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688 Alisertib (MLN8237), an Oral Selective Inhibitor of Aurora Kinase a, Has Clinical Activity and Restores GATA1 Expression in Patients with Myelofibrosis

Program: Oral and Poster Abstracts
Type: Oral
Session: 634. Myeloproliferative Syndromes: Clinical: Emerging Therapies and Prognostic Scoring in Myelofibrosis and Other MPNs
Hematology Disease Topics & Pathways:
apoptosis, Biological, Diseases, Adult, Non-Biological, Therapies, cellular interactions, Biological Processes, chemotherapy, enzyme inhibitors, MPN, Study Population, Clinically relevant, Myeloid Malignancies
Monday, December 3, 2018: 11:15 AM
Grand Hall A (Manchester Grand Hyatt San Diego)

Naseema Gangat, MBBS1, Brady Lee Stein, MD2, Christian Marinaccio3*, Ronan Swords, MD, PhD4, Justin M. Watts, MD5, Sandeep Gurbuxani6, Olga Frankfurt, MD7*, Jessica K. Altman, MD8, Jeremy Q. Wen, MD, PhD9*, Noushin Farnoud, PhD10*, Christopher Famulare, MS11*, Akshar Patel, BA12*, Roberto Tapia, BS13, Amy Handlogten14*, Yvonne Trang Dinh, BS15*, Kristen Englund15*, Shradha Patel16*, Juan Carlos Nobrega16*, Dalissa Tejera, MSN15*, Amber Thomassen16*, Harald Stein, MD, PhD, Dr. h.c.17*, Juehua Gao, MD, PhD18*, Peng Ji, MD, PhD,19, Raajit K. Rampal, MD, PhD20, Francis J. Giles, MD, FRCPI, FRCPath21, Ayalew Tefferi, MD1 and John D. Crispino, PhD, MBA22

1Division of Hematology, Mayo Clinic, Rochester, MN
2Dept. of Medicine, Division of Hematology/Oncology and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL
3Northwestern University, Chicago, IL
4University of Miami/Sylvester Comprehensive Cancer Center, Miami, FL
5Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, FL
6The University of Chicago, Chicago, IL
7Northwestern Memorial Hospital, Chicago, IL
8Northwestern Univ., Chicago, IL
9Hematology and Oncology, Chicago, IL
10Center for Molecular Oncology and Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
11Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
12Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY
13Division of Hematology/Oncology, Northwestern University, Chicago, IL
14Mayo Clinic, Rochester, MN
15University of Miami Sylvester Comprehensive Cancer Center, Miami, FL
16Sylvester Cancer Center, University of Miami, Miami, FL
17Universitätsklinikum Benjamin Franklin Institut für Pathologie, Berlin, DEU
18Department of Pathology, Northwestern University, Chicago, IL
19Northwestern University, Feinberg School of Medicine, Chicago, IL
20Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center; Myeloproliferative Neoplasm Research Consortium (MPN-RC), New York, NY
21Northwestern Medicine Developmental Therapeutics Institute, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL
22Division of Hematology and Oncology, Northwestern University, Chicago, IL

Background:

The selective AURKA inhibitor alisertib (MLN8237) exhibits disease modifying activity in murine models of myelofibrosis by eradicating atypical megakaryocytes resulting in reduction of marrow fibrosis (Nat Med 2015). Here, we present long term follow-up results from the investigator initiated pilot study of alisertib in patients with myelofibrosis (clinical trials.gov Identifier NCT 02530619).

Methods:

24 patients with DIPSS intermediate 1, intermediate-2, or high risk myelofibrosis who were in need of therapy, refractory/intolerant or unlikely to respond to JAK inhibitors with neutrophil count ≥ 1 x109/L, and platelet count ≥ 50 x109/L, received alisertib (provided by Millennium Pharmaceuticals Inc) at a dose of 50 mg twice daily for one week every 21 days. Toxicity assessment was performed by the standard common terminology criteria (Version 4.0). Response was assessed by the international working group for myelofibrosis research and treatment (IWGMRT) criteria. Correlative studies included assessments of JAK2V617F, CALR, and MPL mutant allele burden, degree of fibrosis and GATA1 expression in bone marrow samples obtained pre and post therapy.

Results:

We enrolled 17 patients with primary myelofibrosis, 4 with post essential thrombocythemia myelofibrosis and 3 with post polycythemia vera myelofibrosis. Median age was 72 years with 66% males. 79% of patients were DIPSS intermediate risk, and the remainder were high risk with 15 patients (62.5%) having received prior JAK inhibitor therapy. Driver mutational status was as follows; 58% JAK2V617F, 29% CALR, and 13% MPL mutated. At study entry, 54% of patients demonstrated palpable splenomegaly ≥ 5 cm below the left costal margin, 54% were transfusion dependent with all patients experiencing constitutional symptoms.

At the time of data cut-off, patients received a median of 7.5 cycles (range; 1-29 cycles) of therapy. The 7 patients presently on study have received a median of 23 cycles (range; 8-29 cycles). Reasons for treatment discontinuation included progressive disease/lack of response in 11 (65%) patients, toxicity in 4 (24%) patients and refusal of further therapy in 2 (11%) patients.

  • Safety and Efficacy assessments

The most common treatment-emergent grade 3/4 adverse events included neutropenia (42%), thrombocytopenia (29%) and anemia (21%), with 4% each experiencing neutropenic fever, diarrhea, vertigo, elevated creatinine and elevated alanine aminotransferase.

22 patients were considered for response evaluation with 4 of 14 patients (29%) with palpable splenomegaly ≥ 5 cm achieving a spleen response, 1 of 13 patients (8%) becoming transfusion independent, and 5 of 22 patients (23%) experiencing symptom response with ≥ 50% reduction in the MPN-SAF total symptom score. However, when response assessment was restricted to 13 patients who had received a minimum of 5 cycles of therapy, spleen responses were observed in 4 of 7 (57%) patients, 1 of 5 (20%) achieved transfusion independence and 5 of 13 (38%) achieved symptom response. All patients presenting with leukocytosis (n=4) and thrombocytosis (n=2) had resolution with therapy.

Of the 7 patients presently on study, four patients continue to demonstrate symptom response, two patients with both spleen and symptom response, and another patient with sustained anemia response.

  • Correlative assessments

We compared the intensity of staining of GATA1, a factor that is required for maturation, in sequential bone marrow biopsies from six patients at baseline and after a minimum of five cycles and observed a striking increase in the numbers of GATA1-positive megakaryocytes in five of six cases (Figure 1a). In addition, we observed a one grade reduction in marrow fibrosis in 4 of 6 paired samples (Figure 1b). This reduction in fibrosis was accompanied by sustained responses to the drug. Finally, we compared JAK2, MPL or CALR mutant allele burden in eight paired baseline and cycle 5 or 6 samples and observed decreases in 4 of 8 patients (Figure 1c).

Conclusions: Alisertib is safe and well tolerated in patients with myelofibrosis with prolonged administration up to 1.7 years. In addition to providing clinical benefit, alisertib restored normal morphology and GATA1 expression in atypical megakaryocytes and reduced marrow fibrosis and mutant allele burdens. These findings demonstrate that AURKA inhibition should be further explored as a therapeutic option in myelofibrosis.

Disclosures: Swords: AbbVie: Employment. Watts: Jazz Pharma: Consultancy, Speakers Bureau; Takeda: Research Funding. Frankfurt: Celgene, Jazz, Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees. Altman: GSK: Other: payment to the institution to conduct clinical trial work; Incyte: Other: payment to the institution to conduct clinical trial work; Boeringer Ingelheim: Other: payment to the institution to conduct clinical trial work; Pfizer: Other: payment to the institution to conduct clinical trial work; BMS: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Immune Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Genetech: Other: Payment to the institution to conduct clinical trial work; Epizyme: Other: payment to the institution to conduct clinical trial work; Cyclacel: Other: payment to the institution to conduct clinical trial work; Agios: Other: Payment to the institution to conduct the trial ; Astellas Pharma: Other; FujiFilm: Other: payment to the institution to conduct clinical trial work; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: payment to the institution to conduct clinical trial work; Bayer: Other: payment to the institution to conduct clinical trial work; Ariad: Other: payment to the institution to conduct clinical trial work; Celator: Other: payment to the institution to conduct clinical trial work. Rampal: Celgene: Honoraria; Stemline: Research Funding; Incyte: Honoraria, Research Funding; Constellation: Research Funding; Jazz: Consultancy, Honoraria. Giles: Actuate Therapeutics Inc: Employment, Equity Ownership. Crispino: Forma Therapeutics: Research Funding; Scholar Rock: Research Funding.

*signifies non-member of ASH