Investing in stem cells, the building blocks of the body – MoneyWeek

Imagine being able to reverse blindness, cure multiple sclerosis (MS), or rebuild your heart muscles after a heart attack. For the past few decades, research into stem cells, the building blocks of tissues and organs, has raised the prospect of medical advances of this kind yet it has produced relatively few approved treatments. But that could be about to change, says Robin Ali, professor of human molecular genetics of Kings College London. Just as gene therapy went from being a fantasy with little practical value to becoming a major area of treatment, stem cells are within a few years of reaching the medical mainstream. Whats more, developments in synthetic biology, the process of engineering and re-engineering cells, could make stem cells even more effective.

Stem cells are essentially the bodys raw material: basic cells from which all other cells with particular functions are generated. They are found in various organs and tissues, including the brain, blood, bone marrow and skin. The primary promise of adult stem cells lies in regenerative medicine, says Professor Ali.

Stem cells go through several rounds of division in order to produce specialist cells; a blood stem cell can be used to produce blood cells and skin stem cells can be used to produce skin cells. So in theory you can take adult stem cells from one person and transplant them into another person in order to promote the growth of new cells and tissue.

In practice, however, things have proved more complicated, since the number of stem cells in a persons body is relatively limited and they are hard to access. Scientists were also previously restricted by the fact that adult stem cells could only produce one specific type of cell (so blood stem cells couldnt produce skin cells, for instance).

In their quest for a universal stem cell, some scientists initially focused on stem cells from human embryos, but that remains a controversial method, not only because harvesting stem cells involves destroying the embryo, but also because there is a much higher risk of rejection of embryonic stem cells by the recipients immune system.

The good news is that in 2006 Japanese scientist Shinya Yamanaka of Kyoto University and his team discovered a technique for creating what they call induced pluripotent stem cells (iPSC). The research, for which they won a Nobel Prize in 2012, showed that you can rewind adult stem cells development process so that they became embryo-like stem cells. These cells can then be repurposed into any type of stem cells. So you could turn skin stem cells into iPSCs, which could in turn be turned into blood stem cells.

This major breakthrough has two main benefits. Firstly, because iPSCs are derived from adults, they dont come with the ethical problems associated with embryonic stem cells. Whats more, the risk of the body rejecting the cells is much lower as they come from another adult or are produced by the patient. In recent years scientists have refined this technique to the extent that we now have a recipe for making all types of cells, as well as a growing ability to multiply the number of stem cells, says Professor Ali.

Having the blueprint for manufacturing stem cells isnt quite enough on its own and several barriers remain, admits Professor Ali. For example, we still need to be able to manufacture large numbers of stem cells at a reasonable cost. Ensuring that the stem cells, once they are in the recipient, carry out their function of making new cells and tissue remains a work in progress. Finally, regulators are currently taking a hard line towards the technology, insisting on exhaustive testing and slowing research down.

The good news, Professor Ali believes, is that all these problems are not insurmountable as scientists get better at re-engineering adult cells (a process known as synthetic biology). The costs of manufacturing large numbers of stem cells are falling and this can only speed up as more companies invest in the area. There are also a finite number of different human antigens (the parts of the immune system that lead a body to reject a cell), so it should be possible to produce a bank of iPSC cells for the most popular antigen types.

While the attitude of regulators is harder to predict, Professor Ali is confident that it needs only one major breakthrough for the entire sector to secure a large amount of research from the top drug and biotech firms. Indeed, he believes that effective applications are likely in the next few years in areas where there are already established transplant procedures, such as blood transfusion, cartilage and corneas. The breakthrough may come in ophthalmology (the treatment of eye disorders) as you only need to stimulate the development of a relatively small number of cells to restore someones eyesight.

In addition to helping the body repair its own tissues and organs by creating new cells, adult stem cells can also indirectly aid regeneration by delivering other molecules and proteins to parts of the body where they are needed, says Ralph Kern, president and chief medical officer of biotechnology company BrainStorm Cell Therapeutics.

For example, BrainStorm has developed NurOwn, a cellular technology using peoples own cells to deliver neurotrophic factors (NTFs), proteins that can promote the repair of tissue in the nervous system. NurOwn works by modifying so-called Mesenchymal stem cells (MSCs) from a persons bone marrow. The re-transplanted mesenchymal stem cells can then deliver higher quantities of NTFs and other repair molecules.

At present BrainStorm is using its stem-cell therapy to focus on diseases of the brain and nervous system, such as amyotrophic lateral sclerosis (ALS, also known as Lou Gehrigs disease), MS and Huntingtons disease. The data from a recent final-stage trial suggests that the treatment may be able to halt the progression of ALS in those who have the early stage of the disease. Phase-two trial (the second of three stages of clinical trials) of the technique in MS patients also showed that those who underwent the treatment experienced an improvement in the functioning of their body.

Kern notes that MSCs are a particularly promising area of research. They are considered relatively safe, with few side effects, and can be frozen, which improves efficiency and drastically cuts down the amount of bone marrow that needs to be extracted from each patient.

Because the manufacture of MSC cells has become so efficient, NurOwn can be used to get years of therapy in one blood draw. Whats more, the cells can be reintroduced into patients bodies via a simple lumbar puncture into the spine, which can be done as an outpatient procedure, with no need for an overnight stay in hospital.

Kern emphasises that the rapid progress in our ability to modify cells is opening up new opportunities for using stem cells as a molecular delivery platform. Through taking advantage of the latest advances in the science of cellular therapies, BrainStorm is developing a technique to vary the molecules that its stem cells deliver so they can be more closely targeted to the particular condition being treated. BrainStorm is also trying to use smaller fragments of the modified cells, known as exosomes, in the hope that these can be more easily delivered and absorbed by the body and further improve its ability to avoid immune-system reactions to unrelated donors. One of BrainStorms most interesting projects is to use exosomes to repair the long-term lung damage from Covid-19, a particular problem for those with long Covid-19. Early preclinical trials show that modified exosomes delivered into the lungs of animals led to remarkable improvements in their condition. This included increasing the lungs oxygen capacity, reducing inflammation, and decreasing clotting.

Overall, while Kern admits that you cant say that stem cells are a cure for every condition, there is a lot of evidence that in many specific cases they have the potential to be the best option, with fewer side effects. With Americas Food and Drug Administration recently deciding to approve Biogens Alzheimers drug, Kern thinks that they have become much more open to approving products in diseases that are currently considered untreatable. As a result, he thinks that a significant number of adult stem-cell treatments will be approved within the next five to ten years.

Adult stem cells and synthetic biology arent just useful in treatments, says Dr Mark Kotter, CEO and founder of Bit Bio, a company spun out of Cambridge University. They are also set to revolutionise drug discovery. At present, companies start out by testing large numbers of different drug combinations in animals, before finding one that seems to be most effective. They then start a process of clinical trials with humans to test whether the drug is safe, followed by an analysis to see whether it has any effects.

Not only is this process extremely lengthy, but it is also inefficient, because human and animal biology, while similar in many respects, can differ greatly for many conditions. Many drugs that seem promising in animals end up being rejected when they are used on humans. This leads to a high failure rate. Indeed, when you take the failures into account, it has been estimated that it may cost as much to around $2bn to develop the typical drug.

As a result, pharma companies are now realising that you have to insert the human element at a pre-clinical stage by at least using human tissues, says Kotter. The problem is that until recently such tissues were scarce, since they were only available from biopsies or surgery. However, by using synthetic biology to transform adult stem cells from the skin or other parts of the body into other types of stem cells, researchers can potentially grow their own cells, or even whole tissues, in the laboratory, allowing them to integrate the human element at a much earlier stage.

Kotter has direct experience of this himself. He originally spent several decades studying the brain. However, because he had to rely on animal tissue for much of his research he became frustrated that he was turning into a rat doctor.

And when it came to the brain, the differences between human and rat biology were particularly stark. In fact, some human conditions, such as Alzheimers, dont even naturally appear in rodents, so researchers typically use mice and rats engineered to develop something that looks like Alzheimers. But even this isnt a completely accurate representation of what happens in humans.

As a result of his frustration, Kotter sought a way to create human tissues. It initially took six months. However, his company, Bit Bio, managed to cut costs and greatly accelerate the process. The companys technology now allows it to grow tissues in the laboratory in a matter of days, on an industrial scale. Whats more, the tissues can also be designed not just for particular conditions, such as dementia and Huntingdons disease, but also for particular sub-types of diseases.

Kotter and Bit Bio are currently working with Charles River Laboratories, a global company that has been involved in around 80% of drugs approved by the US Food and Drug Administration over the last three years, to commercialise this product. They have already attracted interest from some of the ten largest drug companies in the world, who believe that it will not only reduce the chances of failure, but also speed up development. Early estimates suggest that the process could double the chance of a successful trial, effectively cutting the cost of each approved drug by around 50% from $2bn to just $1bn. This in turn could increase the number of successful drugs on the market.

Two years ago my colleague Dr Mike Tubbs tipped Fate Therapeutics (Nasdaq: FATE). Since then, the share price has soared by 280%, thanks to growing interest from other drug companies (such as Janssen Biotech and ONO Pharmaceutical) in its cancer treatments involving genetically modified iPSCs.

Fate has no fewer than seven iPSC-derived treatments undergoing trials, with several more in the pre-clinical stage. While it is still losing money, it has over $790m cash on hand, which should be more than enough to support it while it develops its drugs.

As mentioned in the main story, the American-Israeli biotechnology company BrainStorm Cell Therapeutics (Nasdaq: BCLI) is developing treatments that aim to use stem cells as a delivery mechanism for proteins. While the phase-three trial (the final stage of clinical trials) of its proprietary NurOwn system for treatment of Amyotrophic lateral sclerosis (ALS, or Lou Gehrigs disease) did not fully succeed, promising results for those in the early stages of the disease mean that the company is thinking about running a new trial aimed at those patients. It also has an ongoing phase-two trial for those with MS, a phase-one trial in Alzheimers patients, as well as various preclinical programmes aimed at Parkinsons, Huntingtons, autistic spectrum disorder and peripheral nerve injury. Like Fate Therapeutics, BrainStorm is currently unprofitable.

Australian biotechnology company Mesoblast (Nasdaq: MESO) takes mesenchymal stem cells from the patient and modifies them so that they can absorb proteins that promote tissue repair and regeneration. At present Mesoblast is working with larger drug and biotech companies, including Novartis, to develop this technique for conditions ranging from heart disease to Covid-19. Several of these projects are close to being completed.

While the US Food and Drug Administration (FDA) controversially rejected Mesoblasts treatment remestemcel-L for use in children who have suffered from reactions to bone-marrow transplants against the advice of the Food and Drug Administrations own advisory committee the firm is confident that the FDA will eventually change its mind.

One stem-cell company that has already reached profitability is Vericel (Nasdaq: VCEL). Vericels flagship MACI products use adult stem cells taken from the patient to grow replacement cartilage, which can then be re-transplanted into the patient, speeding up their recovery from knee injuries. It has also developed a skin replacement based on skin stem cells.

While earnings remain relatively small, Vericel expects profitability to soar fivefold over the next year alone as the company starts to benefit from economies of scale and runs further trials to expand the range of patients who can benefit.

British micro-cap biotech ReNeuron (Aim: RENE) is developing adult stem-cell treatments for several conditions. It is currently carrying out clinical trials for patients with retinal degeneration and those recovering from the effects of having a stroke. ReNeuron has also developed its own induced pluripotent stem cell (iPSC) platform for research purposes and is seeking collaborations with other drug and biotech companies.

Like other small biotech firms in this area, it is not making any money, so it is an extremely risky investment although the rewards could be huge if any of its treatments show positive results from their clinical trials.

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Investing in stem cells, the building blocks of the body - MoneyWeek

Catalent to Acquire RheinCell Therapeutics, Strengthening a Path Towards Industrialization of Induced Pluripotent Stem Cell-based Therapies – PR Web

RheinCell's facility in Langenfeld, near Dsseldorf, Germany

SOMERSET, N.J. (PRWEB) June 24, 2021

Catalent, the leading global provider of advanced delivery technologies, development, and manufacturing solutions for drugs, biologics, cell and gene therapies, and consumer health products, today announced that it has reached an agreement to acquire RheinCell Therapeutics GmbH, a developer and manufacturer of GMP-grade human induced pluripotent stem cells (iPSCs). Upon completion, the acquisition will build upon Catalents existing custom cell therapy process development and manufacturing capabilities with proprietary GMP cell lines for iPSC-based therapies. The deal will enable Catalent to offer the building blocks to scale iPSC-based cell therapies while reducing barriers to entry to the clinic for therapeutic companies and is expected to close before the end of 2021, subject to customary conditions. Financial details of the transaction have not been disclosed.

iPSCs are cells that can be differentiated into various cell types to address a wide range of therapeutic indications. Founded in 2017, RheinCell has undertaken significant research and development of full GMP human leukocyte antigen (HLA)-matched cell banks with superior genomic integrity, as well as investing in development-scale operational capabilities. RheinCell is based in Langenfeld, near Dsseldorf, Germany. Upon closing, RheinCells current employees will join Catalents Cell & Gene Therapy business.

We formed RheinCell based on our deep scientific and regulatory expertise in the promising field of cell-based therapies, commented Juergen Weisser, Chief Executive Officer, RheinCell Therapeutics. He added, We are convinced Catalent will be able to substantially accelerate RheinCells future growth and help to support customers around the globe that are interested in our GMP-grade iPSC lines and iPSC-based services to feed their development pipelines in this exciting and highly demanding new therapeutic field.

By offering a renewable, and standardized, source of cells for further product development, iPSCs have the potential to be a disruptive technology that could fuel the development of the next generation of cell therapies and substantially enhance the ability to manufacture at scale, said Julien Meissonnier, Vice President and Chief Scientific Officer, Catalent. He added, Catalent is committed to building a full-scale value chain for emerging modalities and accelerating their path to market through expertise and innovation. This acquisition further strengthens Catalents position in these new therapeutic areas, by pioneering tools and techniques to substantially advance scale-up to meet the demands of clinical and commercial manufacturing.

This latest acquisition fuels the extraordinary growth of Catalent Cell & Gene Therapy, and the expertise and deep knowledge in iPSC cell lines that RheinCell brings will immediately boost our cell therapy portfolio, allowing us to offer iPSC banks to our customers as a premium source for their therapeutic development pathway, said Manja Boerman, Ph.D., President, Catalent Cell & Gene Therapy. She added, The addition of the RheinCell team to our growing cell therapy network will create an opportunity to share cutting-edge expertise across our global centers of excellence.

Since 2020, Catalent has invested in its cell therapy capabilities with four strategic expansions at its Gosselies, Belgium, campus the location of its European Center of Excellence for cell and gene therapy. Together with its U.S. cell and gene therapy facilities across Texas and Maryland, Catalent continues to increase its clinical and commercial-scale manufacturing capabilities across the full range of cell and gene therapy activity.

About RheinCell Therapeutics GmbH RheinCell develops and manufactures GMP-grade human induced pluripotent stem cells (iPSCs) for the next generation of cell therapies. Its production pipeline focuses on high immune compatibility and low rejection potential, with a spotlight on solutions for off-the-shelf, allogenic therapeutics. RheinCell provides exclusive access to clinically approved and consented cord blood cells, proprietary cell reprogramming protocols, state-of-the-art cleanroom and cell culture facilities, GMP-compliant manufacturing processes, and a first-class community of iPSC workflow experts who also develop GMP-compliant differentiation protocols in close cooperation with customers. For more information, visit http://www.rheincell.de

About Catalent Cell & Gene Therapy Catalent Cell & Gene Therapy is an industry-leading technology, development, and manufacturing partner for advanced therapeutics. Its comprehensive cell therapy portfolio includes a wide range of expertise across a variety of cell types including CAR-T, TCR, TILs, NKs, iPSCs, and MSCs. With deep expertise in viral vector development, scale-up and manufacturing for gene therapies, Catalent is a full-service partner for plasmid DNA, adeno-associated viral (AAV), lentiviral and other viral vectors, oncolytic viruses, and live virus vaccines. An experienced and innovative partner, Catalent Cell & Gene Therapy has a global network of dedicated, small- and large-scale clinical and commercial manufacturing facilities, including an FDA-licensed viral vector facility, and fill/finish capabilities located in both the U.S. and Europe.

About Catalent Catalent is the leading global provider of advanced delivery technologies, development, and manufacturing solutions for drugs, biologics, cell and gene therapies, and consumer health products. With over 85 years serving the industry, Catalent has proven expertise in bringing more customer products to market faster, enhancing product performance and ensuring reliable global clinical and commercial product supply. Catalent employs over 15,000 people, including approximately 2,400 scientists and technicians, at more than 45 facilities, and in fiscal year 2020 generated over $3 billion in annual revenue. Catalent is headquartered in Somerset, New Jersey. For more information, visit http://www.catalent.com

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Catalent to Acquire RheinCell Therapeutics, Strengthening a Path Towards Industrialization of Induced Pluripotent Stem Cell-based Therapies - PR Web

Discrepancies Between Real-World Patterns of Care and Recommendations Based on Clinical Trials Exist in MCL – OncLive

Results from a retrospective, observational study, presented during the 2021 ASCO Annual Meeting, showed that such discrepancies were notable in patients aged 65 years and younger, in that only 30.5% were treated with a cytarabine-containing chemotherapy regimen, and 23.3% underwent stem cell transplant. Additionally, among patients who were aged 65 years or older, approximately 65% received treatment with bendamustine and rituximab (Rituxan) or R-CHOP.

Moreover, the real-world median time to next treatment for patients younger than 65 years was 28 months and 22.3 months in patients older than 65 years, which appeared worse than what has been reported with standard therapies in this population. These results suggest a need to focus on developing treatments that can be delivered effectively in the real-world setting, according to Martin.

MCL is clearly a complicated [disease], and many different presentations and patient factors are worth consideration. Community physicians have their work cut out for them when they are dealing with someone who has MCL, Martin said. Fortunately, there are many who are willing to help, and more educational programs than ever before. Many of us who work in community or academic practices are easy to get ahold of and happy to see someone, talk to them, and give them [our opinions].

In an interview with OncLive, Martin, chief of the Lymphoma Program at the Meyer Cancer Center and an associate professor of medicine at Weill Cornell Medicine, discussed discrepancies in real-world patterns of care for patients with MCL and what can be done to overcome them.

Martin: Over the past decade, we have seen some significant improvements in the outcomes of patients with MCL who are treated in the context of clinical trials. This, of course, [includes] generally younger patients treated with more intensive induction, consolidation, and maintenance strategies, [as well as] older patients treated with bendamustine and rituximab-based strategies. [However,] we know very little about how patients in the real world are managed in the United States, particularly those who are [receiving care] outside of major academic centers. We performed this study to evaluate patterns of care.

Additionally, we were interested in the treatment outcomes of patients treated with standard-of-care regimens outside of academic centers. Separately, we were interested in [knowing more about] the role that stem cell transplantation plays in younger patients.

This was a retrospective, observational study that used the Flatiron data set. The Flatiron group extracts medical records, in this case, for [patients with] MCL; this roughly [included] about 4000 patients treated from January 2011 to January 2021. Eighty percent of these patients were treated in community practice settings, and those data were then [plugged] into computer software, which helped us perform statistical analysis.

There were really 3 highlights. [First], we found that the practice patterns that you might expect based on clinical trials were not necessarily met [in clinical practice]. For example, among older patients, we found that [approximately] 40% were treated with bendamustine/rituximab-based therapy. Of the younger patients, only one-quarter were treated with high-dose cytarabine, and there might be different reasons for that. One reason might be that we have not done the best job of communicating with general practitioners about what kinds of therapies they should be using; that is one possible scenario. Another scenario is that many of the patients we are seeing in community practices are not the types of patients who were typically enrolling on clinical trials held at academic centers. Both of those, may play some role [in this discrepancy], and both have significant implications with respect to how we approach future research studies and educational programs.

Second, potentially related to that, we found that outcomes in patients in the Flatiron dataset were not consistent with the outcomes that we have found in clinical trials. They are, unfortunately, not as good. That [finding] suggests that we need to [consider] how we can develop treatment regimens that are likely to be administered more broadly and have the potential to be more effective.

Lastly, we defined a patient population who were stem cell transplant eligible; these were patients who were younger than 65 years of age and who had not received other lines of therapy within 6 months of treatment initiation. These were, theoretically, patients who responded to their induction treatment, and who could have gone on to receive a stem cell transplant. Interestingly, when we looked at those patients, no difference in outcomes associated with receipt of stem cell transplantation [was observed].

The most relevant finding is directed toward those who are designing clinical trials. When we design clinical trials, it is important for us to understand that these trials are being developed to treat patients who [will] be treated in the community. If we design regimens that cannot be delivered there, either because the patients [are] not being eligible for them, or we design something that is too complicated, then we have not done anyone any real favors. We need to think about that.

Another related question that we asked from the same data set was the role of rituximab maintenance therapy [on outcomes], particularly after bendamustine-based induction therapy. We know that rituximab maintenance after R-CHOPbased therapy in older patients has been associated with an improvement in overall survival [OS]. Similarly, rituximab maintenance after autologous stem cell transplant has been associated with an improvement in OS. There has only been 1 randomized trial after bendamustine induction therapy, and this was a very small trial with [approximately] 50 patients in each arm; it did not show a benefit in terms of either progression-free survival [PFS] or OS. That is, frankly, a little bit unexpected based on the other data that exist.

Since then, several groups around the world have attempted to look at observational, retrospective datasets, and that is exactly what we did here. Those data were presented at the 2021 EHA Virtual Congress and they do, in fact, suggest that there may be a benefit to rituximab maintenance therapy after bendamustine/rituximab induction.

That is also consistent with the data that we saw from the phase 2 E1411 trial [NCT01415752], which [examined] bendamustine/rituximab-based induction followed by rituximab-based maintenance [and showed that] the median PFS was approximately 5 years; that is a little bit better than what we would expect [to see] from bendamustine/rituximab, [which] would typically be more like 3 years. We may not have randomized trials, but from my perspective, if we do not have a reason to not treat someone with rituximab, then we probably should.

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Discrepancies Between Real-World Patterns of Care and Recommendations Based on Clinical Trials Exist in MCL - OncLive

Disparities in Utilization of Autologous Stem Cell Transplantation as Consolidative Therapy for Multiple Myeloma: A Single Institution Retrospective…

This article was originally published here

Clin Lymphoma Myeloma Leuk. 2021 May 25:S2152-2650(21)00149-X. doi: 10.1016/j.clml.2021.04.006. Online ahead of print.

ABSTRACT

BACKGROUND: Most guidelines recommend induction therapy followed by autologous hematopoietic cell transplantation. A Surveillance, Epidemiology, and End Results-Medicare database analysis from 2000 to 2011 noted a lower use of HCT and bortezomib among Black patients, despite adjusting for care barriers, and this practice was associated with a poorer outcome. The goal of this study was to evaluate patterns of acceptance of HCT as consolidative therapy for MM.

METHODS: Cox proportional hazards model was used to investigate the association between the survival time of the patients (overall survival) and age of the diagnosis, race, socioeconomic status, disease cytogenetic, and initial induction regimens. A total of 194 patients with a confirmed diagnosis of MM who were referred for HCT between January 1, 2009, and June 30, 2019, were included in this study. Patients who received autologous stem cell transplant for relapsed MM were excluded.

RESULTS: We found that income category was not significantly associated with overall survival, time to transplant or transplant-/relapse-related mortality. High-risk cytogenetic was significantly associated with shorter overall survival, higher transplant-related mortality and relapse-related mortality (P < .002). The use of aggressive induction choices was associated with poorer transplant outcomes (P = .02). Time to transplant tended to be shorter in African American compared with other ethnic groups (P = .07).

CONCLUSION: There was no significant difference in the use rate of the HCT between Caucasians and AA patients with MM. Further comparative studies of MM induction therapy and access to clinical trials in African Americans and other racial minorities are warranted.

PMID:34148850 | DOI:10.1016/j.clml.2021.04.006

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Vita Therapeutics Raises $32 Million in Oversubscribed Series A Financing Led by Cambrian Biopharma to Advance the Development of Therapies to Treat…

BALTIMORE, Md.--(BUSINESS WIRE)--Vita Therapeutics, a cell engineering company harnessing the power of genetics to develop cellular therapies that follow an autologous and universal hypoimmunogenic approach, today announced the completion of an oversubscribed $32 million Series A. The financing was led by Cambrian Biopharma with participation from Kiwoom Bio, SCM Life Sciences, and Early Light Ventures.

At Vita Therapeutics our mission is to deliver long-term disease-modifying cell engineered treatments for patients living with muscular dystrophies and other high unmet medical needs, said Douglas Falk, M.S., Chief Executive Officer of Vita Therapeutics. We are pleased this high-caliber group of new and existing investors share our enthusiasm and belief in Vitas ability to progress our innovative treatments to help these patients. This oversubscribed round of financing will enable the company to take the next steps toward achieving our mission.

"Cell therapies have two grand challenges - getting enough cells and differentiating them into the right cell type to make a long-term impact on a patient's disease," said James Peyer, PhD., newly appointed board member of Vita and Chief Executive Officer of Cambrian Biopharma. By mastering the transition from iPSC to muscle stem cell, Vita can make an unlimited amount of carefully defined muscle stem cells, which has never been possible before. I am so glad to count Vita as a Cambrian affiliate, and I have no doubt Vita will become a genre-defining cell therapy company.

Vitas lead therapy, VTA-100, is currently undergoing investigational new drug (IND)-enabling studies for the treatment of limb-girdle muscular dystrophy (LGMD) 2A/R1. It is designed to be an autologous treatment that combines gene correction and induced pluripotent stem cell (iPSC) technology to help repair and replace muscle cells. Vitas second therapeutic, VTA-200, is a genetically engineered iPSC derived hypoimmunogenic treatment designed to treat multiple types of muscular dystrophy.

The Series A financing will support the completion of all remaining IND-enabling studies for VTA-100 and its subsequent IND submission to the U.S. Food and Drug Administration. This funding will also support the manufacturing of cells needed for clinical evaluation as well as patient recruitment efforts for the first clinical trial. In addition, this financing will be used to further the development of VTA-200 and the development of VTA-300, an undisclosed cell type.

About Limb-Girdle Muscular Dystrophy

Limb-girdle muscular dystrophy (LGMD) is a group of disorders that cause weakness and wasting of muscles closest to the body (proximal muscles), specifically the muscles of the shoulders, upper arms, pelvic area, and thighs. The severity, age of onset, and disease progression of LGMD vary among the more than 30 known sub-types of this condition and may be inconsistent even within the same sub-type. As the atrophy and muscle weakness progresses, individuals with LGMD begin to have trouble lifting objects, walking, and climbing stairs, often requiring the use of assistive mobility devices. There is currently no cure for LGMD, with treatments limited to supportive therapies such as corticosteroids.

About Vita Therapeutics

Vita Therapeutics, a Cambrian Biopharma affiliate, is a cell engineering company harnessing the power of genetics to develop cellular therapies that follow a dual manufacturing strategy, first beginning autologously before moving to a universal hypoimmunogenic cell line. Vita was originally founded out of the labs of Dr. Gabsang Lee and Dr. Kathryn Wagner at Johns Hopkins University and the Kennedy Krieger Institute in 2019 by Douglas Falk, M.S. and Peter Andersen, PhD. The company utilizes induced pluripotent stem cell (iPSC) technology to engineer specific cell types designed to replace those that are defective in patients. We are currently working to progress our lead therapeutic, VTA-100, for the treatment of limb-girdle muscular dystrophy (LGMD), into clinical trials. For more information and important updates, please visit http://www.vitatx.com or follow us on Twitter @Vita_Tx and LinkedIn.

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Vita Therapeutics Raises $32 Million in Oversubscribed Series A Financing Led by Cambrian Biopharma to Advance the Development of Therapies to Treat...

Updates in the treatment of peripheral T-cell lymphomas | JEP – Dove Medical Press

Introduction

Peripheral T-cell Lymphomas (PTCLs) represent a relatively rare disease accounting for 610% of all cases of non-Hodgkin lymphomas (NHLs) in western countries.1 The incidence of PTCLs exhibits a geographical dependence, reaching 2025% of NHLs in some parts in Asia and South America.2 PTCLs constitute a heterogeneous group of hematologic malignancies that differ in clinical behavior and anatomical location. The World Health Organization (WHO) recognizes at least 29 distinct entities of mature post thymic T-cell NHLs in the updated classification of hematological and lymphoid neoplasms.3 The last classification proposed several provisional subtypes and introduced the T-follicular helper (TFH) phenotype. TFH lymphoma and nodal T-cell lymphoma with TFH phenotype are thus separate subtypes different from PTCLs not otherwise specified (PTCL-NOS). PTCLs could be anatomically classified as nodal, extranodal, cutaneous and leukemic forms (Table 1). The most frequent subtypes are PTCL-not otherwise specified (NOS) (30% of PTCLs), angioimmunoblastic T-cell lymphoma (AILT; 1530% of PTCLs), anaplastic large T-cell lymphoma (ALCL; 15% of PTCLs), extranodal natural killer (NK) cell/T cell lymphoma (ENKTCL; 10% of PTCLs), and intestinal T cell lymphomas (~56% of PTCLs, including enteropathy-associated T cell lymphoma (EATL) and monomorphic epitheliotropic intestinal T cell lymphoma (MEITL).4 Adult T-cell leukemia/lymphoma (ATLL) is most commonly diagnosed in countries with a high prevalence of human T-cell lymphotropic virus type 1 (HTLV-1) infection, especially in Japan and the Caribbean.5 The intrinsic variability of PTCLs and their scarcity had stymied progress in the treatment outcome. Despite the recent major advances in the understanding of PTCLs, including new laboratory methods for diagnosis and new therapeutic approaches, the prognosis of the majority of PTCLs remains poorer than with aggressive B-cell lymphoma, except for anaplastic lymphoma kinase (ALK)-positive ALCL. The 5-year overall survival (OS) for ALK+ ALCL, ALK- ALCL, AITL, and PTCL-NOS is 80.2%, 44.7%, 35.4%, and 25.4%, respectively.6 This review aims to discuss the molecular and genetic patterns of PTCLs, first-line treatment including bone marrow transplantation, as well as treatment of relapsed/refractory PTCLs and future therapeutic directions.

Table 1 Mature T-Cell and NK-Cell Neoplasm Based on the WHO 2016 Classification

As previously mentioned, there are 29 different subtypes of PTCLs according to the 2016 WHO classification. PTCL-NOS harbors no specific characteristic immunophenotype. However, two subgroups have been identified using the Gene Expression Profiles (GEPs) with different gene expression driven by the transcription factors TBX-21 or GATA-3. The GATA-3 PTCL-NOS subgroup has significantly poor survival outcomes.7,8

Patients with ALK+ ALCL most frequently present t(2;5) that fuses nucleophosmin gene (NPM) with the ALK gene leading to an oncogenic tyrosine kinase (NPM-ALK) that promotes signaling of the JAK/STAT pathway. GEPs showed hyperactivation of STAT3 in ALCL caused mainly by ALK rearrangements or activating mutations in the JAK/STAT pathway. Based on rearrangements revealed by cytogenetics, ALK negative patients could be classified into three groups: DUSP22 +, TP63 +, and triple negative group (ALK-, DUSP22- and TP63-). ALK-negative ALCLs have chromosomal rearrangements of DUSP22 or TP63 in 30% and 8% of the cases respectively. DUSP22-rearranged cases have favorable outcomes similarly to ALK+ ALCLs, whereas other genetic variants have inferior outcomes.9

The molecular profiling of other PTCLs revealed several mutations of genes involved in DNA methylation such as TET2, IDH2 and DNMT3.10 TET2 mutations have been described in 47% of patients with AITL, and in 38% of patients with PTCL-NOS. This high incidence in PTCL-NOS is probably related to the TFH phenotype being included in this subgroup in the previous 2008 WHO classification.11 Furthermore, 76% of patients with AITL have TET2 mutations.10 DNMT3A mutations occurred in 33% of patients with AITL, and are frequently associated with TET2 mutations (100% of the patients with reference to Odejide et al). IDH2 mutations, initially reported in patients with acute myeloid leukemia (AML) and Glioblastoma Multiforme, had also been found in 20 to 45% of patients with AITL, and were detected in different loci.12 Moreover, IDH2 mutations co-occur frequently with TET2 mutations.10 These mutations are highly reported in patients with AITL (67%), and less frequently in patients with PTCL-NOS (18%). RHOA mutations do not seem to have an epigenetic influence, despite being associated with T-cell proliferation and invasiveness.13,14 GEPs revealed multiple mutations in patients with ATLL such as RHOA, TET2, loss-of-function mutations in TP53, and overexpression of PD-L1.15

Other interesting mutations in PTCLs are those affecting T-cell receptor (TCR)-related genes such as PLCG1 (14%), CD28 (9%, exclusively in AITL), PI3K elements (7%), CTNNB1 (6%), and GTF2I (6%). More importantly, most variants in TCR-related genes represent gain-of-function mutations that could be addressed by new potential drugs.16

Activating mutations in TCR pathway genes had also been reported especially in patients with AITL and PTCL-NOS leading to lymphomagenesis by activating NF-kB pathway. The most common mutation leads to PLCG1 and was also described in CTCL.17

Due to the paucity of randomized clinical trials in this setting, no clear gold standard exists for the treatment of patients with newly diagnosed PTCLs. Treatment regimens are extrapolated from those initially developed in aggressive B-cell lymphoma. CHOP (cyclophosphamide, Adriamycin, vincristine and prednisolone) or CHOP-like regimens have been widely considered as the standard of care in patients with newly diagnosed PTCLs. Controlled studies are rare and the largest studies in PTCLs are retrospective. Up to one-third of patients with PTCLs may progress during first-line treatment.18 The adoption of CHOP regimen was initially based on the results of a large randomized phase III clinical trial of patients with high-grade and/or advanced stage B-cell or T-cell NHLs. This study compared CHOP with more dose-dense regimens (MACOP-B, ProMACE-CytaBOM and m-BACOD), and failed to demonstrate a significant benefit when compared to CHOP.19 Reyes et al found that ACVBP was superior to CHOP in patients with low-risk localized aggressive lymphoma.20 More intense chemotherapy regimens such as hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone followed by methotrexate and cytarabine) and DA-EPOCH (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) showed good results in terms of response rate and progression-free survival (PFS), but at the cost of higher myelosuppression rates leading to poor treatment adherence and early deaths.21,22 Retrospective and non-randomized studies suggested that the addition of etoposide to CHOP (CHOEP) in young and fit patients could be associated with a better outcome.23,24

More recently, the results of the first multicenter, double blind, randomized, placebo-controlled phase III trial in PTCLs were reported. The ECHELON-2 compared brentuximab vedotin (BV), cyclophosphamide, doxorubicin and prednisone (BV + CHP) with the standard CHOP regimen in previously untreated CD30+ PTCLs. The study met its primary endpoint of PFS, demonstrating the superiority of BV containing regimen. At a median follow-up of 36 months, BV + CHP was associated with significantly longer PFS than CHOP: 48.2 months (95% CI, 35.2-not reached) vs 20.4 months (95% CI, 12.747.6), with a hazard ratio 0.71 (95% CI, 0.540.93, p=0.0110). The 3-year PFS rate was 57.1% (95% CI, 49.963.7%) for the BV + CHP arm versus 44.4% (95% CI, 37.650.9%) for the CHOP arm. The two groups had similar adverse events, including incidence and severity of febrile neutropenia (41 [18%] patients in the BV + CHP group and 33 [15%] in the CHOP group) and peripheral neuropathy (117 [52%] in the BV + CHP group and 124 [55%] in the CHOP group).25 In addition, more than 70% of patients included in the trial had ALCL including ALK+ or ALK- disease, an entity characterized by high expression of CD30. Importantly, the inclusion criteria of the ECHELON-2 trial required an expression of at least 10% of CD30 on tumor cells. Based on the results of this trial, The Food and Drug Administration (FDA) approved the BV + CHP regimen in patients with CD30+ PTCLs in November 2018.26 Nowadays, most experts recognize BV + CHP treatment as standard of care for patients with any level CD30+ ALCL. However, the debate concerning the extrapolation of the results to other histologic subtypes continues since the ECHELON-2 trial was not powered enough to answer this question by performing histology-based subgroup analysis. In fact, the European Medicines Agency (EMA) restricted the approval of BV + CHP to the patients with CD30+ systemic ALCL only.

Histone deacetylase inhibitor (HDACi) romidepsin can be combined with CHOP in the first-line setting.27 It has been investigated in a phase III randomized double-blind trial in comparison with standard CHOP. The addition of romidepsin to CHOP did not improve PFS, the primary endpoint of the study. In addition, response rates and OS were similar with the combination.28 Other combinations are ongoing in for previously untreated PCTLs patients, and are summarized in Table 2.

Table 2 Novel Combinations Under Investigation in Previously Untreated PTCLs

The role of autologous stem cell transplantation (ASCT) in patients with PTCLs is controversial due to limited data, heterogeneous populations in the current studies, and the lack of randomized trials clearly evaluating ASCT procedure. ASCT has been investigated to prevent the high relapse rate in chemosensitive patients.29 The largest prospective studies based on cohort or registry were conducted by the Nordic Lymphoma Group, the German Group, Lysa French group, and United States of America group. The Nordic Lymphoma Group trial enrolled 160 patients with a confirmed diagnosis of PTCLs excluding those with ALK+ ALCL. Patients received 6 cycles of biweekly CHOEP-14 except for those aged 60 years and older who received CHOP-14. One hundred fifteen patients underwent ASCT. At a median follow-up of 60.5 months, OS rate was 51% and PFS rate was 44%. Patients with ALK ALCL had the highest OS and PFS (70% and 61%, respectively) compared with other histological subtypes (PTCL-NOS, AITL and EATL). The differences between the four groups were not statistically significant.30 In the German study, the second largest prospective trial reported by Reimer et al, 83 patients with newly diagnosed PTCLs were enrolled. Patients received 4 to 6 cycles of CHOP followed by mobilization, and those who were in CR or PR underwent myeloablative chemo-radiotherapy (fractionated total-body irradiation and high-dose cyclophosphamide) and ASCT. Fifty-five (66%) of the 83 patients received transplantation. The main reason for not receiving ASCT was progressive disease. At a median follow-up of 33 months, the estimated 3-year OS was 48% for the intention-to treat population. Failure to achieve CR was associated with markedly inferior results.31 More recently, the role of up-front ASCT in PTCLs for responders after induction was reported by the French LYSA study. Two hundred sixty-nine patients were analyzed; they had mostly PTCL-NOS, AITL, or ALK+ ALCL with partial (N = 52, 19%) or complete response (N = 217, 81%) after induction. One hundred and thirty-four patients were allocated to ASCT in ITT, and 135 were not. The median PFS was 3.7 years, and the median OS was 8.4 years for the entire cohort. No OS difference was observed according to histological subtype. The authors failed to depict a survival advantage in favor of ASCT as a consolidation procedure for patients who responded after induction. Subgroup analyses did not reveal any further difference for patients with respect to response status, stage disease, or risk category.29 Moreover, a large multi-center prospective study was reported from the COMPLETE registry (Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment).This cohort compared the survival outcomes in patients with nodal PTCLs who received or not consolidative ASCT in the upfront setting. The authors did not find any statistical difference in terms of survival between the ASCT and non-ASCT groups. They also suggested that subgroups of patients with nodal PTCLs, especially those with AITL and/or high-risk features (advanced-stage disease or intermediate-to-high IPI scores), might benefit from consolidative ASCT in terms of initial complete response.32

Collectively, these results did not sufficiently support the use of ASCT for up-front consolidation in patients with PTCLs in complete or partial response after induction therapy. The role of consolidative ASCT after first remission needs to be defined in prospective randomized trials.

Evidence for ASCT in the relapsed/refractory (R/R) setting is scarce and comes from registry data and retrospective studies. The results suggest that the outcomes could be improved with the use of consolidation HSCT, with the most benefiting group being the ALCL subtype, reaching a 3-years OS of 50% and a PFS of 65%.33 Data from the CIBMTR registry revealed no significant difference in survival between ASCT and allogenic stem cell transplantation (SCT), although a 34% TRM was reported with allogenic SCT by contrast to only 6% with ASCT.34 All these results show that SCT could be considered for eligible patients in the salvage setting and in chemotherapy-sensitive patients who have never had it before.

The role of allogenic SCT has been investigated recently by a randomized Phase 3 trial comparing ASCT and allogenic SCT as part of first-line therapy in poor-risk PTCL patients.35 Patients received conventional chemotherapy with 4 cycles of CHOEP and 1 cycle of DHAP followed by intensification. Patients were randomized to receive BEAM followed by ASCT or myeloablative conditioning (fludarabine, busulfan, cyclophosphamide) followed by allogenic SCT from a matched related or unrelated donor. One hundred and three patients were enrolled (ASCT: 54, allogenic SCT: 49), of whom 36 35%) could not proceed to transplantation mostly due to early disease progression. The 3-year event-free survival (EFS) and OS did not significantly differ between allogenic SCT and ASCT (EFS: 43% vs 38%, p=0.58, and 57% vs 70%, p=0.41 respectively). However, the treatment-related mortality (TRM) after allogenic SCT was 31%, with no reported deaths after ASCT. In younger patients with T-cell lymphoma, standard chemotherapy consolidated by either autologous or allogeneic transplantation result in comparable survival, thus eliminating a role for allogenic stem cell transplantation in the first-line setting.35 These results are in line with the retrospective analysis of the MD Anderson Cancer Center for patients with PTCLs that failed to show any difference in outcomes between ASCT and allogenic SCT. In addition, a CR prior to SCT initiation was associated with improved outcomes.36

In a prospective Phase II trial, Corradini et al evaluated the graft-versus-lymphoma effect of reduced-intensity conditioning (RIC) (thiotepa, cyclophosphamide and fludarabine) followed by allogenic SCT in relapsed PTCLs. Seventeen patients were enrolled, of whom two had chemo-refractory disease and 15 had relapsed disease. Eight patients (47%) had disease relapse after ASCT. Salvage therapy consisted of 4 to 6 cycles of DHAP followed by RIC and allogenic SCT. At a median follow-up of 28 months, the estimated 3-year OS and PFS rates were 81% and 64% respectively, and the transplantation-related mortality rate was 12%. Donor lymphocyte infusions induced a response in two patients progressing after transplantation, suggesting the existence of a graft-versus-lymphoma effect.37

Zain et al retrospectively reported the results of a case series of patients with R/R PTCLs, undergoing related or unrelated donors allogenic SCT between 2000 and 2007. Thirty-seven pretreated patients were enrolled, 68% (25 patients) of whom had either relapsed or progressive disease. All patients were ineligible for ASCT. Thirteen patients received fully ablative conditioning regimens, while 24 patients underwent reduced-intensity conditioning. The 5-year OS and PFS were 52.2% and 46.5%, respectively. At the time of analysis, nine (24.3%) patients had either relapsed (n = 6) or progressed (n = 3) post allogenic SCT. At 5 years, the cumulative incidences of non-relapse and relapse/progression mortality were 28.9% and 24.3%, respectively. There were no statistically significant predictors for survival or relapse by univariate Cox regression analysis of disease and patient characteristics; differences between CTCL and other histologies were not significant. The relapse/progression curves reached and maintained a plateau after 1 year post-transplant, demonstrating that long-term disease control is possible after allogenic SCT in patients with PTCLs with advanced disease.38 Collectively, these results indicate that allogenic SCT remains an option in patients with R/R PTCLs.

In relapsing patients, the subsequent treatment is not clearly defined. Conventional chemotherapy and/or autologous or allogenic SCT may result in disease control in a small number of patients. New drug development is the most promising way to improve survival for patients with R/R disease. Over the past decade, the FDA approved 4 new agents for the treatment of R/R PTCLs: pralatrexate, romidepsin, belinostat, and brentuximab vedotin. Two other drugs are approved in China and Japan. These molecules showed a single-agent activity based on the results of published phase II trials summarized in Table 3. However, the EMA did not recognize pralatrexate, romidepsin, and belinostat for the treatment of patients with PTCLs. In fact, these agents were associated with a good response rate, yet the PFS remains largely unchanged in this high risk group of patients.

Table 3 Approved Agents for the Treatment of PTCLs

Pralatrexate, a novel folate analogue metabolic inhibitor with high affinity for reduced folate carrier type 1 (RFC-1), was the first drug approved for the treatment of relapsed and/or refractory PTCLs in September 2009 based on the results of the PROPEL study (Pralatrexate in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma). Pralatrexate was given intravenously weekly at a dosage of 30mg/m2 for 6 weeks in a 7-week cycle. The ORR was 29%.39 Maruyama et al reported the results of a Japanese phase I/II trial evaluating pralatrexate in 20 patients with R/R PTCLs. The ORR was 45%, including two CR; median PFS was 150 days. The median duration of response (DOR) and OS were not reached, and the safety profile was comparable to the PROPEL study.40 More recently, Hong et al published the outcomes of a single-arm multicenter study of 71 patients with R/R PTCLs after a median of two previous treatment lines. The ORR was 52% with a median DOR of 8.7 months, median PFS of 4.8 months, and median OS of 18.0 months.41 This suggests that earlier treatment with pralatrexate may be associated with better clinical outcome.

Romidepsin is a bicyclic class 1 selective HDAC inhibitor. It has been isolated form Chromobacterium violaceum. In June 2011, the FDA approved romidepsin for the treatment of patients with R/R PTCLs who have progressed after at least one systemic therapy regimen. In a phase II trial conducted by the National Cancer Institute, the ORR with romidepsin in patients with R/R PTCLs was 38%, and the median DOR was 8.9 months.42 The pivotal registration-directed phase II trial enrolled 130 patients who were treated with romidepsin 14mg/m2 intravenously on days 1, 8 and 15 every 28-day cycle. Coiffier et al reported an ORR of 25% including 15% CR/CRu (unconfirmed CR) with a median PFS of 4 months and median DOR of 28 months among responders, leading to an accelerated FDA approval.43

Belinostat, a hydroxamic acid-derived pan-class I and II HDAC inhibitor, has also been approved by the FDA in July 2014 for the treatment of patients with R/R PTCLs who failed at least one previous treatment line. This was based on the results of the pivotal phase II BELIEF trial, a multicenter open label trial of belinostat in patients with relapsed or refractory T-cell lymphoma. A total of 129 patients were enrolled and received 1000mg/m2 of belinostat on days 15 in 21-day cycles. The median number of previous treatment lines was 2, and the authors reported an ORR of 25.8% including 10.8% CRs. Patients with PTCL-NOS achieved an ORR of 23%, those with AITL had an ORR of 46%, and patients with ALK- ALCL had an ORR of 15%. The median DOR, PFS and OS were 13.6 months, 1.6 months, and 7.9 months, respectively.44

Chidamide is an oral class I/II HDAC inhibitor that has been studied in a pivotal Chinese phase II trial in patients with R/R PTCLs (mainly PTCL-NOS, ALCL, ENKTL, and AITL). Eighty-three patients had been enrolled and received chidamide 30 mg orally twice per week. The ORR was 28% including 14% of CR/CRu. The median PFS was 2.1 months and the median OS was 21.4 months.45 Based on these results, chidamide was approved only in China for the treatment of patients with R/R PTCLs.

Brentuximab vedotin is the fourth drug approved by the FDA for the treatment of patients with R/R ALCL in August 2011, and extended for primary CTCL and CD30-expressing Mycosis Fungoides in November 2017. In a pivotal phase II trial, BV was evaluated for patients with R/R systemic ALCL. It was administered intravenously as single-agent at a dose of 1.8mg/kg every 3 weeks for up to 16 cycles. Fifty-eight patients were enrolled; the ORR was 86% with 57% of CR, and the median PFS was 13.6 months. Among patients who achieved CR, 5-year OS was 79% and 5-year PFS was 57%.46 These data led to approval of BV in the USA, European Union, and Japan for patients with sALCL. Many ongoing trials are evaluating the combination of BV with other drugs in both relapsed and upfront settings.

Mogamulizumab is a defucosylated humanized IgG1 monoclonal antibody that targets CC chemokine receptor 4 (CCR4) which is mainly expressed in ALK- ALCL, PTCL-NOS, AITL, and transformed mycosis fungoides. It was approved in Japan for patients with R/R CCR4+ ATLL and cutaneous T-cell lymphoma based on the results of a multicenter phase II trial evaluating mogamulizumab for the treatment of patients with relapsed ATLL. The study enrolled 28 patients who received intravenous infusions of mogamulizumab once per week for 8 weeks at a dose of 1.0 mg/kg. The ORR was 50% including 30% of CR. Median PFS and OS were 5.2 months and 13.7 months, respectively.47 Furthermore, mogamulizumab was approved in the USA for the treatment of R/R mycosis fungoides and Sezary syndrome.

Crizotinib, an oral ALK-ROS1-MET inhibitor, was associated with an ORR of 90% in a pediatric study of 26 patients having R/R ALK+ ALCL with a good safety profile. Among the 23 patients who achieved a response, 39% maintained their response for at least 6 months, and 22% maintained their response for at least 12 months.48 Crizotinib was approved by the FDA for the treatment of patients with R/R ALK+ ALCL in children and young adults in January 2021.

Duvelisib, an oral PI3K-delta-gamma inhibitor was associated with an ORR of 50% in PTCL, and 31.6% in CTCL with 3 complete responses in a phase II trial when used as monotherapy for patients with R/R PTCLs.49 Everolimus, an oral mammalian target of rapamycin (mTOR) pathway inhibitor, given at 10 mg daily continuously resulted in an ORR of 44% in a phase II trial of 16 patients with R/R PTCL. The median PFS was 4.1 months and the median OS was 10.2 months. Six patients (38%) required a dose reduction to 5mg daily.50

Hypomethylating agents (HMAs), initially approved for the treatment of AML and myelodysplastic syndrome, have been studied in R/R PTCLs. HMAs are the pharmacologic counterbalance of epigenetics modified tumor by IDH2, TET2 and DNMT3A mutations.12 5-Azacitidine used as monotherapy at a dose of 75 mg/m2 subcutaneously for 7 consecutive days every 28-days cycle in patients with AITL was associated with an ORR of 75% (9/12) and CR rate of 50% (6/12). Patients presented durable responses with a median PFS and OS of 15 and 21 months, respectively.51 An ongoing phase III trial is comparing oral 5-Azacitidine with investigators choice therapy (romidepsin, bendamustine or gemcitabine) in patients with R/R AITL (NCT03593018).

Lenalidomide, an immunomodulatory agent targeting cereblon and aiolos/ikaros transcription factors and approved in B-cell NHL and multiple myeloma, has shown modest activity when used as monotherapy in the EXPECT phase II trial with an ORR of 22%.52 In patients with R/R ATLL, lenalidomide demonstrated clinically meaningful antitumor activity with an ORR of 42% including 4 CR and 1 unconfirmed CR in a multicenter phase II trial.53

Programmed death-ligand 1 (PD-L1) was mainly detected in AITL (>90%) and PTCL-NOS (3060%), and rarely in other subtypes.54 In NKTCL, PD-L1 expression ranged between 56 and 93% in different studies, while PD-1 level was consistently low.55 In addition, Kataoka et al demonstrated that PD-L1 amplifications represent a strong genetic predictor of worse outcomes in patients with both aggressive and indolent ATLL.56 The efficacy of nivolumab, a PD-1 inhibitor, was evaluated in a Phase I, open-label, dose-escalation, cohort expansion trial for the treatment of patients with R/R TCL. Twenty-three patients were enrolled. The ORR among these patients was 17%.57 In a retrospective case series, pembrolizumab, another PD-1 inhibitor, showed high efficacy (100%) in 7 patients with R/R NK/T cell lymphoma that relapsed after treatment with L-asparaginase. Complete response was observed in 5 patients (71%), and this was sustained after a median follow-up of 6 months.58 In a multicenter single-arm phase II trial, pembrolizumab given at a dosage of 200mg intravenously every three weeks, was evaluated for patients with R/R PTCLs. Of 18 enrolled patients, 13 were evaluable for the primary endpoint. The ORR was 33%, with 4 patients showing a CR. The median PFS was 3.2 months and the median OS was 10.6 months. The median duration of response was 2.9 months. Two of the 4 patients who presented CR remained in remission for at least 15 months. The trial was halted early after a preplanned interim futility analysis.59 PD-1 inhibitors had modest activity when used as monotherapy and these drugs could be more active when combined with another agent such as HDAC inhibitors, HMAs, or antifolates. Table 4 summarizes the major clinical trials evaluating novel combinations of immunotherapy in R/R PTCLs.

Table 4 Novel Combinations of Immunotherapy Under Investigation in R/R PTCLs

A new strategy was adopted for the treatment of patients with R/R PTCLs based on the combination of approved and non-approved medications in the field. Available data concerning these combinations are summarized in Table 5. However, most of these data are reported from small single-center studies without central pathology review.

Table 5 Experimental Combinations of Approved Agents in R/R PTCLs

Romidepsin is an HDAC inhibitor approved for R/R PTCLs. In preclinical models of PTCLs, romidepsin and pralatrexate showed a potent synergy in in-vitro and in-vivo models at dose levels of 50% of the maximal tolerated dose (MTD).60 Amengual et al reported the results of the first Phase I trial evaluating the combination of these two drugs to determine the MTD, pharmacokinetic profile, and response rate. Pralatrexate 25mg/m2 and romidepsin 12 mg/m2 administered concurrently every other week were recommended for the Phase 2 trial. In this phase I study, the ORR for all patients was 57% (13/23), whereas the response rate in patients with PTCLs was 71% (10/14), and 33% (3/9) in patients with B-cell lymphoma.61 The phase II trial is still ongoing (NCT01947140).

The combination of HDACi and HMAs could be a novel approach for the treatment of PTCLs, targeting the epigenetic dysregulation of the disease. Marchi et al demonstrated a marked synergy between HDACi and HMAs in preclinical models of PTCLs.62 The encouraging results of a multicenter phase I trial evaluating the combination of romidepsin and oral 5-Azacitidine in R/R PTCLs were recently reported. The ORR for all patients was 32%, for non-TCL was 10%, and 73% for patients with T-cell lymphoma. The CR rates were 23%, 5% and 55%, respectively. The MTD retained for phase 2 trial was 5-Azacitidine 300mg on days 1 to 14 and romidepsin 14mg/m2 on days 8, 15 and 22 of a 35-day cycle.63 The phase II trial is still ongoing (NCT01998035).

A novel interesting combination in the treatment of R/R PTCLs is the association of HDACi and duvelisib. The results of the phase I/II trial evaluating the association of duvelisib and romidepsin were reported in an abstract form by Horwitz et al The MTD of duvelisib was 75mg BID on days 1 to 28, given with romidepsin 10mg/m2 on days 1, 8 and 15 of a 28-day cycle. The ORR was 55%, and CR occurred in 27% of the patients. Grade 3 or higher adverse events were seen in 65% of patients.64 These results suggest that romidepsin + duvelisib could be a potential therapeutic strategy to be evaluated in larger studies.

Another experimental combination was the association of HDACi and proteasome inhibitors based on the activity and the efficacy of these two classes in PTCLs. Tan et al reported the results of a phase II trial evaluating the combination of panobinostat and bortezomib. Patients received 20 mg oral panobinostat three times a week and 13 mg/m(2) intravenous bortezomib two times a week, both for 2 of 3 weeks for up to eight cycles. The ORR was 43% (10 of 23 patients), and the CR rate was 22% (5 of 23 patients). However, the PFS was very limited, which can be attributed to the short response time in highly aggressive disease.65

The management of patients with PTCLs remains challenging, with slow progress being made in the field, and only few drugs are currently approved. This is mainly due to the rarity of the disease and its aggressiveness, much complicating trial recruitment. Furthermore, given the various biological and molecular patterns, and the increasingly precise dissection of the molecular and immunological abnormalities of the disease, international collaboration seems crucial, and pan T-cell lymphomas trials are more and more regarded as a failed strategy. Innovative drugs targeting epigenetic mechanisms, immune checkpoint modulations, CD30 and TCR abnormalities with cellular therapies portend much hope to improve the outcomes of these patients in the upcoming years.

Dr Jean-Marie Michot reports being a principal/sub-investigator of clinical trials for Abbvie, Amgen, Astex, AstraZeneca, Debiopharm, Lilly, Roche, and Xencor, during the conduct of the study. Dr Vincent Ribrag reports non-financial support from Astex, Abbvie, BMS, Sanofi, and Servier, grants and non-financial support from Argenx, personal fees from Gilead, Roche, Incyte, and Nanostring, and personal fees and non-financial support from MSD and AZ, during the conduct of the study. The authors report no other potential conflicts of interest for this work.

1. Vose J, Armitage J, Weisenburger D. International T-cell lymphoma project. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol. 2008;26(25):41244130. doi:10.1200/JCO.2008.16.4558

2. dAmore F, Gaulard P, Trmper L, et al. Peripheral T-cell lymphomas: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(Suppl 5):v108115. doi:10.1093/annonc/mdv201

3. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):23752390. doi:10.1182/blood-2016-01-643569

4. Fiore D, Cappelli LV, Broccoli A, Zinzani PL, Chan WC, Inghirami G. Peripheral T cell lymphomas: from the bench to the clinic. Nat Rev Cancer. 2020;20(6):323342. doi:10.1038/s41568-020-0247-0

5. Hermine O, Ramos JC, Tobinai KA. Review of new findings in adult T-cell leukemia-lymphoma: a focus on current and emerging treatment strategies. Adv Ther. 2018;35(2):135152. doi:10.1007/s12325-018-0658-4

6. Timmins MA, Wagner SD, Ahearne MJ. The new biology of PTCL-NOS and AITL: current status and future clinical impact. Br J Haematol. 2020;189(1):5466. doi:10.1111/bjh.16428

7. Iqbal J, Wright G, Wang C, et al. Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma. Blood. 2014;123(19):29152923. doi:10.1182/blood-2013-11-536359

8. Wang T, Feldman AL, Wada DA, et al. GATA-3 expression identifies a high-risk subset of PTCL, NOS with distinct molecular and clinical features. Blood. 2014;123(19):30073015. doi:10.1182/blood-2013-12-544809

9. Parrilla Castellar ER, Jaffe ES, Said JW, et al. ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes. Blood. 2014;124(9):14731480. doi:10.1182/blood-2014-04-571091

10. Odejide O, Weigert O, Lane AA, et al. A targeted mutational landscape of angioimmunoblastic T-cell lymphoma. Blood. 2014;123(9):12931296. doi:10.1182/blood-2013-10-531509

11. Lemonnier F, Couronn L, Parrens M, et al. Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters. Blood. 2012;120(7):14661469. doi:10.1182/blood-2012-02-408542

12. Marchi E, OConnor OA. The rapidly changing landscape in mature T-cell lymphoma (MTCL) biology and management. CA Cancer J Clin. 2020;70(1):4770. doi:10.3322/caac.21589

13. Palomero T, Couronn L, Khiabanian H, et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat Genet. 2014;46(2):166170. doi:10.1038/ng.2873

14. Sakata-Yanagimoto M, Enami T, Yoshida K, et al. Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat Genet. 2014;46(2):171175. doi:10.1038/ng.2872

15. Kataoka K, Nagata Y, Kitanaka A, et al. Integrated molecular analysis of adult T cell leukemia/lymphoma. Nat Genet. 2015;47(11):13041315. doi:10.1038/ng.3415

16. Vallois D, Dobay MPD, Morin RD, et al. Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell-derived lymphomas. Blood. 2016;128(11):14901502. doi:10.1182/blood-2016-02-698977

17. Rohr J, Guo S, Huo J, et al. Recurrent activating mutations of CD28 in peripheral T-cell lymphomas. Leukemia. 2016;30(5):10621070. doi:10.1038/leu.2015.357

18. Ghez D, Danu A, Ribrag V. Investigational drugs for T-cell lymphoma. Expert Opin Investig Drugs. 2016;25(2):171181. doi:10.1517/13543784.2016.1121994

19. Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkins lymphoma. N Engl J Med. 1993;328(14):10021006. doi:10.1056/NEJM199304083281404

20. Reyes F, Lepage E, Ganem G, et al. ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma. N Engl J Med. 2005;352(12):11971205. doi:10.1056/NEJMoa042040

21. Escaln MP, Liu NS, Yang Y, et al. Prognostic factors and treatment of patients with T-cell non-Hodgkin lymphoma: the M. D. Anderson Cancer Center experience. Cancer. 2005;103(10):20912098. doi:10.1002/cncr.20999

22. Maeda Y, Nishimori H, Yoshida I, et al. Dose-adjusted EPOCH chemotherapy for untreated peripheral T-cell lymphomas: a multicenter phase II trial of west-JHOG PTCL0707. Haematologica. 2017;102(12):20972103. doi:10.3324/haematol.2017.167742

23. Schmitz N, Trmper L, Ziepert M, et al. Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study Group. Blood. 2010;116(18):34183425. doi:10.1182/blood-2010-02-270785

24. Ellin F, Landstrm J, Jerkeman M, Relander T. Real-world data on prognostic factors and treatment in peripheral T-cell lymphomas: a study from the Swedish lymphoma registry. Blood. 2014;124(10):15701577. doi:10.1182/blood-2014-04-573089

25. Horwitz S, OConnor OA, Pro B, et al. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet. 2019;393(10168):229240. doi:10.1016/S0140-6736(18)32984-2

26. Research C for DE and FDA approves brentuximab vedotin for previously untreated sALCL and CD30-expressing PTCL. FDA; December 20, 2019. Available from: https://www.fda.gov/drugs/fda-approves-brentuximab-vedotin-previously-untreated-salcl-and-cd30-expressing-ptcl. Accessed January 9, 2021.

27. Dupuis J, Morschhauser F, Ghesquires H, et al. Combination of romidepsin with cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated patients with peripheral T-cell lymphoma: a non-randomised, phase 1b/2 study. Lancet Haematol. 2015;2(4):e160165. doi:10.1016/S2352-3026(15)00023-X

28. Bachy E, Camus V, Thieblemont C, et al. Final analysis of the ro-CHOP phase III study (conducted by LYSA): romidepsin plus CHOP in patients with peripheral T-cell lymphoma. Blood. 2020;136(Supplement 1):3233. doi:10.1182/blood-2020-134440

29. Fossard G, Broussais F, Coelho I, et al. Role of up-front autologous stem-cell transplantation in peripheral T-cell lymphoma for patients in response after induction: an analysis of patients from LYSA centers. Ann Oncol. 2018;29(3):715723. doi:10.1093/annonc/mdx787

30. dAmore F, Relander T, Lauritzsen GF, et al. Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01. J Clin Oncol. 2012;30(25):30933099. doi:10.1200/JCO.2011.40.2719

31. Reimer P, Rdiger T, Geissinger E, et al. Autologous stem-cell transplantation as first-line therapy in peripheral T-cell lymphomas: results of a prospective multicenter study. J Clin Oncol. 2009;27(1):106113. doi:10.1200/JCO.2008.17.4870

32. Park SI, Horwitz SM, Foss FM, et al. The role of autologous stem cell transplantation in patients with nodal peripheral T-cell lymphomas in first complete remission: report from COMPLETE, a prospective, multicenter cohort study. Cancer. 2019;125(9):15071517. doi:10.1002/cncr.31861

33. Abeyakoon C, van der Weyden C, Harrop S, et al. Role of haematopoietic stem cell transplantation in peripheral T-cell lymphoma. Cancers (Basel). 2020;12(11):3125. doi:10.3390/cancers12113125

34. Smith SM, Burns LJ, van Besien K, et al. Hematopoietic cell transplantation for systemic mature T-cell non-Hodgkin lymphoma. J Clin Oncol. 2013;31(25):31003109. doi:10.1200/JCO.2012.46.0188

35. Schmitz N, Truemper LH, Bouabdallah K, et al. A randomized phase 3 trial of auto vs. allo transplantation as part of first-line therapy in poor-risk peripheral T-NHL. Blood. 2020;(blood.2020008825). doi:10.1182/blood.2020008825

36. Beitinjaneh A, Saliba RM, Medeiros LJ, et al. Comparison of survival in patients with T cell lymphoma after autologous and allogeneic stem cell transplantation as a frontline strategy or in relapsed disease. Biol Blood Marrow Transplant. 2015;21(5):855859. doi:10.1016/j.bbmt.2015.01.013

37. Corradini P, Dodero A, Zallio F, et al. Graft-versus-lymphoma effect in relapsed peripheral T-cell non-Hodgkins lymphomas after reduced-intensity conditioning followed by allogeneic transplantation of hematopoietic cells. J Clin Oncol. 2004;22(11):21722176. doi:10.1200/JCO.2004.12.050

38. Zain J, Palmer JM, Delioukina M, et al. Allogeneic hematopoietic cell transplantation for peripheral T-cell NHL results in long-term disease control. Leuk Lymphoma. 2011;52(8):14631473. doi:10.3109/10428194.2011.574754

39. OConnor OA, Pro B, Pinter-Brown L, et al. Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol. 2011;29(9):11821189. doi:10.1200/JCO.2010.29.9024

40. Maruyama D, Nagai H, Maeda Y, et al. Phase I/II study of pralatrexate in Japanese patients with relapsed or refractory peripheral T-cell lymphoma. Cancer Sci. 2017;108(10):20612068. doi:10.1111/cas.13340

41. Hong X, Song Y, Huang H, et al. Pralatrexate in Chinese patients with relapsed or refractory peripheral T-cell lymphoma: a Single-Arm, Multicenter Study. Target Oncol. 2019;14(2):149158. doi:10.1007/s11523-019-00630-y

42. Piekarz RL, Frye R, Prince HM, et al. Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood. 2011;117(22):58275834. doi:10.1182/blood-2010-10-312603

43. Coiffier B, Pro B, Prince HM, et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol. 2012;30(6):631636. doi:10.1200/JCO.2011.37.4223

44. OConnor OA, Horwitz S, Masszi T, et al. Belinostat in patients with relapsed or refractory peripheral T-cell lymphoma: results of the Pivotal Phase II BELIEF (CLN-19) Study. J Clin Oncol. 2015;33(23):24922499. doi:10.1200/JCO.2014.59.2782

45. Shi Y, Dong M, Hong X, et al. Results from a multicenter, open-label, pivotal phase II study of chidamide in relapsed or refractory peripheral T-cell lymphoma. Ann Oncol. 2015;26(8):17661771. doi:10.1093/annonc/mdv237

46. Pro B, Advani R, Brice P, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012;30(18):21902196. doi:10.1200/JCO.2011.38.0402

47. Ishida T, Joh T, Uike N, et al. Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a multicenter phase II study. J Clin Oncol. 2012;30(8):837842. doi:10.1200/JCO.2011.37.3472

48. Moss YP, Voss SD, Lim MS, et al. Targeting ALK with crizotinib in pediatric anaplastic large cell lymphoma and inflammatory myofibroblastic tumor: a Childrens Oncology Group Study. J Clin Oncol. 2017;35(28):32153221. doi:10.1200/JCO.2017.73.4830

49. Horwitz SM, Koch R, Porcu P, et al. Activity of the PI3K-, inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma. Blood. 2018;131(8):888898. doi:10.1182/blood-2017-08-802470

50. Witzig TE, Reeder C, Han JJ, et al. The mTORC1 inhibitor everolimus has antitumor activity in vitro and produces tumor responses in patients with relapsed T-cell lymphoma. Blood. 2015;126(3):328335. doi:10.1182/blood-2015-02-629543

51. Lemonnier F, Dupuis J, Sujobert P, et al. Treatment with 5-azacytidine induces a sustained response in patients with angioimmunoblastic T-cell lymphoma. Blood. 2018;132(21):23052309. doi:10.1182/blood-2018-04-840538

52. Morschhauser F, Fitoussi O, Haioun C, et al. A phase 2, multicentre, single-arm, open-label study to evaluate the safety and efficacy of single-agent lenalidomide (Revlimid) in subjects with relapsed or refractory peripheral T-cell non-Hodgkin lymphoma: the EXPECT trial. Eur J Cancer. 2013;49(13):28692876. doi:10.1016/j.ejca.2013.04.029

53. Ishida T, Fujiwara H, Nosaka K, et al. Multicenter phase II study of lenalidomide in relapsed or recurrent adult T-cell leukemia/lymphoma: ATLL-002. J Clin Oncol. 2016;34(34):40864093. doi:10.1200/JCO.2016.67.7732

54. Krishnan C, Warnke RA, Arber DA, Natkunam Y. PD-1 expression in T-cell lymphomas and reactive lymphoid entities: potential overlap in staining patterns between lymphoma and viral lymphadenitis. Am J Surg Pathol. 2010;34(2):178189. doi:10.1097/PAS.0b013e3181cc7e79

55. Jo J-C, Kim M, Choi Y, et al. Expression of programmed cell death 1 and programmed cell death ligand 1 in extranodal NK/T-cell lymphoma, nasal type. Ann Hematol. 2017;96(1):2531. doi:10.1007/s00277-016-2818-4

56. Kataoka K, Iwanaga M, Yasunaga J-I, et al. Prognostic relevance of integrated genetic profiling in adult T-cell leukemia/lymphoma. Blood. 2018;131(2):215225. doi:10.1182/blood-2017-01-761874

57. Lesokhin AM, Ansell SM, Armand P, et al. Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a Phase Ib Study. J Clin Oncol. 2016;34(23):26982704. doi:10.1200/JCO.2015.65.9789

58. Kwong Y-L, Chan TSY, Tan D, et al. PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase. Blood. 2017;129(17):24372442. doi:10.1182/blood-2016-12-756841

59. Barta SK, Zain J, MacFarlane AW, et al. Phase II study of the PD-1 inhibitor pembrolizumab for the treatment of relapsed or refractory mature T-cell lymphoma. Clin Lymphoma Myeloma Leuk. 2019;19(6):356364.e3. doi:10.1016/j.clml.2019.03.022

60. Jain S, Jirau-Serrano X, Zullo KM, et al. Preclinical pharmacologic evaluation of pralatrexate and romidepsin confirms potent synergy of the combination in a murine model of human T-cell lymphoma. Clin Cancer Res. 2015;21(9):20962106. doi:10.1158/1078-0432.CCR-14-2249

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Updates in the treatment of peripheral T-cell lymphomas | JEP - Dove Medical Press

Novel Tafasitamab Combination Finds a Role in Second-line DLBCL Treatment – Targeted Oncology

Targeted OncologyTM: What are the approved treatment options for such a patient in the second-line setting? What disease characteristics would help to determine which regimen should be used?

SVOBODA: Once we would determine that the patient is not a candidate for transplant, the NCCN [National Comprehensive Cancer Network] guidelines [say that] the preferred regimens as of early 2021the next meeting is in September, so well have some other updatesare gemcitabine/oxaliplatin plus or minus rituximab [Rituxan] and polatuzumab vedotin [Polivy] plus or minus bendamustine plus or minus rituximab.1

The regimens [most oncologists are more] familiar with [include] dose-adjusted EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin] if the patient is not a transplant candidate in the second lineIm not sure where that would be, and Im not sure that people would use [this here]and CEOP [cyclophosphamide, etoposide, vincristine, prednisone], which is basically etoposide instead of erythromycin. Some of the other regimens that are mentioned [in the guidelines are] gemcitabine-based regimensthe GDP [gemcitabine, dexamethasone, carboplatin] and gemcitabine/vinorelbine. Rituximab monotherapy in the [older] or very fragile patients [has a] 20% response rate; and tafasitamab [Monjuvi] plus lenalidomide [Revlimid] is now approved for second line for those patients who are not eligible for autologous stem cell transplant [ASCT].

DLBCL is pretty heterogeneous, so we have been trying to always determine [if it is the] germinal center B-cell [GCB] origin or the nongerminal center activated B-cell [ABC] type. And for the nongerminal center type, which [is] CD10 negative, it seems that ibrutinib [Imbruvica] works particularly well, so its sometimes used in these more fragile patients as a monotherapy.

What is different about the novel agent tafasitamab?

Tafasitamab has been approved now for several months in combination with lenalidomide for adult patients with relapsed or refractory DLBCLthis can include the patients with lymphoma that transforms from, lets say, follicular or low-grade lymphoma and who are not eligible for ASCT.2

Tafasitamab is an antibody against CD19. For simplification purposes, you can think of [it as similar to rituximab] which is an anti-CD20 antibody, but this is an anti-CD19 monoclonal antibody. With rituximab or other monoclonal antibodies, the mechanism of action is binding the antibody to CD19-positive B cells, which causes direct cell death but also cell-mediated cytotoxicity and cellular phagocytosis.

Then I think the lenalidomide has synergy, in some ways, and potentiation of activity both in vivo and in vitro, and we know the lenalidomide can activate the T cells and natural killer cells. It can have activity alone, especially in the ABC subtype of DLBCL.

What data support the approval and use of this regimen in this setting?

So again, this is a combination. We know [that as a] single agent, tafasitamab may also have activity. It was fairly low activity in DLBCL, 25% or so, when it was studied as a monotherapy.3 But the interesting thing was that the patients who responded had a very nice, long duration of response [DOR] that lasted for quite some time. The median duration was around 20 months, so those were quite impressive data.

The study that was the basis for the FDA to approve tafasitamab with lenalidomide was a phase 2 study, single arm, open label [L-MIND trial; NCT02399085].4 It included about 80 patients with DLBCL. They were deemed not eligible for ASCT. Primary refractory patients were to be excluded initially, but some of the primary refractory patients got on the study.

Tafasitamab was given as an intravenous infusion, very similar to [rituximab], and its given weekly for the first 3 cycles for the first 3 months, with the asterisk [being] that, for the first cycle, they give the tafasitamab on day 1 and day 4so, Monday and Thursday, then another Monday, and then just on Mondays. For cycles 4 [through] 12, you would give it only twice a month, on day 1 and day 15, and you give the lenalidomide in the typical multiple myeloma dose25 mg per day, 3 weeks on, 1 week off.

This was done for a year for 12 cycles; and patients who had stable disease or better were allowed to continue on with tafasitamab maintenance, just twice a month, until progression. The primary end point was overall response; secondary end points were progression-free survival [PFS], DOR, safety, and biomarker analysis.

The 81 patients who were enrolled [had a] median age of 72, the majority had stage III or IV disease [75%], and the median [number of] prior lines of therapy was 2. They did sneak in some primary refractory patients, about 19%; those were the patients who didnt respond to their frontline [therapy]. There were also a few patients who had prior stem cell transplant. When you look at the GCB versus non-GCB [subtype], the majority were patients who were difficult to determine [67%], but it looked [like for patients for whom] we have the data, more had the non- GCB than the GCB [subtype]. The data [we have show that] the older the patients get, the more likely they are [to have] the non-GCB subtype.

What did the study findings show?

Response was pretty excellent for this situation. Again, this is in patients who are progressing after R-CHOP and are not candidates for transplant. There was a 43% complete response [CR] rate. I like the updated data from the 2-year follow-up, where the median DOR is 34 months. Thats pretty good3 years.5 There was partial response in 14 patients, or 17%; stable disease, 15%; progressive disease, 16%; not evaluable, 10%. The disease control rate was 74%. The Kaplan-Meier curves [for] DOR after 24 months of follow-up [show] pretty long durations, especially in the CR group, and so it looks like a good agent in that setting.

When you look at PFS rate at 1 year, its 50%. Median overall survival, which I think is quite important for this type of population, is 74% at 12 months and 18 months, 64%.4 With 2 years of follow-up, the median PFS was 16.2 months [and the] median overall survival was 31.6 months for all the patients.5

What was the safety profile like for the combination regimen?

The most common adverse events [AEs] were hematologic. I think that [the AEs are] not very different from the lenalidomide monotherapy. Im not sure whether there is a great mechanical or physiologic reason why the cytopenias, other than lymphopenia, would be clearly affected by the CD19 antibody. There were no deaths and no grade 5 hematologic or nonhematologic toxicities on the L-MIND study. There were definitely neutropenias, thrombocytopenias, but the numbers were fairly low.

There were a few episodes of neutropenic fever; there was 1 patient with agranulocytosis. Im not familiar with exactly what happened, but like with any treatment, you have to watch blood counts quite closely. Overall, the numbers look very good in terms of the AEs.

[For the] nonhematologic AEs, rashes we see with lenalidomide; diarrhea; fatiguedifficult to attribute to one or the otherbut overall, it was a well-tolerated [regimen].

In these older patients, the serious AEs that were found to be treatment related by investigator were about 19% of the patients15 out of 81. The serious AEs would [include] any hospitalization, for example, or longer [emergency department] visit, over 24 hours. These types of things happen over a year of active lymphoma. Twelve percent discontinued the combination due to AEs. So even though there were treatment-emergent AEs leading to death, that was defined by protocol. None were considered related to the study treatment, but they occurred during the treatment with this regimen. Im not sure exactly what details, but 4 patients out of the 81 died while on the study.

The combination had many more AEs than the tafasitamab alone, which is understandable because the combination has lenalidomide, [which] can cause cytopenias, anemia, and all of these other issues that we discussed already. For the tafasitamab monotherapy, there have been some cases of cytopenias, but its hard to know whether its just carried over, to some extent, from the lenalidomide. You could think, like with [rituximab] maintenance, whether you could have some increased infections. There were 2 cases of febrile neutropenia, but overall [it was] well tolerated.

References:

1. NCCN. Clinical Practice Guidelines in Oncology. B-cell lymphomas, version 3.2021. Accessed May 12, 2021. https://bit.ly/3geoS5N

2. FDA grants accelerated approval to tafasitamab-cxix for diffuse large B-cell lymphoma. FDA. Updated August 3, 2020. Accessed May 12, 2021. https://bit.ly/3bodb9v

3. Jurczak W, Zinzani PL, Hess G, et al. A phase IIa, open-label, multicenter study of single-agent tafasitamab (MOR208), an Fc-optimized anti-CD19 antibody, in patients with relapsed or refractory B-cell non-Hodgkins lymphoma: long-term follow-up, final analysis. Blood. 2019;134(suppl 1):4078. doi:10.1182/blood-2019-124297

4. Salles G, Duell J, Gonzlez Barca E, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol. 2020;21(7):978-988. doi:10.1016/S1470-2045(20)30225-4

5. Salles G, Duell J, Gonzlez Barca E, et al. Primary analysis results of the single arm phase II study of MOR208 plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma (L-MIND). Abstract presented at: 15th International Conference on Malignant Lymphoma; June 18-23, 2019; Lugano, Switzerland. Accessed April 15, 2021. https://bit.ly/3wZgJIt

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Novel Tafasitamab Combination Finds a Role in Second-line DLBCL Treatment - Targeted Oncology

Global Nerve Repair and Regeneration Devices Market to Reach $11. 8 Billion by 2026 – GlobeNewswire

New York, June 23, 2021 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Global Nerve Repair and Regeneration Devices Industry" - https://www.reportlinker.com/p05957490/?utm_source=GNW The rapid rise in the incidence of nerve injuries worldwide, increasing prevalence of various neurological disorders, especially in the expanding elderly population, and development of advanced technology-based nerve repair and regeneration products are fueling growth in the global market. The constant increase in incidence of nerve injuries is leading to high demand for nerve repair and regeneration products. The growing incidence of chronic nervous system disorders such as Parkinson`s and Alzheimer`s disease is also driving demand for nerve repair and regeneration procedures and devices. There is also increased funding for clinical trials aimed at development of effective and safe therapies for treatment of various neurological disorders. Initiatives such as stem cells in umbilical blood infusion for cerebral palsy; and the use of Polyethylene glycol (PEG) drug for promoting axonal fusion technique for repairing peripheral nerve injuries are favoring market growth.

- Amid the COVID-19 crisis, the global market for Nerve Repair and Regeneration Devices estimated at US$6.6 Billion in the year 2020, is projected to reach a revised size of US$11.8 Billion by 2026, growing at a CAGR of 10% over the analysis period. Neurostimulation & Neuromodulation Devices, one of the segments analyzed in the report, is projected to grow at a 9.7% CAGR to reach US$10.9 Billion by the end of the analysis period. After a thorough analysis of the business implications of the pandemic and its induced economic crisis, growth in the Biomaterials segment is readjusted to a revised 11.7% CAGR for the next 7-year period. This segment currently accounts for a 13.8% share of the global Nerve Repair and Regeneration Devices market. The neurostimulation and neuromodulation devices segment growth will be fueled by rising incidence of peripheral nerve injuries, development of technologically advanced products and favorable reimbursement scenario. Within the segment, internal neurostimulation and neuromodulation devices category is being driven due to the devices` ability to lower occurrence of post-surgical complications and reducing duration of hospitalization. Biomaterials segment is expected to witness high growth, driven by broadening application range, increased availability of government funding for innovations, and development of advanced products.

The U.S. Market is Estimated at $2.2 Billion in 2021, While China is Forecast to Reach $1.8 Billion by 2026

- The Nerve Repair and Regeneration Devices market in the U.S. is estimated at US$2.2 Billion in the year 2021. The country currently accounts for a 30.45% share in the global market. China, the world`s second largest economy, is forecast to reach an estimated market size of US$1.8 Billion in the year 2026 trailing a CAGR of 13% through the analysis period. Among the other noteworthy geographic markets are Japan and Canada, each forecast to grow at 7.7% and 8.8% respectively over the analysis period. Within Europe, Germany is forecast to grow at approximately 9.2% CAGR while Rest of European market (as defined in the study) will reach US$2 Billion by the end of the analysis period. Increasing incidence of neurological diseases and expanding geriatric population, increasing spending on healthcare sector, positive reimbursement framework and presence of several leading industry players are fueling growth in the North America region. Asia-Pacific is poised to grow at a robust pace, driven by sizeable patient pool, favorable healthcare initiatives and high unmet healthcare needs. The Asia-Pacific market is expected to gain from notable surge in aging population, increasing awareness regarding neurological disorders, and rising incidence of cancer and osteoporosis. Select Competitors (Total 61 Featured)

Read the full report: https://www.reportlinker.com/p05957490/?utm_source=GNW

CONTENTS

I. METHODOLOGY

II. EXECUTIVE SUMMARY

1. MARKET OVERVIEW Impact of Covid-19 and a Looming Global Recession 2020 Marked as a Year of Disruption & Transformation EXHIBIT 1: World Economic Growth Projections (Real GDP, Annual % Change) for 2019 to 2022 Global Nerve Repair & Regeneration Market Buckles under COVID- 19 Strain Covid-19 Patients in Prone Position Suffering Nerve Damage Bodes Well for Market Growth Nerve Repair and Regeneration Market Set for a Robust Growth Neurostimulation & Neuromodulation Devices Hold Commanding Slot in Nerve Repair & Regeneration Market Biomaterials to Exhibit Rapid Growth Nerve Repair and Regeneration Market by Application US and Europe Dominate the Market Asia-Pacific and other Emerging Regions Display Impressive Growth Potential Recent Market Activity

2. FOCUS ON SELECT PLAYERS

3. MARKET TRENDS & DRIVERS High Incidence of Neurological Disorders: A Key Market Driver EXHIBIT 2: Annual Incidence of Adult-Onset Neurologic Disorders in the US Effects of COVID-19 on the Nervous System Sheds Focus on Neuromodulation Applications Increasing Cases of Peripheral Nerve Injuries Drive the Nerve Repair and Regeneration Market Growing Number of Vehicular Accidents Drive the Peripheral Nerve injuries Repair Market Rising Geriatric Population and Subsequent Growth in Prevalence of Neurological Disorders EXHIBIT 3: Global Population Statistics for the 65+ Age Group in Million by Geographic Region for the Years 2019, 2025, 2035 and 2050 Growing Incidence of Neurodegenerative Diseases Propels the Market for Deep Brain Stimulation Devices EXHIBIT 4: Global Alzheimers Prevalence by Age Group EXHIBIT 5: Diagnosed Prevalence Cases of Parkinson?s Disease Across Select Countries EXHIBIT 6: Global DBS Market by Leading Player (2020E): Market Share Breakdown of Revenues for Medtronic, Boston Scientific, and Abbott Select Available Deep Brain Stimulation Devices Available in the Market Intensified Research Activity Across Various Neural Disciplines Induces Additional Optimism Stem Cell Therapy: A Promising Avenue for Nerve Repair and Regeneration Increasing Cases of Epilepsy Drives the Demand for Vagus Nerve Stimulation Devices EXHIBIT 7: Epilepsy Incidence by Type (2019): Percentage Share Breakdown for Idiopathic and Symptomatic Epilepsy EXHIBIT 8: Symptomatic Epilepsy Incidence by Type (2019): Percentage Share Breakdown of Congenital, Degenerative, Infective, Neoplastic, Trauma, and Vascular Epilepsy Spinal Cord Injuries Propel the Demand for Spinal Cord Stimulation Devices Recent Developments in Spinal Cord Injury Treatment Biomaterials (Nerve Conduits and Nerve Wraps) to Witness Rapid Growth New Biomaterials Pave the Way for Innovative Neurodegeneration Therapies Role of Nerve Conduits in the Treatment of Peripheral Nerve Injury Innovative Nerve Conduits from Stryker TENS (Transcutaneous electrical nerve stimulation devices) Market Witnesses Rapid Growth Non-Invasiveness of TMS (Transcranial Magnetic Stimulation) Propelling the adoption of TMS devices Nerve Grafts for Bridging Larger Nerve Gaps Role of Nerve Grafting in Treatment of Peripheral Nerve Injuries FDA-approved Nerve Tubes for Peripheral Nerve Repair

4. GLOBAL MARKET PERSPECTIVE Table 1: World Current & Future Analysis for Nerve Repair and Regeneration Devices by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 2: World Historic Review for Nerve Repair and Regeneration Devices by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 3: World 15-Year Perspective for Nerve Repair and Regeneration Devices by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets for Years 2012, 2020 & 2027

Table 4: World Current & Future Analysis for Neurostimulation & Neuromodulation Devices by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 5: World Historic Review for Neurostimulation & Neuromodulation Devices by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 6: World 15-Year Perspective for Neurostimulation & Neuromodulation Devices by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa for Years 2012, 2020 & 2027

Table 7: World Current & Future Analysis for Biomaterials by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 8: World Historic Review for Biomaterials by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 9: World 15-Year Perspective for Biomaterials by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa for Years 2012, 2020 & 2027

Table 10: World Current & Future Analysis for Neurostimulation & Neuromodulation Surgeries by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 11: World Historic Review for Neurostimulation & Neuromodulation Surgeries by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 12: World 15-Year Perspective for Neurostimulation & Neuromodulation Surgeries by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa for Years 2012, 2020 & 2027

Table 13: World Current & Future Analysis for Neurorrhaphy by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 14: World Historic Review for Neurorrhaphy by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 15: World 15-Year Perspective for Neurorrhaphy by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa for Years 2012, 2020 & 2027

Table 16: World Current & Future Analysis for Nerve Grafting by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 17: World Historic Review for Nerve Grafting by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 18: World 15-Year Perspective for Nerve Grafting by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa for Years 2012, 2020 & 2027

Table 19: World Current & Future Analysis for Stem Cell Therapy by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 20: World Historic Review for Stem Cell Therapy by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 21: World 15-Year Perspective for Stem Cell Therapy by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa for Years 2012, 2020 & 2027

Table 22: World Current & Future Analysis for Hospitals & Clinics by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 23: World Historic Review for Hospitals & Clinics by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 24: World 15-Year Perspective for Hospitals & Clinics by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa for Years 2012, 2020 & 2027

Table 25: World Current & Future Analysis for Ambulatory Surgery Centers by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 26: World Historic Review for Ambulatory Surgery Centers by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 27: World 15-Year Perspective for Ambulatory Surgery Centers by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa for Years 2012, 2020 & 2027

III. MARKET ANALYSIS

UNITED STATES Table 28: USA Current & Future Analysis for Nerve Repair and Regeneration Devices by Product - Neurostimulation & Neuromodulation Devices and Biomaterials - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 29: USA Historic Review for Nerve Repair and Regeneration Devices by Product - Neurostimulation & Neuromodulation Devices and Biomaterials Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 30: USA 15-Year Perspective for Nerve Repair and Regeneration Devices by Product - Percentage Breakdown of Value Sales for Neurostimulation & Neuromodulation Devices and Biomaterials for the Years 2012, 2020 & 2027

Table 31: USA Current & Future Analysis for Nerve Repair and Regeneration Devices by Application - Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 32: USA Historic Review for Nerve Repair and Regeneration Devices by Application - Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 33: USA 15-Year Perspective for Nerve Repair and Regeneration Devices by Application - Percentage Breakdown of Value Sales for Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy for the Years 2012, 2020 & 2027

Table 34: USA Current & Future Analysis for Nerve Repair and Regeneration Devices by End-Use - Hospitals & Clinics and Ambulatory Surgery Centers - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 35: USA Historic Review for Nerve Repair and Regeneration Devices by End-Use - Hospitals & Clinics and Ambulatory Surgery Centers Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 36: USA 15-Year Perspective for Nerve Repair and Regeneration Devices by End-Use - Percentage Breakdown of Value Sales for Hospitals & Clinics and Ambulatory Surgery Centers for the Years 2012, 2020 & 2027

CANADA Table 37: Canada Current & Future Analysis for Nerve Repair and Regeneration Devices by Product - Neurostimulation & Neuromodulation Devices and Biomaterials - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 38: Canada Historic Review for Nerve Repair and Regeneration Devices by Product - Neurostimulation & Neuromodulation Devices and Biomaterials Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 39: Canada 15-Year Perspective for Nerve Repair and Regeneration Devices by Product - Percentage Breakdown of Value Sales for Neurostimulation & Neuromodulation Devices and Biomaterials for the Years 2012, 2020 & 2027

Table 40: Canada Current & Future Analysis for Nerve Repair and Regeneration Devices by Application - Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 41: Canada Historic Review for Nerve Repair and Regeneration Devices by Application - Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 42: Canada 15-Year Perspective for Nerve Repair and Regeneration Devices by Application - Percentage Breakdown of Value Sales for Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy for the Years 2012, 2020 & 2027

Table 43: Canada Current & Future Analysis for Nerve Repair and Regeneration Devices by End-Use - Hospitals & Clinics and Ambulatory Surgery Centers - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 44: Canada Historic Review for Nerve Repair and Regeneration Devices by End-Use - Hospitals & Clinics and Ambulatory Surgery Centers Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 45: Canada 15-Year Perspective for Nerve Repair and Regeneration Devices by End-Use - Percentage Breakdown of Value Sales for Hospitals & Clinics and Ambulatory Surgery Centers for the Years 2012, 2020 & 2027

JAPAN Table 46: Japan Current & Future Analysis for Nerve Repair and Regeneration Devices by Product - Neurostimulation & Neuromodulation Devices and Biomaterials - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 47: Japan Historic Review for Nerve Repair and Regeneration Devices by Product - Neurostimulation & Neuromodulation Devices and Biomaterials Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 48: Japan 15-Year Perspective for Nerve Repair and Regeneration Devices by Product - Percentage Breakdown of Value Sales for Neurostimulation & Neuromodulation Devices and Biomaterials for the Years 2012, 2020 & 2027

Table 49: Japan Current & Future Analysis for Nerve Repair and Regeneration Devices by Application - Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 50: Japan Historic Review for Nerve Repair and Regeneration Devices by Application - Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 51: Japan 15-Year Perspective for Nerve Repair and Regeneration Devices by Application - Percentage Breakdown of Value Sales for Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy for the Years 2012, 2020 & 2027

Table 52: Japan Current & Future Analysis for Nerve Repair and Regeneration Devices by End-Use - Hospitals & Clinics and Ambulatory Surgery Centers - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 53: Japan Historic Review for Nerve Repair and Regeneration Devices by End-Use - Hospitals & Clinics and Ambulatory Surgery Centers Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 54: Japan 15-Year Perspective for Nerve Repair and Regeneration Devices by End-Use - Percentage Breakdown of Value Sales for Hospitals & Clinics and Ambulatory Surgery Centers for the Years 2012, 2020 & 2027

CHINA Table 55: China Current & Future Analysis for Nerve Repair and Regeneration Devices by Product - Neurostimulation & Neuromodulation Devices and Biomaterials - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 56: China Historic Review for Nerve Repair and Regeneration Devices by Product - Neurostimulation & Neuromodulation Devices and Biomaterials Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 57: China 15-Year Perspective for Nerve Repair and Regeneration Devices by Product - Percentage Breakdown of Value Sales for Neurostimulation & Neuromodulation Devices and Biomaterials for the Years 2012, 2020 & 2027

Table 58: China Current & Future Analysis for Nerve Repair and Regeneration Devices by Application - Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 59: China Historic Review for Nerve Repair and Regeneration Devices by Application - Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 60: China 15-Year Perspective for Nerve Repair and Regeneration Devices by Application - Percentage Breakdown of Value Sales for Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy for the Years 2012, 2020 & 2027

Table 61: China Current & Future Analysis for Nerve Repair and Regeneration Devices by End-Use - Hospitals & Clinics and Ambulatory Surgery Centers - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 62: China Historic Review for Nerve Repair and Regeneration Devices by End-Use - Hospitals & Clinics and Ambulatory Surgery Centers Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 63: China 15-Year Perspective for Nerve Repair and Regeneration Devices by End-Use - Percentage Breakdown of Value Sales for Hospitals & Clinics and Ambulatory Surgery Centers for the Years 2012, 2020 & 2027

EUROPE Table 64: Europe Current & Future Analysis for Nerve Repair and Regeneration Devices by Geographic Region - France, Germany, Italy, UK, Spain, Russia and Rest of Europe Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 65: Europe Historic Review for Nerve Repair and Regeneration Devices by Geographic Region - France, Germany, Italy, UK, Spain, Russia and Rest of Europe Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 66: Europe 15-Year Perspective for Nerve Repair and Regeneration Devices by Geographic Region - Percentage Breakdown of Value Sales for France, Germany, Italy, UK, Spain, Russia and Rest of Europe Markets for Years 2012, 2020 & 2027

Table 67: Europe Current & Future Analysis for Nerve Repair and Regeneration Devices by Product - Neurostimulation & Neuromodulation Devices and Biomaterials - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 68: Europe Historic Review for Nerve Repair and Regeneration Devices by Product - Neurostimulation & Neuromodulation Devices and Biomaterials Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 69: Europe 15-Year Perspective for Nerve Repair and Regeneration Devices by Product - Percentage Breakdown of Value Sales for Neurostimulation & Neuromodulation Devices and Biomaterials for the Years 2012, 2020 & 2027

Table 70: Europe Current & Future Analysis for Nerve Repair and Regeneration Devices by Application - Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 71: Europe Historic Review for Nerve Repair and Regeneration Devices by Application - Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 72: Europe 15-Year Perspective for Nerve Repair and Regeneration Devices by Application - Percentage Breakdown of Value Sales for Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy for the Years 2012, 2020 & 2027

Table 73: Europe Current & Future Analysis for Nerve Repair and Regeneration Devices by End-Use - Hospitals & Clinics and Ambulatory Surgery Centers - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 74: Europe Historic Review for Nerve Repair and Regeneration Devices by End-Use - Hospitals & Clinics and Ambulatory Surgery Centers Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 75: Europe 15-Year Perspective for Nerve Repair and Regeneration Devices by End-Use - Percentage Breakdown of Value Sales for Hospitals & Clinics and Ambulatory Surgery Centers for the Years 2012, 2020 & 2027

FRANCE Table 76: France Current & Future Analysis for Nerve Repair and Regeneration Devices by Product - Neurostimulation & Neuromodulation Devices and Biomaterials - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 77: France Historic Review for Nerve Repair and Regeneration Devices by Product - Neurostimulation & Neuromodulation Devices and Biomaterials Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 78: France 15-Year Perspective for Nerve Repair and Regeneration Devices by Product - Percentage Breakdown of Value Sales for Neurostimulation & Neuromodulation Devices and Biomaterials for the Years 2012, 2020 & 2027

Table 79: France Current & Future Analysis for Nerve Repair and Regeneration Devices by Application - Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 80: France Historic Review for Nerve Repair and Regeneration Devices by Application - Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 81: France 15-Year Perspective for Nerve Repair and Regeneration Devices by Application - Percentage Breakdown of Value Sales for Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy for the Years 2012, 2020 & 2027

Table 82: France Current & Future Analysis for Nerve Repair and Regeneration Devices by End-Use - Hospitals & Clinics and Ambulatory Surgery Centers - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 83: France Historic Review for Nerve Repair and Regeneration Devices by End-Use - Hospitals & Clinics and Ambulatory Surgery Centers Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 84: France 15-Year Perspective for Nerve Repair and Regeneration Devices by End-Use - Percentage Breakdown of Value Sales for Hospitals & Clinics and Ambulatory Surgery Centers for the Years 2012, 2020 & 2027

GERMANY Table 85: Germany Current & Future Analysis for Nerve Repair and Regeneration Devices by Product - Neurostimulation & Neuromodulation Devices and Biomaterials - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 86: Germany Historic Review for Nerve Repair and Regeneration Devices by Product - Neurostimulation & Neuromodulation Devices and Biomaterials Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 87: Germany 15-Year Perspective for Nerve Repair and Regeneration Devices by Product - Percentage Breakdown of Value Sales for Neurostimulation & Neuromodulation Devices and Biomaterials for the Years 2012, 2020 & 2027

Table 88: Germany Current & Future Analysis for Nerve Repair and Regeneration Devices by Application - Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Link:
Global Nerve Repair and Regeneration Devices Market to Reach $11. 8 Billion by 2026 - GlobeNewswire