Myeloproliferative Neoplasms (MPN): From ASH 2019
MPN Clinical Research
Ruxolitinib (JAK1/2 inhibitor) has been a truly transformative medication for myelofibrosis (MF) and became the global standard of care. The pivotal clinical trials that Dr. Verstovsek led globally resulted in the FDA approval of ruxolitinib as the frontline medication for myelofibrosis (MF) in 2011 and the second line treatment for PV in late 2014. Ruxolitinib was the first and sole medication that was approved for MF until 2019 when fedratinib (JAK2 inhibitor) was approved. There was a dearth of MF treatments prior to the clinical development of ruxolitinib, which dramatically improved the quality of life, reduced very large spleen and liver, and prolonged survival of patients with MF.
Presently, it is a very exciting time in research of myeloproliferative neoplasms (MPN), particularly for MF, because an array of new medications are in clinical development as monotherapies or in combination with ruxolitinib. With the new agents, we aim to augment the therapeutic potential of ruxolitinib, improve deficiencies not addressed by JAK inhibitors (for example anemia), or provide options for patients who develop resistance/intolerance to the approved JAK inhibitors.
Dr. Verstovsek and the MPN Team are currently leading several highly promising MPN medications in advanced phase clinical trials, including the JAK inhibitors momelotinib and pacritinib; the two JAK inhibitors may receive FDA approval in the next few years and cover major unmet medical needs of specific subgroups with MF.
- Momelotinib is currently assessed in MF patients who stopped responding to ruxolitinib and suffer from anemia and low quality of life (pivotal Phase 3 MOMENTUM trial). In previous clinical trials, momelotinib consistently elicited high rates of red blood cell transfusion-independence in MF patients who previously were transfusion-dependent.
- Pacritinib is evaluated in MF patients with thrombocytopenia (low platelet counts), for which the currently approved JAK2 inhibitors are not suggested (pivotal Phase 3 PACIFICA trial).
Other medications that are being investigated in Phase 3 randomized clinical trials at MD Anderson for possible approval include the following:
- Pelabresib (previously CPI-0610) is a BET inhibitor that appears to augment the activity of ruxolitinib in improving quality of life and splenomegaly. The MANIFEST-2 trial compares the combination of pelabresib + ruxolitinib to ruxolitinib alone.
- Luspatercept is evaluated for anemia benefit and its potential to eliminate the necessity of blood transfusions in MF patients who are receiving ruxolitinib (INDEPENDENCE trial).
- Imetelstat (telomerase inhibitor) is a pioneering medication in treatment of MF because it appears to significantly prolong survival of MF patients who failed ruxolitinib. Currently, the possible survival benefit of imetelstat in MF patients is being evaluated in a pivotal Phase 3 trial (IMpactMF); survival benefit is an unprecedented clinical trial endpoint for investigational MF medications.
- Navitoclax (Bcl-xL inhibitor) is evaluated in combination with ruxolitinib in two Phase 3 trials in MF patients who relapsed or were refractory to ruxolitinib (TRANSFORM-II) and in the frontline setting (TRANSFORM-I), similar to the aforementioned CPI-0610 study.
- KRT-232 (HDM2 inhibitor) is evaluated in advanced phase studies, including the pivotal Phase 3 trial (BOREAS), in MF patients who have suboptimal response or failed ruxolitinib.
- Ropeginterferon alpha-2b: novel long-acting interferon that is evaluated in patients who have essential thrombocythemia and are resistant or intolerant to hydroxyurea (SURPASS ET).
"Myeloproliferative Neoplasms (MPN):
From ASH 2019 to EHA 2020"
Emil J Freireich Hematology Grand Rounds
(Presented June 10, 2020, 8:00-9:00 am)
Speaker: Srdan Verstovsek, MD, PhD
Dr. Verstovsek is a global leader in MPN and the Founder/Director of the largest MPN Clinical Research Center worldwide. Dr. Verstovsek has achieved international acclaim for his leadership in developing landmark MPN therapeutics. Dr. Verstovsek led more than 60 early/advanced phase clinical trials of novel MPN drugs, including ruxolitinib, the only FDA-approved medication for myelofibrosis until 2019, and second-line treatment for polycythemia vera. Dr. Verstovsek is leading pivotal phase 3 trials for several promising MPN medications.
Professor Srdan Verstovsek, MD, PhD (center) with the MPN Laboratory Team
Taghi Manshouri, PhD, Laboratory Manager; Ivo Veletic, MD, Instructor (to the right of Dr. Verstovsek); Joseph Bove, Senior Research Assistant; Sanja Prijic, PhD (former member); Ying Zhang, PhD, Senior Research Scientist (to the left of Dr. Verstovsek)
MPN Laboratory Research
Dr. Verstovsek’s laboratory houses a large number of tissue and blood samples collected from patients with MPN. These samples are also cataloged in a database that includes information on patient demographics, disease stage and characteristics, responses to treatment, time to progression and other valuable clinical information (e.g., blood counts). During the past five years, we have made several exciting discoveries in the laboratory that we believe will shed light on how and why MPNs develop. Understanding, at the cellular and molecular level, how cancer develops is the key to developing effective and potentially curative therapies. However, this is painstaking work that requires a focused and concerted effort by many people with expertise in basic science research. While finding the answers often takes several years, we believe the time and energy invested is well worth the effort. Without an understanding of the fundamental mechanism by which MPNs develop, we cannot hope to cure the disease.
Deciphering the Cause of Bone Marrow Fibrosis
Our clinical research is characterized
by a high degree of integration with basic/translational research. A
main focus of our research in the laboratory is to understand what
causes bone marrow fibrosis, which ultimately leads to failure of
the bone marrow to produce blood cells and severe anemia. In the
past few years, we made important strides in understanding the
mechanism of bone marrow fibrosis (scarring), which is the hallmark
of myelofibrosis. We demonstrated that bone marrow fibrosis in
primary myelofibrosis is induced by blood cells named monocytes,
which are the precursors of fibrocytes (spindle-shaped cells in the
Our investigations showed that neoplastic monocyte-derived fibrocytes play a pivotal role in bone marrow fibrosis and in promotion of osteosclerosis (bone hardening) in myelofibrosis patients. The bone marrow of myelofibrosis patients is rich in neoplastic fibrocytes, which contribute to induction of bone marrow fibrosis by producing collagen and fibronectin proteins. Furthermore, osteosclerosis (bone hardening) appears to also be a consequence of the abnormal activity of cells called osteoclasts; they exhibit impaired activity compared to normal osteoclasts, which results in osteosclerosis. Due to its importance, our study was published in the leading medical journal Blood in 2019 and was featured on the cover of the journal (cover depicted in photo; Blood 2019;133(21):2320-2324).
Contrary to conventional belief, our studies established the clonal neoplastic nature of bone marrow fibrosis in myelofibrosis (fibrocytes harbor the JAK2 V617F driver mutation); these findings constitute important advancements in understanding the mechanism that causes myelofibrosis, and potentially reversing, and halting fibrotic transformation.