d’Investigation Clinique, Hopital Saint-Louis, Paris, FRA
10Dept. of Haematology, Cambridge University and Addenbrooke’s Hospital, Cambridge, United Kingdom
11Department of Haematology, Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom


Introduction: Prospective randomized trials have shown that patients with “high-risk” essential thrombocythemia (aged >60, prior thrombotic history and/or cardiovascular risk factors) have a lower thrombotic risk if treated with hydroxycarbamide compared to no cytoreduction, and that hydroxycarbamide reduces risks of major vascular events, arterial thrombosis, serious hemorrhage and post-ET myelofibrosis (PET-MF) compared to anagrelide. However there are no prospective data evaluating the effects of cytoreduction in ET patients lacking high-risk factors. We undertook a prospective, open-label, randomized trial comparing hydroxycarbamide plus aspirin with aspirin alone in patients with “intermediate-risk” ET.

Methods: Patients were recruited from 198 hospitals in 5 countries. Intermediate-risk patients were aged 40 to ≤ 59 years and lacked the following high-risk criteria: current or previous platelet count ≥1000x109/l (≥1500x109/l from 06/05/2004); previous ischemia, thrombosis or embolism; hemorrhage due to ET; hypertension or diabetes requiring therapy. 382 patients were randomized between 21/07/1997 and 31/07/2012 in a 1:1 ratio to aspirin alone or aspirin plus hydroxycarbamide; 24 were subsequently identified to be ineligible and excluded (Fig 1A). The composite primary endpoint was time from randomization to arterial or venous thrombosis, serious hemorrhage or death from vascular causes. Secondary endpoints were time to first arterial or venous thrombosis or to first serious hemorrhage; time to death; incidence of transformation to PET-MF, acute myeloid leukemia (AML), myelodysplasia (MDS) or polycythemia vera (PV); and patient-reported quality of life. The required duration of follow-up was calculated as the maximum period of time required for either a significantly different treatment effect or a point estimate for the number needed to treat to prevent one endpoint per year of >100, with a lower limit of the 95% confidence interval (CI) >50. Intention-to-treat analyses were performed.

Results: Median duration of follow-up was 73 months (range, 0 to 187) with total follow-up of 2373 patient-years. 47% of the aspirin alone group started cytoreduction during follow-up whilst 21% of the aspirin plus hydroxycarbamide arm stopped hydroxycarbamide and/or started another cytoreductive agent (Fig 1A). Median time without treatment change was 36 months in the aspirin alone arm and 55 months in the aspirin plus hydroxycarbamide arm (p<0.001). Platelet counts were significantly different between the arms early on and started to overlap 5-6 years after entry (Fig 1B). The composite primary endpoint of time from randomization to arterial or venous thrombosis, serious hemorrhage or death from vascular causes was not significantly different between the arms (hazard ratio 0.98, 95% CI 0.43-2.27, p=1.0, Fig 1C). The incidence of significant vascular events for the whole study was 0.93 per 100 patient-years (95% CI 0.61-1.41). There was no significant difference in overall survival between the arms (p=0.5, Fig 1D), nor in the composite endpoint of rate of transformation to PET-MF, AML or MDS (p=0.7, Fig 1E). The rate of PV transformation was significantly higher in the aspirin alone arm (p=0.01, Fig 1E), most likely reflecting the non-specific effect of hydroxycarbamide in constraining erythropoiesis. A pre-specified analysis for any major disease-related complication – arterial thrombosis, venous thromboembolism, major hemorrhage, transformation to AML, MDS, PET-MF or death from any of these causes – showed no difference between the arms (p=0.6). There were no significant differences in the frequency of adverse events including non-hematological cancers. Quality of life data were recorded annually for five years using the EORTC QLQ-C30 questionnaire (v2), with no significant differences in summary scores in any year Conclusion: In ET patients aged 40-59 who lack high-risk factors pre-emptive addition of hydroxycarbamide to aspirin did not reduce the risk of vascular events or myelofibrotic or leukemic transformation. These results indicate that intermediate-risk ET patients should be treated with aspirin alone until another clinical indication for cytoreduction arises. Moreover patients receiving hydroxycarbamide showed no increase in leukemic transformation or other malignancies, supporting the concept that hydroxycarbamide is a safe therapy for ET.

A Two-Part Study of Givinostat in Patients with Polycythemia Vera: The Maximum Tolerated Dose Selection and the Proof of Concept Final Results

Result Type: Paper
Number: 253
Presenter: Alessandro Rambaldi
Program: Oral and Poster Abstracts
Session: 634. Myeloproliferative Syndromes: Clinical: Phase I/II Trials of Novel Agents in MPNs

Alessandro Rambaldi, MD, Prof1, Alessandra Iurlo, MD, PhD2*, Alessandro M. Vannucchi, MD3, Richard Noble, MD4*, Nikolas von Bubnoff, MD5*, Attilio Guarini, MD6*, Andrzej Hellmann, MD7*, Bruno Martino8*, Antonio Pezzutto, MD, PhD9*, Giuseppe Carli, MD10*, Marianna De Muro, MD11*, Paolo Di Bartolomeo, M.D12, Mary Frances Frances McMullin, MB, Bch BAO, MD, FRCPath13, Nathalie Cambier, MD14*, Jean-Pierre Marolleau, MD, PhD15, Ruben A. Mesa, MD16, Raoul Tibes, MD, PhD17*, Paolo Bettica, MD, PhD18*, Sara Manzoni, DHSC, BSc18* and Silvia DI Tollo, DHSC, BSc18*

1Hematology and Bone Marrow Transplant Unit, University of Milan, ASST Papa Giovanni XXIII, Bergamo, Italy
2Hematology Division, IRCCS Cà Granda – Maggiore Policlinico Hospital Foundation, Milano, Italy
3Center for Research and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliero-Universitaria Careggi, University of Florence, Florence, Italy
4Department of Hematology, Royal Cornwall Hospital, Truro, United Kingdom
5Department of Hematology, Oncology and Stem Cell Transplantation, University of Freiburg, Freiburg, Germany
6Hematology Unit – Oncological Department, Istituto Tumori Giovanni Paolo II I.R.C.C.S. Ospedale Oncologico, Bari, Bari, Italy
7Klinika Hematologii i Transplantologii, Uniwersyteckie Centrum Kliniczne, Gdansk, Poland
8Hematology Unit, A.O. Bianchi-Melacrino-Morelli, Reggio Calabria, Italy
9Department of Hematology, Charité University School of Medicine, Berlin, Germany
10U.O. Ematologia, Ospedale San Bortolo di Vicenza, Vicenza, Italy
11Hematology Department, Policlinico Universitario Campus Bio-Medico, Rome, Italy
12Department of Hematology, Transfusion Medicine and Biotecnology, ” Spirito Santo ” Civic Hospital, Pescara, Italy
13Centre for Medical Education, Queen’s University Belfast, Belfast, GBR
14Service d’Oncologie Hématologie, Hospital Saint Vincent de Paul – GHICL Lille, Lille cedex, France
15Hematology Department, Amiens University Hospital, Amiens, France
16Division of Hematology & Medical Oncology, Mayo Clinic Cancer Center, Scottsdale, AZ
17Hematology and Medical Oncology, Mayo Clinic Arizona, Scottsdale, AZ
18Clinical R&D Department, Italfarmaco S.p.A., Cinisello Balsamo, Italy

Background and purpose of the study: Several reports have documented that histone deacetylase inhibitors induce neoplastic cells to undergo growth arrest, differentiation and/or apoptotic cell death. Among these agents, Givinostat inhibits proliferation of cells bearing the JAK2V617F mutation [Guerini et al., Leukemia 2008 Apr; 22(4): 740-7; Calzada et al., Exp. Hematol. 2012; 40 (8): 634-45]. In two phase II studies conducted in patients with chronic myeloproliferative neoplasms (cMPN), Givinostat was generally well tolerated at the maximum administered dose (150 mg/day) [Rambaldi et al., Br. J. Haematol. 2010; 150 (4): 446-55; Finazzi et al., Br. J. Haematol. 2013;161(5):688-94]. To formally assess the safety and tolerability, Maximum Tolerated Dose (MTD) and preliminary efficacy of Givinostat in patients with JAK2V617F positive Polycythemia Vera (PV), this two-part, multicenter, open label, non-randomized, phase Ib/II study dose was conducted.

Methods: Part A of the study (i.e. phase Ib) was the dose optimization portion, while Part B was the cohort expansion part of the study, assessing the preliminary clinical efficacy of Givinostat at the MTD defined in Part A. Eligible patients for this study included JAK2V617F positive PV patients of both genders, with active and/or uncontrolled disease, defined as: (i) Hematocrit (HCT) ≥ 45% or HCT <45% normalized by phlebotomy, and (ii) PLT > 400 x109/L, and (iii) WBC > 10 x109/L. Study therapy was administered in 28 day cycles (the cycle being defined as 4 weeks of treatment). Disease response was evaluated by the Investigators according to the clinico-hematological European LeukemiaNet (ELN) criteria [Barosi et al., Blood. 2009 May 14; 113(20): 4829-33] at Cycles 3 and 6. Disease-related symptoms were reported by the patients using the MPN-SAF QoL Form [Scherber et al., Blood, 2011 July 14; 118(2): 401-408; Emanuel et al., JCO November 20, 2012; 30 (33): 4098-4103]. The study lasted up to a maximum of 24 weeks of treatment. However, after completion of the trial, all patients achieving clinical benefit were allowed to continue treatment with Givinostat in a long-term study ( ID: NCT01761968).

Results: In Part A, the MTD of Givinostat in PV patients has been defined as the daily dosage of 200 mg (chronic schedule).

In Part B, 36 patients with active and/or uncontrolled disease were treated with Givinostat at the starting dose of the MTD defined in Part A (200 mg/die).

Complete/partial response was observed in 86% of evaluable patients (ITT population; n = 30) at the primary endpoint assessment time, i.e. at Cycle 3. At that time, WBC, PLT and HCT values had been normalized in the majority of patients (93%, 77% and 77% – without phlebotomy -, respectively). A net improvement in term of QoL was noted both in the single and in the total symptom scores of MPN-SAF Form. In addition, a decrease of JAK2V617Fallele burden have been noted at Cycle 3. Givinostat treatment was confirmed to be generally well tolerated: no death nor grade 4 adverse drug reaction (ADR) occurred; only one serious ADR (grade 3 diarrhea, resolved in 7 days) and a total of eight grade 3 ADRs (mainly gastrointestinal and hematological events) were reported at the cut-off date of 21st July 2017 (safety population; n = 36).

From Cycle 3 to the secondary endpoints assessment time at Cycle 6, the overall response rate as well as the hematological response rate further improved, with a good tolerability profile. Notably, complete/partial response was observed in more than 90% of evaluable patients at the cut-off date of 21st July 2017, when 4 patients are still ongoing.

At the time of ASH Meeting 2017, the final data related to the primary objective (as above reported) and also to the secondary and explorative endpoints will be presented.

Conclusions: With a continuous dosing schedule, a daily dosage of 200 mg was identified in this study as the MTD for Givinostat in PV patients. At that dosage, Givinostat demonstrated to be an effective and well tolerated treatment for PV patients with active/uncontrolled disease.

Results from the 208-Week (4-Year) Follow-up of RESPONSE Trial, a Phase 3 Study Comparing Ruxolitinib (Rux) with Best Available Therapy (BAT) for the Treatment of Polycythemia Vera (PV)

Result Type: Paper
Number: 322
Presenter: Jean-Jacques Kiladjian
Program: Oral and Poster Abstracts
Session: 634. Myeloproliferative Syndromes: Clinical: Phase III and Long-Term Outcome Studies in MPNs

Jean-Jacques Kiladjian, MD, PhD1, Srdan Verstovsek, MD, PhD2, Martin Griesshammer3*, Tamás Masszi, MD, Prof.4*, Simon Durrant, FRCP, FRCPath, MBBS5, Francesco Passamonti, MD6*, Claire N. Harrison, BMBCh, DM7, Fabrizio Pane, MD8, Pierre Zachee, MD, PhD9*, Keita Kirito, MD10, Carlos Besses, MD, PhD11, Masayuki Hino, MD, PhD12, Ana Ines Varela13*, Carole B. Miller, MD14*, Elisa Rumi, MD15*, Vittorio Rosti, MD16, Igor Wolfgang Blau, MD17*, Ruben A. Mesa, MD18, Tuochuan Dong19*, Nathalie Francillard20*, Mary Laughlin19* and Alessandro M. Vannucchi, MD21

1Hôpital Saint-Louis et Université Paris Diderot, Paris, France
2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
3Johannes-Wesling Academic Medical Center, University of Hannover Teaching Hospital, Minden, Germany
43rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
5Royal Brisbane & Women’s Hospital, Brisbane, Australia
6Hematology, Department of Medicine and Surgery, University of Insubria, Varese, Italy
7Department of Haematology, Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom
8Hematology – Departments of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
9ZNA Stuivenberg, Antwerp, Belgium
10Department of Hematology and Oncology, University of Yamanashi, Chuo, Japan
11Haematology Department, Hospital del Mar-IMIM, Universidad Autónoma de Barcelona, Barcelona, Spain
12Department of Hematology, Osaka City University, Osaka, Japan
13Hospital Jose Maria Ramos Mejia, Buenos Aires, Argentina
14St. Agnes Healthcare Cancer Institute, Baltimore, MD
15Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
16Center for the Study of Myelofibrosis, Foundation IRCCS Policlinico San Matteo, Pavia, Italy
17Medical Department, Division of Hematology, Oncology, and Tumor Immunology, Charité Universitätsmedizin, Berlin, Germany
18UT Health San Antonio Cancer Center, San Antonio, TX
19Novartis Pharmaceuticals Corporation, East Hanover
20Novartis Pharma S.A.S, Rueil Malmaison, France
21Center for Research and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliero-Universitaria Careggi, University of Florence, Florence, Italy


Background: RESPONSE is an ongoing, multicenter, open-label, phase 3 trial comparing the efficacy and safety of rux with BAT in patients (pts) with PV who are resistant to or intolerant of hydroxyurea (HU). Primary analysis and 80-week (wk) follow-up results from RESPONSE have been published previously. The 80-wk follow-up data confirmed that the probability of maintaining primary and hematocrit (Hct) responses with rux treatment was 92% and 89%, respectively, and hence, rux could be an effective long-term therapy option for hydroxyurea (HU)-resistant/intolerant (R/I) pts with PV. Here, we report the long-term efficacy and safety updates of rux treatment in RESPONSE trial after a follow-up of 208 wks (after last pt first treatment visit).

Methods: This was a preplanned follow-up when all pts completed the wk 208 visit or discontinued. Pts who were R/I of HU per modified ELN criteria, were aged ≥ 18 years (y), with splenomegaly, and phlebotomy (PBT) requirement to control Hct were eligible. Pts were randomized 1:1 to receive open-label rux 10 mg bid or BAT (selected based on investigator’s choice). Pts randomized to BAT could crossover (CO) to rux after wk 32. The primary response was a composite endpoint of achieving both Hct control without PBT (defined as no PBT eligibility between wks 8 to 32 with no more than 1 PBT eligibility from randomization to wk 8) through wk 32 and a ≥ 35% of reduction in spleen volume (SVR) by imaging at wk 32. Durability of the primary response, overall clinicohematologic response (CLHM; Hct control without PBT, platelet count ≤ 400 × 109/L, a WBC count ≤ 10 × 109/L, SVR ≥ 35% by imaging) as well as the long-term safety were updated at wk 208.

Results: Overall, 222 pts were randomized (rux, 110; BAT, 112) and BL characteristics were overall similar between arms, though more pts randomized to rux had prior history of nonmelanoma skin cancer (NMSC) or pre-cancerous skin conditions (10.9 vs 6.3%) and longer prior exposure to HU (162.9 vs 145.6 wks) compared to BAT arm. At the wk 208 analysis, 41 pts (37%) originally randomized to rux arm were still receiving therapy (median exposure, 225 wks) vs no pts on BAT (median exposure, 34 wks). Among the pts in rux arm, 29% completed the treatment as per protocol. Of 98 pts who crossed over to rux after wk 32, 38% remained on rux (median exposure, 189 wks) and 31% completed treatment. Other main reasons for the study drug discontinuations (rux + CO pts) were disease progression (11% + 8%), pt decision (6% + 6%), and adverse events (AE, 14% + 14%).

At the time of analysis in rux arm, 6 of 25 primary responders and 21 of 70 pt who achieved overall CLHM have progressed. Median duration of primary and CLHM responses has not been reached (Figure 1). The KM estimate at 208 wks of duration of primary and CLHM responses for rux arm are 0.73 (95% CI: 0.49, 0.87) and 0.67 (95% CI: 0.54, 0.77), respectively. The KM estimates for overall survival at 5 y were 90.6% (95% CI: 80.1, 95.7) in the rux arm and 87.7% (95% CI: 74.8, 94.3) in the BAT arm. Since wk 80 in rux arm, there were 2 new on-treatment deaths (adenocarcinoma gastric [n = 1, investigator-suspected event to be related to study drug] and neoplasm malignant [n = 1, investigator assessed it not related to study drug]). In the CO population, there were 4 pts who died and had fatal AEs leading to 4 on-treatment deaths (not related to rux).

The most frequent AEs (> 20%) in the rux arm (wk 208 vs wk 80) were anemia (35% vs 27%), pruritus (27% vs 20%), diarrhea (26% vs 20%), headache (23% vs 22%), arthralgia (22% vs 13%), weight increased (21% vs 16%), and muscle spasms (20% vs 16%). The most frequent AE (> 20%) in CO pts (wk 208 vs wk 80) was anemia (29.6% vs 22.4%). In the rux arm and CO pts, incidence of thromboembolic events (wk 208 vs wk 80) was 4.5% vs 6% and 9.2% vs 6.1%. The exposure-adjusted rate of overall malignancies in rux was 6.8 (wk 208) vs 6.1 (wk 80) per 100 pt-ys and 4.5 per 100 pt-ys in CO pts (wk 208).The exposure-adjusted rate of NMSC in rux was 5.1 (wk 208) vs 4.4 (wk 80) per 100 pt-ys. In the CO pts, exposure-adjusted rate of NMSC was 2.6 (wk 208) vs 2.0 (wk 80) per 100 pt-ys. At wk 208, the rates of transformation to MF and AML in rux arm were 2.2 and 0.2 per 100 pt-yrs, respectively, and 1.9 and 0.3 in CO pts.

Conclusion: At wk 208 analysis of data from RESPONSE study, the overall safety profile remained consistent with the 80-wk data, and the response was durable. In both the rux arm and CO population, around 30% of pts completed the study treatment and 37% of pts were still receiving the treatment.

Long Term Outcome of Patients with MPN-Associated Myelofibrosis Treated with Peg-Interferon-α2a, a French Intergroup of Myeloproliferative Neoplasms (FIM) Study

Result Type: Paper
Number: 323
Presenter: Jean-Christophe Ianotto
Program: Oral and Poster Abstracts
Session: 634. Myeloproliferative Syndromes: Clinical: Phase III and Long-Term Outcome Studies in MPNs

Jean-Christophe Ianotto, MD1*, Aurélie Chauveau, MD2*, Francoise Boyer-Perrard, MD3*, Emmanuel Gyan, MD-PhD4, Kamel Laribi5*, Pascale Cony-Makhoul, MD, PhD6*, Jean-Loup Demory, MD, PhD7*, Benoit De Renzis, MD8*, Christine Dosquet, MD9*, Jerome Rey, MD10*, Lydia Roy, MD11*, Brigitte Dupriez, MD, PhD12, Laurent Knoops, MD, PhD13*, Laurence Legros, PhD, MD14*, Mohamed Malou, MD, PhD15*, Pascal Hutin, MD16*, Dana Ranta, MD17*, Omar Benbrahim, MD18*, Valerie Ugo, MD, PhD19, Eric Lippert, MD, PhD20* and Jean-Jacques Kiladjian, MD, PhD21

1Clinical Hematology, Institut de Cancéro-Hématologie, Brest University Hospital, Brest, France
2Laboratoire d’Hématologie, Brest, France
3Service des Maladies du Sang, Angers, France
4CHU de Tours, Service d’Hematologie et Therapie Cellulaire, Tours Cedex, France
5Department of Hematogy, Centre Hospitalier Le Mans, Le Mans, France
6Centre Hospitalier Annecy-Genevois, Pringy, France
7Hopital St. Vincent De Paul, Lille, FRA
8Service d’Hématologie Clinique Adulte, Clermont Ferrand, FRA
9Hopital Saint-Louis, Cell Biology Department, Paris, FRA
10Institut PAoli-Calmette, Département d’Hématologie, Marseille, France
11Hopital de Créteil, Service d’Hématologie, Créteil, FRA
12CH de Lens, Service Hematologie Clinique, Lens, FRA
13Clin. Univ. St Luc, Brussels, BEL
14Service d’Hématologie, France, FRA
15CH de Morlaix, Serive d’Hématologie et Médecine Interne, Morlaix, FRA
16CHIC de Quimper, Service de Médecine Interne et Maladies Infectieuses, Quimper, France
17Hopital Universitaire de Nancy, Département d’Hématologie, Nancy, France
18Hopital La Source-CHR Orléans, Service d’Hématologie, Orleans, FRA
19CHU Angers, Institut De Biologie En Sante, Angers, FRA
20Hopital de la Cavale Blanche-CHRU de Brest, Laboratoire d’Hématologie, Brest, FRA
21Centre d’Investigation Clinique, Hopital Saint-Louis, Paris, FRA


Myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF) can occur as a de novo (Primary MF, PMF), or as secondary MF (SMF) resulting from transformation of Polycythemia Vera or Essential Thrombocythemia. In all cases, altered hematopoiesis results in abnormal blood counts (either hyperproliferation or cytopenias), splenomegaly and general symptoms related to inflammation, all of which are the intended targets of treatments.

Unfortunately, few therapeutic options exist and, besides allogeneic stem cell transplantation (ASCT), none is curative. We previously reported that pegylated-interferon-a2a (Peg-Ifn-α2a ) treatment in MF was able to induce significant clinical and hematological responses (1). We now present the long-term follow-up of this prospective cohort and correlations with driver and non-driver mutations.

Sixty-two MF patients (pts) treated with Peg-Ifn-α2a were included between 2006 and 2011 in a prospective observational study in 17 centers of the FIM group. Clinical and biological parameters and treatments were collected at Peg-Ifn-α2a initiation, every 3 months during two years and every 6 months thereafter. All 62 pts were genotyped for the 3 major MPN mutations (JAK2V617F, CALRMPL), and 49 were also screened by next generation sequencing (NGS) for mutations in the whole coding sequence of 25 genes frequently mutated in chronic myeloid disorders.

The median age at Peg-Ifn-α2a initiation was 64 and 70.5 years-old, in PMF (n=29) and SMF (n=33) pts, respectively. The median follow-up was 58 months (range: 9-107) after Peg-Ifn-α2a initiation and 69.6 months (range: 10-178) from MF diagnosis. Median Peg-Ifn-α2a treatment duration was 39 months (range: 6-107). At the time of analysis, 30 patients (48.4%) were still alive. The median overall survival (OS) was 7.4 years from MF diagnosis. The Lille and the DIPSS scores clearly differentiated pts in terms of OS, but median OS observed in this cohort was clearly longer than that reported in the reference cohorts used for the establishment of these prognostic scores, especially in higher risk categories: according to the Lille score (8.9 vs. 7.75 yrs for low, 5.42 vs. 2.17 yrs for intermediate and 4.46 vs. 1.08 yrs for high risks) and to the DIPSS score (6.9 vs. 4 yrs for intermediate-2 and 4.58 vs. 1.5 yrs for high-risk pts).

The type of driver mutation statistically impacted survival: CALR-mutated pts had 13.5 yrs of median OS compared to 7 yrs for JAK2-mutated pts (p<0.0001). Forty-five pts (72.6%) discontinued Peg-Ifn-α2a: 25 (55.6%) due to resistance and 20 (44.4%) due to intolerance. Patients developing intolerance to Peg-Ifn-α2a had longer median OS and leukemia-free survival (LFS) than those with resistance (p=10-5 and p=0.048, respectively). The median survival after Peg-Ifn-α2a cessation was 17 months (3-62m), but differed according to the subsequent treatment received: 22 months for those who received ruxolitinib compared to 14 months for those who received another drug (p=0.12) and 10 months for pts who underwent ASCT (p=0.003).

Sequential quantification of JAK2V617F allele burden was available in 27 pts, showing a decrease of mutant allele burden of more than 50% in 10/27 pts (37%). Four pts (15%) achieved a reduction over 90% including 3 complete molecular responses. Of the 49 pts analyzed with targeted NGS, 28 (57.1%) carried at least one additional mutation. Patients who harbored at least one non-driver mutation had shorter OS (6.1 vs. not reached, p=0.06) and LFS (not reached both, p=0.026) than those with only driver mutations. The presence of “high molecular risk” mutations previously associated with poorer prognosis (in ASXL1, EZH2, SRSF2, IDH1/2) was not associated with a poorer OS or LFS than other mutations in this series of pts treated with interferon.

In conclusion, this large cohort of MF pts treated with Peg-Ifn-α2a demonstrates that a long-term use of this treatment is safe, and is associated with improved OS compared to historical series as well as significant decrease in driver mutation allele burden. The presence of additional mutations remains associated with poorer prognosis. The role of interferon therapy should be discussed in pts with MF, optimal target population possibly being high-risk pts without ASCT project and with a proliferative disease.

Characteristics and Survival of Patients with Chronic Phase Myelofibrosis and Elevated Blasts (5-9%), and the Effect of Therapy with JAK2 Inhibitor Ruxolitinib

Result Type: Paper
Number: 201
Presenter: Lucia Masarova
Program: Oral and Poster Abstracts
Session: 634. Myeloproliferative Syndromes: Clinical: Biologic-Clinical Correlative Studies in MPNs, Including Transplant

Lucia Masarova, MD1*, Prithviraj Bose, MD1, Naveen Pemmaraju, MD2, Naval Daver, MD1, Jorge E. Cortes, MD3, Zeev Estrov, MD4, Hagop M. Kantarjian, MD1 and Srdan Verstovsek, MD, PhD3

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Leukemia department, The University of Texas MD Anderson Cancer Center, Houston, TX
3Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX
4University of Texas M.D. Anderson Cancer Center, Houston, TX


Introduction: Patients with accelerated phase (AP) myelofibrosis (MF) (10-19% blasts in bone marrow [BM] or peripheral blood [PB]) have higher risk of leukemic transformation and shorter overall survival (OS) than those in the chronic phase (<10% BM / PB BL, CP). Clinical characteristics of patients in “chronic phase and elevated” BM / PB blasts (5-9%, CP-e) are not well described, and the effect of available therapy is largely unknown. Objective: We aimed to identify clinical characteristics, and survival, as well as evaluate effect of JAK2 inhibitor ruxolitinib (RUX) on outcome of patients with 5-9% PB / BM blasts seen at MD Anderson Cancer Center (MDACC). Methods: Medical charts of 1199 patients who presented to MDACC between years 1984 – 2015 with MF and available blast percentage in PB and BM, were retrospectively evaluated. All relevant clinical characteristics were collected at the time of referral. Chronic phase (CP) was defined as <5% BM / PB blasts; chronic phase with elevated blasts (CP-e) as 5-9% BM / PB blasts; and accelerated phase (AP) as 10-19% BM / PB blasts. Categorical and continuous variables were analyzed using the Fisher’s exact, Kruskal–Wallis or Mann–Whitney U tests, as appropriate. Survival analysis was done using Kaplan-Meier analysis with the log-rank test, and patients were censored for stem cell transplantation (n=103, 9%; 81 patients with CP [15%], 16 with CP-e [13%], and 6 with AP [11%]). Results: Eighty five percent of patients (n=1020) were in CP; 10% (n=123) in CP-e, and 5% (n=56) in AP. Clinical characteristics and demographics are shown in Table 1. Patients with CP-e had similar clinical characteristics as patients in AP, and furthermore, both had higher white blood cell counts, lower hemoglobin and platelets, more frequent splenomegaly, systemic symptoms, and presence of abnormal and unfavorable karyotype (Caramazza, Leukemia 2011) than patients in CP.

After median follow-up of 27 months (range, 1-251), 50% (n=594) of patients have died. Fourteen percent of patients (n=169) were untreated while being followed at MDACC. Among the remaining 1030 patients, 52% (n=533), 16% (n=162), and 12% (n=126) have received one, two, and ≥3 therapies. RUX was used in 30% of patients (n=328): in 289 (28%), 33 (27%) and 6 (11%) patients in CP, CP-e and AP, respectively.

The median overall survival (OS) of the entire group was 48 months (range, 40-65). The median OS for patients in CP, CP-e and AP was 56, 34, and 23 months, respectively (p<0.001, Graph 1A). Patient in CP-e had similar OS as those in AP (p=0.26), which was inferior to patients in CP (p<0.001, HR 0.58, 95% CI 0.37-0.66, favoring CP). OS rates for CP, CP-e and AP patients were at 1-year 86, 73, and 65%, and at 5-year 46, 24, and 21%, respectively. As the next step we analyzed the impact of RUX on OS in each of the groups. Patients who were exposed to RUX have superior overall survival within CP as well as CP-e groups, with respective OS of 61 vs 52 months in CP (with vs without RUX; p=0.002, HR 0.85, 95% CI 0.69-0.97), and 54 vs 27 months in CP-e (with vs without RUX; p=0.001, HR 0.50, 95% CI 0.29-0.85, Graph 1B, C). Furthermore, OS of patients in CP-e who were exposed to RUX has reached OS of patients in CP group, both with and without RUX, with respective OS of 54, 61, and 52 months (p>0.05, Graph 2B, C). RUX had no impact on OS among AP patients (with and without RUX, 23 vs 23.4 months, p>0.05, graph not shown).

Progression to AML occurred in total of 139 (9%) patients, with overall incidence of 3.96 cases per 100 persons-years. Nine percent (n=93), 20% (n=25), and 39% (n=22) of patients have progressed to AML among CP, CP-e, and AP groups, respectively, (p<0.0001 with 3 distinct groups). RUX therapy had no impact on the rate of AML progression (CP with and without RUX both 9%; CP-e with and without RUX 22 and 18%, respectively). Conclusions: RUX, the only FDA approved JAK2 inhibitor for patients with MF, has a potential to significantly improve an outcome of patients with 5-9% blast percentage whose clinical characteristics and outcome appear to be worse than patients with CP MF and <5% blasts.[/et_pb_text][et_pb_image src="" _builder_version="3.0.92"][/et_pb_image][et_pb_text _builder_version="3.0.92"]

Sotatercept (ACE-011) Alone and in Combination with Ruxolitinib in Patients (pts) with Myeloproliferative Neoplasm (MPN)-Associated Myelofibrosis (MF) and Anemia

Result Type: Paper
Number: 255
Presenter: Prithviraj Bose
Program: Oral and Poster Abstracts
Session: 634. Myeloproliferative Syndromes: Clinical: Phase I/II Trials of Novel Agents in MPNs

Prithviraj Bose, MD1, Naval Daver, MD1, Naveen Pemmaraju, MD1, Elias J. Jabbour, MD 2, Zeev Estrov, MD1, Allison Pike, RN1*, Julie Huynh-Lu, Physician Assistant1*, Madeleine Nguyen-Cao, Physician Assistant1*, Xuemei Wang3*, Lingsha Zhou1*, Sherry Pierce, BSN, BA1*, Hagop M. Kantarjian, MD1 and Srdan Verstovsek, MD, PhD1

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Leukemia, University of Texas M.D. Anderson Cancer Ctr., Houston, TX
3Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX


Introduction: Anemia is common in MPN-associated MF and current treatment options are unsatisfactory. Furthermore, anemia is often worsened by ruxolitinib (rux), the only FDA-approved therapy for MF, frequently leading to premature discontinuation of rux/impairing dose optimization. Sotatercept is a first-in-class, activin receptor IIA ligand trap that improves anemia by sequestering TGF-ß superfamily ligands, e.g., growth and differentiation factor 11 (GDF11), which suppress terminal erythroid differentiation. Early results from this phase 2 study (NCT01712308) were presented previously (Bose, ASH 2016). Here, we report updated results from the sotatercept monotherapy cohort and the first results from the rux/sotatercept combination cohort.

Methods: Eligible pts are adults with primary, post-polycythemia vera (PPV) or post-essential thrombocythemia (PET) MF with hemoglobin (Hgb) <10 g/dL on every determination during the 84 days preceding study entry, Hgb <10 g/dL with sporadic RBC transfusions, or transfusion-dependent (TD) as defined by IWG-MRT 2013 criteria. Sotatercept is administered subcutaneously every 3 weeks at a dose of either 0.75 mg/kg or 1 mg/kg in the monotherapy cohort and 0.75 mg/kg in combination with rux. The overall response rate (ORR) is a composite of the rate of transfusion independence (TI), as defined by the IWG-MRT 2013 criteria, and Hgb response (increase from baseline of ≥1.5 g/dL on every determination consecutively over ≥12 weeks without RBC transfusions). Pts in the rux combination cohort must have been on rux for ≥6 months with a stable dose during the preceding ≥2 months. Results: To date, 33 pts have been treated, 24 in the monotherapy cohort and 9 in the rux combination cohort.

Monotherapy cohort: Of the 24 pts, 10 were female and 14 male, with a median age of 66.5 (47-83) years. Twenty had primary MF (PMF), 3 PET MF and 1 PPV MF. JAK2V617F was detected in 16, MPLW515L in 3, and CALR exon 9 indels in 3; 1 pt was “triple negative” and driver mutation status was unknown in 1. All were DIPSS intermediate (int)-2 (n=19) or high (n=5) risk. Bone marrow (BM) fibrosis grade was 3 in 15 pts, 2 in 8 pts and 1 in 1 pt. Five pts were previously untreated; 19 had received 1-5 prior therapies (median 1). Median time from diagnosis was 1.2 (0.2-5.8) years. Eleven pts received 0.75 mg/kg and 13, 1 mg/kg. Five pts remain on study and have received a median of 15 (2-29) cycles; 19 pts are off study (median no. of cycles 5, range 1-23). Reasons for discontinuation include: no response (7), SCT (3), patient decision (3), hypertension (1), progressive MF necessitating alternate therapy (3), transformation to AML (1), and unrelated medical complications (1). Six of 17 (35%, exact 95% CI: 14% – 62%) evaluable patients (on study for ≥84 days) responded. Two responses occurred at the 1 mg/kg dose, and 4 at 0.75 mg/kg. Hgb rose by ≥1.5 g/dL in 2 other pts who only received 2 cycles each and were, thus, not evaluable. Responses occurred in previously treated and treatment-naïve pts, across driver mutation types and in both RBC TD and -independent pts.

Rux combination cohort: Nine pts, 4 female and 5 male, with a median age of 67 (57-75) years have been treated. Six have PMF, 2 PPV MF and 1 MDS/MPN. One pt each had a MPL and a CALR mutation; the rest had JAK2V617F. DIPSS risk was int-2 in 8 pts and int-1 in 1 pt. BM fibrosis grade was 3 in 5 pts, 2 in 3 pts and 1 in 1 pt. Median time from diagnosis was 1.9 (0.4-11) years, and pts had received 1-4 (median 2) prior therapies. The rux dose at study entry was 10 mg bid in 6 pts, 20 mg bid in 2 and 5 mg bid in 1. Six pts remain on study; 3 have come off for lack of response (1) or to move to SCT (2). One of 8 evaluable pts (12.5%, exact 95% CI: 0.3% – 52.7%) has responded thus far.

Sotatercept was very well tolerated. Two pts, 1 in each cohort, reported grade 2 bilateral lower limb pain possibly related to sotatercept. Hypertension was felt to be possibly related to sotatercept in 1 pt. A number of responders had to have the drug held on multiple occasions due to Hgb levels ≥11.5 g/dL and resumed upon their return to ≤11 g/dL, as defined in the protocol.

Conclusions: As a single agentsotatercept is effective in improving anemia in pts with MPN-associated MF. Efficacy is also possible in the setting of concurrent rux use, but more experience is required in this setting. Enrollment continues to both cohorts of this trial. A similarly designed trial (NCT03194542) of a closely related drug, luspatercept (ACE-536), will soon open to accrual.

Advanced Forms of the Myeloproliferative Neoplasms  Are Associated with   Chromosomal Abnormalities Involving  1q and 12q: Implicating   MDM2 and MDM4   in Disease Progression

Result Type: Paper
Number: 204
Presenter: Bridget Marcellino
Program: Oral and Poster Abstracts
Session: 634. Myeloproliferative Syndromes: Clinical: Biologic-Clinical Correlative Studies in MPNs, Including Transplant 

Bridget Marcellino, MD. Ph.D.1*, Joseph Tripodi2*, Min Lu, PhD, MD3, Heidi Kosiorek, MS4*, John Mascarenhas, MD5, Raajit K. Rampal, MD, PhD6, Amylou Constance Dueck, PhD4, Ronald Hoffman, MD7 and Vesna Najfeld, PhD2

1Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York
2Department of Pathology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
3Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
4Mayo Clinic, Scottsdale, AZ
5Icahn School of Medicine at Mount Sinai, New York, NY
6Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
7Division of Hematology/Medical Oncology, The Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY


Inevitably patients (pts) with myeloproliferative neoplasms (MPNs) including polycythemia vera (PV) and essential thrombocythemia (ET) progress to more advanced forms of myelofibrosis (MF) and acute myeloid leukemia (AML). Loss of TP53 function plays a critical role in cancer biology yet, the MPNs are characterized predominately by wild type (WT) TP53 (Rampal et al, PNAS, 2014;111: 5401-10). The major protein regulators of TP53 are MDM2 and MDM4. TP53 activity has been reported to be down-regulated in MPNs due to overexpression of MDM2 (Lu et al, Blood, 2012;120:3098-3105, Nakatake et al, Oncogene, 2012: 311: 323-33). Since the gene for MDM4 is located on chromosome 1q and the gene for MDM2 is located on chromosome 12q, we hypothesized that cytogenetic abnormalities involving these locations might lead to disease progression This hypothesis is supported by the recent observation that mice engineered to possess JAK2V617F and lack TP53 are prone to develop AML as compared to JAK2V617F+ mice with WT TP53 (Rampal et al, PNAS, 2014:111:5401-10). Gain of 1q (+1q) in the form of jumping translocations in pts with MPN was previously reported to be associated with transformation to AML (Najfeld et al, Br.J. Haematol., 2010; 151: 285-291).These studies were extended to 362 MPN pts enrolled in 5 different MPN-RC clinical trials involving pts with ET or PV (222), MF and MPN –Blast Phase (MPN-BP)(140) and 989 pts with MPNs, ET(177), PV (400), MF (385) and MPN-BP(27) who were studied at the Icahn School of Medicine at Mount Sinai (ISMMS) between 1986 and June 2017. 92 pts in the various MPN-RC trials (25.4%) and 344 (34.7%) of the pts from ISMMS were chromosomally abnormal. Among the abnormalities, 23 pts in the MPN-RC trials had either +1q/dup(1q)(n=16) or rearrangements of 12q (n=7) (6.3% of the total pts and 25.0% of the chromosomally abnormal pts). Similarly, the most frequently observed chromosomal abnormality at ISMMS associated with disease progression, either as a sole abnormality or as a subclone with other chromosomal abnormalities, was gain of 1q, identified in 59 pts (6.0% of total, 17.4% of the abnormal pts). Gain of 1q was observed in three forms: 1) as an unbalanced translocation with the breakpoint at 1q21. 2) a duplication of 1q region and/or 3) as a jumping +1q translocation. The most frequent unbalanced translocation identified was +der(9)t(1;9)(q21;q12) (24%) resulting in three copies of 1q and 3 copies of 9p. Rearrangement of 12q most frequently involved balanced translocations and/or inv(12q) with 50% of these pts having a breakpoint at 12q15 where the gene for MDM2 is located. Gain of 1q/dup(1q) and rearrangements of 12q were mutually exclusive with the exception of one patient with a translocation between chromosomes 1 and 12 [der(12)t(1;12)(q24;q15)]. Among PV/ET pts enrolled in MPN-RC trials, 1.3% (3/222) had +1q and 0.0% (0/222) had 12q abnormalities, while 11% (15/140) of pts enrolled in MF and MPN-BP treatment protocols had +1q and 5% (7/140) had 12q abnormalities. These findings indicate that +1q and structural abnormalities of 12q are associated with more advanced forms of MF and MPN-BP (p<0.001). In both, the MPN-RC and the ISMMS data bases, 42 cases with +1q and 13 cases with 12q abnormalities were identified where the driver mutational status was known. The JAK2V617F mutation was observed in 83.3% (35/42)of pts with +1q while 23.1% (3/13) pts with 12q abnormalities were JAK2V617F+.These data indicate that gain of 1q but not 12q abnormalities are associated with the JAK2V617F mutation (p<0.001). In a limited number of pts (n=10) we were able to monitor the chronological acquisition of 1q and 12q abnormalities. The 1q abnormalities occurred 5-7 years following the initial cytogenetic evaluation of PV pts and the proportion of cells with gain of 1q increased over time being present in 100% of cells over the next 4-5 years of observation. By contrast, 12q abnormalities occurred exclusively in MF pts as the sole abnormality and appeared in 90-100% of the examined cells at presentation. In 5 MF pts with +1q, qPCR demonstrated upregulation of MDM4 mRNA transcripts (86%) when compared to 5 pts without +1q. These data suggest that MPN disease progression is associated with specific chromosomal abnormalities that result in up regulation of MDM2 or MDM4 which further down-regulate p53 .These data provide the rationale for the use of MDM2/MDM4 antagonists as a means of halting MPN disease progression.

Open Label Phase I Study of Single Agent Oral RG7388 (idasanutlin) in Patients with Polycythemia Vera and Essential Thrombocythemia

Result Type: Paper
Number: 254
Presenter: John Mascarenhas
Program: Oral and Poster Abstracts
Session: 634. Myeloproliferative Syndromes: Clinical: Phase I/II Trials of Novel Agents in MPNs

John Mascarenhas, MD1, Min Lu, PhD, MD2, Elizabeth Virtgaym3*, Heidi Kosiorek, MS4*, Marina Stal5*, Lonette Sandy2*, Alicia Orellana, MEd, MPH2*, Lijuan Xia2*, Marina Kremyanskaya, MD, PhD2*, Bruce Petersen, MD6, Amylou Dueck, PhD7 and Ronald Hoffman, MD8

1Icahn School of Medicine at Mount Sinai, New York, NY
2Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
3Tisch Cancer Institute, Icahn School of Medicine at Mount SInai, New York
4Mayo Clinic, Phoenix, AZ
5Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York
6Department of Pathology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
7Mayo Clinic Arizona, Phoenix, AZ
8Division of Hematology/Medical Oncology, The Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY


Background: Polycythemia vera (PV) and essential thrombocythemia (ET) are associated with an increased risk of thrombosis, progression to myelofibrosis (MF) and significant symptom burden. While hydroxyurea, interferon, and JAK2 inhibitors are used to treat these myeloproliferative neoplasms (MPNs), hematopoietic stem cell-depleting therapies may result in an alternative mechanism to alter disease course and improve outcome. MDM2, a negative regulator of P53, is overexpressed in CD34+ MPN cells harboring wild type P53. It is the target of idasanutlin (IDA), an oral MDM2 antagonist that results in up-regulation of P53 and down-stream activators of apoptosis. Preclinical data from our laboratory group supports the clinical evaluation of IDA in patients (pts) with ET/PV (Lu et al Blood. 2014;124(5):771-9). We evaluated the safety and tolerability of IDA in a phase I dose escalation trial of pts with JAK2V617F-positive ET or PV [NCT02407080].

Methods: 13 pts (1 withdrew prior to treatment) resistant/intolerant to hydroxyurea and/or interferon therapy and without prior JAK2 inhibitor therapy were enrolled in a single institution phase I trial of oral IDA at two dose levels of 100 mg and 150 mg daily for five consecutive days and repeated every 28 day cycles. The first cycle consisted of 56 days for the evaluation of dose limiting toxicities (DLT). A DLT was defined as any non-hematologic AE of grade 3+ or a hematologic AE of grade 2+ thrombocytopenia, or grade 3+ neutropenia or anemia. The absence of DLT in the initial cohort of 100 mg daily in 3 evaluable pts allowed for dose escalation in a new cohort to 150 mg and after a total of 6 pts were treated at this level an additional 3 pts were treated at 100mg to complete the intended study. Pts that did not attain at least a partial response (PR) by modified European LeukemiaNet (ELN) criteria after cycle 6 and met eligibility were able to continue receiving IDA in combination with pegylated interferon-α (PEG) at 45ug weekly. Correlative studies included baseline mutational profiling, MDM2 protein levels, changes in serum MIC-1 levels and JAK2V617F variant allele frequency (VAF) with therapy.

Results: 12 pts (6 at 100 mg; 6 at 150 mg) were treated and their baseline characteristics are shown in Table 1. Pts received a median of 7 cycles (range, 1-12) over a median of 33 weeks (range, 8-107) on study. Three pts discontinued treatment due to pt decision (n=2) and physician decision (n=1). A DLT was not identified for either dose level during cycle 1, and no hematologic treatment emergent adverse events (TEAE) were seen at any time point. Table 2 shows the non-hematologic TEAEs that occurred in at least 2 pts regardless of attribution. Grade 3 fatigue (n=1) and grade 3 headache (n=1) were the only significant TEAE noted at any time on study (both in 100mg cohort). The overall response rate by modified ELN criteria by cycle 7 for the 9 evaluable pts was 7/9 (78%). 7 of 10 (70%) evaluable pts achieved a ≥50% improvement in total symptom score (TSS) from baseline. There were no thrombotic or major hemorrhagic episodes, or progression to MF. Bone marrow pathologic response was assessed in 2 pts after 5 cycles. One case showed histological improvement, with normalization of overall marrow cellularity and megakaryocyte number, and less pronounced megakaryocytic atypia. The median JAK2V617F VAF at baseline, 7 cycles, and 9 cycles of therapy was 45% (n=12), 12% (n=6) and 13% (n=6), respectively. One pt was eligible to receive combination therapy and achieved phlebotomy freedom, normalization of palpable spleen (baseline 18cm), leukocyte count (baseline 44 x109/L), and PV-related symptoms by cycle 8. This pt also attained a 20% reduction in JAK2V617F VAF.

The percentage of mononuclear cells expressing MDM2 was dramatically increased as compared to normal controls (p=0.01) (Figure 1). Serum levels of MIC-1 was used to assess pharmacodynamic effects of IDA therapy. Serum MIC-1 levels were elevated (~ 5 fold) after 5 days of administration of IDA in 85% of the pts (Figure 2), indicating activation of P53 by the low doses of IDA administered. Persistent elevation in MIC-1 levels was observed on day 15 in 6 of the 12 pts treated.

Conclusion: IDA is well tolerated and demonstrates a clear signal of clinical activity in pts with therapy refractory PV. Correlatives support on-target activity. Mature follow up on the entire cohort will be presented. A multicenter phase II trial of IDA at a dose of 150 mg is underway