ASH 2019 Preview: Key Expert-Selected MPN Studies

Raajit K. Rampal, MD, PhD

Assistant Member
Assistant Attending Physician
Leukemia Service
Department of Medicine
Memorial Sloan Kettering Cancer Center
New York, New York


Raajit K. Rampal, MD, PhD, has disclosed that he has received consulting fees from BeyondSpring, Celgene, Constellation, Jazz, Partner Therapeutics, and Stemline and funds for research support from Constellation and Stemline.


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Released: December 2, 2019

The ASH annual meeting always features a plethora of new data on optimization of current therapies and emerging treatment strategies. As a hematologist with a focus on myeloproliferative neoplasms, the following ASH 2019 studies are among those that I am most excited about.

New Strategies for Ruxolitinib-Experienced Patients With Myelofibrosis
The JAK1/2 inhibitor ruxolitinib has been the standard first-line therapy for patients with symptomatic and/or higher-risk myelofibrosis based on findings from the randomized phase III COMFORT-I and -II studies, which showed significant improvements in spleen responses, symptom reduction, and survival with ruxolitinib vs placebo and/or best available therapy. Despite this, the response to ruxolitinib is often finite. For patients who lose response to ruxolitinib, prognosis has historically been poor. Several agents and regimens are currently in clinical development for the management of patients with MF who are intolerant of or resistant to ruxolitinib, and we will see new data for several of these at ASH 2019. Of note, several of the agents listed below target novel molecules outside of the traditional JAK/STAT pathway, which is of great interest in the field.

One such agent is CPI‑0610, a small-molecule bromodomain and extraterminal domain inhibitor; preclinical data suggest that BET and JAK inhibition may have synergistic effects in myeloproliferative neoplasms (MPNs). At ASH, we will see results from the multicenter, open-label phase II MANIFEST study, in which (1) patients who were refractory to or intolerant of ruxolitinib were treated with CPI-0610 monotherapy, or (2) patients who were JAK inhibitor naive and anemic or who were receiving ruxolitinib but had demonstrated suboptimal responses with this agent were treated with ruxolitinib plus CPI-0610. MANIFEST will evaluate spleen volume response, transfusion independence after baseline transfusion dependence, and total symptom score. This study is novel in that it looks at multiple different subgroups of patients with MF and multiple aspects of responses to the experimental agent/regimen.

Another study of interest at ASH 2019 is a single-arm, open-label phase II study of navitoclax plus ruxolitinib for patients with MF and previous ruxolitinib experience. Navitoclax is a small-molecule inhibitor that binds to the BCL-2 family of proteins; there has been a lot of interest in targeting of BCL-2 in myeloid malignancies, most notably in AML and CLL, for which the efficacy of the BCL-2 inhibitor venetoclax has been demonstrated, suggesting a mechanism of action that could be exploited in multiple diseases. The current study will evaluate the effect of navitoclax plus ruxolitinib on spleen size reduction, symptom score, anemia response, and improvement in bone marrow fibrosis.

Also of potential interest is a phase IIa study of IMG‑7289 in patients with intermediate 2–risk or high-risk MF and resistance or intolerance to ruxolitinib. IMG‑7289 targets the lysine‑specific demethylase (LSD1), which is an important epigenetic modifier. Preclinical data published in 2018 supported the use of LSD1 inhibitors in patients with MF, and the data from the current presentation are highly anticipated.

Strategies for Patients With MF and Thrombocytopenia and Anemia
Treatment options for patients with MF and thrombocytopenia represent an unmet need in the MPN field, as currently approved JAK inhibitors are labelled for use in patients with platelet counts of > 50 x 109/L. Several studies that will be presented at ASH assessed agents with the potential to address this need.

PAC203 was a randomized, dose‑finding phase II study of pacritinib for patients with MF and resistance or intolerance to ruxolitinib. Pacritinib is a JAK2 and IRAK1 inhibitor that had previously shown efficacy in a randomized phase III trial in the first-line setting for patients with high-risk MF (vs non-JAK inhibitor treatments). A second randomized phase III trial demonstrated that pacritinib was associated with improved symptoms and spleen response vs best available therapy (which included ruxolitinib) for patients with MF and platelets < 100 x 109/L. Although the development of pacritinib was put on hold by the FDA due to reports of patient deaths related to intracranial hemorrhage, cardiac failure, and cardiac arrest, the clinical hold was removed in 2017 and PAC203 was initiated. In this study, patients were randomized into 3 dosing arms: pacritinib at 200 mg BID, 100 mg BID, and 100 mg QD. Of importance, in this study, 43% of patients had profound thrombocytopenia with platelet counts of < 0.5 x 109/L. The ongoing randomized phase III PACIFICA study of pacritinib vs physician’s choice of therapy for patients with MF and severe thrombocytopenia will also be introduced.

The results of a phase I/II trial of tagraxofusp—also known as SL‑401—for patients with MF and ruxolitinib intolerance/resistance will also be reported. Tagraxofusp targets CD123 and is approved by the FDA for treating patients with blastic plasmacytoid dendritic cell neoplasms. CD123 is expressed in a variety of cells, including plasmacytoid dendritic cells and dendritic cells that share precursors with monocytes. Since monocytosis is associated with a poor prognosis in patients with MF, targeting CD123 in these patients may be a beneficial therapeutic strategy. Of importance, a large proportion of patients in the current study had a platelet count < 50 x 109/L.

Fedratinib is a JAK2 and FLT3 inhibitor that was recently approved by the FDA for patients with intermediate 2–risk or high-risk MF based on the randomized phase III JAKARTA trial, which demonstrated a significantly higher rate of spleen volume reduction with fedratinib vs placebo for patients with MF who were naive to JAK2 inhibitors. Continued research into the use of this agent will be presented at ASH, including an analysis of spleen and symptom responses associated with this agent in patients with low platelet counts (< 100 x 109/L) who were treated in JAKARTA or JAKARTA2, the latter of which was a single-arm phase II study of fedratinib for patients with intermediate-risk or high-risk MF previously treated with ruxolitinib.

The management of anemia in patients with MF is also an area of clinical need. At ASH 2019, we will see preliminary results from an ongoing, open-label phase II study of luspatercept (an erythroid maturation agent) for the management in patients with MF-associated anemia (either those not receiving ruxolitinib or RBC transfusions, those not receiving ruxolitinib but with RBC transfusion–dependent anemia, or those with anemia and on a stable dose of ruxolitinib). Of note, luspatercept was recently approved for treating anemia in adult patients with β-thalassemia who require regular RBC transfusions.

Your Thoughts
What MPN studies are you most interested in at this year’s ASH meeting? Please answer the polling question on your screen and share your thoughts in the comments box.

Attending the 2019 ASH annual meeting in Orlando? Sign up here to attend CCO’s satellite symposium, “Approaches to the Individualized Management of MPNs: Best Practices and Guidance to Optimize Care,” on the evening of Friday, December 6, during which I will discuss patient case studies and recent advances in the treatment of MPNs with our esteemed panel, including Srdan Verstovsek, MD, PhD; Jean-Jacques Kiladjian, MD, PhD; and Alessandro M. Vannucchi, MD. Not attending ASH but still want to view this exciting educational event? Sign up here to watch the live simulcast from your computer. After ASH concludes, remember to check the CCO Web site for a downloadable slideset summarizing the data from these studies and more.

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