Disease Modification and OS

[biopearl123]

Disease modification is defined by Wikipedia as :

disease-modifying treatment, disease-modifying drug, or disease-modifying therapy is a treatment that delays, slows or reverses the progression of a disease by targeting its underlying cause.
[11 They are distinguished from symptomatic treatments that treat the symptoms of a disease but do not address its underlying cause.

We have seen strong evidence for disease modification in ET, MDS and MF. Translating this into OS is more difficult hence the Herculean efforts in the ongoing MF study. The current abstract submitted to EHA concludes that OS is not adversely affected by treatment. But why when there is strong evidence for disease modification are we (as yet) not seeing an improvement in OS? (Not taking into consideration the PII IMbark study. I do think we see improved OS at the 1 year and 18 month mark but not at 2 years) We have a drug that uniquely targets the malignant stem cell and the malignant clones. Why as yet are we not seeing strong improvements in life expectancy? The answer surly lies in the fact that there has been no front line data (not considering the ET data or Dr. T’s fragmented study). The Geron studies have required advanced disease with documented failure of existing front line therapies that have not shown disease modification is almost surly part of the answer. We have seen how difficult it its to get a new drug approved, especially since the studies required targeting the worst of the worst first. We saw first hand the FDA’s skepticism even when confronted with extraordinary genetic marker data to support disease modification. We saw first hand the FDA’s failure to acknowledge the dramatic improvements in hemoglobin and transfusion independence which they tried to ignore by using outdated evaluation criterion. That shameful episode should be put to rest by the overwhelming ODAC vote led by true experts with first hand clinical experience.The march toward front line therapies, alone and in combination seems at this point to carry the best chance to finally prove improvements in OS. But that will require more studies and brave researchers and a whole lot of time which after all is the limiting factor in waiting for enough patients to die in order to prove OS. bp

[LWS]

Once we get Imetelstat approved for something (such as TI before June 16) more theories about how and why this medicine works will evolve. Disease modification (including TI, OS, hemoglobin levels, quality of life, killing cancer stem cells (2 ways), etc.) from Imetelstat is apparently one major process with many molecular extensions that will be fully realized with combinations. These are early times, as we wait for a confusing FDA to speak. OS (with partial remissions, complete remissions, and (hopefully) some cures) plus an improved quality of life is the ultimate objective for the many blood cancers patients & beyond.
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As John Scarlett said: These are not separate processes, but all part of the blood-cancer transformations (paraphrase) at the molecular level. --from LWS

[LWS]

It is a strange world that we live in. I cannot imagine any reason that the FDA would "deep-six" Imetelstat after all of the positive news in trials, conferences and from blood cancer experts.

We have only seen the abstract of the EHA presentation. Considering the presenter (Valeria Santini) and the list of prestigious blood cancer experts who contributed, I am expecting an exceptional paper. I cannot conceive why the FDA would be opposing this group or the ODAC committee.
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EHA Abstract (Many authors)


OVERALL SURVIVAL, CLINICAL BENEFIT, AND DURABLE TRANSFUSION INDEPENDENCE WITH IMETELSTAT IN THE IMERGE PHASE 3 TRIAL OF RED BLOOD CELL-TRANSFUSION DEPENDENT LOWER-RISK MYELODYSPLASTIC SYNDROMES

Prof. Valeria Santini
Author(s): Valeria Santini, Rami S. Komrokji, Mikkael A. Sekeres, Michael Savona, Pierre Fenaux, Yazan Madanat, Esther Oliva, Rena Buckstein, Anna Jonasova, Ulrich Germing, Moshe Mittelman, Sylvan Thepot, Jennifer Riggs, Souria Dougherty, Tymara Berry, Shyamala Navada, Qi Xia, Libo Sun, Amer M. Zeidan, Uwe Platzbecker
(Abstract release date: 05/14/24) EHA Library. Santini V. 06/13/2024; 422288; S184

[LWS]

Remember the EAP (Expanded Access Program) is still in place. John Scarlett said that this was equivalent to a phase 4 trial. Surely, some have taken advantage of this availability. This is a continuous source of data as we wait for the FDA to speak. We all expect approval (sans shenanigans & conspiracies).

[LWS]

June will be here tomorrow. The FDA will speak before June 16th.

Some important and unique disease modification considerations beyond TI (Transfusion Independence):

1/ 2018 IYG data analysis updates
2/ Overall Survival time longer
3/ Better quality of life
4/ Higher hemoglobin levels
5/ Less fatigue
6/ In combinations
7/ With chemotherapy
8/ Off label uses
9/ Molecular level interactions
10/ Two ways to kill cancer stem cells

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Previous Notes:

EHA Paper (June 13 -16) --- OVERALL SURVIVAL, CLINICAL BENEFIT, AND DURABLE TRANSFUSION INDEPENDENCE WITH IMETELSTAT IN THE IMERGE

Some familiar names: Prof. Valeria Santini, Amer M. Zeidan, Uwe Platzbecker

Remember the EAP (Expanded Access Program) is still in place. John Scarlett said that this was equivalent to a phase 4 trial. This is a continuous source of USA data as we wait for the FDA to speak.

This is the tip of the iceberg for the Cancer Moonshot (NIH), and an important building block for developing new treatments and cures for all cancers.

[LWS]

Two Important Backgrounds in Europe and the USA:

Blood Cancer Experts
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Academic history

Valeria Santini, MD, is an Associate Professor of Hematology at the University of Florence Medical School in Florence, Italy, where she received her degree in Medicine and Postgraduate diploma in hematology. Prof. Santini is a member of the European Hematology Association (EHA), MDS Foundation, and Italian Society of Experimental Hematology.

Prof. Santini is a member of the Executive Board of the Italian Society of Hematology, and the Medical Advisory Board of the Aplastic Anemia & MDS International Foundation. She has authored and co-authored over 100 peer-reviewed research papers.

Speaking on MDS, myeloid leukemias and epigenetics

Prof. Santini’s scientific interests and publications are focused on maturation induction and therapeutic targeting of epigenetic modifications, myeloid leukemias and myelodysplastic syndromes (MDS). She is an Investigator for several trials investigating new treatments for MDS, such as the use of azacitidine, and personalized drug combinations.
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Amer Zeidan

After an extensive national search, Amer Zeidan, MBBS, MHS, has been appointed inaugural Chief of the Division of Hematologic Malignancies at Yale Cancer Center.

Dr. Zeidan is from Jordan and received his medical degree from The University of Jordan School of Medicine, followed by a preliminary year internship in Jordan.

He then completed a residency in internal medicine at Rochester General Hospital followed by three years as an academic hospitalist at Rochester General Hospital.

Dr. Zeidan then pursued a fellowship in hematology and medical oncology at Johns Hopkins Medicine, followed by an additional year as a fellow focused on myelodysplastic syndromes. In 2014, Dr. Zeidan joined the Yale faculty as an Assistant Professor of Medicine (Hematology) and was promoted to Associate Professor in 2019. He has more than 330 peer-reviewed publications, is the principal investigator on numerous phase II and III clinical trials and has rapidly become a leading clinical expert and trialist in the areas of acute myeloid leukemia and myelodysplastic syndromes.

Dr. Zeidan brings a tremendous skill set to his new position. He is an accomplished clinician, clinical and translational investigator, mentor, and educator. He is bright, insightful, and dedicated. He is passionate about making a difference for patients with hematologic malignancies. Dr. Zeidan is also committed to building a world-class hematologic malignancy program at Yale Cancer Center and Smilow Cancer Hospital. He enjoys the confidence of his colleagues in the leukemia, lymphoma, myeloma, and transplant groups, as well as the senior leadership in Yale Cancer Center, Smilow Cancer Hospital, and Yale School of Medicine. Of note, Dr. Zeidan will continue to lead the leukemia program and his position as Assistant Director in the Clinical Trials Office.

Please join us in welcoming Dr. Zeidan into this new role.

[LWS]

The ASCO poster is the perfect lead-in to the EHA oral paper (June 14th). The conclusions from ASCO will be expanded in detail.

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ASCO poster– Efficacy of imetelstat on red blood cell (RBC)-transfusion independence (TI) in the absence of platelet transfusions or myeloid growth factors in IMerge.

Some familiar names: Prof. Valeria Santini, Amer M. Zeidan, Uwe Platzbecker (from many authors)

Conclusions:

1/ Results from this subanalysis confirm that pts who achieve RBC-TI with imetelstat do so without developing severe neutropenia and thrombocytopenia (functionally defined as needing myeloid growth factors or platelet transfusions, respectively), therefore not negating the clinical benefit of the drug.

Comment: No severe effects. Clinical benefits of Imetelstat dominate.

2/ Imetelstat also led to significant rise in Hb levels in RBC-TI responders, particularly longterm responders.

Comment: Hb (Hemoglobin) levels rise (in many if not in all)

3/. These data further support the efficacy of imetelstat in TD pts with LR-MDS.

Comment: Imetelstat works in unique ways and is needed now.

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EHA Paper (June 14th, oral) --- OVERALL SURVIVAL, CLINICAL BENEFIT, AND DURABLE TRANSFUSION INDEPENDENCE WITH IMETELSTAT IN THE IMERGE

Some familiar names: Prof. Valeria Santini, Amer M. Zeidan, Uwe Platzbecker (from many authors)

Remember the EAP (Expanded Access Program) is still in place. John Scarlett said that this was equivalent to a phase 4 trial. This is a continuous source of USA data as we wait for the FDA to speak.

This is the tip of the iceberg for the Cancer Moonshot (NIH), and an important building block for developing new treatments and cures for all cancers.