2023 European Hematology Congress MPN Highlights
2023 European Hematology Congress MPN Highlights
The European Hematology Association (EHA) Congress 2023 in Frankfurt, Germany in June, brought more than 10,000 participants together, with a much higher representation of MPN research and clinical advances than in previous years.
In one major session, presentations by leaders of an MPN specialized working group represented the work of a number of active networks of researchers and clinicians. Updates included novel findings and recent developments in MPN research. In total, there were seven oral presentations, 35 abstracts, and 14 poster presentations. Some highlights from EHA2023 are summarized below.
MPN-Specialized Working Group
Chaired by Rajko Kusec, MD, PhD, (Croatia) session highlights include those below.
Who should have more intensive mutation testing?
Dr. Nicholas (United Kingdom) discussed who should have more intensive mutation testing in accordance with WHO (World Health Organization) and ICC (International Chamber of Commerce) recommendations. He said that genomics is enabling greater precision to establish diagnosis and prognosis in MPNs, concluding that the value of mutational information for actionable clinical management should be considered.
What are pitfalls and standardization challenges of genetic tests?
Dr. Paola Guglielmelli (Italy) spoke about JAK2 and other quantitative tests in MPNs. She emphasized that genetic testing has become an integral part of “state-of-the-art care diagnosis for MPNs.” External quality assessment (EQA) and standardization programs are an essential part of monitoring the performance of molecular tests in MPN. The insufficient standardization of some molecular tests such as CALR, MPL, DNA sequencing, limits their implementations in the clinic. Molecular responses are commonly used in clinical trials to measure their progress in terms of disease modification (alleviation).
What is the case for routine genetic testing?
Dr. Jean-Jacques Kiladjian (France) presented an argument in favor of “implementing JAK2 VAF (variant allele frequency) testing routinely in risk assessment and disease monitoring in MPN.” He argued that it will better define the disease phenotype and prognosis. It will also predict longer-term outcomes in terms of disease progression, and if therapy needs to be stopped at an appropriate time.
What is the case against routine genetic testing?
Dr. Mary Frances McMullin (United Kingdom) supported a stance against implementing JAK2 VAF (variant allele frequency) testing as routine for risk assessment and disease monitoring in MPN. She believes that currently this testing won’t change the disease management. Rather, “it will incur huge costs to the laboratories, and create a climate of fear and uncertainty amongst patients without altering outcomes at present.”
Recent developments in MPNs
Transformation to leukemia
Florian Heidel (Germany) brought attention to the “mechanisms of leukemia evolution in MPN.” He explained the frequency and risk assessment, the mechanisms of leukemia evolution, and current therapeutic interventions. He emphasized that the probability of transformation to leukemia is the highest in myelofibrosis (MF), relatively lower in polycythemia vera (PV), and lowest in essential thrombocythemia (ET). In some cases, he said, interferon treatment could be a way to prevent this progression.
Some clinical risk factors that might contribute to malignant transformations are:
- •Presence of TP53, TET2, ASXL1, EZH2, SRSF2, IDH1/2, RUNX1, and U2AF1Q157, as well as some chromosomal aberrations.
- •Presence of two or more mutations, which both increased the risk of leukemia transformation and decreased survival in MPN patients.
- •Evolution of a particular cancer cell clone with epigenetic mutation in it.
- •Epigenetic mutations such as TET2, ASXL1, and others acquired before or after the JAK2 mutation could lead to various routes to leukemia in MPN patients.
Dr. Heidel expressed concern about the poor efficacy of post-leukemia therapies in MPN patients due to the drug resistance found in the cancer cell clone (MPN blast cell), and low rates of overall survival in bone marrow transplanted patients. Therefore he suggested, “considering progression as a relevant end point for MPN clinical trials, and engaging in early intervention and disease-modifying therapies/approaches.” He gave an example of clinical trials that are currently taking this approach by using a combination therapy of fedratinib and CC-486.
Leveraging genetic information
Dr. Jyoti Nangalia (United Kingdom) discussed the landscape of DNA mutations in MPN patients and how they could be leveraged for a positive clinical outcome, by understanding the disease origin and utilizing this for outcome prediction through a “personalized prognosis” for patients. This resulted in the development of a tool, called “Predict Blood,” which could potentially predict survival, progression, and other disease-modifying outcomes. She mentioned how the disease driving mutations (e.g. JAK2, CALR, MPL) are acquired over a patient’s lifetime, and how testing these over a long time could potentially be clinically beneficial to MPN patients in predicting prognosis and early intervention. (Dr. Nangalia is a member of the MPNRF Scientific Advisory Board. Her related research was funded by a 2019-2021 MPNRF MPN Challenge award.)
JAK2 therapy resistance
Dr. Alessandro Vannucchi (Italy) elaborated upon resistance to JAK2 inhibitor therapies. He gave examples of some clinical trials, such as COMFORT-1 and COMFORT-2, which include treatment with ruxolitinib. Only 50% of patients still show positive response to this JAK2 inhibitor after three to five years, according to Dr. Vannucchi.
He advised considering appropriate transition to the next line of therapy after JAK2 inhibitor failure by the following approaches:
• JAK2 inhibitor tapering based on current dose and disease status.
• Overlapping tapering by introduction of the second line treatment, introducing steroid treatment in a timely fashion, or immediately starting second line of treatment after JAK2 treatment failure.
• Considering clinical trials with novel agents such as pelabresib, navitoclax, imetelstat, parsaclisib, luspatercept, BMS-986158, and navtemadlin for JAK2 resistant MPN patients.
Dr. Vannucci said that because the loss of drug response is directly connected to lower survival of patients, there is an increasing need to standardize ruxolitinib resistance, to understand the mechanism of drug resistance and to test mutations for prediction of disease progression.
Latest in MPN research
Dr. Beth Psaila (United Kingdom) discussed the “communication between the MPN cancer cell and its surrounding healthy cells through inflammatory molecules (e.g. TFG-B),” and how this contributes to the disease. She described that complex inflammatory pathways such as the one between basophils (a type of white blood cell) can be targeted by therapeutics. The ability to recreate the bone marrow cellular and molecular environment in the laboratory, known as organoids, will enable us to test various therapeutics that could potentially alleviate the disease.
Dr. Hélène Gleitz (The Netherlands) elucidated how “the inhibition of the communication between blood forming and stromal cells (cells that do not form blood but support the blood forming cells) in primary myelofibrosis (MF) ameliorates bone marrow fibrosis.” This work is with Dr. Rebecca Schneider’s group (MPNRF 2017-2019 Challenge award recipient.) Deactivating a gene called s100a9 in the blood forming cells is a key to delaying the progression in MPN. Tasquinimod, a drug that inhibits this gene, ameliorates MF and reduces extramedullary hematopoiesis and therefore the spleen size. A clinical trial is beginning at the end of this year as a second line of treatment for MPNs.
Dr. Ian Ghezzi (Germany) explained the relevance of dormant cancer stem cells in disease propagation and therapy resistance in JAK2V617F mutation- driven MPN. He explained how these dormant cancer stem cells evade the JAK2 inhibition, and that they are depleted by the combination of the two drugs fedratinib and low-dose peg-interferon-alpha.
Dr. Xiaoli Wang (USA) showed how navtemadlin, an oral drug that inhibits MDM2, a protein that blocks the tumor suppressor gene, P53. Hence P53 becomes active and eliminates MPN blast phase (MPN-BP) initiating cells. This results in prolonged leukemia-free survival in MPN-BP patients who have a normal copy of the P53 gene. This work is associated with Dr. Ron Hoffman’s group at Mount Sinai, NY, previously funded by MPNRF.
Dr. Sarah Jungius (Switzerland), presented her pre-clinical work involving a new potential drug target for MPNs called SHP2, a protein in a cytokine pathway known as the MAPK pathway, which is relevant in the pathogenesis of MPNs. She demonstrated how a dual drug targeting of JAK2 and SHP2 could enhance the therapeutic efficacy and thereby modify the disease towards alleviation.
Overwhelming progress in MF
There were a number of research and clinical updates on myelofibrosis at the 2023 EHA, some of which are summarized below.
Addressing the challenges of anemia and thrombocytopenia in MF
This interactive symposium was focused on the significant challenges experienced by patients with myelofibrosis and anemia and/or thrombocytopenia (low platelets); current and emerging treatment strategies for myelofibrosis-associated anemia and/or thrombocytopenia; and supplemented by a case-based faculty discussion on clinical decision making.
Dr. Martin Griesshammer (Germany) helped attendees understand the burden of anemia and thrombocytopenia in myelofibrosis. Current landscape of treatment options and remaining challenges in MF were discussed by Dr. Francesco Passamonti (Italy). Dr. Vikas Gupta (Canada) highlighted the emerging treatments in myelofibrosis. A panel discussion between the speakers was moderated by Dr. Ruben Mesa (USA).
Raising treatment expectations for patients with Myelofibrosis
This session was intended to bring hope about new treatments to MF patients. An international panel of experts consisting of Drs. Francesca Palandri (Italy), Timothy Devos (Belgium), and Gabriela S. Hobbs (USA) reviewed MF pathophysiology, evaluated clinical endpoints beyond spleen and symptoms reduction, and discussed how emerging treatment options may have the potential to alter the course of the disease.
At diagnosis, approximately 90% of patients with myelofibrosis have intermediate- or high-risk disease, which carries a worse prognosis and a higher likelihood of disease-associated symptoms. Upon referral, the median overall survival is 2.9 to 6.5 years for patients with intermediate-risk and about 1.3 years for patients with high-risk. The current standard of care, JAK inhibitors, provides adequate control in 50% of patients, but treatment responses are limited in their duration. Thus, patients are in need of new and tolerable treatment options that go beyond symptom management and provide deep and durable responses.
Advances in myelofibrosis: exploring the current and evolving treatment landscape
Speakers in this session discussed the ongoing unmet needs in the treatment of myelofibrosis and provided their insights on managing treatment failure and disease-associated cytopenias, as well as how the MF treatment landscape may evolve. Dr. Andreas Reiter (Germany) elucidated the ongoing unmet needs in MF patients. Dr. Francesca Palandri (Italy) explained how to manage the challenges of MF in context of treatment failure and disease-associated cytopenias (low blood counts). Dr. Naveen Pemmaraju (USA) raised hope by giving an overview of the future paradigm for MF treatment.
Clinical advances in myelofibrosis
Dr. Gabriela M. Baerlocher (Switzerland) co-chaired a session on the clinical advances in MF. In this session, Dr. John Mascarenhas (USA) presented updates on a clinical trial that involved adding navtemadlin (NVTM) to ruxolitinib (RUX) in patients with primary or secondary MF who have a suboptimal response to ruxolitinib. Dr. Harry Gill (Hong Kong) gave updates on a clinical trial on genomic characteristics, efficacy and safety of ropeginterferon alfa-2b for pre-fibrotic primary MF, and DIPSS low/intermediate-1 risk MF. Dr. Jie Jin (China) presented a randomized double-blind phase 3 clinical trial of jaktinib versus hydroxyurea in patients with intermediate-2 or high risk MF. Haifa Kathrin Al-Ali ( Germany) shared the results from the phase 1/2 trial on BMS-986158, a potent BET inhibitor, as monotherapy and in combination with ruxolitinib or fedratinib in intermediate- or high-risk MF. Pankit Vachhani (USA) described how the disease-modifying activity of navtemadlin (NVTM) correlated with survival outcomes in JAK inhibitor relapsed MF patients.