Advances of Note From EHA2022 

  • MPNRF | July 29, 2022

    The European Hematology Association’s EHA2022 Congress in Vienna brought together global research leaders, practitioners, and other participants in June to share the latest advances in hematology. Among those on MPNs were the following: 

    “ASXL1 mutations accelerate bone marrow fibrosis via EGR1-TNFa axis mediated inflammation and fibrocyte generation in myeloproliferative neoplasms” 

     This study illustrated the crucial role of ASXL1 mutation in causing bone marrow fibrosis among MPN patients. ASXL1 mutations help monocytes/macrophages white blood cells involved in the immune system – lead to inflammation through the EGR1-TNFA pathway, thereby activating fibrosiscausing cells called fibrocytes, which are responsible for fibrosis. Besides the JAK/STAT signaling pathway, ASXL1 mutations are the most common mutations in MPNs and are more frequent in myelofibrosis than in essential thrombocythemia (ET) and polycythemia vera (PV) patients. The findings of this study suggest that the well know MPN drug Ruxolitinib, along with drugs that work against TNFR (tumor necrosis factor receptor), may stop fibrocytes from causing myelofibrosis.

    Zhongxun Shi, MDS/MPN center, Chinese Academy of Medical Sciences, Tianjin, China 

    Take away: This study reveals an understanding of fibrosis formation through the immune system, driven by the ASXL-1 mutation. It proposes that Ruxolitinib and similar drug therapies may mitigate myelofibrosis. 

    “Calreticulin-mutated hematopoietic cells are vulnerable to the combined inhibition of the proteasome and the IRE1a-XBP1 axis of the unfolded protein response” 

     Chaperone calreticulin (CALR) is a gene responsible for a protein’s folding mechanism when under stress. Mutations in CALR result in MPN, particularly in ET, through the IRE1-XPB1 pathway that leads to unfolded protein response. Proteasome is a protein complex that degrades proteins and is expressed at unusually high levels in platelet forming cells. This study suggests a promising therapeutic strategy for CALR-mutant MPN.It involves combining inhibition of IRE1 (a protein involved in multiple cellular processes, including regulating both cell survival and cell death), with the proteasome with KIRA6 (a small molecule IRE1a kinase inhibitor) and bortezomib, respectively. 

    Take away: When protein processing that is modulated by CALR goes awry due to mutations, it may lead to MPN. The study proposes a combination target therapy for such an MPN. 

    Jonas S. Jutzi, Ann Mullally,, Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Boston, United States

    Pegylated interferon-alfa found to control the differentiation of blood stem cells in MPNs, which could lead to new treatments to stop this process.

     Interferon-alpha (IFN), the first approved immunotherapy for cancer, remains an effective therapy for patients with MPN. The mechanisms of action of IFN on MPN cells are poorly understood, particularly in patients with CALR mutated MPNs, who often exhibit clinical but not molecular responses. This study performed RNA sequencing on master blood stem cells and platelet forming cells and found that IFN works through the TNF-a and TGF-b signaling pathways. This study exemplifies how the malfunctioning molecular pathway can disrupt the function of blood stem cells, leading to MPN and treatable by Interferons-alfa. 

    Take away: The benefit of this research is that ET patients could receive more personalized treatment by identifying which of their mutations is more likely to get treated by a particular treatment modality, such as interferon.

    Anna S Nam, MD, Weill Cornell Medicine, New York 

    Quality of life and unmet needs among ph-negative myeloproliferative neoplasm patients: results of the nationwide survey

     A national survey was conducted in Russia to evaluate the quality of life and symptom burden in 1100 patients with MPN, as well as to examine the perceptions of patients and physicians about the impact of MPN and its treatment. The survey included patients aged ≥18 years with a confirmed diagnosis of MF, PV, or ET. It measured patient-reported outcomes consisting of physical behavior, social wellbeing, emotional behavior, and eating and drinking habits, along with physician measured clinical parameters. The findings demonstrate differences in the impact on quality of life and symptom burden across MPNs. Also identified were different perspectives between patients and physicians about MPN and its treatment, as well as unmet needs among patients with MPN.

    Take away: The effects of MPN symptom burden on quality of life can be understood from this study through patient reported surveys. This could lead to better treatment regimens for MPN patients and to improved quality of life. 

    Tatiana Ionova, Multinational Center for Quality of Life Research, Saint-Petersburg, Russian Federation 

    Allogeneic stem cell transplantation in myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndromes – a single center experience and dissection of mutational profile

     MDS/MPN overlap syndromes are myeloid malignancies for which allogeneic hematopoietic stem cell transplant (allo-HSCT) is potentially curative. Mutations in signaling pathways seem to confer poor prognosis as a late event in the disease course, and provide more aggressive clinical behavior. This study demonstrated that only one-third of the MDS/MPN overlap syndromes patients survived long term. Mutations in signaling pathways seem to point to poor prognosis as a late event in the disease course and provide more aggressive clinical behavior. Next generation sequencing data may help to refine prognostic scores and help with a patient’s decision about having a bone marrow transplant.  

    Take away: This study allows us to identify which MPN patients could respond to bone marrow stem cell transplant by understanding the mutation profile in important blood-forming signaling pathways. 

    Alejandro Avendaño Pita, Hematology, University Hospital of Salamanca / IBSAL, Salamanca, Spain