2019 ASH MEETING REPORT
While there were no major breakthroughs at this year’s ASH, there was a high level of clinical activity reported, both in terms of new therapies advancing through clinical trials as well as new drug mechanisms entering trials or in preclinical development. Furthermore, we continue to see new studies to better understand the factors leading to disease progression and more studies where multi-center databases are being used to assess the association between longitudinal lab data and disease outcomes. One such example was a study where persistent leukocytosis did not appear to be associated with thrombotic risk but was associated with disease evolution. Other examples included studies that may enable better prediction of which patients are more likely to respond or be resistant to existing therapies. More clinical trials and greater use of existing data are all very positive signs of progress on multiple fronts needed to develop more personalized therapeutic strategies and improve outcomes for patient with MPNs.
Update on JAK inhibitors and Interferon
Pacritinib: With the recent approval of fedratinib (marketed as Inrebic), much attention has turned to the advanced study of the JAK2/IRAK1 inhibitor pacritinib. The results of the PAC203 randomized phase 2 study of pacritinib in patients who were intolerant or resistant to ruxolitinib were reported by Dr. Gerds. The study primarily was aimed at determining the dose that should be used in more advanced studies, but nevertheless revealed that the drug has clinical activity in this high risk, heavily pre-treated population with extreme thrombocytopenia. Of note, pacritinib continues to be well tolerated in patients with severe thrombocytopenia. The phase 3 PACIFICA study is currently enrolling MF patients with platelets less than 50k.
Interferon: Interferon continues to be an exciting area of study as a treatment for of the MPNs. One study, presented by Dr. Kiladjian, reported the 4 year follow up data of the PROUD-PV trial of ropeginterferon alpha-2b. This drug showed superior activity as compared to hydroxyurea or best available therapy in all categories, including hematological response and decreased thromboembolic adverse events. Ropeginterferon alpha-2b also had an impressive sustained reduction in the allele burden, a measure of the extent of the disease.
New agents or drug combinations under clinical investigation
Several sessions and posters were devoted to summarizing data from clinical studies of novel single agents or combination therapies. These new agents included regulators of cell death, gene expression, and cell signaling. A few highlights include:
Ruxolitinib plus navitoclax: An interesting talk presented by Dr. Garcia described the results of a Phase 2 study that combined navitoclax, a molecule that overrides the mechanisms by which cells evade death (through BCL2 family members), with ruxolitinib. Patients were eligible if they had been on ruxolitinib for more than 12 weeks. About 30% of patients experienced a spleen volume reduction of more than 35% by 24 weeks and a similar proportion had more than a 50% reduction in the total symptom score. Of note, 25% showed a decrease in the extent of fibrosis, either one or two grades. The most common side effects were thrombocytopenia and anemia. Overall, this drug combination was well tolerated and displayed preliminary clinical benefits that may stimulate advanced trials.
Ruxolitinib plus CPI-0610: In another interesting presentation, Dr. Mascarenhas reported the results of the MANIFEST Phase 2 study of CPI-0610, a drug that inhibits a pathway that regulates gene expression (through BET proteins). Patients who had prior exposure to ruxolitinib with a sub-optimal response were eligible to enroll into one of two groups: CPI-0610 a monotherapy or the combination of CPI-0610 with ruxolitinib. At 24 weeks, among the patients who had been on prior ruxolitinib therapy, 25% had a striking decrease in spleen volume, more than half showed a >50% reduction in total symptom score, and notably 6 of 14 achieved transfusion independence. Another notable finding was that more than 40% of the patients treated with the combination of CPI-0610 and ruxolitinib displayed a reduction in the degree of fibrosis. With respect to adverse events, the drug was overall well tolerated with a low incidence of anemia and thrombocytopenia. These encouraging results will stimulate additional clinical studies with a focus on combination therapy in JAK inhibitor naive patients with MF.
Ruxolitinib plus pomalidomide: Updated results were presented from the German MPN Study Group for the combination trial of Ruxolitinib plus pomalidomide in poor-risk MF patients with anemia. This study has been ongoing since 2013 with a 2nd cohort starting in 2017. Those patients that remained on treatment long term (~40%) showed a long-lasting stabilization of disease with an improvement in hemoglobin and quality of life.
Img-7289 (Bomedemstat): A presentation given by Dr. Pettit gave an update on the phase 2 clinical study of Img-7289, a drug that targets a regulator of gene expression named LSD1. The results of this study revealed that the drug could improve symptom burden and decrease spleen size in a subset of patients. An interesting aspect of the drug is that, in concert with the known biological activity of LSD1, it reduced platelet counts in some patients and thus could be considered for a trial in patients with essential thrombocytopenia. Overall the interesting results support moving forward to a combination study with a JAK inhibitor.
LCL-161: Dr. Pemmaraju presented the final results of a phase 2 study of LCL161, a SMAC mimetic that targets molecules that allow for survival of malignant cells in patients with high risk myelofibrosis. This study of 50 patients revealed that the drug had an overall response rate of 30% which is significant in that this study was skewed towards older patients who had failed at least 2 prior therapies and those with low platelet counts.
Metformin: Preliminary results from a small phase 2 trial evaluating Metformin on bone marrow and disease progression in patients with myelofibrosis were presented. Metformin reduced bone marrow collagen levels after 6 months of treatment and down regulated STAT and insulin pathway regulated genes. This study (FIRBROMET) will follow patients for 2 years.
Luspatercept: Dr. Gerds presented interim results from a phase 2 study in patients with myelofibrosis-associated anemia. Four different cohorts of patients (receiving a stable dose of Ruxolitinib or not and those transfusion dependent or not) are being followed and all treated with Luspatercept. This study is ongoing but the initial results showed that luspatercept improved anemia in all cohorts with a more profound effect in patients treated with Ruxolitinib.
Tagraxofusp: Dr. Pemmaraju presented preliminary results from a phase 1/2 clinical trial evaluating Tagraxofusp, a CD-123 targeted therapy in 29 relapsed or refractory patients with myelofibrosis. Some clinical efficacy was shown in this patient population and the study is now being expanded with more patients. Preclinical data was presented demonstrating that CD-123 may be a viable drug target in more advanced phase MPNs.
A few new clinical trials were also introduced:
KRT-232: KRT-232 is an MDM2 inhibitor designed to increase or stabilize p53 levels. The phase 2 trial design and clinical site locations were presented. This is a 2-part, open label study in patients with relapsed or refractory myelofibrosis.
PU-H71: PU-H71 is a chaperone inhibitor which, in combination with Ruxolitinib, was shown to degrade levels of mutant JAK2 protein levels in preclinical models. The clinical study design was presented for this multicenter, Phase 1b study to assess the safety and preliminary efficacy of PU-H71 in combination with Ruxolitinib in patients with myelofibrosis.
Basic Science and Pre-clinical Study Updates:
There were many presentations on the basic biology of the MPNs. Interesting abstracts in this category described the functions of normal versus mutant forms of calreticulin, the contributions of gene regulatory factors such as HMGA1, and the role of cytokines such as IL-1b in development and progression of the MPNs. A number of presentations also focused on pre-clinical studies of novel drugs. Highlights of these abstracts included the following:
Targeting HDAC11 in the MPNs: Work by Dr. Epling-Burnette and colleagues is focused on targeting a regulator of gene expression named HDAC11. There have been a number of pre-clinical and clinical studies of different HDAC inhibitors in the MPNs with mixed results. In this study, the researchers wondered whether specific targeting of HDAC11 would show improved efficacy with a reduction in side effects. Using an animal model of the MPNs driven by expression of the MPLW515L mutation, they demonstrated that loss of HDAC11 led to a reduction in fibrosis and improved survival. They further showed that HDAC11 targeting affects cellular metabolism. HDAC11 inhibition may be a viable strategy for targeting these metabolically active cancers.
Combining JAK inhibition with PRMT5 inhibition: Dr. Levine’s laboratory investigated the effect of targeting a protein named PRMT5 which modifies other proteins to promote cell growth. Using MPN cell lines and the MPLW515L animal model of MPNs, they showed that PRMT5 inhibition led to reduction in spleen size and inflammatory cytokines, improvement of blood counts, and decreased fibrosis. Dual inhibition of PRMT5 and JAK2 led to an even greater therapeutic benefit. These results support a clinical study of PRMT5 inhibitors in patients.
A few other potential new drugs or drug targets in preclinical development presented were Palbociclib, a CDK6 inhibitor, RMC-4550, a SHP2 inhibitor, Obatoclax, a pan-Bcl-2 inhibitor and PPM1D as a potential new drug target which is overexpressed in MPNs and inhibits p53 activity.
The 2019 ASH meeting provided important updates in both the clinical and basic research realms. It is our pleasure to share these with the patient, caregiver and physician community. If you would prefer a printed copy please reach out to email@example.com. Please make sure to subscribe for all of our news updates so you never miss what’s happening with PV, ET and MF research news or updates about treatments.