Anti-transforming growth factor-β therapy in patients with myelofibrosis

Bone marrow fi brosis (BMF), in the myeloproliferative neoplasm (MPN) myelofi brosis (MF), is the result of a complex and yet not fully understood interaction between megakaryocytes, monocytes, fi broblasts, endothelial cells, cytokines and marrow stroma [1]. Th ere are substantial data to support the clonal nature of MPNs from primitive progenitor hematopoietic cells which then secrete factors that activate polyclonal fi broblasts in the bone marrow [2]. BMF is not an irreversible process, and morphologic evidence of reversal can be achieved after hematopoietic stem cell transplant and occasionally drug therapy [3 – 5]. Transforming growth factorβ (TGFβ ) is a pleiotropic cytokine implicated in the promotion of angiogenesis, tumor growth, collagen fi brosis, metastatic spread and down-regulation of antitumor immunity, and paradoxically, tumor-suppressive eff ects [6]. TGFβ likely plays a dual role in promoting myelofi brosis and myeloproliferation, both of which are the morphologic hallmarks of MF [2]. Degree of BMF can be correlated with a variety of clinical features such as anemia, thrombocytopenia, leukopenia, splenomegaly and peripheral blood blasts, and can be predictive of survival in patients with MF [7,8]. Preclinical studies support a pathobiological role of TGFβ in MF [9 – 11]. Th e development of BMF in GATA-1 low and TPO high murine models of MF is associated with high levels of TGFβ expression in extracellular fl uids and spaces within the bone marrow and spleen [10]. A working hypothesis linking abnormal megakaryocyte/neutrophil interaction with enhanced TGFβ expression in MF has been developed based on these observations [11]. Para-apoptosis leading to the release of TGFβ from megakaryocyte alpha-granules may be the result of impaired neutrophil emperipolesis due to abnormal P-selectin localization on the demarcation membrane of MF megakaryocytes [10]. Additionally, TGFβ mRNA levels are signifi cantly elevated in megakaryocytes of patients with MF and correlate with the degree of BMF [9]. We hypothesized that inhibiting the TGFβ signaling pathway in MF would decrease the fi brogenic stimuli leading to BMF and concomitantly interrupt myeloproliferation. GC1008 is a human immunoglobulin G4 (IgG4) kappa monoclonal antibody capable of neutralizing each of the mammalian isoforms of TGFβ (i.e. β 1, β 2 and β 3). Animal toxicology studies of TGFβ antibodies in normal rodents and primates have shown that administration of inhibitory antibodies to TGFβ is well tolerated, and a phase 1 clinical trial of GC1008 in advanced melanoma and renal cell carcinoma has also proven to be well tolerated in humans [12]. A total of 29 patients were enrolled in this study, and doses up to 15 mg/kg were found to be safe without the development of dose limiting toxicities (DLTs). Th e most frequently reported drug-related adverse events (AEs) were gingival bleeding and fatigue, and the most serious AEs were skin rashes (including keratocanthomas and squamous cell carcinoma) that were noted in sun-exposed areas of patients with melanoma only. Based on an existing preclinical rationale, we conducted an investigator-initiated, single institution, open label, phase 1, dose escalation study investigating the tolerability and safety of GC1008 (Fresolimumab; Genzyme) in patients with intermediate-1 or higher primary myelofi brosis (PMF) or post-polycythemia vera/essential thrombocythemia myelofi brosis (post-PV/ET MF) [13]. Th is trial was registered at www.ClinicalTrials. gov (NCT01291784), approved by the Mount Sinai School of Medicine Program for the Protection for Human Subjects (PPHS), and informed written consent was obtained in accordance with the Declaration of Helsinki. Patients were eligible if they had documented BMF of MF-2 or higher as assessed by the European consensus grading score and grade 3 or higher by modifi ed Bauermeister scale [14 – 16]. Th e primary objective of this study was to determine the safety and tolerability of GC1008 treatment in patients with MF. Secondary objectives included treatment response assessment by International Working Group for Myelofi brosis Research and Treatment (IWG-MRT) criteria; assessment of degree of change in BMF grade measured by the modifi ed Bauermeister scale and European consensus grading system after six and 12 cycles; evaluation of exploratory markers for their potential to predict treatment response; and assessment of symptom response using the Myeloproliferative L eu k L ym ph om a D ow nl oa de d fr om in fo rm ah ea lth ca re . c om b y N yu M ed ic al C en te r on 0 7/ 24 /1 5