Naveen Pemmaraju, MD, Provides an Overview of Novel Therapies for MPNs
During the virtual Great Debates & Updates in Hematologic Malignancies, Naveen Pemmaraju, MD, Associate Professor, Department of Leukemia, University of Texas, MD Anderson Cancer Center, Houston, discussed new therapies for myeloproliferative neoplasms (MPNs) with a focus on chronic myelomonocytic leukemia (CMML).
“These new therapies for MPNs are important as they are emerging quickly and quite a few of them as compared to just a few years ago,” Dr Pemmaraju said.
In the genomic landscape of CMML, Dr Pemmaraju said, diploid karyotype is seen in over half of the patients (>60%). However, there is a frequency of high-risk mutations, such as ASXL1 (40-50%), SRSF2 (50%) and TET2 (60%). In addition, kinase signaling is present in 30% of patients, including the PTPN11 family, NRAS or KRAS mutations, and more.
“The concept is, it’s frequent to have molecular mutations in CMML, and this raises the question that there might be molecular targeting available," he told attendees.
In terms of targeted therapies for CMML, Dr Pemmaraju said there’s quite a few. Most of them have been derived from some other myeloid malignancies, including IDH1 and IDH2 mutations and their according inhibitors, but there are also new concepts being actively studied, including the CBL mutation, FLT3 inhibitors and NRAS, KRAS, PTPN11 and NF1.
In the world of MPNs, there’s been a number of new findings, Dr Pemmaraju said.
The CONTI-PV Design trial evaluated the long-term safety and efficacy of ropeginterferon alfa-2b. Dr Pemmaraju said it is one of the most promising new agents and has been approved in Europe for polycythemia vera. The drug, Dr Pemmaraju said, has a clinical benefit over both hydroxyurea and the best available therapy. The key to this drug is that it’s less frequent dosing and less side effects, he said.
Shifting the focus to JAK inhibitors, Dr Pemmaraju mentioned the FDA approved therapy fedratinib. The drug, Dr Pemmaraju said, provided clinically meaningful reductions in splenomegaly and symptom burden in patients with myelofibrosis (MF), even in those who had prior ruxolitinib at a rate of 30% with symptom reduction.
Momelotinib is another unique Phase 3 JAK inhibitor that hits the novel target ACVR1, Dr Pemmaraju said. In this randomized trial, 180 patients were given momelotinib plus placebo and randomized against danazol plus placebo. The primary and secondary endpoints were notable, Dr Pemmaraju said, with a total symptom score (TSS) response rate at week 24 and a transfusion independence (TI) rate at week 24, respectively.
Dr Pemmaraju then discussed a Phase 2 study of CPI-0610, a bromodomain and extraterminal domain protein (BET) inhibitor in combination with ruxolitinib in JAK-inhibitor naive patients with MF. Dr Pemmaraju said bromodomain inhibitors are a new class of drugs that purportedly may help to suppress cytokine production, promote erythrocyte differentiation, and normalize megakaryocyte differentiation. Investigators of the study saw a spleen volume reduction (SVR) response in week 24 of 67% (42/63) (95% CI, 54-78), a median SVR of -50%, a total symptom score (TSS) response at week 24 of 57% (34/60) (95% CI, 43-69), and a median TSS reduction of -59%. CPI-0610 in combination with ruxolitinib was generally well tolerated, Dr Pemmaraju said. There were improvements in bone marrow findings, which suggest potential disease modification.
Another notable PPhase 2 study Dr Pemmaraju focused on was the addition of navitoclax to ruxolitinib, demonstrating efficacy within different high-risk populations in patients with relapsed/refractory MF. Navitoclax is an oral novel agent which hits BCL-XL in addition to BCL-2. Preclinical studies show that a combination of JAK2 and BCL-2/BCL-XL inhibition can enhance malignant cell death over JAK2 inhibition alone. In addition, JAK2 + BCL-2/BCL-XL inhibition could overcome acquired resistance to single-agent JAK inhibitor treatment. Out of the 34 patients enrolled, 27% achieved an SVR ≥35% at week 24. In addition, 35% of patients had a TSS reduction ≥50% at week 24, and 29% saw bone marrow fibrosis improvements of at least 1 grade. Every patient experienced a treatment-emergent adverse event, with the most common being thrombocytopenia (88%), diarrhea (68%) and fatigue (62%). The most notable Grade 3 ≥ TEAEs occurred in 85% of patients, the most common being thrombocytopenia (53%), anemia (32%), and pneumonia (12%).
Dr Pemmaraju then discussed data on imetelstat, a first-in-class telomerase inhibitor, and found that favorable overall survival correlates with other clinical benefits in intermediate 2 or high-risk MF relapsed/refractory to Janus Kinase inhibitor. The study had a median overall survival for the 4.7 mg/kg arm at 19.9 months and in the 9.4 mg/kg arm at 28.1 months. In addition, 3 patients from the 4.7 mg/kg arm and 19 from the 9.4 mg/kg arm had symptom response at week 24. The median PFS in months was 14.8 in the 4.7 mg/kg arm and 20.7 in the 9.4 mg/kg arm.
He also overviewed the Phase 2 study of the LSD1 inhibitor, IMG-7289 (bomedemstat) in patients with advanced MF. LSD1 inhibition, Dr Pemmaraju said, impairs function of both “activated” megakaryocytes and malignant stem cells. Megakaryocytes produce cytokines and growth factors that drive bone marrow remodeling. At week 12, 78% of patients (25) had a decrease in symptom score, and 25% (8) had a reduction of ≥50%. Dr Pemmaraju concluded that bomedemstat appears to be safe and well tolerated in patients with advanced MF.
Lastly, Dr Pemmaraju examined a Phase 1/2 clinical trial of tagraxofusp, an FDA-approved CD123-targeted agent in patients with poor-risk primary and secondary MF. Overall, 48% (13/27) of evaluable patients had symptom burden reduction, including 3 with total symptom score (TSS) reduction per IWG-MRT 2013 MF response criteria. Nearly half (56%) of patients were assessed as Stable Disease per IWG 2013 criteria.—Emily Bader
