Srdan Verstovsek, MD, PhD

Srdan Verstovsek, MD, PhD, a professor, Department of Leukemia, Division of Cancer Medicine, director, Hanns A. Pielenz Clinical Research Center for Myeloproliferative Neoplasms, and chief, Section for Myeloproliferative Neoplasms, Department of Leukemia at the University of Texas MD Anderson Cancer Center, discusses the impacts of an analysis demonstrating longer survival in patients with myelofibrosis who received ruxolitinib (Jakafi) versus those who didn’t.

The real benefits in every practice that used ruxolitinib are improving quality-of-life and decrease in spleen size, according to Verstovsek. With a longer-term follow up, there was prolongation of life. Verstovsek says it was questionable because the study so far did not have the primary aim to prolong survival and the survival benefit was discovered during a post hoc analysis.

Verstovsek feels there is some worry about physicians not endorsing that benefit. The data presented at the 2020 American Society of Hematology Annual Meeting may have changed the mind of the treating physicians in a community setting from focusing only on a quality-of-life and the degree of a spleen reduction to prolongation of life. The understanding of that benefit will lead to better improvement in the spleen response, he hopes.

The degree of spleen reduction correlated well with the prolongation of life in other studies published. Changing focus from improving quality-of-life, which is valuable, to controlling the spleen size in a safe way during the first 6 months of therapy may lead to prolongation of life at some point, says Verstovsek. He also thinks these data will enhance understanding of that benefit and hopes it will improve the management of patients.

Videos

Srdan Verstovsek, MD, PhD, discusses the impacts of an analysis demonstrating longer survival in patients with myelofibrosis who received ruxolitinib versus those who didn’t.

Analysis Shows Ruxolitinib Makes an Impact in Myelofibrosis Setting

Srdan Verstovsek, MD, PhD, medical oncologist, and professor, Department of Leukemia, University of Texas MD Anderson Cancer Center, discusses how research and future clinical trials can better determine the benefit of ruxolitinib as treatment of patients with myelofibrosis, which is often measured in improvements in the quality of life (QOL) and spleen reductions.

Ruxolitinib (Jakafi) has demonstrated improvements in QOL and spleen reduction in prior clinical trials, but longer follow-up have demonstrated that the QOL end point may not be necessary in evaluating how treatment has induced prolongation of life. This is questionable as the data came from a post-hoc analysis, says Verstovsek, but a correlation has been observed in the degree of spleen reduction and prolongation of life.

These data will be important for moving the field forward and understanding improvements in outcomes, says Verstovsek. Overall, physicians should focus on controlling spleen size as much as they can safely within the first 6 months of therapy.

Srdan Verstovsek, MD, PhD, discusses how research and future clinical trials can better determine the benefit of ruxolitinib as treatment of patients with myelofibrosis, which is often measured in improvements in the quality of life and spleen reductions.

Improving Patient Outcomes With Ruxolitinib in Advanced Myelofibrosis

Building on the transformative impetus from the first Food and Drug Administration (FDA)-approved Janus kinase (JAK) 1/2 inhibitor, ruxolitinib (Jakafi), in the clinical landscape of myeloproliferative neoplasms (MPNs), we are entering a new era of multiple JAK inhibitors and other diverse classes of drugs in rapid clinical development. Advancements in elucidating the pathophysiology of MPNs have spurred significant progress in developing novel promising agents or combination regimens with ruxolitinib to treat patients who are unresponsive to standard treatments or have specific clinical needs.

In myelofibrosis (MF), the most aggressive MPN, with an average survival of 5 to 7 years, abnormal clonal hematopoietic stem cell proliferation in the bone marrow (BM) leads to liberation of pro-inflammatory cytokines and extensive fibrosis, causing progressive pancytopenia, especially anemia and thrombocytopenia, along with splenomegaly and other symptoms, compromising quality of life.

For nearly a decade, ruxolitinib has been the centerpiece therapy for patients with MF, markedly improving splenomegaly and constitutional symptoms and providing survival benefit.2 The second FDA-approved JAK2 inhibitor, fedratinib (Inrebic), may actually be a good second-line option for patients who are ruxolitinib-resistant with intermediate-2 and high-risk MF (primarily thrombocytopenic and characterized by platelet counts 50−100 × 109/L).3 At present, 2 ongoing phase 3 clinical trials, the single-arm FREEDOM trial (NCT03755518) and the double-arm FREEDOM 2 trial (NCT03952039), are assessing the efficacy and safety of fedratinib in patients with MF who are resistant/refractory/intolerant to ruxolitinib. The FREEDOM trials are important because the previous JAKARTA studies (NCT01523171, NCT01437787) were placed on hold or terminated given concerns for the development of Wernicke encephalopathy. Pacritinib is a potent inhibitor of both JAK2 and fms-related receptor tyrosine kinase 

3, or FLT3, but does not affect JAK1. Pacritinib is being evaluated in comparison with the physician’s choice in an ongoing phase 3 trial (PACIFICA; NCT03165734) in patients with MF and severe thrombocytopenia (baseline platelet count < 50 × 10

/L) at the optimal dose determined in the PAC203 study (200 mg twice daily; NCT03165734).

 Successful clinical development of pacritinib will provide a non-myelosuppressive JAK2 inhibitor for frontline treatment of patients with MF who have severe thrombocytopenia, a setting currently lacking approved drugs. Another JAK1/2 inhibitor that is in advanced clinical development and complements its predecessors is momelotinib, possessing the exclusive attribute to improve anemia, which becomes severe in patients with MF.

 At present, momelotinib is undergoing evaluation in patients who are symptomatic and anemic with advanced MF, previously treated with a JAK inhibitor, in a phase 3 trial (MOMENTUM; NCT04173494); the comparator drug is danazol.

Given that patients with MF experience disease-associated and JAK inhibitor-induced anemia, several clinical trials have been evaluating drugs counteracting anemia, as monotherapies or in combination with ruxolitinib, in patients with MF-associated anemia.

Currently, a global, multicenter phase 2 trial is under way to evaluate the safety and efficacy of luspatercept-aamt (Reblozyl), an activin receptor ligand trap that enhances late-stage erythropoiesis in patients with anemia and MF, including ruxolitinib-treated, transfusion-dependent individuals; a phase 3 trial (INDEPENDENCE) is planned for 2020. Interim results of the phase 2 study demonstrated significant efficacy of luspatercept-aamt, achieving reduction in red blood cell transfusion burden in ruxolitinib-treated patients with MF. Thalidomide (Thalomid), an immunomodulatory agent, significantly improved anemia and thrombocytopenia (platelet counts increased in 60% of patients) in a phase 2 trial evaluating ruxolitinib-treated patients with MF and baseline thrombocytopenia (NCT03069326).

Synergistic combinations with ruxolitinib targeting epigenetics and JAK2 

CPI-0610 is a selective bromodomain and extraterminal protein inhibitor that improved spleen volume, anemia, BM fibrosis, total symptom score, and transfusion dependence (alone or with ruxolitinib) in patients with MF who are enrolled in the global phase 2 MANIFEST study (NCT02158858).

 Furthermore, a phase 1 clinical trial combining an inhibitor of heat shock protein 90 (JAK2 is its chaperone protein), PU-H71, with ruxolitinib in patients with primary/secondary MF is under way (NCT03935555).

 The previous 2 trials are supported by preclinical data showing drug synergism. In a phase 2 trial of ruxolitinib/azacitidine (hypomethylating agent) in patients with MF, synergism was demonstrated in spleen length reduction and BM fibrosis improvement compared with ruxolitinib monotherapy (NCT01787487).

Synergistic combinations with ruxolitinib targeting antiapoptotic proteins and JAK2. 

Navitoclax is an orally bioavailable inhibitor of the antiapoptotic B-cell lymphoma 2 (BCL2) family of proteins (primarily BCL extra-large [XL]). In preclinical studies, the nonclinical analogue of navitoclax, ABT-737, in combination with ruxolitinib showed synergism in inducing apoptosis of 

V617F-driven MPN cell lines. Interim data from an ongoing phase 2 clinical trial evaluating navitoclax in combination with ruxolitinib in ruxolitinib-treated patients with MF (with baseline platelet count ≥ 100 × 10

/L) showed reduction in spleen volume and BM fibrosis (≥1 grade) and improvement in total symptom score in a proportion of the patients (NCT03222609).

Imetelstat is a short oligonucleotide telomerase inhibitor that possibly prolonged median overall survival in patients with MF in the higher-dose (9.4-mg/kg) arm of the phase 2 IMbark study (NCT02426086).

A phase 3 trial comparing imetelstat to best available therapy in patients with refractory MF is planned for early 2021.

PRM-151, a plasma-derived analogue of the human antifibrotic protein pentraxin 2, improved BM fibrosis in mice models and patients with MF in preclinical and phase 1/2 clinical studies, respectively.

 The promising results merit a phase 3 trial, especially given the scarcity of antifibrotic agents.

Polycythemia Vera and Essential Thrombocythemia

The two relatively indolent MPN subtypes, polycythemia vera (PV) and essential thrombocythemia (ET), are characterized by abnorabnormal proliferation of myeloid cells, resulting in elevated blood counts (erythrocytosis and thrombocytosis in PV and ET, respectively), considerable risk of thrombosis and hemorrhage, and progression to secondary MF and acute myeloid leukemia (more common in PV than ET).

 In PV and ET, therapies are aimed at reducing risk of thrombosis, which is higher in patients over 60 years old or with a history of thrombosis, and in ET, when the calreticulin gene, 

is absent. A particularly promising agent for the two indolent MPNs is the long-acting ropeginterferon α-2b, which was approved in Europe for frontline treatment of high-risk patients with PV and without symptomatic splenomegaly on the basis of the PROUD/CONTINUATION-PV studies [EudraCT, 2012-005259-18 (PROUD-PV) and 2014-001357- 17 (CONTINUATION-PV)].

 The previous investigations demonstrated superiority of ropeginterferon α-2b versus hydroxyurea after 3 years of therapy. Besides awaiting possible approval of ropeginterferon α-2b to treat patients with PV in the United States, a phase 3 trial of ropeginterferon α-2b versus anagrelide in hydroxyurea-resistant/intolerant patients with ET has been planned to start in 2020. Givinostat, an inhibitor of histone deacetylases, demonstrated promising clinical responses (reduction in pruritus and thrombosis, and normalization of hematological parameters) in phase 1/2 studies in patients with 

V617F– positive PV and is entering a phase 3 trial in 2021.

 Currently, hydroxyurea and ruxolitinib are the first- and second-line treatments for high-risk patients with PV, respectively, and hydroxyurea is the first-line treatment for ET.

Herein we highlighted an array of drugs— ranging from new JAK inhibitors to an antifibrotic agent, epigenetic modifiers, and telomerase and BCL-XL/BCL2 inhibitors—that are in early or advanced clinical development in MPN. We are looking forward to enrichment of the MPN arsenal with new disease-modifying agents complementing the clinical benefits of ruxolitinib and fulfilling unmet needs in this population.

1. Verstovsek S, Gotlib J, Mesa RA, et al. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. 

. 2017;10(1):156. doi:10.1186/s13045-017-0527-7

2. Bose P, Verstovsek S. Management of myelofibrosis after ruxolitinib failure. Leuk Lymphoma. Published online April 16, 2020. doi:10.1080/1 0428194.2020.1749606

3. Bose P, Verstovsek S. Management of myelofibrosis-related cytopenias. 

. 2018;13(3):164-172. doi:10.1007/s11899- 018-0447-9

3. Bose P, Alfayez M, Verstovsek S. New concepts of treatment for patients with myelofibrosis. 

. 2019;20(1):5. doi:10.1007/s11864-019-0604-y

4. Bose P, Verstovsek S. Updates in the management of polycythemia vera and essential thrombocythemia. 

. 2019;10:2040620719870052. doi:10.1177/2040620719870052

5. Gisslinger H, Klade C, Georgiev P, et al. Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study. 

. 2020;7(3):e196-e208. doi:10.1016/S2352- 3026(19)30236-4

6. Chifotides HT, Bose P, Verstovsek S. Givinostat: an emerging treatment for polycythemia vera. 

. 2020;29(6):525- 536. doi:10.1080/13543784.2020.1761323

Articles

Building on the transformative impetus from the first FDA-approved JAK 1/2 inhibitor, ruxolitinib, in the clinical landscape of myeloproliferative neoplasms, we are entering a new era of multiple JAK inhibitors and other diverse classes of drugs in rapid clinical development. 

New Therapies in Development for Myelofibrosis

Srdan Verstovsek, MD, PhD, medical oncologist, and professor, Department of Leukemia, University of Texas MD Anderson Cancer Center, shares his take home message from his presentation on accelerated and blastic phase myeloproliferative neoplasms (MPNs) during the first Annual Texas MPM Workshop.

The main development in the field has been the new treatment strategies in this patient population of accelerated and blastic MPNs where we now have the ability to use medications in different ways for different clinical situations, says Verstovsek. Understanding the genetic complexity of disease, patterns of development or disease progression to accelerated and blastic phase, and timely interventions are all important for the primary intervention with new medications in combinations to get patients to respond.

Verstovsek says he is happy to have been able to project this message to the public and peers at this year’s meeting to demonstrate the significant progress that has been made in the field. Only 5 years ago, he believes he would not have been able to give a presentation on this topic due to a lack of knowledge, so being able to say something that not only makes sense but impacts patient and provider decisions for treatment is an incredible development on its own for the field.

<< View more from the first annual Texas MPN Meeting

Srdan Verstovsek, MD, PhD, shares his take home message from his presentation on accelerated and blastic phase myeloproliferative neoplasms during the first Annual Texas MPM Workshop.

Srdan Verstovsek, MD, PhD | Authors

Articles

Analysis Shows Ruxolitinib Makes an Impact in Myelofibrosis Setting

Improving Patient Outcomes With Ruxolitinib in Advanced Myelofibrosis

New Therapies in Development for Myelofibrosis

Developing Therapeutic Strategies for Treating Accelerated and Blastic Phase MPN