Ruben Mesa, MD, director, Mays Cancer Center at The University of Texas Health San Antonio, MD Anderson Cancer Center San Antonio, TX, reviewed a case of a 68-year-old woman with a myeloproliferative neoplasm, during a virtual Case Based Peer Perspectives event.
Targeted Oncology: What type of testing would you perform on this patient? Are there certain mutations in particular that you are looking for?
MESA: The NGS [next-generation sequencing] panels are helpful. In myelofibrosis, theyre the most necessary in the potential transplant candidate [who is] of intermediate risk [and for whom] youre uncertain of the [prognosis]. In patients who are high risk, its also useful information. If someone hasoverwhelmingly high-risk disease, theyre not going to be at higher risk [based on these results], but I think its helpful information that we continue to learn about in terms of clonal evolution. Or, if they go to transplant, we know what the clones look like at the onset prior to undertaking [the trans- plant]. Our medical therapies have not resolved these muta- tions, but of course that could change. Its helpful information for us to know.
There are bad actors like ASXL1, EZH1/2, [and] the IDH1 muta- tions. The absence of a bunch of these somatic mutations is somewhat reassuring. Its helpful in combination with the clini- cal data. How are they feeling as far as their spleen, cytopenias, etcetera? There are [many] of these models that have been created, and some of which now have genetic data only. Thats probably incomplete. I can put the stained clone in 2 different patients, but if one is 45 years old and healthy and the other is 70 years old with comorbidities, theres no way those patients are doing the same. I think the clone is important, but the clone always has to live in a person.
Which risk-assessment tool do you use most often?
MIPSS [Mutation-Enhanced International Prognostic Score System] is the most popular, and it has a couple of advantages. One is that it has its own website; you can Google it and book- mark it on your computer. I always tell my trainees, dont bother to memorize any prognostic score in terms of how to calculate it because we have [a] calculator. But have a sense of what...the biological [characteristics are] that make a difference in terms of the prognosis for patients that give you some insight into the behavior of the disease. Have a sense of where and when that [is] useful.
There have been multiple models that have been validated. They help to stratify patients in terms of their outcomes in a range of ways. They are largely surrogates [of transformation to acute myeloid leukemia] as well, although its a different issue. The outcome for the patient with myelofibrosis if they pass away from the diseasewhich is still the majority of patientsis [that] they either die of progressive features of myelofibrosis, which can include progressive debilitation, cytopenias, and a range of complications related to that, or they progress to acute leuke- mia and can pass away from those sets of difficulty.
Why are prognostic models referenced in the National Comprehensive Cancer Network (NCCN) guidelines?
I was involved with the original NCCN guidelines for MPNs [myeloproliferative neoplasms].1 Originally, we had the prog- nostic score, or at that point the DIPSS [Dynamic International Prognostic Scoring System] or the DIPSS-Plus...to help stratify whos lower risk or whos higher risk in terms of therapy to get rid of some of the granularity.
Would you consider transplant in this case?
I have had patients who have done well with transplant. Transplant can be curative, but we can also wait too long, partic- ularly in the setting of myelofibrosis. I think when its being used as salvage therapy in myelofibrosis, the outcomes are less [successful] than we would like. In my estimation, the best time to have a transplant is probably before either the patient or physician really feels the patient needs one. Its during their optimal JAK inhibitor response that they probably do the best. Now, on the flip side, thats the time that they have the most to lose in that their quality of life is good and theyre stable. Its a difficult decision.
Which systemic therapies might you consider in this patient?
In terms of medical therapy, we now have 2 approved ther- apies in the front line, both ruxolitinib [Jakafi] and fedratinib [Inrebic], and many others in development that were discussed at the ASCO [American Society of Clinical Oncology] Annual Meeting and at the 25th Annual Congress of EHA [European Hematology Association].
Ruxolitinib has now been approved for a long time with data from the randomized studiesnow almost historical in nature with the COMFORT studies, both COMFORT-I [NCT00952289] and COMFORT-II [NCT00934544]. It showed for the first time in randomized settings a drug that was effective in myelofibrosis. Ruxolitinib was clearly better than placebo [and best alternative therapy] in the COMFORT-I study that Srdan Verstovsek, MD, PhD, and I led, and which was a European study.2
That was relevant because at the time the standard of care was Hydrea [hydroxyurea]. We recognized in retrospect that hydroxyurea is not as great a therapy for myelofibrosis. Its good therapy for ET [essential thrombocytopenia]. It helps to control platelets reasonably well in many, but its not a perfect drug. In polycythemia vera, its a reasonable frontline therapy, although interferon may have advantages. In myelofibrosis, it might help with leukocytosis but doesnt do much for splenomegaly symp- toms, anemia, fibrosis, or progression toward acute leukemia.
Would you send her for transplant, start ruxolitinib or fedratinib, observation, or something else?
Ill remind [you that] this patient is 68 years old, has a big spleen, has a JAK2 mutation, and leukoerythroblastosis...most physicians would start her on ruxolitinib. That would surely be consistent with our NCCN guidelines.1 Some would refer [her] for stem cell transplant. That would not be incorrect. She has some higher- risk features. She has anemia, 2% [peripheral blood] blasts, and mild thrombocytopenia. In all honesty, some of these things we do in parallel.
I dont typically [rely on transplant], but I do send patients who are potentially eligible to visit with a transplant physician so that that process can start. The patient can learn more about the process. We could see what a potential donor solution would be. We could see what sort of initial response to therapy that they have. Patients who go to transplant would likely start JAK inhibi- tion before they would go [for their transplant]. Even if they found a good sibling match, and the patient wants to go through with that, its probably going to take 3 to 4 months and they can be on JAK inhibition before that. They might have a better outcome with the spleen being smaller and going to transplant better. [Its] a bit of an artificial question in that you might choose to do more than one of these things in parallel.
What are the advantages of JAK inhibition with ruxolitinib?
There are patients from the phase 1 study of ruxolitinib at our centers that are still on the therapy. These are individuals that had expected survival [times] of under 3 years. I think that patients that are having a great response to JAK inhibition have their natural history improved. Splenomegaly symptoms were both clinically meaningful [and measurable according to early ruxolitinib activity].
Every time weve looked at it, there is an indication that ruxoli- tinib improves survival for patients. Now, the studies were not survival studies in their design, and that was for a variety of reasons. It would have been largely unethical and unrealistic to expect patients to stay on placebo forever so that they could do worse on a control arm [to prove] survival advantage. Having been involved with caring for patients with myelofibrosis before JAK inhibitors and after, theres no question that these drugs improve survival. Id say that the rate by which patients passed away...has decreased significantly over the past decade as opposed to my first 15 years of treating myelofibrosis. [Ruxolitinib] does not cure the disease, and its not [successful] in every patient. I dont think we yet truly know why we see that difference.
Why is the spleen response with ruxolitinib so important?
I do not believe...that shrinking the spleen because of its mechan- ical effect leads to an improvement in survival. However, the spleen is a good barometer of the quality of JAK inhibitor response, and responding to JAK inhibitors improves survival. I think tracking this thing is important, not just because it shrinks but because it means that whatever benefit were getting from JAK inhibition is present.
What is the optimal dose of ruxolitinib in this patient population?
Weve learned several things over time, including the issue of dosing, as it relates to efficacy and survival. Patients probably need to be on 10 mg twice a day or more to be getting the optimal benefit. Ideally, [we should be] getting them to 15 mg twice a day, or, if reasonable, 20 mg twice a day. There is contro- versy. My colleague...strongly believes we should start everyone at the higher dose. I think its OK to start lower, but you must accelerate the dose. There are likely too many patients out there on a suboptimal dose of ruxolitinib. Starting with those doses is fine, but rapidly increasing the dose where you truly see a signif- icant reduction in the size of the spleen and improvement in the symptoms [is necessary]. If youre not achieving that, then that is when its important to think about second-line therapy, dose adjustments, or a clinical trial.
What adverse effects (AEs) of ruxolitinib are there that treating physicians should be concerned with?
In terms of toxicities, there are issues of cytopenias. In the phase 1 studies, it was thrombocytopenia that was the dose-limiting toxicity. Anemia is the most functional difficulty in that the throm- bocytopenia is present, but it usually is not the driver in terms of limiting your dose.
When would you choose to use fedratinib?
Since last September, we have the approval of fedratinib as well for these patients.3 It was supported by the phase 3 JAKARTA study [NCT01437787], a randomization between fedratinib at 2 different dose levels versus placebo in patients that had intermediate- or high-risk myelofibrosis. The timing of the trial overlapped with the period before ruxolitinib was approved.
There was a nice response in terms of splenomegaly compared with placebo. There was a 500-mg arm that performed reasonably well in terms of efficacy but had more toxicity, so the approved dose is 400 mg.
In terms of toxicity, there are gastrointestinal toxicities. Typically, patients are [given] prophylaxis with antidiarrheals and antinausea drugs. Id have to say most patients dont tend to have a lot of difficulties with that. They can have cytopenias; there [are] no direct head-to-head data between fedratinib and ruxolitinib in terms of rates of cytopenias, but its not clear that there is necessarily a clear advantage between one or the other.
What does the black box warning say for encephalopathy in patients who receive fedratinib?
It was recognized that there were several cases of individuals who had had some degree of CNS [central nervous system] toxicity in 8 cases out of about the 900 patients that were treated. It was suspected that it was Wernicke encephalopathy. The drug was put on a clinical hold. Those cases were subsequently looked at in great detail by neurologists and others, and what was seen was that there was a rare CNS-confusion episode that did occur. It was only clear that 1 of the patients met the criteria of having Wernicke encephalopathy, but they likely had [that] when they were enrolled in the study. In addition, the Wernickes may have been worsened because this patient, at the 500-mg dose, did have a lot of nausea and vomiting.4
With an abundance of caution the drug was approved, but with a black box warning [cautioning physicians to] measure thiamine, replace thiamine if need be, and monitor for Wernicke [enceph- alopathy]. Having prescribed it after its approval, [I have found that] its not a major limiting factor, but just something to be mindful of and exercise every caution.
1. NCCN. Clinical Practice Guidelines in Oncology. Myeloproliferative neoplasms, version 1.2020. Accessed June 29, 2020. https://www.nccn.org/professionals/ physician_gls/pdf/mpn.pdf
2. Mesa RA, Kiladjian JJ, Verstovsek S, et al. Comparison of placebo and best available therapy for the treatment of myelofibrosis in the phase 3 COMFORT studies. Haematologica. 2014;99(2):292-298. doi:10.3324/haematol.2013.087650
3. FDA approves fedratinib for myelofibrosis. FDA. August 16, 2019. Accessed June 29, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/ fda-approves-fedratinib-myelofibrosis
4. Mullally A, Hood J, Harrison C, Mesa R. Fedratinib in myelofibrosis. Blood Adv. 2020;4(8):1792-1800. doi:10.1182/bloodadvances.2019000954
See original here:
Mesa Discusses Treating Myelofibrosis and Other MPNs - Targeted Oncology
- 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
- Silicon Therapeutics Announces Members of Scientific Advisory Board - Business Wire - December 10th, 2020
- Israeli Neurogenesis' NG-01 slows progressive MS by up to 90% in phase II study - BioWorld Online - December 10th, 2020
- ADC Therapeutics Announces Updated Clinical Data on Lead Antibody Drug Conjugate Programs Loncastuximab Tesirine (Lonca) and Camidanlumab Tesirine... - December 10th, 2020
- Magenta Therapeutics Announces Commencement of First Phase 2 Clinical Trial of MGTA-145 for Stem Cell Mobilization, Oral Presentation of MGTA-145... - December 8th, 2020
- Precigen Presents New Data Supporting the Safety, Clinical Activity, Expansion and Persistence of PRGN-3006 UltraCAR-T at the 62nd ASH Annual Meeting... - December 8th, 2020
- ALLO-715, Off-the-Shelf CAR T-Cell Therapy, Produces Early Promise in Multiple Myeloma - Cancer Network - December 8th, 2020
- Rocket Pharmaceuticals Presents Positive Clinical Data from its Fanconi Anemia and Leukocyte Adhesion Deficiency-I Programs at the 62nd American... - December 8th, 2020
- Negrin Shines Light on the Orca-T Story in GVHD - OncLive - December 8th, 2020
- Preliminary Results from NexImmune's Phase 1/2 Trial of NEXI-001 in AML Presented at 62nd ASH Annual Meeting and Exposition - GlobeNewswire - December 8th, 2020
- BeiGene Announces the Approval in China of BLINCYTO (Blinatumomab) for Injection for Adult Patients with Relapsed or Refractory B-Cell Precursor Acute... - December 8th, 2020
- Sutro Biopharma Presents Data from Ongoing Phase 1 Dose-Escalation Study for STRO-001 for the Treatment of B-cell Non-Hodgkin Lymphoma at the 62nd... - December 8th, 2020
- Data from the ANDROMEDA Study Show Hematologic Response for DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) in Newly Diagnosed Light Chain (AL)... - December 8th, 2020
- US FDA Approves Naxitamab for the Treatment of Neuroblastoma - OncoZine - November 29th, 2020
- Coronavirus treatments and vaccines. Here are the latest developments - San Francisco Chronicle - November 29th, 2020
- Dr Apar Kishor Ganti Outlines the Effectiveness of Lurbinectedin and Benefits Over Competition - AJMC.com Managed Markets Network - November 26th, 2020
- Commonly used antibiotic shows promise for combating Zika infections - National Institutes of Health - November 26th, 2020
- A real life Superman celebrates 5 years of survival from one of the deadliest cancers - Newswise - November 26th, 2020
- Global Cell Harvesting Market to Reach US$381,4 Million by the Year 2027 - Salamanca Press - November 26th, 2020
- Tanya Siddiqi, MD, Discusses the Promise of Reduced Toxicity With Liso-Cel - AJMC.com Managed Markets Network - November 26th, 2020
- Tetracycline-based Antibiotics Show Promise for Combating Zika Infections - Global Biodefense - November 26th, 2020
- Study Suggests AYAs Treated for AML Have High Risk of Developing Long-Term Complications - Cancer Network - November 26th, 2020
- Mustang Bio Announces Positive Opinion from the European Medicines Agency on Orphan Drug Designation for Its Lentiviral Gene Therapy for the Treatment... - November 26th, 2020
- Study Finds Racial and Ethnic Disparities in Treatment of AL Amyloidosis - DocWire News - November 22nd, 2020
- New Virtual Reality Tool, Domestic Cats are SARS-CoV-2 Carriers, Combination Therapy Advances: COVID-19 Updates - Bio-IT World - November 22nd, 2020
- SEE | Smoking worsens Covid-19 infection in the airways, new study reveals - Health24 - November 22nd, 2020