The addition of vedolizumab (Entyvio) added to standard prophylaxis following unrelated allogeneic hematopoietic stem cell transplantation (HSCT) was superior to placebo at preventing lower gastrointestinal (GI) acute graft-vs-host disease (aGVHD), according to findings from the global, phase 3 GRAPHITE study (NCT03657160) presented data at the 2023 Transplantation & Cellular Therapy Meetings.1

Vedolizumab was more effective than placebo for the prevention of lower GI GVHD after unrelated allogeneic transplant when added to a standard calcineurin inhibitorbased GVHD platform, said Yi-Bin Chen, MD, director of the Hematopoietic Cell Transplant & Cell Therapy Program and the Allen B. Rogers Jr and Cara J. Rogers Endowed Chair at Massachusetts General Hospital.

Its safety profile was comparable to placebo with no new safety signals identified, given as part of GVHD prophylaxis, he added. This is the first positive phase 3 study for this specific prevention of lower GI GVHD.

In patients assigned to vedolizumab, the rate of intestinal aGVHD-free survival by 180 days following allogeneic HSCT, the primary end point, was 85.52% (95% CI, 79.17%-90.05%) vs 70.85% (95% CI, 61.63%-77.22%) for those assigned to placebo (HR, 0.45; 95% CI, 0.27-0.73; P < .001). Sixteen (9.7%) patients died in the placebo arm vs 12 (7.1%) in the experimental arm. Fourteen (8.5%) patients in the placebo arm developed stage 2 to 4 intestinal aGVHD compared with 4 (2.4%) for vedolizumab.

In the sensitivity analysis, which excluded clinical stage 0 lower GI GVHD events, 13.7% of patients in the experimental arm had GI aGVHD by day 180 following allogeneic HSCT, compared with 27.3% in the placebo arm (HR, 0.44; 95% CI, 0.27-0.73; P = .001).

Despite progress in prophylaxis and treatment, approximately 40% to 70% of patients who undergo allogenic HSCT will develop grade 2 to 4 aGVHD. Investigators have found mixed results in small studies assessing vedolizumab, a gut-selective anti- integrin antibody that inhibits migration of Gl-homing T lymphocytes across the gut endothelium, as a preventative for aGVHD. The agent is currently approved to treat ulcerative colitis and Crohns disease.2

Investigators conducted this global investigation from February 2019 through May 2022 at 94 centers in North and South America, Europe, Asia, and Australia. Investigators hoped to enroll 558 patients, but the study closed after enrolling 343 patients because the COVID-19 pandemic hampered recruitment. A total of 169 patients were randomly assigned to placebo and 165 were included in the safety and efficacy populations. In the vedolizumab arm, 169 patients were evaluated for safety and 168 for efficacy.

Patients aged 12 years or older undergoing a first allogeneic HSCT for treatment of hematological malignancies from unrelated donors were eligible. Unrelated donors were human leukocyte antigen (HLA)matched (8/8) or 7/8 matched (a single mismatch at HLA-A, -B and -C, and HLA-DRB1) were allowed. All patients received a standard GVHD prophylaxis regimen consisting of a combination of a calcineurin inhibitor plus methotrexate or mycophenolate mofetil.

All patients were assigned to standard of care prophylaxis on day 13, day 41, day 69, day 97, day 125, and day 153 after allogeneic HSCT plus placebo (n = 169) or intravenous 300 mg vedolizumab on day 1 before allogeneic HSCT (n = 174).

In the placebo group, the median age was 55.0 years (range, 16-74), 64.2% of patients were male, and the most common primary disease was acute myeloid leukemia (AML; 43.6%). More than half (52.4%) of patients had an ECOG performance status of 1, 39.6% had an ECOG performance status of 0, and 7.9% had a score of 2.

Stem cells came from the peripheral blood in 86.6% of patients, and 90.9% were 8/8 matched for HLA compatibility. Eighty-four percent of patients were in complete remission 1.

In the experimental group, the median age was 53.0 years (range, 19-74), 61.3% of patients were male, and the most common primary disease was AML (43.5%). More than half (53.0%) of patients had an ECOG performance status of 1, 38.1% had an ECOG performance status of 0, and 8.3% had a score of 2.

Stem cells came from the peripheral blood in 83.9% of patients and 90.5% were 8/8 matched for HLA compatibility. More than two-thirds of patients (71.4%) patients were in complete remission 1.

Chen noted that vedolizumab induced superior results for the primary end point, irrespective of conditioning, prophylaxis, calcineurin inhibitor, or HLA match.

Vedolizumab outperformed placebo across key secondary end points including intestinal aGVHD-free and relapse-free survival events (20.8% for vedolizumab vs 33.9% for placebo; HR, 0.56; 95% CI, 0.37-0.86; P =.0043), grade C-D aGVHD-free survival events (20.8% vs 31.5%; HR, 0.59; 95% CI, 0.39-0.91; P =.0204), non-relapse mortality events (6.0% vs 11.5%; HR, 0.48; 95% CI, 0.22-1.04; P = .0668), overall survival events (10.1% vs 15.2%; HR, 0.63; 95% CI, 0.34-1.17; P = .1458), and grade B-D aGVHD survival events (33.3% vs 46.7%; HR, 0.64; 95% CI, 0.46-0.91; P .0105). Intestinal aGVHD-free and relapse free survival events excluding clinical grade 0 patients also favored vedolizumab (20.2% vs 32.7%; HR, 0.56; 95% CI, 0.36-0.86; P = .0062).

All patients in both groups experienced any-grade adverse effects (AEs). Grade 3 or higher AEs were 89.1% in the placebo group and 92.3% in the experimental arm. Drug-related grade 3 or higher AEs occurred in 11.5% and 10.7% of patients in the vedolizumab and placebo arms, respectively. AEs leading to discontinuation occurred in 30.9% of patients in the placebo arm and 26.0% in the experimental arm.

Serious AEs leading to discontinuation occurred in 23.0% of patients in the placebo arm and 23.1% in the experimental arm. Drug-related serious AEs occurred in 8.5% and 6.5% of patients, respectively. Twenty-seven (16.4%) patients in the placebo arm experienced AEs leading to death compared with 21 (12.4%) in the experimental arm.

Approximately two-thirds (67.3%) of the placebo arms experienced serious infections, 82.4% experienced hypersensitivity/injection site reactions, and 41.8% experienced liver injury. Those results were 74.0%, 79.3%, and 40.2% in the vedolizumab arm, respectively.

Chen said that vedolizumab should be evaluated with combination with post-transplant cyclophosphamide. He added that vedolizumab requires more evaluation to define its optimal role in treatment.

Some further analysis we'll need to do islook at maximum stage of GI GVHD to truly understand the impact of what we presented here and also perhaps the impact on chronic GVHD, as well, he said. With the changing landscape of GVHD prevention, as weve seen recently and even at this meeting, its unclear how to incorporate this and the other new agents into what is a rapidly changing landscape, which is interesting. It's also great for our field.

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Vedolizumab Plus Standard Prophylaxis Reduces Rate of Lower GI ... - OncLive

Because of an economic burden on the healthcare system occurring through the per-patient cost of allogeneic hematopoietic cell transplant (alloHCT), novel treatments to replace transplant and prevent graft-vs-host disease (GVHD) are necessary to improve patient outcomes while controlling healthcare costs, according to an analysis presented during the 2023 Transplantation & Cellular Therapy Meetings.

Results showed that the curr ent average per-patient medical cost of alloHCT over a lifetime was estimated at $1,247,917, 53% of which was due to treatment for chronic GVHD (cGVHD); the discounted expected quality-adjusted life years (QALY) was 4.7. Based on the expected availability of new cGVHD agents, the future per-patient medical cost of alloHCT was estimated to be between $1,370,839 and $1,616,684 with 4.8 discounted expected QALYs.

In a projection analysis that evaluated the current and future estimated lifetime costs over a 10-year period, data showed that the annual number of alloHCTs was 8326, and 76% of those transplants were for patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndromes (MDS). The average allo-HCT growth, based on the past 5 years, was calculated at 0.34%, along with an average Medicare inflation rate of 2.53%.

The aggregate costs associated with allo-HCT are expected to increase and pose an increased burden on the healthcare system, lead study author Miguel-Angel Perales, MD, chief of the Adult Bone Marrow Service at Memorial Sloan Kettering Cancer Center, New York, New York, and coinvestigators, wrote in the poster presented at the meeting. Novel drugs have recently emerged. Clinical use and data on their utilization and impact are currently sparse.

The number of HCT procedures has increased annually, the investigators noted. Emerging agents have been designed to address and manage posttransplant complications, such as GVHD. However, such agents are not widely utilized and their impact on clinical practice is unclear.

In the analysis presented, investigators sought to estimate the total lifetime medical costs of an alloHCT patient, and the aggregate lifetime burden over the next decade for incident alloHCT patients while considering newly available therapies for chronic GVHD.

Investigators utilized a 100-day and long-term Semi-Markov Partitioned survival model with peer-reviewed evidence and data from the CIBMTR of US patients with AML, ALL, and MDS who had undergone alloHCT. The clinical inputs studied were overall survival (OS), GVHD-free relapse-free survival (GRFS), incidence of both acute GVHD (aGVHD) and cGVHD, relapse of primary disease, and infections. Economic inputs included alloHCT cost, aGVHD, cGVHD, relapse episode, infection hospitalization, maintenance treatment, and end-of-life costs.

The primary outcomes were total direct medical costs, total expected life years (LYs), and quality-adjusted QALYs. Investigators noted that all cost and outcomes were discounted at 3% annually.

Moreover, patient characteristics, estimated time spent in each health state, OS, and GRFS outcomes came from CIBMTR and published literature data.

Based on the data pulled, the age at transplant was 53 years and 58% were male. Fifty-one percent of patients had AML, 21% had ALL, and 28% had MDS. In related donors (32%), 8% were from bone marrow and 92% were from peripheral blood stem cell (PBSC); in unrelated donors, 9% and 91% were from bone marrow and PBSC, respectively.

Regarding costs, an alloHCT was $182,642, and the 100-day and annual costs of acute GVHD treatment were $79,197 and $158,938, respectively. For cGVHD treatment, the current cost was $220,202, with an estimated 25% future uptake in costs totaling $261,413 and an estimated 75% future uptake totaling $343,836. Relapse episodes had a cost of $206,003 and infection hospitalization at $53,214; the annual costs of maintenance sorafenib (Nexavar) and imatinib mesylate (Gleevec) were $277,765 and $184,861, respectively. End-of-life costs were $174,102.

Patient utilities were also calculated, posttransplant without GVHD (0.86) and with GVHD (current, 0.69; future, 0.76), and relapsed/progressed AML (0.53), ALL (0.74), and MDS (0.60); a disutility was infection (-0.23).

The projection analysis was run to account for a likely increased growth of allogeneic transplants in the projected years 1 through 10. Here, an average annual growth rate was applied to the current number of alloHCT recipients; this was based on the mean alloHCT growth from the past 5 years. Based on this information, there is an estimated 6544 allogeneic recipients occurring in year 10 and a total of 64,461 alloHCTs over the 10-year span.

Volume and costs were also analyzed in the projection analysis. The cumulative total over the 10-year span was calculated at $92.6 billion. When including the future alloSCT costs with a 25% uptake, this total was $101.7 billion, which was a $9.1-billion net difference vs the current cost; this was $120.0 billion with a 75% uptake, which was a $27.4-billion net difference vs the current cumulative total.

The analysis suggests that the small gain in QALYs [0.1 QALY average per patient] as a result of new treatment approaches for active [chronic] GVHD would cost an additional $9 billion to $27 billion in the aggregate over 10 years, the authors noted.

Because 15-year OS and GRFS outcomes were used to inform the model consisted of a cohort of allo-HCT recipients from 2000 to 2005, the authors stated that the data may not fully be representative to outcomes observed in present dayespecially as cancer treatment and care continues to evolve and improve.

They added that the OS/GRFS outcomes were adjusted by utilizing data from 2016 to 2019 for the first 3 years, before using the observed trend from a 2000 to 2005 cohort. This permitted the inputs to be more representative of current treatment outcomes.

Further limitations the authors cited were that inputs were obtained from published claims analyses and mirror averages of multiple populations, which can introduce heterogeneity into the model. Finally, off-label maintenance therapy for patients with FLT3-ITDpositive AML and Philadelphia chromosomepositive ALL is not fully adopted in clinical practice, so not all patients in these subgroups may receive this treatment. Incorporating the costs of such treatment may result in an overestimation of the total lifetime costs of allo-HCT, the authors concluded.

Perales M-A, Devine SM, Garrison LP, et al. Estimating the current and future costs and health outcomes of patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). Presented at: 2023 Transplantation & Cellular Therapy Meetings; February 15-19, 2023; Orlando, FL. Abstract 495

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Novel Therapies Are Needed to Reduce Cost Burden With AlloHCT ... - OncLive

Dog owners are being warned to 'remain vigilant' after a second fatal case of Alabama Rot in 2023 has been confirmed in Berkshire, tragically killing six-year-old Hungarian Vizsla Marnie

Pet owners are being warned to spot the signs of Alabama Rot after the deadly disease took the life of Marnie the six-year-old Hungarian Vizsla in Berkshire. Also known as cutaneous and renal glomerular vasculopathy (CRGV), Alabama Rot is an extremely rare disease which claims the lives of 90 percent of infected dogs.

The caution comes after a three-year-old Labrador sadly died last month, marking two deaths already in 2023. Marnie's owner, Sabina Richardson, wants to highlight the early symptoms of the canine disease, including sores on paws, to ensure other pet parents are fully aware of the warning signs of CRGV.

Sabina told the Mirror: "Marnie's first symptoms were sores on her paws which then began to spread onto her legs. She also stopped eating and started to vomit.

"We took her to local vets who gave her antibiotics but she couldn't keep the tablets down and continued to deteriorate.

"By this point, we were very concerned and visited another vets, who said they feared it was Alabama Rot.

"They gave Marnie an injection of antibiotics and took blood tests which confirmed her kidneys were failing.

"That was such a shock and it was really tough when we finally had to make the heart-breaking decision to put her to sleep."

The anguish was all the more acute as a dog belonging to Sabina's partner, a two-year-old whippet called Goose, had shown similar symptoms but, thankfully, survived.

Sabina added: "Goose had very similar sores that were oozing puss and had the same sort of treatment but he survived and is absolutely fine now.

"It's so hard to understand. We keep going over it all and trying to identify where they could have come in touch with such a rare disease.

"We have re-traced our walks and can't think of anywhere we went that was unusual.

"Everyone in the village tends to walk their dogs in the same spots so it's baffling how there haven't been more cases."

Anderson Moores Veterinary Specialists has been leading research since 2012 and confirmed the latest case, which is the second in the county in the past six weeks.

Josh Walker, from Anderson Moores, told the Mirror: "There were 11 cases recorded across the UK in 2022, so to report two deaths in Berkshire in a six-week period is unusual.

"However, I must emphasise this is a very rare disease and we're advising dog owners to remain calm but vigilant and seek advice from their vet if their dog develops unexplained skin lesions.

"Treatment largely revolves around management of the sudden onset kidney failure and is only successful in around 10 per cent of cases."

Josh advises pet owners to use the veterinary specialists' bespoke online map to see the exact location of confirmed cases in the UK.

Do you have a dog story to share? Email nia.dalton@reachplc.com.

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Urgent warning to dog owners as new deadly Alabama Rot case confirmed in UK - The Mirror

Physicians speak on personalizing treatment for graft-versus-host disease, arming CAR T cells against macrophages

ORLANDO, FL Two experts from Roswell Park Comprehensive Cancer Center are delivering presentations this week at an international conference highlighting research aimed at extending and improving the lives of patients with blood-related cancers. Nataliya Buxbaum, MD, from the Department of Pediatric Oncology and Marco Davila, MD, PhD, Vice Chair for Cellular Therapies and Senior Vice President and Associate Director for Translational Research, were invited to highlight their work in podium talks at the 2023 Tandem Transplantation & Cellular Therapy Meetings of the American Society for Transplantation and Cellular Therapy (ASTCT) and Center for International Blood and Marrow Transplant Research (CIBMTR) this week in Orlando, Florida.

A biology-based approach to GvHD

Dr. Buxbaum, a member of the Chronic GvHD National Institutes of Health (NIH) Consensus Project Biology Task Force, described recent advances in understanding the biology of chronic graft-versus-host disease (GvHD) a potentially fatal condition that affects between 25% and 75% of patients who undergo allogeneic hematopoietic cell transplant. She also discussed her research on the immunometabolism of GvHD that may lead to new imaging approaches and therapy for this condition.

If its successful, the strategy may:

We are still uncovering the complex biological underpinnings of GvHD, Dr. Buxbaum observes. For four decades we treated all patients with the same systemic treatment corticosteroids. Not only do many patients not respond, but those who do respond end up being on them a long time, and they have many side effects.

She notes that preclinical work has opened insights into the biological pathways involved in GvHD and has led to the development of targeted therapies for this transplant barrier. At the same time, the work of the NIH Consensus Project Biology Task Force has better defined the disease, laying the groundwork for the FDA to approve three drugs for chronic GvHD and one to prevent acute GvHD in the last five years alone. Thats groundbreaking, she says.

However, while blood-based biomarkers are being developed for GvHD, it is still challenging to pinpoint the exact areas of the body where GvHD is developing based on blood sampling alone. Because there currently is no diagnostic imaging for detecting GvHD, a minimum of 28 days must elapse after the start of treatment before a biopsy can determine whether or not the disease has responded to treatment and a biopsy is challenging to do in somebody whos sick, Dr. Buxbaum notes. If the initial treatment hasnt worked, a different drug is started and more time is needed before re-evaluation for response.

Locating areas of high glucose metabolism is key to detecting the presence of cancer. This is currently accomplished with a positron emission tomography (PET) scan after having the patient ingest a radioactive sugar molecule. PET is then able to map where glucose is being absorbed by cancer cells. But high sugar metabolism can also indicate the presence of GvHD: When you first start getting GvHD, the immune system fires up the T cells, and they start using a lot of sugar, explains Dr. Buxbaum.

She and her team see great potential in performing metabolic imaging with magnetic resonance imaging (MRI), which uses a magnetic field and radio waves to produce images and, unlike PET, does not require radioactive sugar molecules. Within the next six to 12 months, Dr. Buxbaum and her colleagues hope to run a pilot study to gauge the effectiveness of locating GvHD with metabolic MRI, using a sugar molecule labeled with deuterium, a nonradioactive form of hydrogen.

Targeting this metabolic pattern of high glycolysis is something we should do therapeutically, says Dr. Buxbaum. Were studying it in preclinical models right now and having some success. She says previous work with preclinical models has shown that GvHD can be detected this way in the liver and gut, and we think the same can happen in a human being. We then use a drug that inhibits the processing of sugar to ameliorate GvHD.

Allogeneic stem cell transplants are especially challenging. Each time its a unique mismatch between the host and donor, if theyre unrelated, says Dr. Buxbaum. Its a unique situation every time, so it requires personalized therapy.

Dr. Buxbaums talk, Biology of GvHD, was presented Wednesday, Feb. 15, from 11-11:30 a.m. EST.

Identifying the cause of poor outcomes in CAR T-cell therapy for B-cell malignancies

Dr. Davila will discuss his teams efforts to determine why some patients with B-cell malignancies do not respond well to CAR T-cell therapy targeting CD19, a surface protein expressed by most B cells. What accounts for poor outcomes in those patients?

Using patient samples, the investigators identified gene signatures and cell signatures showing that the lymphoid tissue in those patients contained high numbers of myeloid cells, which originate in the bone marrow and can develop into various types of adult blood cells, including macrophages, which are capable of killing tumor cells and other cells. They then developed assays of CD19-targeted CAR T cells, tumors and macrophages, and cultured them together and discovered that certain types of macrophages were capable of killing CAR T cells.

While macrophages might kill up to 90% of the CAR T cells, the remaining 10% that survive proliferate and persist, says Dr. Davila, which means it would be possible for the surviving CAR T cells to continue attacking the cancer cells. But how well would they function? We compared them to other CD19-targeted T cells that had never been exposed to macrophages, and they performed worse, he explains. They didnt kill as well, they didnt secrete as much cytokine which can stimulate the immune system and they didnt proliferate as well.

Further investigation using preclinical models revealed the specific metabolic pathways that Dr. Davila and his colleagues believe are key to how macrophages trigger this dysfunction in CD19-targeted CAR T cells. Our goal now, he says, is to retrain the CAR T cells to be more resistant to this metabolic dysfunction. We hope this will result in better outcomes for patients.

Dr. Davila will present Mechanisms of Resistance to CD19-Targeted CAR T Cells: Lessons from Mice and Patients, Friday, Feb. 17, from 3-3:30 p.m. EST, World Center Marriott, Cypress 3.

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Roswell Park Comprehensive Cancer Center is a community united by the drive to eliminate cancers grip on humanity by unlocking its secrets through personalized approaches and unleashing the healing power of hope. Founded by Dr. Roswell Park in 1898, it is the only National Cancer Institute-designated comprehensive cancer center in Upstate New York. Learn more at http://www.roswellpark.org, or contact us at 1-800-ROSWELL (1-800-767-9355) or ASKRoswell@RoswellPark.org.

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Is it still worth pursuing the repurposing of metformin as a cancer ... - Nature.com

Yago L. Nieto, MD, PhD, professor, Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses findings from a phase 2 trial investigating panobinostat (Farydak), gemcitabine, busulfan, and melphalan plus autologous stem cell transplant (ASCT) in patients with high-risk or relapsed/refractory multiple myeloma.

This trial enrolled 80 patients to 1 of 2 cohorts. The first cohort consisted of patients who were receiving a first transplant for relapsed/refractory disease or as frontline consolidation for disease with high-risk cytogenetics, Nieto says. The second cohort consisted of patients who were receiving a second transplant after progressing on a previous transplant, Nieto explains.

This trial showed that the combination of panobinostat, gemcitabine, busulfan, and melphalan plus ASCT was safe, with manageable toxicities, Nieto notes. This regimen was also associated with high overall response rates and complete response rates, at 67% and 40%, respectively, in cohort 1 and 93% and 64%, respectively, in cohort 2, Nieto emphasizes. Additionally, minimal residual disease (MRD) negativity rates improved after transplant in both cohorts, and MRD negativity conversion was associated with better outcomes, Nieto says. The MRD negativity rate increased from 8.5% to 23% after transplant in cohort 1 and from 34% to 55% in cohort 2.

The second part of this trial was a comparison between both cohorts of the study and a concurrent control cohort consisting of patients who were eligible for the trial but instead received off-trial transplant with either busulfan and melphalan or melphalan alone, Nieto explains. A matched pair analysis showed progression-free survival (PFS) superiority with the study regimen vs the control arm in patients receiving a first transplant, Nieto says. Conversely, the matched pair analysis of patients receiving a second transplant showed no significant difference in PFS between the study regimen and control arm, Nieto notes.

Based on these findings, the investigators concluded that panobinostat, gemcitabine, busulfan, and melphalan plus ASCT is more effective than standard-of-care transplant with busulfan and melphalan or melphalan alone in patients receiving a first transplant for relapsed/refractory or high-risk multiple myeloma, Nieto concludes.

Editors Note:Dr. Nieto has received research funding from Novartis, Secura Bio, AstraZeneca, and Affimed.

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Continue Reading To See This Amazing Video

Bernese Mountain dogs were originally bred as farm dogs in Switzerland. Today, theyre popular family dogs, as they are intelligent, tolerant of other pets, and good with kids. If youre looking to add a dog to your family, an important factor to consider is the lifespan of your chosen breed.

A Bernese Mountain dog lover named Karlo Laforteza has kept an informal database of Bernese Mountain dogs that have reached old age. While these individuals are not verified, this anecdotal list provides a snapshot of this dogs lifespan.

These are 10 of the oldest Bernese Mountain dogs:

There are unsubstantiated reports of a Bernese Mountain dog that lived to be 25 years old! The dog lived in Ronsberg, Bavaria. Considering the oldest verified dog on earth is younger than that, the likelihood that this German dog lived 25 years is highly unlikely.

Bernese Mountain dogs originally arrived in the USA via a farmer from Kansas in 1926. The American Kennel Club, an organization for purebred dogs registered in the USA, officially recognized the breed in 1937.

The oldest verified Bernese mountain dog lived 15 years and two months, as documented by the AKC.

iStock.com/Kriste Sorokaite

Since these dogs are a large breed, their life expectancy is on the short side. In fact, this breed has the shortest lifespan of all dog breeds. Females live almost nine years, while males dont quite reach eight. This means that the average dog, regardless of gender, may live between eight and nine years.

In comparison, the average lifespan across all dog breeds is about 10 years old. No one is quite sure why smaller dogs live longer than large ones. It may have something to do with cell division in the larger mass of tissue present in bigger animals.

All dogs are prone to diseases. However, Bernese Mountain dogs are uniquely susceptible to certain ailments. These diseases include histiocytosis, gastric volvulus, and joint dysplasia.

Some diseases that affect old Bernese Mountain dogs are:

Making sure that your pet is as healthy as it can be is undoubtedly your top priority. Before purchasing a Bernese Mountain dog, request genetic testing that will help you avoid some of these common ailments. However, it is not possible to predict every malady that may affect your dog.

Gastric volvulus, a condition in which gas becomes trapped in the stomach, comes on fast and may kill a dog if not addressed. However, only about two percent of afflicted dogs end up losing their lives. It is common in large dogs, so its important for owners to know the signs and symptoms.

Common symptoms include bloating and retching, caused by a gas buildup in the stomach. Sometimes it resolves itself but can quickly become fatal.

In extreme cases, both entrances of the stomach become blocked. Immediate care from a veterinarian is required at this stage for the dog to survive. Older dogs are more at risk and need to be monitored closely.

Progressive retinal atrophy is an eye disease that often causes blindness in affected individuals. Blindness comes on slowly and is usually preceded by a sensitivity to light at nighttime. It isnt painful and sometimes it goes unnoticed until its advanced.

This disease is related to the retina, which refers to a cell layer on the back of the eyeball. This cell layer detects incoming light and turns it into electrical stimuli, which the brain interprets into images. Progressive retinal atrophy occurs when these retina cells slowly degrade and die.

This disease is genetic. Because of its recessive nature, both dog parents must carry the genes for the disease to appear in their offspring.

Some other affected breeds include Bedlington terriers, American cocker spaniels, rottweilers, golden retrievers, and English springer spaniels.

Over half of Bernese Mountain dogs die because of some form of cancer. More than 25 percent of this breed dies from histiocytosis in particular.

The two particular diseases associated with the term histiocytosis include systemic histiocytosis and malignant histiocytosis. Both involve the immune system cells called histiocytes. However, systemic histiocytosis affects younger dogs and is treatable, while malignant histiocytosis afflicts older dogs and is almost always fatal.

Histiocytosis is a genetic disease. As a result, the family members of affected dogs are at risk of developing the disease. Additionally, this disease skips generations, making predictions more complicated.

When the histiocytes of the immune system begin malfunctioning, they sometimes cause tumors throughout a dogs body. Fever, appetite loss, lethargy, and a quick drop in weight are common and observable symptoms.

Affected dogs will show symptoms once tumor formation causes organ degradation. Commonly afflicted organs include the spinal cord, lungs, spleen, kidneys, lymph nodes, and liver. There is no cure for this disease and symptoms usually only occur once it is advanced.

How about the fastest dogs, the largest dogs and those that are -- quite frankly -- just the kindest dogs on the planet? Each day, AZ Animals sends out lists just like this to our thousands of email subscribers. And the best part? It's FREE. Join today by entering your email below.

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Carmelo Carlo-Stella, MD, PhD, Department of Biomedical Sciences, Humanitas University, Department of Oncology and Hematology, IRCCS Humanitas Research Hospital in Rozzano, Italy, discusses the evaluation of subcutaneous and intravenous (IV) RG6234 in relapsed/refractory multiple myeloma.

A phase 1 dose-escalation trial (NCT04557150) evaluated both subcutaneous and IV RG6234 in patients with heavily pretreated multiple myeloma who previously received treatment with an immunomodulatory drug and proteasome inhibitor and are intolerant to or have no other option for standard-of-care treatment.

Updated results presented at the 2022 ASH Annual Meeting showed that patients who received IV RG6234 experienced an overall response rate (ORR) of 71.4%, and those in the subcutaneous RG6234 cohort had an ORR of 63.6%. Notably, 50% of patients in the IV cohort achieved a very good partial response or better. Additionally, 71.4% of patients who achieved complete remission (CR) became minimal residual disease negative.

RG6234 is a GPRC5DxCD3 T-cell engaging bispecific antibody that targets CD3 cells and multiple myeloma plasma cells, Carlo-Stella explains. Upon the antibody aligning with the bindings of the T-cells and myeloma cells, the T-cells are activated, in turn producing cytokines that target myeloma plasma cells, Carlo-Stella says.

Due to their off-the-shelf nature and ease of use, bispecific antibodies have gained more traction across hematologic malignancies in recent years, Carlo-Stella notes, adding that this shift has largely occurred across the landscape of lymphoproliferative disorders. These agents have created high expectations for both physicians and patients, Carlo-Stella emphasizes.

At this stage in development, RG6234 remains under evaluation in a phase 1 clinical trial that has enrolled 108 patients with relapsed/refractory multiple myeloma. Approximately half of these patients have been treated with IV RG6234, and the other half were treated subcutaneously, Carlo-Stella notes. Investigators hope to develop RG6234 as a subcutaneous drug as a fixed-duration therapy, Carlo-Stella concludes.

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Dr. Carlo-Stella on the Investigation of RG6234 in R/R Multiple ... - OncLive

The Jockey Club Press Release

LEXINGTON, Ky.The board of directors of Grayson-Jockey Club Research Foundation announced today that it has authorized expenditure of $1,498,077 to fund 12 new projects and nine continuing projects at 13 universities as well as two career development awards. The 2023 slate of research brings Graysons totals since 1983 to more than $34.1 million to underwrite 426 projects at 45universities.

The Grayson Foundation is dedicated to tackling a variety of equine health challenges, which is clearly reflected in our selected projects for this year, said Jamie Haydon, president of Grayson. Our research projects and career development awards wouldnt be possible without the kindness of our donors, and we thank them for their understanding of the significance of equine veterinary research.

Below is an alphabetical list by school of the new projects:

Transcriptomic Response To OsteoarthritisLynn Pezzanite, Colorado State UniversityThis study will highlight the role that cells of the immune system play to contributing to disease progression of osteoarthritis toward the goal of developing treatments for each stage of disease.

Efficacy of Recombinant Equine Lubricin for OsteoarthritisHeidi Reesink, Cornell UniversityThis study will assess efficacy of recombinant equine lubricin (rEqLub) in mitigating equine joint disease and identify gene and protein pathways affected by rEqLub in equine joints.

Treatment Of Meniscal Injury With Mesenchymal Stem Cells

Aimee Colbath, Cornell University

This study will determine whether intra-articular mesenchymal stem cells lead to improved meniscal healing, providing an immediate impact on how veterinarians treat equine meniscal disease.

Stem Cell Neotissue Implants for Equine Tendon HealingMandi J. Lopez, Louisiana State UniversityThis study will determine if viable neotissue implants generated from stem cells will augment current therapies to treat debilitating tendon injuries in equine athletes and companions.

Gallium Nitrate to Treat Bacterial Endometritis in MaresDale Kelley, Oklahoma State UniversityThis study proposes to develop new, safe, and efficacious antimicrobial strategies to treat antimicrobial resistance.

A VapA mRNA Vaccine for R. equi PneumoniaNoah Cohen, Texas A&M AgriLife ResearchThis grant evaluates an mRNA vaccine administered intramuscularly to foals to protect against pneumonia caused by the bacterium Rhodococcus equi, a major cause of disease and death in foals worldwide.

Genomics of Thoroughbred Stallion Subfertility

Terje Raudsepp, Texas A&M University

This project aims to identify candidate genes and regulatory variants underlying impaired acrosome reaction and subfertility in Thoroughbred stallions using multi-platform genomics.

Validation of Biomarkers for Equine NeurodegenerationCarrie J. Finno, University of California DavisIt is expected that this study will improve the diagnosis of spinal cord disease in horses.

PET MRI Sport Horse FetlockMathieu Spriet, University of California DavisThis study will compare 18F-NaF positron emission tomography (PET) with magnetic resonance imaging (MRI) for assessment of fetlock injuries in sport horses.

Antibiotic Effects On Uterine Microbiome and ResistomeIgor Canisso, University of IllinoisThis is a study of uterine microbiome and resistome of mares resistant and susceptible to endometritis treated with post-mating antibiotics.

Nanoparticle Vaccines For Equine Rotavirus BFeng Li, University of KentuckyThe vaccine candidate developed from this project will help the equine industry to control and prevent equine rotavirus B infection.

An efficacious EPM vaccine is on the waySharon Witonsky, Virginia-Maryland CVMThis study plans to identify potential MHC class I CD8 and MHC class II CD4 protective epitopes for an efficacious vaccine against Equine Protozoal Myeloencephalitis due to Sarcocystis neurona.

Career Development Awards

The Storm Cat Career Development Award, inaugurated in 2006, grants $20,000 to an individual considering a career in equine research. This year, Graysonawarded Dr. Shun Shune Kimura of University of Georgia. Dr. Kimuras research will investigate how immune and metabolic responses in systemic inflammatory response syndrome (SIRS) impact disease severity, and determine if metformin has beneficial anti-inflammatory and metabolic effects in equine SIRS.

The Elaine and Bertram Klein Career Development Award was first awarded in 2015 and grants $20,000 to a prospective equine researcher. This years recipient isDr. Bethanie Cooper of North Carolina State University. Dr. Coopers research, entitled, Myristoylated Alanine Rich C-Kinase Substrate (MARCKS) protein as a therapeutic target in equine asthma, will examine this new protein-based therapy as a potential treatment for horses suffering with equine asthma.

The track record of Graysons career development awards in supporting up-and-coming equine researchers is undeniable, and we are thrilled to extend grants to two deserving recipients this year, said Dr. Johnny Mac Smith, who serves as a consultant for the research advisory committee and is the A. Gary Lavin Chair of the foundation.

Click here for Details on the new projects.

Grayson-Jockey Club Research Foundation is traditionally the nations leading source of equine research funding. The projects it supports enhance the health and safety of horses of all breeds. Additional information about the foundation is available atgrayson.jockeyclub.org.

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Grayson-Jockey Club Research Foundation Approves 2023 Funding - Past The Wire

The expansion of Bruton tyrosine kinase (BTK) inhibitors in the treatment of patients with mantle cell lymphoma (MCL) has led to unique combinations that have resulted in improved progression-free survival (PFS) compared with standard-of-care therapy. These novel combinations have demonstrated promising efficacy in patients who have significant unmet needs. At the same time, BTK inhibitors have refined the use of autologous stem cell transplant (ASCT). Recent findings that stratify the use of BTK inhibitors in combination with ASCT were explored during major medical conferences in 2022.

In younger, fit patients, standard of care for patients with MCL consists of cytarabine, followed by ASCT and rituximab (Rituxan) maintenance.1 In patients who are less fit, the standard-of-care regimen consists of less intense immunotherapy, such as the combination of bendamustine-rituximab, followed by rituximab maintenance therapy.2

Now recent findings from the phase 3 TRIANGLE study (NCT02858258) presented at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition have suggested that adding the BTK inhibitor ibrutinib (Imbruvica) to standard chemoimmunotherapy induction, followed by ASCT and maintenance with ibrutinib for 2 years improved outcomes compared with chemoimmunotherapy and ASCT alone.3

Based on failure-free survival, the combination of ASCT plus ibrutinib is significantly superior to ASCT alone, lead author Martin Dreyling, MD, said during a presentation of the data. ASCT is not superior to ibrutinib without ASCT. Currently, there [are] no decisions about whether autologous stem cell transplant adds to ibrutinib, but certainly right now toxicity favors ibrutinib only. Dreyling is a professor of medicine and head of the Lymphoma Program in Medical Clinic III at Grosshadern Clinic at Ludwig-Maximilians-University in Munich, Germany. The open-label 3-arm trial (N=870) randomly assigned patients to arm A, arm B, and arm C. All 3 arms received 3 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine [Oncovin], and prednisone)/R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin).

In arm A (n=288) following R-CHOP/R-DHAP, patients underwent ASCT and observation. In arm B (n=292), patients underwent ASCT, followed by 2 years of ibrutinib maintenance and observation. The third arm (n=290) was treated with 2 years of ibrutinib and observation. Patients in all 3 arms received rituximab maintenance (58% in arm A, 57% in arm B, and 54% in arm C). The trial was designed to detect an HR of 0.60 and 1-sided of 0.01665, powered at 90%.

The median age of patients was 57 years (range, 27-68), and most patients (76%) were male. Overall, baseline characteristics were balanced across all 3 arms.

The 3-year failure-free survival rate was 72% with standard induction and ASCT vs 88% with ibrutinib added to induction, ASCT, and 2 years of ibrutinib maintenance (HR, 0.52; P=.0008). Investigators reported that the 3-year overall survival rate (OS) was 86% in arm A, 91% in arm B, and 92% in arm C.3

The objective response rate (ORR) after induction therapy was determined to be 94% in arm A, and patients had a complete response (CR) rate of 36%. When combining the findings from both arm B and arm C (n=559), the ORR was 98% and the CR rate was 45%.3

Dreyling said the CR rates were comparable to other US-based trials and noted that, This [study] is CT based. It is not PET [positron emission tomography]CT based. It is in line with previously published data [using this method], and when we looked at other induction regimens, this is highly comparable.

To further refine the use of ASCT, in the phase 3 SHINE study (NCT01776840), older patients with MCL who were not candidates for intensive chemotherapy or ASCT because of toxicities received ibrutinib with bendamustine-rituximab and rituximab maintenance.4 The patients were stratified by low-, intermediate-, or highrisk disease based on the MCL International Prognostic Index and randomly assigned to receive ibrutinib (560 mg daily) or placebo, plus 6 cycles of bendamustine (90 mg/m2) and rituximab (375 mg/m2).

During the 2022 American Society of Clinical Oncology Annual Meeting, Michael Wang, MD, reported on data showing that at a median follow-up of 84.7 months, treatment with the ibrutinib-based regimen (n = 261) induced a median PFS of 6.7 years (80.6 months) compared with a median of 4.4 years (52.9 months) in the placebo-based arm (HR, 0.75; 1-sided P = .011). This was a 50% improvement compared with placebo and standard of care, Wang noted.

I think this is huge progress [in the MCL landscape], Wang, lead study author and Puddin Clarke Endowed Professor, Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center in Houston, said in an interview with Targeted Therapies in Oncology.

Transplant will not be replaced totally, but I think its use will decrease dramatically based on this study.

The median age of the patients at study entry was 71 years (range, 65-87). Additional results demonstrated a CR rate of 65.5% in the ibrutinib arm and 57.6% in the placebo arm (P = .0567). However, there was no statistical significance in OS between the 2 treatment arms (P = .648).4

Wang said that based on findings from SHINE, in the frontline setting for patients older than 65 years, the combination of ibrutinib, bendamustine, and rituximab will be useful.

Despite its benefits, patients treated with BTK inhibitors will eventually experience resistance, so the search for next-generation BTK inhibitors continues. Clinicians can look towards the approval of pirtobrutinib (Jaypirca) for relapsed or refractory MCL after at least 2 lines of systemic therapy.5 Efficacy was based on findings from the phase 1/2 BRUIN study (NCT03740529), which also explored unique combinations explored during the 2022 ASH meeting.

Updated findings from the BRUIN study demonstrated durable efficacy for pirtobrutinib.6 Previously treated patients with B-cell malignancies were eligible to participate in which pirtobrutinib monotherapy was given in either the dose-escalation or dose-expansion portion of the multicenter study.

In 90 heavily pretreated patients with MCL, 77 (86%) received the recommended phase 2 dose of pirtobrutinib (200 mg once daily). The ORR was 58% (95% CI, 47%-88%) and included 18 CRs (20%) and 34 partial responses (PRs; 38%).6

The median duration of response (DOR) at the 12-month follow-up was 22 months (95% CI, 7.5-not estimable [NE]), according to investigators. The 12-month and 18-month estimated DOR rates were 57% (95% CI, 39%-72%) and 52% (95% CI, 34%68%), respectively.6

In the safety cohort that included all patients treated with pirtobrutinib (n=725), study investigators reported that the most common treatment-emergent adverse event (TEAE) of grade 3 or higher was neutropenia (20%; n=143). The most common any-grade treatment-emergent AEs, regardless of attribution, were fatigue (26%; n=191), diarrhea (22%; n=160), and contusion (19%; n=16). Neutropenia was the most common grade 3 or greater TEAE, according to Wang et al. They concluded that the agent was well tolerated with few drug-related toxicities.6

Another noncovalent BTK inhibitor, CG-806 (luxeptinib), is undergoing evaluation in early-phase clinical trials for patients with relapsed/refractory (R/R) hematologic malignancies, including MCL, chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma. Investigators demonstrated that the agent disrupts B-cell receptor signaling and induces metabolic reprogramming and apoptosis in MCL. The investigators noted that targeting BCL2 using CG-806 warrants further exploration.7

The combination of ibrutinib with zilovertamab (NCT03088878) was explored in patients with MCL and CLL in data presented during the 2022 ASH meeting. Results from the dose-finding and dose- expansion cohorts revealed ORRs of 89.3% and 91.2%, respectively, in patients with MCL (n=25) and CLL (n=31).8

We are excited [to see these data] in patients with MCL and CLL who were treated with this combination, lead author Hun Ju Lee, MD, an assistant professor of medicine in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center, said in an interview with Targeted Therapies in Oncology.

In the MCL population, investigators reported a median DOR of 34.1 months (95% CI, 13.67-NE).

At the 6-month, 12-month, and 26-month follow-ups, the CR rate was 29.6%, 37%, and 40.7%, respectively.

The median PFS was 35.9 months (95% CI, 17.3-NE) after a median follow-up of 15.1 months, and the landmark PFS rate was approximately 70% at 30 months.8

In a subpopulation of patients with tumors harboring TP53 mutations, the ORR was 83.3% (with 1 CR and 4 PRs), median DOR was 13.84 months (95% CI, 11.3-NE), median PFS was 17.3 months (95% CI, 2.85NE), and landmark PFS rate at 12 months was greater than 80%. In patients whose Ki67 index score was 30% or greater (n=14), the ORR was 85.7%, with 5 CRs and 7 PRs.8

The combination of ibrutinib and ixazomib (Ninlaro) was evaluated in patients with relapsed/refractory (R/R) MCL.9

In the phase 1 portion, patients could be either ibrutinib nave or ibrutinib pretreated. In phase 2, patients were divided into 2 cohorts: ibrutinib nave or ibrutinib pretreated. Investigators noted that the ibrutinib-pretreated cohort was closed early because of slow enrollment.

In the phase 1 portion (n=12), 2 dose levels of ixazomib were evaluated (3 mg and 4 mg on days 1, 8, and 15 of a 28-day cycle) with ibrutinib at 560 mg daily. Treatment continued until disease progression or unacceptable toxicity.

Thirty-five patients who were ibrutinib-nave were enrolled in phase 2. The CR rate was 42.9% (95% CI, 26.3%-60.6%), and the ORR was 77.1% (95% CI, 59.9%-89.6%).

Median DOR was 8 cycles (range, 1-23), with 23% of patients remaining on treatment after a median of 12 cycles (range, 6-19). Twenty-seven patients discontinued treatment because of AEs (n=13), progression (n=9), death due to an AE (n=1), physician discretion (n=1), and treatment delay (n=1).

The primary end point for the phase 2 portion was CR within the first year of the study treatment.9

Grade 3 AEs including hypertension, lymphopenia, neutropenia, thrombocytopenia, rash, syncope, and atrial fibrillation were reported in 1 patient or more. AEs leading to treatment discontinuation included rash (n=2), atrial fibrillation (n=2), and hepatic failure, sepsis, fatigue/anorexia, peripheral neuropathy, muscle spasms, arthralgia, thrombocytopenia, diarrhea, and heart failure (n=1 each).9

Twelve patients with previously untreated MCL were enrolled in a phase 2 study (NCT04783415).10 Acalabrutinib (Calquence) 100 mg was given twice daily, umbralisib (Ukoniq) 800 mg was given daily, and ublituximab-xiiy (Briumvi) 900 mg was given intravenously on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles. After 6 cycles, patients continued maintenance with oral agents and ublituximab every 2 cycles (planned for 24 cycles).

The primary end point was efficacy as determined by CR rate, and the secondary end point was safety. Enrollment was suspended by the FDA in February 2022 due to general safety concerns with umbralisib and other PI3K inhibitors.11

Because the first 2 patients who enrolled developed grade 3 and 4 aspartate aminotransferase and alanine transaminase levels, the trial design was amended so that umbralisib was given on days 1 through 14 of cycle 1 and days 1 through 7 of subsequent cycles. Four patients were unable to continue taking acalabrutinib because of elevated aspartate aminotransferase and alanine transaminase levels and continued on umbralisib/ublituximab alone.10

All 12 patients achieved CR (ORR, 100%; CR, 100%). As of data presented at the 2022 ASH meeting, 10 patients remained on therapy. Danilov et al concluded that the combination of continuous umbralisib and acalabrutinib resulted in liver function abnormalities but that intermittent dosing of umbralisib was well tolerated.10

BTK inhibitors in combination with cellular therapies such as chimeric antigen receptor (CAR) T-cell therapy are under evaluation in ongoing trials. Whether to use these agents sequentially or concomitantly remains to be determined.12 The TABLE13-16 summarizes a sample of trials that explore the combination of CAR T-cell therapy with BTK inhibitors.

The evolution of BTK inhibitors in MCL has established this class of agent as a mainstay in the R/R setting, and their potential for further benefit continues to be explored. Unique combinationsincluding those that pair BTK inhibitors with targeted therapies or cellular therapies and second-generation agents further enhance the efficacy of BTK inhibitors, and their use remains a backbone approach moving forward.

REFERENCES

1. Le Gouill S, Thieblemont C, Oberic L, et al; LYSA Group. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017;377(13):1250-1260. doi:10.1056/NEJMoa1701769

2. Visco C, Chiappella A, Nassi L, et al. Rituximab, bendamustine, and low-dose cytarabine as induction therapy in elderly patients with mantle cell lymphoma: a multicentre, phase 2 trial from Fondazione Italiana Linfomi. Lancet Haematol. 2017;4(1):e15-e23. doi:10.1016/S2352-3026(16)30185-5

3. Dreyling M, Doorduijn JK, Gine E, et al. Efficacy and safety of ibrutinib combined with standard first-line treatment or as substitute for autologous stem cell transplantation in younger patients with mantle cell lymphoma: results from the randomized Triangle trial by the European MCL Network. Blood. 2022;140(suppl 1):1-3. doi:10.1182/ blood-2022-163018

4. Wang M, Jurczak W, Jerkeman M, et al. Primary results from the double-blind, placebo-controlled, phase III SHINE study of ibrutinib in combination with bendamustine-rituximab (BR) and R maintenance as a first-line treatment for older patients with mantle cell lymphoma (MCL). J Clin Oncol. 2022;40(suppl 17):LBA7502. doi:10.1200/JCO.2022.40.17_ suppl.LBA7502

5. FDA grants accelerated approval to pirtobrutinib for relapsed or refractory mantle cell lymphoma. FDA. Accessed January 30, 2023. http://bit.ly/40oYhYC

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BTK Inhibitors Stretch Frontline Approaches in Mantle Cell Lymphoma - Targeted Oncology