Maintenance treatment with eprenetapopt, a novel drug, plus the chemotherapy Vidaza (azacitidine) following allogeneic hematopoietic stem cell transplantation was associated with improved survival outcomes in a group of patients with TP53-mutant, high-risk acute myeloid leukemia and myelodysplastic syndromes, according to new study findings.

Disease relapse is the primary reason why allogeneic hematopoietic stem cell transplants fail, according to the study authors, who noted that novel strategies for stem cell transplant to reduce the risk for disease relapse are severely needed.

Of note, an allogeneic hematopoietic stem cell transplant is a procedure where a patient with cancer receives healthy blood-forming stem cells from a donor to replace their own stem cells that have been damaged by other cancer treatments such as radiation or chemotherapy.

Currently, maintenance strategies (which are used to reduce the risk for disease recurrence) are not standard of care in allogeneic (hematopoietic stem cell transplant) for (acute myeloid leukemia and myelodysplastic syndromes), the study authors wrote.

In preclinical trials, eprenetapopt a small molecule drug that may reactivate mutant p53 proteins was active alongside Vidaza. Moreover, results from prior studies have shown the combination to be safe and effective in patients with other forms of blood cancers.

As a result, investigators aimed to see if maintenance therapy with eprenetapopt and Vidaza would induce similar results in this high-risk patient population.

They conducted a phase 2, multicenter trial to analyze if post-transplant eprenetapopt plus Vidaza improved relapse-free survival (which is the length of time following completion of primary treatment that a patient survives without signs or symptoms of that cancer). Based on prior results, the study investigators determined that a one-year relapse-free survival rate of 50% or greater would be considered successful.

A total of 84 patients were screened to determine if they were eligible for an allogeneic hematopoietic stem cell transplantation. Of the 55 patients who received a transplant, 33 patients (14 with acute myeloid leukemia and 19 with myelodysplastic syndromes) received maintenance treatment with eprenetapopt and Vidaza.

At a median follow-up of 14.5 months, maintenance therapy was associated with a median relapse-free survival of 12.5 months and an estimated one-year relapse-free survival rate of 59.9%. Additionally, the median overall survival (time from treatment to death of any cause) was 20.6 months at a median follow-up of 17 months. It was also estimated that the one-year overall survival rate was 78.8%.

Some of the most frequent severe or worse side effects to occur in the patient population included a decrease in white blood cell count (36%), anemia (27%) and hypertension (12%). There were four serious cases of fever and two serious cases each of febrile neutropenia (fever during a period of low white blood cell count) and difficult or labored breathing.

There were some occurrences of dose reduction (9%), interruption (6%) or delay (6%) because of treatment-related side effects.

Two patient deaths were reported during the study period one that was associated with a side effect not related to study treatment and one attributed to disease progression more than 30 days after study treatment completion.

TP53 mutation is associated with a poor prognosis in (acute myeloid leukemia) and (myelodysplastic syndromes), even in patients who undergo allogeneic (hematopoietic stem cell transplantation), the study authors wrote. Post-(hematopoietic stem cell transplantation) maintenance therapy with eprenetapopt plus (Vidaza) in this high-risk population of patients with TP53 mutant (acute myeloid leukemia) or (myelodysplastic syndromes) led to favorable survival outcomes. These data support future exploration of this maintenance strategy in a phase 3 study of eprenetapopt plus (Vidaza) versus placebo plus (Vidaza) in patients with TP53 mutant myeloid malignancies.

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Excerpt from:
Novel Drug-Chemotherapy Combo After Stem Cell Transplant Associated With 'Favorable Survival Outcomes' in Group of Rare Blood Cancers - Curetoday.com

Stephanie Si Lim

A therapy that helps modify a patients T cells (a type of immune cell) to make them more capable of fighting cancer was recently brought to Hawaii by Stephanie Si Lim, assistant professor at the University of Hawaii Cancer Center and pediatric hematologist oncologist at Kapiolani Medical Center for Women & Children. Chimeric Antigen Receptor T-cell therapy (CAR T-cell therapy) can result in the development of life-saving treatments for cancers that are difficult to treat.

Si Lim is leading the initiative at Kapiolani Medical Center for Women & Childrenpart of Hawaii Pacific Healthto build a broader cellular immunotherapy program. A key goal of the program is to introduce CAR T-cell therapy to the medical community in Hawaii in the form of clinical trials and U.S. FDA (Food and Drug Administration) approved products. This will ensure that patients have access to the best available treatments for cancer.

CAR T-cell therapy is now available to children and young adults with non-Hodgkin lymphoma and B-cell acute lymphoblastic leukemia, and will soon be available to adult patients.

The first CAR T-cell clinical trial opened on May 14, 2022, at Kapiolani Medical Center for Women & Children, leveraging the infrastructure and expertise of the hospitals stem cell transplant and clinical research programs. Moving forward, all patients living in Hawaii, including the neighbor islands who qualify for this clinical trial, will be able to receive treatment on Oahu without having to travel to the continental U.S.

Si Lim said, We are so excited to be able to offer CAR T-cell therapy to our patients here in Hawaii. This is a momentous step for our medical community as we continue to strive to offer the best and most cutting-edge therapies to patients in need.

Currently, CAR T-cell therapy is proven to be particularly effective against B-cell malignancies and multiple myelomaboth common forms of cancer in adults and pediatric populations in Hawaii. Over the next few years, it is expected that new FDA-approved CAR T-cell treatments will also be available for other cancers in the state, including breast and prostate.

Go here to see the original:
Broadening access to cancer fighting therapy led by UH researcher | University of Hawaii System News - University of Hawaii

ROBERT KITCHIN/Stuff

Joan Perry, left, presents ACT deputy leader Brooke van Velden, right, with the petition calling for stem cell therapy to be available for people with multiple sclerosis in New Zealand.

A 10,000-strong petition to Parliament on Tuesday asking Health New Zealand to extend game-changing stem cell treatment to multiple sclerosis (MS) patients has been delivered to Parliament.

The petition was presented to ACT deputy leader Brooke van Velden who will present it to Parliament. The group of about 20 who presented the petition were joined by Green MP Golriz Ghahraman who also has MS.

Aucklander Joan Perry, whose daughter Anne Besley has MS, started the petition which calls for autologous haematopoietic stem cell transplantation (aHSCT) to be made available for selected patients in New Zealand.

Doctors extract blood stem cells and grow them in a laboratory, before the patient undergoes chemotherapy to suppress their immune system. The blood stem cells are then re-introduced back to the body to restart the immune response and stop the disease from getting worse.

READ MORE:* People with multiple sclerosis unable to access 'life-changing' treatment in NZ* Multiple sclerosis patient calls for 'life-changing' treatment to be funded in NZ* Multiple sclerosis sufferer says stem cell treatment in India has 'saved her life'

Anne Besleys MS has gone into remission since her stem cell treatment in 2019.

At present, it is only available in New Zealand for blood cancer patients.

Advocates for the treatment say it is already proven and readily available in Australia and the UK for patients exhibiting early and aggressive symptoms.

Besley, a former operating theatre nurse at Aucklands Middlemore Hospital, had to go to India for the treatment in late 2019 at a cost of $42,000. Since then, her MS has gone into remission, allowing her to return to nursing part-time as a Covid-19 vaccinator.

It comes with huge financial and mental challenges, she said. Being isolated in a foreign country for a month is an emotional and physical struggle, especially when you are so weak while undergoing treatment and having a severely compromised immune system.

ROBERT KITCHIN/Stuff

Green MP Golriz Ghahraman (far left), who has MS, says she would consider the stem cell treatment if it is available in New Zealand. Right: Joan Perry, who started the petition calling for stem cell therapy to be made available for MS patients.

Ghahraman said she would consider stem cell treatment if it was available in New Zealand and hoped the petition would have an impact for public healthcare to provide the most effective options to everyone regardless of their means.

People are ruling it out because they know they cant afford it, she said. In New Zealand, its very few people who would ever be in a position to go.

Van Velden said New Zealand needed better oversight and transparency about the types of medicines and treatment that New Zealanders have access to.

I would like to see more forward planning in New Zealand about the newer medicines, she said. We are falling behind the rest of the world.

ROBERT KITCHIN/Stuff

Brooke van Velden, right, wants to see better forward planning for medicine and treatment options in New Zealand. Left: Petitioner Joan Perry.

Bronwyn Hutchison is a Wellington mother of two who was diagnosed with MS in 2011. She is already on drug-based treatment in New Zealand, meaning trips to hospital for infusions every six weeks and the side effects taking a physical toll.

Hutchison came across stem cell treatment in her research in 2019 after a painful relapse.

She attended a private clinic in Mexico to get the four-week treatment, but had to raise more than $100,000. There have been had been no relapses in the three years since.

I didnt have that money sitting around, she said. That was a year of my family and friends using all their spare time, and I was really lucky with the community support.

My daughter, who's now 9, is still recovering from the effects of me leaving for a month and thinking I might die. I don't think the trauma would have been the same if I had been able to have the treatment here.

Supplied

Bronwyn Hutchison had to travel to Mexico to receive Autologous Haematopoietic Stem Cell Transplantation for her MS diagnosis as it is not available in New Zealand.

Multiple Sclerosis Society of New Zealand, which has been asking the Ministry of Health for five years to approve and fund stem cell treatment for MS, backed the petition.

President Neil Woodhams said patients were fed up waiting for it to be made available here, while more than 100 had gone overseas to countries like Singapore, Mexico, India and Russia for self-funded treatment.

People are still going overseas for treatment and in a Covid environment, it is risky, he said. It is a one-off treatment and if it is successful, they don't have to worry about taking a drug every day or week or going to the hospital every six months.

Read this article:
Petition calling for 'life-changing' MS treatment funding handed to Parliament - Stuff

Lifestyle diseases are gradually moving up the ranks causing deaths globally. Liver diseases appear to be one such condition, with a significantly increased number of patients being diagnosed each year. According to the WHO data published in 2017, liver disease was responsible for around 2.95% of the total deaths in India, accounting for one-fifth of all cirrhosis-associated deaths globally. Earlier, infections such as hepatitis B and C were the main causes; however, alcohol consumption and obesity are now becoming bigger contributors to liver disease.We know that the liver is responsible for detoxifying alcohol and drugs, but also performs multiple other functions, including glucose supply to the brain, food digestion, producing blood during foetal development, storing nutrients, etc. We also know that the liver can regenerate, but that does not mean a fully damaged liver can grow back on its own. Therefore, it is important to pay attention to signs of liver disease and initiate treatments promptly.Liver cirrhosisCirrhosis is a condition where scars form in the liver causing the normal liver tissue to harden, thereby preventing the effective functioning of the organ. Cirrhosis and liver cancer are the prime causes of death due to liver disease globally. Regenerative medicine researcher Dr Pradeep Mahajan shares that alcohol consumption, viral hepatitis, autoimmune diseases, non-alcoholic fatty liver disease, and several inherited metabolic disorders can cause cirrhosis.The disease process begins as inflammation (swelling) in the liver tissue followed by scar formation and ultimately liver failure. Considering that there is no cure for cirrhosis per se, symptom and lifestyle management remain the mainstay of conventional treatment. Liver transplantation is the only curative option for severe cases; however, the issue of organ shortage is a chief and ever-growing concern.How can one get treated?Dr Mahajan says: Since we know that the liver can regenerate itself, the way ahead is to diagnose the liver disease as early as possible and find ways to enhance its regenerative potential. This is where cell and growth factor-based therapy can be beneficial.Stem cells in our body are capable of differentiating into liver (and various other) cells. In addition, they are also capable of regulating the immune system, reducing inflammation, enhancing blood supply, and stimulating other cells to perform their functions more efficiently. Similarly, growth factors can be isolated from blood/platelets, which serve as nutrition for cells of the body. These can help in cirrhosis by stabilising the internal environment of the liver making it more conducive to healing and regeneration.We are simply trying to find ways to capitalise on the healing potential of the liver before issues like scarring happen. Of course, lifestyle modification will be required to enhance the outcomes, but the end goal is to prevent the need for (or at least delay) liver transplantation, which can significantly affect a patients quality of life, adds Dr Mahajan.

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How effective is stem cell therapy for liver cirrhosis? - Times of India

Tecartus (Brexucabtagene Autoleucel) First and Only CAR T in Europe to Receive Positive CHMP Opinion to Treat Adults 26+ with r/r ALL

If Approved, it will Address a Significant Unmet Need for a Patient Population with Limited Treatment Options

SANTA MONICA, Calif.--(BUSINESS WIRE)--Kite, a Gilead Company (Nasdaq: GILD), today announces that the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion for Tecartus (brexucabtagene autoleucel) for the treatment of adult patients 26 years of age and above with relapsed or refractory (r/r) B-cell precursor acute lymphoblastic leukemia (ALL). If approved, Tecartus will be the first and only Chimeric Antigen Receptor (CAR) T-cell therapy for this population of patients who have limited treatment options. Half of adults with ALL will relapse, and median overall survival (OS) for this group is only approximately eight months with current standard-of-care treatments.

Kites goal is clear: to bring the hope of survival to more patients with cancer around the world through cell therapy, said Christi Shaw, CEO, Kite. Todays CHMP positive opinion in adult ALL brings us a step closer to delivering on the promise that cell therapies have to transform the way cancer is treated.

Following this positive opinion, the European Commission will now review the CHMP opinion; the final decision on the Marketing Authorization is expected in the coming months.

Adults with relapsed or refractory ALL often undergo multiple treatments including chemotherapy, targeted therapy and stem cell transplant, creating a significant burden on a patients quality of life, said Max S. Topp, MD, professor and head of Hematology, University Hospital of Wuerzburg, Germany. If approved, patients in Europe will have a meaningful advancement in treatment. Tecartus has demonstrated durable responses, suggesting the potential for long-term remission and a new approach to care.

Results from the ZUMA-3 international multicenter, single-arm, open-label, registrational Phase 1/2 study of adult patients (18 years old) with relapsed or refractory ALL, demonstrated that 71% of the evaluable patients (n=55) achieved complete remission (CR) or CR with incomplete hematological recovery (CRi) with a median follow-up of 26.8 months. In an extended data set of all patients dosed with the pivotal dose (n=78) the median overall survival for all patients was more than two years (25.4 months) and almost four years (47 months) for responders (patients who achieved CR or CRi). Among efficacy-evaluable patients, median duration of remission (DOR) was 18.6 months. Among the patients treated with Tecartus at the target dose (n=100), Grade 3 or higher cytokine release syndrome (CRS) and neurologic events occurred in 25% and 32% of patients, respectively, and were generally well-managed.

About ZUMA-3

ZUMA-3 is an ongoing international multicenter (US, Canada, EU), single arm, open label, registrational Phase 1/2 study of Tecartus in adult patients (18 years old) with ALL whose disease is refractory to or has relapsed following standard systemic therapy or hematopoietic stem cell transplantation. The primary endpoint is the rate of overall complete remission or complete remission with incomplete hematological recovery by central assessment. Duration of remission and relapse-free survival, overall survival, minimal residual disease (MRD) negativity rate, and allo-SCT rate were assessed as secondary endpoints.

About Acute Lymphoblastic Leukemia

ALL is an aggressive type of blood cancer that develops when abnormal white blood cells accumulate in the bone marrow until there isnt any room left for blood cells to form. In some cases, these abnormal cells invade healthy organs and can also involve the lymph nodes, spleen, liver, central nervous system and other organs. The most common form is B cell precursor ALL. Globally, approximately 64,000 people are diagnosed with ALL each year, including around 3,300 people in Europe.

About Tecartus

Please see full FDA Prescribing Information, including BOXED WARNING and Medication Guide.

Tecartus is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:

This indication is approved under accelerated approval based on overall response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

U.S. IMPORTANT SAFETY INFORMATION

BOXED WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES

Cytokine Release Syndrome (CRS), including life-threatening reactions, occurred following treatment with Tecartus. In ZUMA-2, CRS occurred in 91% (75/82) of patients receiving Tecartus, including Grade 3 CRS in 18% of patients. Among the patients who died after receiving Tecartus, one had a fatal CRS event. The median time to onset of CRS was three days (range: 1 to 13 days) and the median duration of CRS was ten days (range: 1 to 50 days). Among patients with CRS, the key manifestations (>10%) were similar in MCL and ALL and included fever (93%), hypotension (62%), tachycardia (59%), chills (32%), hypoxia (31%), headache (21%), fatigue (20%), and nausea (13%). Serious events associated with CRS included hypotension, fever, hypoxia, tachycardia, and dyspnea.

Ensure that a minimum of two doses of tocilizumab are available for each patient prior to infusion of Tecartus. Following infusion, monitor patients for signs and symptoms of CRS daily for at least seven days for patients with MCL and at least 14 days for patients with ALL at the certified healthcare facility, and for four weeks thereafter. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated.

Neurologic Events, including those that were fatal or life-threatening, occurred following treatment with Tecartus. Neurologic events occurred in 81% (66/82) of patients with MCL, including Grade 3 in 37% of patients. The median time to onset for neurologic events was six days (range: 1 to 32 days) with a median duration of 21 days (range: 2 to 454 days) in patients with MCL. Neurologic events occurred in 87% (68/78) of patients with ALL, including Grade 3 in 35% of patients. The median time to onset for neurologic events was seven days (range: 1 to 51 days) with a median duration of 15 days (range: 1 to 397 days) in patients with ALL. For patients with MCL, 54 (66%) patients experienced CRS before the onset of neurological events. Five (6%) patients did not experience CRS with neurologic events and eight patients (10%) developed neurological events after the resolution of CRS. Neurologic events resolved for 119 out of 134 (89%) patients treated with Tecartus. Nine patients (three patients with MCL and six patients with ALL) had ongoing neurologic events at the time of death. For patients with ALL, neurologic events occurred before, during, and after CRS in 4 (5%), 57 (73%), and 8 (10%) of patients; respectively. Three patients (4%) had neurologic events without CRS. The onset of neurologic events can be concurrent with CRS, following resolution of CRS or in the absence of CRS.

The most common neurologic events (>10%) were similar in MCL and ALL and included encephalopathy (57%), headache (37%), tremor (34%), confusional state (26%), aphasia (23%), delirium (17%), dizziness (15%), anxiety (14%), and agitation (12%). Serious events including encephalopathy, aphasia, confusional state, and seizures occurred after treatment with Tecartus.

Monitor patients daily for at least seven days for patients with MCL and at least 14 days for patients with ALL at the certified healthcare facility and for four weeks following infusion for signs and symptoms of neurologic toxicities and treat promptly.

REMS Program: Because of the risk of CRS and neurologic toxicities, Tecartus is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta and Tecartus REMS Program which requires that:

Hypersensitivity Reactions: Serious hypersensitivity reactions, including anaphylaxis, may occur due to dimethyl sulfoxide (DMSO) or residual gentamicin in Tecartus.

Severe Infections: Severe or life-threatening infections occurred in patients after Tecartus infusion. Infections (all grades) occurred in 56% (46/82) of patients with MCL and 44% (34/78) of patients with ALL. Grade 3 or higher infections, including bacterial, viral, and fungal infections, occurred in 30% of patients with ALL and MCL. Tecartus should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after Tecartus infusion and treat appropriately. Administer prophylactic antimicrobials according to local guidelines.

Febrile neutropenia was observed in 6% of patients with MCL and 35% of patients with ALL after Tecartus infusion and may be concurrent with CRS. The febrile neutropenia in 27 (35%) of patients with ALL includes events of febrile neutropenia (11 (14%)) plus the concurrent events of fever and neutropenia (16 (21%)). In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids, and other supportive care as medically indicated.

In immunosuppressed patients, life-threatening and fatal opportunistic infections have been reported. The possibility of rare infectious etiologies (e.g., fungal and viral infections such as HHV-6 and progressive multifocal leukoencephalopathy) should be considered in patients with neurologic events and appropriate diagnostic evaluations should be performed.

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

Prolonged Cytopenias: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Tecartus infusion. In patients with MCL, Grade 3 or higher cytopenias not resolved by Day 30 following Tecartus infusion occurred in 55% (45/82) of patients and included thrombocytopenia (38%), neutropenia (37%), and anemia (17%). In patients with ALL who were responders to Tecartus treatment, Grade 3 or higher cytopenias not resolved by Day 30 following Tecartus infusion occurred in 20% (7/35) of the patients and included neutropenia (12%) and thrombocytopenia (12%); Grade 3 or higher cytopenias not resolved by Day 60 following Tecartus infusion occurred in 11% (4/35) of the patients and included neutropenia (9%) and thrombocytopenia (6%). Monitor blood counts after Tecartus infusion.

Hypogammaglobulinemia: B cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with Tecartus. Hypogammaglobulinemia was reported in 16% (13/82) of patients with MCL and 9% (7/78) of patients with ALL. Monitor immunoglobulin levels after treatment with Tecartus and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement.

The safety of immunization with live viral vaccines during or following Tecartus treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least six weeks prior to the start of lymphodepleting chemotherapy, during Tecartus treatment, and until immune recovery following treatment with Tecartus.

Secondary Malignancies may develop. Monitor life-long for secondary malignancies. In the event that one occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

Effects on Ability to Drive and Use Machines: Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following Tecartus infusion. Advise patients to refrain from driving and engaging in hazardous activities, such as operating heavy or potentially dangerous machinery, during this period.

Adverse Reactions: The most common non-laboratory adverse reactions ( 20%) were fever, cytokine release syndrome, hypotension, encephalopathy, tachycardia, nausea, chills, headache, fatigue, febrile neutropenia, diarrhea, musculoskeletal pain, hypoxia, rash, edema, tremor, infection with pathogen unspecified, constipation, decreased appetite, and vomiting. The most common serious adverse reactions ( 2%) were cytokine release syndrome, febrile neutropenia, hypotension, encephalopathy, fever, infection with pathogen unspecified, hypoxia, tachycardia, bacterial infections, respiratory failure, seizure, diarrhea, dyspnea, fungal infections, viral infections, coagulopathy, delirium, fatigue, hemophagocytic lymphohistiocytosis, musculoskeletal pain, edema, and paraparesis.

About Kite

Kite, a Gilead Company, is a global biopharmaceutical company based in Santa Monica, California, with manufacturing operations in North America and Europe. Kites singular focus is cell therapy to treat and potentially cure cancer. As the cell therapy leader, Kite has more approved CAR T indications to help more patients than any other company. For more information on Kite, please visit http://www.kitepharma.com. Follow Kite on social media on Twitter (@KitePharma) and LinkedIn.

About Gilead Sciences

Gilead Sciences, Inc. is a biopharmaceutical company that has pursued and achieved breakthroughs in medicine for more than three decades, with the goal of creating a healthier world for all people. The company is committed to advancing innovative medicines to prevent and treat life-threatening diseases, including HIV, viral hepatitis and cancer. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, California.

Forward-Looking Statements

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the ability of Gilead and Kite to initiate, progress or complete clinical trials within currently anticipated timelines or at all, and the possibility of unfavorable results from ongoing and additional clinical trials, including those involving Tecartus; the risk that physicians may not see the benefits of prescribing Tecartus for the treatment of blood cancers; and any assumptions underlying any of the foregoing. These and other risks, uncertainties and other factors are described in detail in Gileads Quarterly Report on Form 10-Q for the quarter ended March 31, 2022 as filed with the U.S. Securities and Exchange Commission. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. The reader is cautioned that any such forward-looking statements are not guarantees of future performance and involve risks and uncertainties and is cautioned not to place undue reliance on these forward-looking statements. All forward-looking statements are based on information currently available to Gilead and Kite, and Gilead and Kite assume no obligation and disclaim any intent to update any such forward-looking statements.

U.S. Prescribing Information for Tecartus including BOXED WARNING, is available at http://www.kitepharma.com and http://www.gilead.com .

Kite, the Kite logo, Tecartus and GILEAD are trademarks of Gilead Sciences, Inc. or its related companies .

View source version on businesswire.com: https://www.businesswire.com/news/home/20220722005258/en/

Jacquie Ross, Investorsinvestor_relations@gilead.com

Anna Padula, Mediaapadula@kitepharma.com

Source: Gilead Sciences, Inc.

More:
Kite's CAR T-cell Therapy Tecartus Receives Positive CHMP Opinion in Relapsed or Refractory Acute Lymphoblastic Leukemia (r/r ALL) - Gilead Sciences

SINGAPORE - A Singaporean doctorwho is one of the top cell therapy experts in the worldhas been appointed to a World Health Organisation (WHO) expert panel.

Dr Mickey Koh is so sought-after in his field that for the past 15 years, he has been holding two jobs in two different countries.

The 56-year-old shuttles between England and Singapore, spending six weeks at a time in London, where he oversees the haematology department and looks after bone marrow transplant patients at St George's University Hospital, before returning to Singapore for a week and a half to head the cell therapy programme at the Health Sciences Authority.

Cell therapy is a growing field of medicine that uses living cells as treatment for a variety of diseases and conditions. This is an increasingly important therapeutic area and both his employers have agreed to his unusual schedule.

Over in London, Dr Koh is head of the Haematology Department at St George's Hospital and Medical School. In Singapore, he is the programme and medical director of the cell and gene therapy facility at the Health Sciences Authority.

In May, Dr Koh was selected to be on the WHO Expert Advisory Panel on Biological Standardisation.

Individuals on the panel have to be invited by WHO to apply, and are well recognised in their respective scientific fields. Eminent names on the panel include the current president of the Paul-Ehrlich-Institut in Germany, which is the country's federal agency, medical regulatory body and research institution for vaccines and biomedicine.

The WHO panel, which is made up of about 25 members, provides detailed recommendations and guidelines for the manufacturing, licensing and standardisation of biological products, which include blood, monoclonal antibodies, vaccines and, increasingly, cell-based therapeutics.

The recommendations and advice are passed on to the executive board of the World Health Assembly, which is the decision-making body of WHO.

Dr Koh's role had to be endorsed by the British government and was a direct appointment by the director-general of WHO.

His appointment as a panel expert will last for a term of four years.

Speaking to The Straits Times, Dr Koh shared his thoughts about the importance of regulation: "We are well aware that there is a very lucrative worldwide market peddling unproven stem cell treatments, where side effects are often unknown, and such unregulated practice can result in serious harm.

"This is already happening. People are claiming that you can use stem cells to treat things like ageing, and even very serious conditions like strokes, without any evidence."

With many medications now taking the form of biologics - a drug product derived from biological sources such as cells - the next wave of treatment would be the utilisation of these cells for the treatment of a wide range of diseases, Dr Koh said.

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S'porean doctor, a sought-after top expert in cell therapy, appointed to WHO expert panel - The Straits Times

Many clinicians believe the most significant advance in LBCL treatment in this time is the development of chimeric antigen receptor T-cell therapy.

Over the past 10 years, treatment options for patients with large B-cell lymphomas (LBCLs) have expanded with the approval of several new classes of treatment.

Many clinicians believe the most significant advance in LBCL treatment in this time is the development of chimeric antigen receptor (CAR) T-cell therapy.

I definitely think that this is the most notable agent in the last 10 years, said Sarah Rutherford, MD, an assistant professor of medicine and the John P. Leonard, MD/Gwirtzman Family Research Scholar in Lymphoma at Weill Cornell Medical College, Cornell University, in an interview with Targeted Therapies in Oncology.

Brian T. Hill, MD, PhD, director of the Lymphoid Malignancies Program and a staff physician at Cleveland Clinic Taussig Cancer Institute, agreed. Because there are now patients 5 years out without any signs of relapse with a single treatment of cell therapy 5 years ago, I think its pretty clear that is curative therapy in a proportion of patients who otherwise wouldnt be alive. The clinical impact on patients who received it really cant be understated.

Many subtypes of LBCL have been recognized.1,2 Their clinical and pathologic heterogeneity contributes to variations in prognosis and response to treatment.3,4

In 2012, standard treatment was chemoimmunotherapy with the anti-CD20 monoclonal antibody rituximab (Rituxan) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Response rates in this rituximab era were 80% to 90% in low-risk diffuse LBCL (DLBCL), but 5-year overall survival (OS) rates were only 30% to 50%, indicating a need for additional personalized therapies to improve outcomes, especially following standard R-CHOP therapy.3

CAR-T cells are produced from autologous patient T cells transduced with CARs engineered to bind to a specific tumor antigen via an extracellular domain, CD19 for B-cell malignancies, and containing costimulatory molecules.5 These agents have been welcomed into the treatment paradigm due to high response and survival rates.

Axicabtagene ciloleucel (Yescarta) received FDA approval in 2017 for the treatment of relapsed/ refractory (R/R) DLBCL, primary mediastinal B-cell lymphoma (PMBCL), high-grade BCL, and transformed follicular lymphoma (FL). In 2019, the agency approved the drug for patients with LBCL that had progressed on 2 prior therapies; in 2021, for R/R FL, and in April 2022, for LBCL refractory to or relapsing within 12 months of first-line chemoimmunotherapy (TIMELINE). 5-7

Tisagenlecleucel (Kymriah) was approved in 2018 for adult R/R LBCL, including DLBCL, highgrade BCL, and DLBCL arising from FL.5,8

In 2021, the FDA approved lisocabtagene maraleucel (Breyanzi) for patients with R/R LBCL, including DLBCL, high-grade BCL, PMBCL, and FL grade 3B after at least 2 lines of systemic therapy.5,9 Then in June 2022, the agency approved the CAR T-cell therapy for those with LBCL refractory to or relapsing within 12 months of first-line chemoimmunotherapy.10

CAR T-cell therapy is associated with potentially life-threatening toxicities, including cytokinerelease syndrome and neurologic toxicities, although advances in management have improved outcomes. Loss of the target antigen, CD19, renders treatment ineffective.1,11,12

Although CAR-T therapy results in effective and durable clinical responses for about 40% of patients, not all patients are even candidates due to age, comorbidities, or lack of chemotherapysensitive disease. The length of time required to manufacture this individualized therapy may be too long for those with rapidly progressive disease to wait.11,12 Further, few facilities are able to administer CAR T-cell therapy, as they must be accredited by the Foundation for the Accreditation of Cellular Therapy, making access also an issue.

For those who cant receive CAR T-cell therapy, there are 4 other FDA-approved targeted therapies: polatuzumab vedotin [Polivy], selinexor [Xpovio], tafasitamab [Monjuvi] administered with lenalidomide [Revlimid], and loncastuximab tesirine [Lonca, Zynlonta]. We can tailor our targeted approach to each individual patient in a way much better than we could before because we have many different options, Rutherford said.

R-CHOP as standard therapy has endured for 2 decades despite attempts to improve upon it with added chemotherapy or novel agents.13 More than half of patients who receive R-CHOP can be cured; the survival of those who are event free for 2 years is equivalent to that of an age- and sex-matched population; 10% to 20% have primary refractory disease that is nonresponsive to R-CHOP; and 30% to 40% experience relapse after achieving a complete response (CR) to treatment.14

In 2017, the FDA approved a new formulation of rituximab (Rituxan Hycela), allowing rituximab to be administered via subcutaneous injection in a few minutes rather than an hours-long intravenous infusion, to patients with DLBCL, among other indications.15

Tafasitamab, a cytolytic, humanized, monoclonal antibody directed against CD19, was granted accelerated approval by the agency in 2020 in combination with lenalidomide followed by tafasitamab monotherapy in adults with R/R DLBCL who were not eligible for autologous stem cell transplant. In the open-label single-arm phase 2 L-MIND trial (NCT02399085), the best overall response rate (ORR) was 57.5% (95% CI, 45.9%-68.5%) after at least 35 months of follow-up, with a 40% CR rate. Responses were durable, with a median duration of 43.9 months (95% CI, 26.1-not reached).16,17

There are 2 recognized cell of originbased subtypes of DLBCL: germinal center B cell (GCB) and activated B cell (ABC). Classification of these distinct subtypes was added to the 2016 revision of the World Health Organizations classification of lymphoid neoplasms.2

Patients treated with R-CHOP who have the GCB subtype, which is more common, have better outcomes than those with the ABC subtype.18,19 The current frontline standard of care is the same for both subtypes. Immunohistochemistry (IHC) algorithms can be used to distinguish GCB from nonGCB, although the non-GCB subtype is more heterogeneous than the ABC subtype by gene expression profiling.1

Immunophenotyping by IHC is used for risk stratification as well as diagnosis, and includes CD20, CD3, CD5, CD10, CD45, BCL2, BCL6, Ki-67, IRF4/MUM1, and MYC. The presence of MYC plus either BCL2 or BCL6 by IHC should be followed by fluorescence in situ hybridization or karyotyping to detect rearrangements of these genes.1

Lymphomas with rearrangements of MYC and BCL2 and/or BCL6 (double-hit or triplehit, usually GCB subtype) have become classified as high-grade lymphomas over the past 6 years, and account for about 4% to 8% of all LBCL cases.2,19 Intensified induction treatment is preferred for these patients as outcomes with R-CHOP treatment are poor. When MYC and BCL2 are overexpressed (double-expressor, usually ABC subtype) rather than rearranged, prognosis may also be poor, and improved with intensified induction. Primary DLBCL of the central nervous system (typically ABC subtype) is rare, and is also associated with poor prognosis.18,19

Although understanding molecular and genetic subtypes can enhance treatment allotment in clinical studies, a unified model appropriate for clinical practice has not yet been defined.18

Antibody-drug conjugates selectively deliver cytotoxic agents to malignant cells by linking a monoclonal antibody that targets an antigen on those cells with a cytotoxic payload.4

Polatuzumab vedotin combines an antiCD79b monoclonal antibody with a potent microtubule inhibitor. It was granted accelerated approval by the FDA in 2019 in combination with bendamustine and rituximab (BR) for the treatment of adults with R/R DLBCL after at least 2 prior therapies. The CR rate for polatuzumab plus BR was 40% vs 18% with BR alone, with best ORR of 63% and 25%, respectively.20

Polatuzumab showed activity in a phase 1b/2 trial (NCT01992653) as first-line therapy for DLBCL with rituximab plus cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP), eliminating vincristine from CHOP to avoid the overlapping neurologic toxicity with polatuzumab. Responses were seen in 89% of patients and CRs in 77%.21

The double-blind phase 3 POLARIX trial (NCT03274492) compared pola-R-CHP with R-CHOP in patients with previously untreated, intermediate, or high-risk DLBCL. At a median follow-up of 28.2 months, 76.7% of patients in the pola-R-CHP group survived without progression at 2 years vs 70.2% of the R-CHOP group (HR for progression, relapse, or death, 0.73; 95% CI, 0.57-0.95; P = .02). There was no significant difference in OS rates at 2 years (88.7% with pola-RCHP vs 88.6% with R-CHOP; HR, 0.94; 95% CI, 0.65-1.37; P = .75). The safety profile was also comparable between the groups.22

Lonca combines a humanized anti-CD19 monoclonal antibody with an alkylating cytotoxin causing interstrand DNA crosslinks.23

Lonca monotherapy received accelerated approval in 2021 for patients with R/R LBCL, including DLBCL and high-grade BCL, after at least 2 lines of systemic therapy based on the results of the open-label, single-arm LOTIS-2 trial in DLBCL (NCT03589469). Participants in the phase 2 study included those with highrisk, poor prognosis, and double- and triple-hit lymphoma after at least 2 prior regimens. The ORR was 48.3% (95% CI, 39.9%-56.7%), including a CR rate of 24.1%. The median duration of response was 10.3 months.23,24

Responses in patients who had received prior CD19-directed CAR T-cell therapy (n = 13) were similar to those of study patients overall (n = 145), although enrollment required persistent CD19 expression. Treatment with Lonca also did not interfere with response to subsequent CAR T-cell therapy (n = 15; ORR, 47%), suggesting Lonca could be used either as salvage therapy after CAR T-cell therapy or as an alternative or bridging therapy for those with rapidly progressing disease without compromising subsequent CAR T-cell therapy.23

Recently, the addition of lenalidomide to brentuximab vedotin (Adcetris), an antiCD30 monoclonal antibody with a tubulin disrupting agent, was explored in a phase 1 dose-expansion trial (NCT02086604) in patients with R/R DLBCL. The combination was well tolerated, although most patients had neutropenia requiring granulocyte colony-stimulating factor support. The ORR was 57% (95% CI, 39.6%-72.5%) and the CR rate was 35%, with a median duration of response of 13.1 months.25

Selinexor is an oral, selective small molecule inhibitor of XPO1-mediated nuclear export. It received accelerated approval in 2020 for adults with R/R DLBCL after 2 to 5 prior lines of therapy, including progression after or ineligibility to undergo transplant. In the single-arm, open-label phase 2 SADAL trial (NCT02227251) in heavily pretreated patients, the ORR was 28% (95% CI, 20.7%- 37.0%) and the CR rate was 12%. The disease control rate was 37% (95% CI, 28.6%-46.0%) and the median duration of response was 9.3 months (95% CI, 4.8-23.0). The most common grade 3 or higher AEs were cytopenias.1,26,27

The safety and efficacy of venetoclax (Venclexta), a selective BCL2 inhibitor approved for other hematologic malignancies, was assessed in the phase 2 CAVALLI trial (NCT02055820) in combination with R-CHOP in patients with treatment-nave DLBCL overexpressing BCL2 protein by IHC. At a median follow-up of 32.3 months, the ORR was 83% and the CR rate was 69%. Treatment was associated with increased, manageable myelosuppression. A cross-trial comparison with the GOYA trial (NCT01287741) of standard R-CHOP did not show a progression-free survival advantage.28

Involved-site radiation therapy (ISRT) can follow R-CHOP first-line therapy for bulky stage I and II DLBCL without extensive mesenteric disease. This form of therapy is recommended for patients who are not candidates for chemoimmunotherapy.1

Those with DLBCL that relapses after more than 12 months can be considered for transplant. After second-line therapy, transplant-eligible patients who experience CR or partial response can receive high-dose therapy with autologous stem cell rescue, or in some cases allogeneic hematopoietic cell transplant.1

Bispecific antibodies simultaneously target tumor and immune cell antigens. Several are in development for B-cell lymphomas, including blinatumomab (Blincyto), which binds CD19 and CD3, and mosunetuzumab and glofitamab, which bind both CD20 and CD3.18,29-31 Hill said bispecific antibodies are highly active in R/R lymphomas and appear to be free of many of the toxicities seen with CAR T cells. He speculated that for patients unable to receive CAR T- cell treatment because they are unable to travel to a referral center, bispecific antibodies are likely to be widely available in the community setting, eventually.

Hill said, Theres a lot of excitement about the possibility of delivering therapies that dont require individual patient manufacturing. These could include off-the-shelf cellular therapies.

Approaches may include adoptive transfer of cytotoxic natural killer (NK) cells, which, unlike T cells, are not associated with cytokine release syndrome or graft-vs-host disease. This will rely on pre-expanded, banked cells from different sources to allow transfer with minimal human leukocyte antigen matching.32

In addition to NK cells, other immune effector cells such as invariant NK T cells, - T cells, and macrophages may be amenable to engineering into alternative CAR constructs to treat R/R B-cell malignancies.12

Other biomarkers that may provide treatment targets are being investigated. TP53 mutations are frequently found in patients with R/R DLBCL and are considered a negative prognostic indicator.33 These mutations have also been associated with acquired resistance to rituximab and R-CHOP failure.18 Currently, use of locoregional therapy shows the best survival outcomes for patients with these mutations.33

Magrolimab, which targets CD47, a molecule that when overexpressed in tumor cells allows them to evade phagocytosis, has shown activity in an early trial.18,19

Mutations in the histone-methyl transferase EZH2 have been reported in about 25% of GCB lymphomas. The oral EZH2 inhibitor tazemetostat (Tazverik), which is already approved for EZH2-mutation positive R/R FL after at least 2 prior therapies or if there are no other treatment options, has shown initial encouraging efficacy in combination with R-CHOP in untreated DLBCL, and should be further investigated.34,35

Pembrolizumab, a humanized antiPD-1 monoclonal antibody, is approved for treatment of patients with R/R PMBL after at least 2 prior lines of therapy.1 Otherwise, immunotherapy with immune checkpoint inhibitors (ICIs) has not been effective in DLBCL, although a retrospective analysis suggested ICIs could sensitize lymphomas to subsequent chemotherapy.4 Combinations of ICIs with R-CHOP or other agents are under investigation.18

There are still people with really aggressive diseases that just dont respond to anything you give them. Trying to figure out who they are and why thats happening, and trying to figure out the better targeted approach earlier on, is what I view as the biggest unmet need, Rutherford said.

Its been a fulfilling time to be a researcher and to care for these patients because we used to have not much to offer for them, and even though we do prefer clinical trials for people when we can, there are reasons why people cant get on trials, whether its comorbidities or lack of availability of trials, etc. Its been very fulfilling now to have a lot of options for people to talk about, rather than just giving [these patients] different types of chemotherapy that is unlikely to work, Rutherford said.

Hill agreed. It has been a very remarkable time, he said. I have been at this 11 years, and the treatment options that have been available in 2022 compared [with] 2012 are remarkably improved and likely to be even better in the future.

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15. FDA grants accelerated approval to tafasitamab-cxix for diffuse large B-cell lymphoma. FDA. July 31, 2020. Accessed June 10, 2022. https://bit.ly/3OS0xAO

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20. Tilly H, Morschhauser F, Sehn LH, et al. Polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma. New Engl J Med. 2022;386(4):351-363. doi:10.1056/NEJMoa2115304

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26. Morschhauser F, Feugier P, Flinn IW, et al. A phase 2 study of venetoclax plus R-CHOP as first-line treatment for patients with diffuse large B-cell lymphoma. Blood. 2021;137(5):600-609.doi:10.1182/blood.2020006578

27. Budde LE, Assouline S, SehnLH, et al. Single-agent mosunetuzumab shows durable complete responses in patients with relapsed or refractory B-cell lymphomas: phase I dose-escalation study. J Clin Oncol. 2021;40(5):481-491.doi:10.1200/JCO.21.00931

28. Dufner V, Sayehli CM, Chatterjee M, et al. Long-term outcome of patients with relapsed/refractory B-cell non-Hodgkin lymphoma treated with blinatumomab. Blood Adv. 2019;3(16):2491-2498.doi:10.1182/bloodadvances.2019000025

29. Hutchings M, Morschhauser F, IacoboniG, et al. Glofitamab, a novel, bivalent CD20-targeting T-cell-engaging bispecific antibody, induces durable complete remissions in relapsed or refractory B-cell lymphoma: a phase I trial.J Clin Oncol. 2021;39(18):1959-1970. doi:10.1200/JCO.20.03175

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33. Sarkozy C, Morschhauser F, Dubois S, et al. A LYSA phase 1b study of tazemetostat (EPZ-6438) plus R-CHOP in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) with poor prognosis features. Clin CancerRes.2020;26(13):3145-3153.doi:10.1158/1078-0432.CCR-19-3741

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Top 10 Advances in Large B-Cell Lymphomas in the Past 10 Years - Targeted Oncology