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4277 Outcome of Patients with Myelofibrosis after Ruxolitinib Failure: Role of Disease Status and Treatment Strategies in 214 Patients

Program: Oral and Poster Abstracts
Session: 634. Myeloproliferative Syndromes: Clinical: Poster III
Hematology Disease Topics & Pathways:
Biological, AML, Diseases, Adult, Therapies, Non-Biological, chemotherapy, MPN, Study Population, Clinically relevant, Myeloid Malignancies, pharmacology, TKI
Monday, December 3, 2018, 6:00 PM-8:00 PM
Hall GH (San Diego Convention Center)

Francesca Palandri, PhD, MD1*, Elena Maria Elli, MD2*, Nicola Polverelli, MD3*, Massimiliano Bonifacio4*, Giulia Benevolo, MD5*, Elisabetta Abruzzese6, Micaela Bergamaschi, MD7*, Alessia Tieghi, MD8*, Alessandra Iurlo9*, Monica Crugnola, MD10*, Francesco Cavazzini, MD11*, Gianni Binotto, MD12*, Alessandro Isidori13, Nicola Sgherza, MD14*, Costanza Bosi, MD15*, Roberto Latagliata16*, Giuseppe Auteri, MD17*, Luigi Scaffidi, MD18*, Daniele Cattaneo, MD19*, Lucia Catani, PhD20*, Mauro Krampera, MD, PhD4, Umberto Vitolo21, Franco Aversa, MD22*, Roberto Massimo Lemoli, MD23, Antonio Cuneo, MD24*, Gianpietro Semenzato25*, Robin Foà, MD16, Francesco Di Raimondo, MD26, Michele Cavo, MD27*, Daniela Bartoletti, MSc28*, Nicola Vianelli, MD17*, Massimo Breccia, MD29* and Giuseppe A. Palumbo, MD30*

1Institute of Hematology “L. and A. Seràgnoli”, Azienda Ospedaliero-Universitaria S. Orsola-Malpighi, Bologna, Italy
2Hematology Division, Ospedale San Gerardo - ASST Monza, Monza, Italy
3Bone Marrow Transplant Unit, ASST-Spedali Civili di Brescia, Chair of Hematology, Dpt of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
4Department of Medicine, Section of Haematology, University of Verona, Verona, Italy
5Hematology Division , Città della Salute e della Scienza Hospital, Turin, Italy
6Hematology Unit, S. Eugenio Hospital, Roma, Italy
7Clinical Hematology Unit, IRCCS AOU S.Martino-IST, Genova, Italy
8Hematology, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy
9Hematology Division, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
10Hematology and BMT Center, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
11Division of Hematology, Department of Medical Sciences, University of Ferrara, Azienda Ospedaliera-Universitaria, Arcispedale S. Anna, Ferrara, Italy
12Hematology and Clinical Immunology, Department of Medicine, Padua School of Medicine, Padova, Italy
13Hematology and Stem Cell Transplant Center, AORMN Hospital, Pesaro, Italy
14Division of Hematology, IRCCS Ospedale Casa Sollievo Sofferenza, San Giovanni Rotondo, Italy
15Hematology, Guglielmo da Saliceto Hospital, Piacenza, Italy
16Department of Cellular Biotechnologies and Hematology, University "Sapienza", Rome, Italy
17Institute of Hematology “L. and A. Seràgnoli”, S. Orsola-Malpighi Bologna University Hospital, Bologna, Italy
18Department of Medicine, Section of Hematology, Department of Hematology, University of Verona, Verona, Italy
19Oncohematology Division, IRCCS Ca' Granda - Maggiore Policlinico Hospital Foundation, University of Milan, Milano, Italy
20Institute of Hematology "L. and A. Seràgnoli", Sant'Orsola-Malpighi University Hospital, Bologna, Italy., Bologna, ITA
21Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
22Hematology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
23Clinic of Hematology, Department of Internal Medicine (DiMI), IRCCS Ospedale Policlinico San Martino, Genova, Italy
24Hematology section, Department of Medical Sciences, University of Ferrara - Azienda Ospedaliera-Universitaria di Ferrara, University of Ferrara, Ferrara, Italy
25Dept. of Medicine, Hematology and Clinical Immunology, Padua School of Medicine, Padova, Italy
26A.O.U. Policlinico "Vittorio Emanuele", University of Catania, Catania, Italy
27Institute of Hematology "Seràgnoli", S. Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy
28Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology 'L. and A. Seràgnoli', University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
29Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy
30UO Ematologia, AOU Policlinico-V Emanuele, Catania, ITA

Introduction. Ruxolitinib (RUX) is the only targeted therapy available for the treatment of myelofibrosis (MF)-related splenomegaly and symptoms. Significant clinical responses may be achieved in around 50% of patients (pts). However, half of responding pts lose the response over time.

Aims. To report the outcome of a large cohort of MF pts after RUX failure, in terms of disease status, treatment strategies and survival.

Methods. A clinical database was created in 23 European Hematology Centers including retrospective data of 537 MF pts treated with RUX from Jan 2011 to July 2018. Updated information at the date of July 15th 2018 was available in 442 pts who were included in the present analysis. Spleen and symptoms response (SR & SyR) to RUX were evaluated according to the 2013 IWG-MRT criteria. RUX-related toxicity and infections were graded according to the WHO scale. Overall (OS) was estimated from the date of RUX discontinuation to the date of death or last contact, using the Kaplan-Meyer method (log-rank test).

Results. After a median follow-up of 30.5 months (1.7-84.3), 214 out of 442 evaluable (48.4%) pts had discontinued RUX. 43 (20.1%) died while on therapy because of: MF progression (34.9%), infections (25.6%), heart disease (16.3%), second neoplasia (7%), hemorrhages (7%), other (9.2%).

The median follow-up after RUX discontinuation for the remaining 171 pts was 11.3 months (0.5-66.7). Causes of RUX discontinuation were: drug-related toxicity (28.6%), loss/lack of response (23.4%), MF progression (12.3%), acute leukemia (AL) (13.4%), allogeneic stem cell transplantation (ASCT) (11.1%), second solid neoplasia (4.1%), other unrelated causes (i.e. pts decision; 7.1%).

After stopping RUX, 68 pts received 1 line of therapy, 21 received 2 lines and 9 received >2 treatments; 73 pts did not receive any therapy. Treatments received after RUX discontinuation, alone or in combination, included hydroxyurea (HU) (n. 61, 62.2%), ASCT (n. 20, 20.4%), second-generation JAK2 inhibitors (momelotinib/fedratinib/pacritinib) (n. 11, 11.2%), splenectomy (n. 7, 7.1%), azacytidine/decitabine (n. 5, 5.1%), chemotherapy (n. 4, 4.1%), investigational agents (imetelstat/PRM151: n. 4), danazole (n. 4), erythropoietin-stimulating agents (ESA) (n. 4).

A total of 95 pts (55.6%) died after RUX discontinuation, because of: MF progression (30.5%), AL (25.4%), infections (14.7%), second neoplasia (9.5%), hemorrhages (4.2%), heart disease (4.2%), ASCT (4.2%), thrombosis (2.1%), other (5.2). Median survival time from RUX stop of the 171 evaluable pts was 22.6 mos (95% CI, 13.2-30.7).

Among baseline features, survival after discontinuation was significantly influenced by the dynamic international prognostic score (DIPSS) category (p<0.001), transfusion dependency (p<0.001) and driver mutation status (with triple-negative pts having the worst survival compared to JAK2V617F and CALR-mutated pts, p=0.01).

During therapy, 45 out of 153 (29.4%) and 123 out of 161 (76.4%) evaluable pts achieved a SR and a SyR at any time. Survival was not affected by the previous response to RUX at any time-point. Conversely, survival significantly differed according to the reason for stopping RUX, with pts discontinuing because of AL evolution/second solid neoplasia having the worst outcome (Figure 1a, p<0.001). In pts who discontinued RUX in chronic phase, the use of second generation TKIs and other investigational agents tended to prolong survival compared to the administration of conventional medical treatments (i.e. HU, danazole, ESA) (Figure 1b, p=0.07)

Discussion. After RUX failure, very limited therapeutic options are available and the prognosis of MF pts is dismal, particularly for those pts starting RUX with advanced stage disease (i.e. high DIPSS category and transfusion dependency). Also, disease evolution into AL and occurrence of a second solid neoplasia significantly reduced life expectancy. In chronic phase pts, survival probability may be improved by the use of medical therapies that are still in the experimental phase. Novel investigational agents are needed.

Disclosures: Palandri: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Abruzzese: BMS: Consultancy; Ariad: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Vitolo: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Speakers Bureau; Takeda: Speakers Bureau; Sandoz: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Aversa: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Basilea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Astellas: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cuneo: Gilead: Other: advisory board, Speakers Bureau; Roche: Other: advisory board, Speakers Bureau; Abbvie: Other: advisory board, Speakers Bureau; janssen: Other: advisory board, Speakers Bureau. Foà: ROCHE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; NOVARTIS: Speakers Bureau; CELTRION: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; INCYTE: Other: ADVISORY BOARD; CELGENE: Other: ADVISORY BOARD, Speakers Bureau. Di Raimondo: Celgene: Honoraria; Takeda: Honoraria, Research Funding. Cavo: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Breccia: Pfizer: Honoraria; Incyte: Honoraria; BMS: Honoraria; Novartis: Honoraria. Palumbo: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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