Experts in myeloproliferative neoplasms find janus kinase (JAK) inhibitors to be particularly important to the armamentarium for the treatment of myelofibrosis (MF). With only 2 FDA-approved agents, fedratinib (Inrebic) and ruxolitinib (Jakafi), and the inevitability that not all patients will derive benefit, and some will develop resistance, the option of moving beyond JAK inhibition is widely discussed.
During a presentation at the 1st annual Texas Virtual MPN Workshop, Naveen Pemmaraju, MD, associate professor, Department of Leukemia, University of Texas MD Anderson Cancer Center discussed the novel therapies beyond JAK inhibitors that are making their way into the treatment landscape of MF.1
Currently, novel agents are showing promise in phase 3 clinical trials, include pacritinib (SB1518) in the phase 3 PACIFICA study (NCT03165734), momelitinib (formerly GS-0387) is being evaluated in the phase III MOMENTUM study (NCT04173494), and fedratinib, although approved in the frontline setting, is now being evaluated as second-line treatment.
Modern JAK Inhibition Combinations
Ruxolitinib remains the standard-of-care treatment for patients with MF, even with the emergence of novel therapies, Pemmaraju noted. To improve upon outcomes in the patient population, ruxolitinib is now being rechallenged in patients or combined with other drugs. One study for which data were published in a 2018 issue of Blood, explored the addition of ruxolitinib to the chemotherapy agent azacitidineazacitidine (Vidaza).
The phase 2 study of ruxolitinib plus azacitidineazacitidine included 44 patients with MF whose median age was 66 years (range, 48-87 years). At baseline, 36 patients (82%) had intermediate-2 (int-2)/high IPSS score, 29 patients (66%) had splenomegaly, and 24 patients (55%) were positive for a JAK V61F mutation.
Thirty-nine patients were evaluable for response. The median follow-up time was 20.4 months (range, 0.5-3.7). The results showed objective response in 33 patients (72%) which included 2 partial responses and clinical improvement in 31 patients. The median time to response was 1.8 months (range, 0.7-19 months). In addition, the combination of ruxolitinib and azacitidine led to spleen response in 21 (61%) of the 34 patients who had splenomegaly > 5cm. In 3 other patients whose splenomegaly was 5 to 10 cm at baseline, there was a 50% reduction in spleen size following treatment with the ruxolitinib combination.
Another phase 2 clinical trial evaluated treatment with ruxolitinib plus navitoclax in patients with JAK2-resistant MF (NCT03373877). The combination demonstrated clinical activity in these patients, according to findings presented at the 2019 American Society of Hematology Annual Meeting. In 30% of the study population, there was a spleen volume response of greater than 35%. In addition, there was a 65% reduction in symptoms and 35% of patients had a reduction in total symptom score (TTS) of more than 50%.
Pemmeraju also noted an ongoing phase 1b study of ruxolitinib plus PU-H71 in patients with MF and polycythemia vera (PV, NCT03373877). In addition, the add-on strategy is being explored with lenalidomide (Revlimid), thalidomide (Thalomid), pracinostat, CPI-0610, sotatercept (ACE-011) plus luspatercept (Reblozyl), as well as in combination with a PI3k (phosphoinositide 3-kinase) inhibitors and interferon inhibitors.
Possible Modern JAK Inhibition Strategies
Targeting JAK is no longer the only strategy available for MF in 2020, Pemmaraju explained. Research has shown that there are possibilities for targeting apoptosis and cell death pathways, telomerase, hematopoietic stem cell, and microenvironments, the TP53 pathway, and targeting fibrosis, cytokines, epigenetics, and other pathways.
In relation to targeting apoptosis and cell death pathways, the phase 2 study of single-agent LCL-161 (NCT02098161) investigated 50 patients with primarily relapsed/refractory MF. A phase 2 open-label study of navitoclax alone or in combination with ruxolitinib (NCT03222609) is also testing out this strategy. The telomerase inhibitor, imtelestat, was also studied in this patient population in phase 2 study (NCT02426086).
There are 2 ongoing trials (NCT02268253 and NCT03373877) investigating the targeting of hematopoietic stem cell/microenvironment. One study is also assessing the targeting of the TP53 pathway in patients with MPNs as well as post-MPN acute myeloid leukemia (AML). Other trials that Pemmaraju mentioned that are investigating fibrosis, cytokines, epigenetics, and other pathways as targets include the phase 2 study of pentraxin (PRM-151, NCT01981850), as well as the studies of sotatercept/luspatercept, alisertib (MLN8237), CPI-0610, and PSD1 inhibition.
Promise of MF Treatment Beyond JAK Inhibition
Multiple treatment strategies have shown positive results in clinical trials as treatment of patients with high-risk MF, Pemmaraju shared. First, he shared results of the phase 1/2 trial of a novel CD123-directed therapy, which was designed to address the CD123 expression seen in many myeloid malignancies, including MF.
In the phase 1/2 trial of tagraxofusp, 32 patients were included in the safety analysis for the study, and more than 10% experienced treatment-related adverse events (TRAEs). The most common TRAEs of any grade were hypoalbuminemia (25%), headache (16%), alanine aminotransferase increased (16%), anemia (14%), and thrombocytopenia (14%).
At baseline, 18 patients had splenomegaly 5 cm, and of those patients, 10 (56%) had spleen reductions. Additionally, 2 patients had spleen reductions of greater than 50%. Among patients with thrombocytopenia and platelet counts <100 109/L 8 patients (62%) had spleen size reduction as did 4 patients (57%) with thrombocytopenia and platelets < 50 109/L. Subjects with monocytosis whose monocytes were 1 109/L. In addition, 46% of the 24 patients evaluated to efficacy had a reduction in their TTS.
In terms of survival, the median OS observed was 30.5 months at a median follow-up time of 27 months (range, 0.6-50.3 months).
According to Pemmaraju, the subsets of patients with MF who had thrombocytopenia, monocytosis, or accelerated phase disease are areas of ongoing research.
LCL161 was the second agent Pemmaraju noted as a potential new treatment for high-risk MF. The agent was assessed in a phase 2 clinical trial which was launched to address the unfavorable survival outcomes in the patient population. In addition, no JAK inhibitors are approved by the FDA as treatment of this particular group of patients with MF.
In 50 patients, the objective response rate was 30%, leading clinical improvements in 11 patients with symptoms, 6 patients with anemia, and 1 pain with splenomegaly. Additionally, 1 patient achieved a cytogenetic remission.
The survival data show that 34 patients (68%) were still alive at data cutoff. The median duration of response was 1.4 months (95% CI, 0.9-9.1 months). There was also a number of longer-term responses (n = 8) who experienced a response for 1 year or more. At data cutoff, long-term responses were ongoing in 4 patients. The median OS was not reached in the study.
Based on these data, Pemmaraju stated that LCL161 may be a viable option for older patients, those who failed prior JAK inhibitors, and those with thrombocytopenia that limit entry into clinical trials.
Data presented previously at the 2018 American Society of Hematology (ASH) Annual Meeting showed that a phase 2 study of luspatercept was positive for its primary and secondary end points of transfusion independence.1,2
In a cohort of 22 patients who were not receiving ruxolitinib and had no red blood cell transfusion for 12 consecutive weeks, 14% achieved the primary end point and 18% achieved the secondary end point. In a separate cohort of 21 patients who were not receiving ruxolitinib and had been transfusion dependent for 12 consecutive weeks, 10% were positive for the primary end point and 38% were positive for the secondary end point. In the cohort of 14 patients who were receiving a stable dose of ruxolitinib and were transfusion independent of 12 consecutive weeks, 21% reached the primary end point and 64% achieved the secondary end point. Finally, in the cohort of 19 patients who received a stable dose of ruxolitinib but were transfusion-dependent for 12 consecutive weeks, 32% achieved the primary end point and 53% achieved the secondary end point.
Preliminary results for CPI-0610 were also presented at ASH in 2019. In the phase 2 study CPI-0610 was combined with ruxolitinib in treatment-nave patients with MF.1,3
Compared with baseline measurements, an 80% SVR35 (spleen volume reduction) response was observed at week 12, demonstrating a median change from baseline of -49.7% (range, -80.8% to -17.0%). Responses were also observed in high-risk patients including 86.7% of those with DIPSS Dynamic Prognostic Scoring System (DIPPS) int-2, 80% with hemoglobin < 10g/dL, and 53.3% of patients with high molecular risk (HMR) positivity.
In terms of total symptom score (TSS) improvement, it was observed that 71.4% of patients had a TSS response at week 12, and this included the treatment nave population with an improvement of 45.9%.
In another phase 2 study, navitoclax with or without ruxolitinib demonstrated promise in patients with primary of secondary MF. The drug specifically helped patients overcome resistance to ruxolitinib which resulted in splenomegaly improvement.1,4
Out of 30 patients assessed, SVR35 at week 24 was 43% in 13 patients and 30% in 9 patients. In addition, resolutions of palpable splenomegaly were observed in 53% of patients. Twenty-five percent of patients also demonstrated reductions in bone marrow fibrosis per local assessment.
A randomized phase 2 study of imetelstat as treatment of patients with intermediate-2 or high-risk MF who were relapsed or refractory to JAK inhibition induced responses and a survival benefit.1,5
In a pool of 107 patients, 6 patients (10%) had 35% SVR at week 24 and 23 patients (37%) had a 10% SVR at week 24.
Imetelstat also achieved a median OS of 19.9 months (95% CI, 17.1-not evaluable [NE]) when administered at a dose of 4.7 mg.kg and the median OS climbed to 29.9 months (95% CI, 22.8-NE) when Imetelstat was administered at 9.4 mg/kg.
Pemmaraju noted that a review of the existing and ongoing research on targeting beyond JAK inhibition in patients with MF was recently published in Current Hematologic Malignancy Reports. The paper states that because of the different mechanisms of action other the novel therapies in MPNs, they can improve outcomes in the field when use alone or in combination with ruxolitinib.6
1. Pemmaraju N, et al. Novel Targeted Therapies Beyond JAK Inhibitors. Presented at: Texas Virtual MPN Workshop; August 2728, 2020; Virtual.
2. Gerds AT, Vannucchi AM, Passamonti F, et al. A Phase 2 Study of Luspatercept in Patients with Myelofibrosis-Associated Anemia. Blood. 2019;34(supplement_1):557. doi: 10.1182/blood-2019-122546
3. Mascarenhas J, Kremyanskaya M, Hoffman R, et al. MANIFEST, a Phase 2 Study of CPI-0610, a bromodomain and extraterminal domain inhibitor (beti), as monotherapy or "add-on" to ruxolitinib, in patients with refractory or intolerant advanced myelofibrosis. Blood. 2019; 134 (Supplement_1): 670. doi: /10.1182/blood-2019-127119
4. Harrison CN, Garcia JS, Mesa RS, et al. Results from a phase 2 study of navitoclax in combination with ruxolitinib in patients with primary or secondary myelofibrosis. Blood. 2019;134(supplement_1):671. doi: 10.1182/blood-2019-130158
5. Mascarenhas J, Komrokji RS, Cavo M, et al. Imetelstat is effective treatment for patients with intermediate-2 or high-risk myelofibrosis who have relapsed on or are refractory to janus kinase inhibitor therapy: results of a phase 2 randomized study of two dose levels. Blood. 2018;132(supplement_1):685. doi: 10.1182/blood-2018-99-115163
6. Economides, M.P., Verstovsek, S. & Pemmaraju, N. Novel therapies in myeloproliferative neoplasms (mpn): beyond jak inhibitors.Curr Hematol Malig Rep.2019;14,460468. doi: 10.1007/s11899-019-00538-4
- Cell Therapy Global Market Report 2021: COVID-19 Growth and Change to 2030 - ResearchAndMarkets.com - Business Wire - July 7th, 2021
- A New Era For FDA Regulation Of Cell And Tissue Products - Law360 - July 7th, 2021
- UM School Of Medicine Researchers Receive NIH Avant Garde Award For Out-Of-Box, Innovative Concept To Cure HIV And Treat Co-Existing Addiction -... - July 7th, 2021
- Antengene Announces Acceptance of IND Application in China for the Phase II Clinical Trial of Single-Agent Selinexor for the Treatment of... - July 7th, 2021
- The Top Doctors in the Twin Cities, 2021 - Mpls.St.Paul Magazine - July 7th, 2021
- The stem cell market was valued at USD 14.7 billion in 2020, and it is expected - GlobeNewswire - June 8th, 2021
- Innovative Regenerative Medicine Therapies Safety Comes First - FDA.gov - June 8th, 2021
- Early Promise of AntiCLL-1 CAR T-Cell Therapy Reported in Pediatric AML - Cancer Network - June 8th, 2021
- Part 3: Moving Forward and Keeping Stem Cell Treatments Safe - MedShadow - June 8th, 2021
- In Some Heavily Pretreated Patients with R/R MM Ide-Cel Continues to Show Deep and Durable Responses - Targeted Oncology - June 8th, 2021
- Innovative research refines the treatment of patients with advanced cancers and the use of immunotherapy - Network News, Press Releases - Hackensack... - June 8th, 2021
- Mustang Bio to Host Key Opinion Leader Webinar on MB-106 CD20-Targeted CAR T for the Treatment of High-Risk B-Cell Non-Hodgkin Lymphomas and Chronic... - June 8th, 2021
- Karen Hasty Named Among 2021 Super Women In Business by Memphis Business Journal - UTHSC News - June 8th, 2021
- High Overall Response Rates Achieved With Cirmtuzumab/Ibrutinib in MCL and CLL - Targeted Oncology - June 8th, 2021
- New Data on KEYTRUDA (pembrolizumab) Plus LENVIMA (lenvatinib) Versus Sunitinib in First-Line Treatment for Patients With Advanced Renal Cell... - June 8th, 2021
- Chao family gifts to UCI Health for cancer care top $50 million - UCI News - June 8th, 2021
- Sorrento and Researchers at Karolinska Institutet Have Signed a Research Collaboration Agreement on iPSC-Derived Dimeric - GlobeNewswire - June 8th, 2021
- Responses to Tafasitamab/Lenalidomide in DLBCL Sustained at Three Years - Cancer Network - June 8th, 2021
- The regenerative medicine market size to grow at a CAGR of around 30% during the period - GlobeNewswire - June 8th, 2021
- 'Natural Killer Cells' and Other Promising Cancer Treatments - Barron's - April 18th, 2021
- Capturing the Pandemic Experience in Haiku Poetry - Duke Today - April 18th, 2021
- Chemotherapy for Prostate Cancer: When It's Used and What to Expect - Healthline - April 18th, 2021
- Signs that Chemo Is Working: How Effectiveness Is Measured and Defined - Healthline - April 18th, 2021
- Some experts fear next-generation Covid vaccines may be worse - STAT - April 18th, 2021
- How Long is Chemotherapy? What to Expect - Healthline - April 18th, 2021
- Regenerative Medicine - Stem Cell Therapy Little Rock - March 8th, 2021
- Center for Stem Cell Biology & Regenerative Medicine ... - March 8th, 2021
- Dynamic Stem Cell Therapy Offers Regenerative Medicine - Las Vegas Review-Journal - March 8th, 2021
- Anti-EGFR VHH-armed death receptor ligandengineered allogeneic stem cells have therapeutic efficacy in diverse brain metastatic breast cancers -... - March 8th, 2021
- Research Antibodies Market Size to Reach USD 5325.8 Million by 2027 | Increasing R&D Activities in the Fields of Oncology, Neurobiology, and Stem... - March 8th, 2021
- Microwave Processing Isolates Red Ginseng Compounds That Suppress Lung Cancer Metastasis - Genetic Engineering & Biotechnology News - March 8th, 2021
- Longeveron Expands Enrollment Criteria for its Phase 1 RECOVER Trial Evaluating Lomecel-B Infusion to Treat Acute Respiratory Distress Syndrome due to... - March 8th, 2021
- Be The Match BioTherapies Announces Expansion of Multi-Year Strategic Alliance with Orchard Therapeutics to Support European Commercial Launch of... - March 8th, 2021
- Autologous Stem Cell and Non-Stem Cell Based Therapies Market 2021: Focuses at the key worldwide companies to Define, Describe and Analyses the sales... - March 8th, 2021
- Editing Reproduction: CRISPR and preventing heritable diseases, With Dr. Dietrich Egli and Dr. Sam Sternberg - Columbia University Irving Medical... - March 8th, 2021
- U. Cancer Center pilot projects: investigating cancer connections - The Brown Daily Herald - March 8th, 2021
- COVID-19 can kill heart muscle cells, interfere with contraction Washington University School of Medicine in St. Louis - Washington University School... - March 8th, 2021
- Vaccinating by age groups is unfair, particularly to minorities, advisory panel tells CDC - USA TODAY - March 8th, 2021
- Winter Weather Impacting Blood and Platelet Donations - Milwaukee Community Journal - February 17th, 2021
- Joshua Shirk continues to fight the odds; mom says God placed people where they needed to be to help him - Keyser Mineral Daily News Tribune - February 17th, 2021
- Evotec and Medical Center Hamburg-Eppendorf Enter Partnership to Develop iPSC-Based Tissue Therapy for Heart Failure - GuruFocus.com - February 7th, 2021
- ProgenCell - Stem Cell Therapies offers an updated Stem Cell Therapy for Anti Aging Protocol - PR Web - January 30th, 2021
- Doctors urge immunocompromised to get COVID vaccine when it becomes available - KMTV - 3 News Now - January 30th, 2021
- Autologous Stem Cell and Non Stem Based therapies Market Share, Size 2021 Global Industry Future Trends, Growth, Strategies,, Segmentation, In-depth... - January 30th, 2021
- Studies Indicating T-Cells May Be Needed For Long-Term Protection From The SARS-Cov-2 Virus - PRNewswire - January 30th, 2021
- Researchers use patients' cells to test gene therapy for rare eye disease - National Institutes of Health - January 30th, 2021
- Two Gene Therapies Fix Fault in Sickle Cell Disease and -thalassemia - MD Magazine - January 30th, 2021
- If I Have Cancer, Dementia or MS, Should I Get the Covid Vaccine? - Kaiser Health News - January 30th, 2021
- L-MIND Trial Results Show CD19 Antibody Is Reasonable in R/R DLBCL - Targeted Oncology - January 30th, 2021
- Profile of T Cells, Broadly Neutralizing Antibodies, Anti-Viral Targets: COVID-19 Updates - Bio-IT World - January 30th, 2021
- HealthLynked's The Future of Healthcare Summit Brings Healthcare Experts and Technology Innovators from Around the World to Naples, Florida - WFMZ... - January 30th, 2021
- Tevogen Bio Secures Funding from Team of Doctors to Support Clinical Trials of Its Investigational Curative T Cell Therapy for COVID-19 - PRNewswire - January 25th, 2021
- Novel Treatment Leads to Dog's Recovery - The Bark - January 25th, 2021
- Identification and Targeting of ThomsenFriedenreich and IL1RAP | OTT - Dove Medical Press - January 25th, 2021
- Regenerative Medicine Market Size Worth $74831.35 Million With CAGR of 22.27% By 2024 | Segmented by Product Type, Top Manufacturers, By End-User... - January 25th, 2021
- Immunotherapy Inches Forward in Development of Myeloid Malignancies - OncLive - January 14th, 2021
- Cytovia Therapeutics Partners with National Cancer Institute to Develop Novel Gene-Edited, iPSC-Derived GPC3 CAR NK Cells for the Treatment of Solid... - January 14th, 2021
- Kaleido Biosciences Announces Positive Interim Results of Controlled Study of KB109 in Patients with Mild-to-Moderate COVID-19 - BioSpace - January 14th, 2021
- Doctors Make Medical Breakthrough In Treating Severe Cases Of COVID - CBS San Francisco - January 9th, 2021
- Mana joins the hectic fight against solid tumors with an 'off-the-shelf' candidate angling for an IND this year - Endpoints News - January 9th, 2021
- Versiti Blood Centers and Noodles & Company Serve Up Thanks to Blood Donors - PRNewswire - December 31st, 2020
- Global CAR-T Pipeline Insight Report 2020: Overview, Landscape, Therapeutic Assessment, Current Treatment Scenario and Emerging Therapies -... - December 31st, 2020
- 2020 health care year in review - Crain's Cleveland Business - December 31st, 2020
- The Top 10 FDA Oncology Drug Approvals of 2020 - Curetoday.com - December 31st, 2020
- Gut microbiota: How does it interact with the brain? - Medical News Today - December 31st, 2020
- Numerous Indian American STEM Researchers Named Fellows of American Association for the Advancement of Sciences - India West - December 31st, 2020
- Four years after devastating spinal injury, former St. Paul's football player reunites with caregivers - NOLA.com - December 24th, 2020
- New Combination Therapy Tested By Children's May Offer Hope For Leukemia Patients - WVXU - December 24th, 2020
- Real-time observation helpful in Stem cell for vascular diseases: Study - Hindustan Times - December 21st, 2020
- NurOwn May Be Given to Early ALS Patients in US Who Finished Phase... - ALS News Today - December 21st, 2020
- Follow the Money: Spatial Omics, CAR-NK Cells, AI-Powered Biology - Bio-IT World - December 21st, 2020
- Explained: Process of transporting stem cell from donor to patient for a successful transplant - Firstpost - December 18th, 2020
- Research That Saves Lives: Four COVID-19 Therapies Being Tested at UVA - University of Virginia - December 18th, 2020
- Even if You've Had COVID-19 You Still Need the Vaccine - Healthline - December 18th, 2020
- What Patients With Cancer, Survivors Need to Know About the Emergency Use Authorization of COVID-19 Vaccine - Curetoday.com - December 16th, 2020
- 2020 at the U: The year in review - University of Miami - December 16th, 2020
- Five Mobile County hospitals to get Pfizer vaccine this week - AL.com - December 16th, 2020
- Donor Stem Cell Transplant Improves Survival in Older Patients with Myelodysplastic Syndrome - Cancer Health Treatment News - December 10th, 2020
- Positive Phase 2 Proof-of-Concept Data for Viralym-M and Burden of Disease Data Presented in Oral Presentations at the 62nd American Society of... - December 10th, 2020
- Dr. Kansagra: Quadruplet Therapy for Newly Diagnosed Multiple Myeloma and Combination CAR T-Cell Opportunities - DocWire News - December 10th, 2020