Atrial Fibrillation

An engineer experienced with radiofrequency (RF) ablation systems might wonder what all the fuss is about when looking at the design of a pulsed field ablation (PFA) system. Compared to an RF ablation generator, a PFA generator is going to look much less complicated, perhaps with only a tenth as many parts. But the seemingly simpler schematics can be deceiving. “The difference is that in a PFA power supply, the way that those components are being used is just so different, and they’re being stressed to the limits of what their ratings are in a way that just isn’t obvious to most engineers,” said Dan Friedrichs, an engineer at Minnetronix Medical. “… There’s more complexity than meets the eye.” Friedrichs leads development engineering efforts at Minnetronix Medical for the commercialization of surgical energy devices. He’s also shared his expertise with Medical Design & Outsourcing readers through several contributions on the topic. As the first PFA systems win FDA approval for treating atrial fibrillation (AFib), we asked Friedrichs and his colleague, Aaron McCabe (who, as Minnetronix’s technology segment director, focuses on surgical energy applications), to explain some of the design considerations for PFA generators. These generators send energy pulses through catheters inside the heart to disrupt erratic cardiac cells. “Some of the specs for these PFA systems require that you pick just these enormous transistors, even though the transistors aren’t processing a lot of power — they don’t actually get hot,” Friedrichs said. “… You open the lid of one of these power supplies and see these giant transistors, but they aren’t mounted to heat sinks. They aren’t processing any large amount of power, but those are the types of parts that you have to select to meet what turns out to be very esoteric requirements around delivering the types of pulses that are necessary in PFA.” “And that extends basically to all the components. Something like a capacitor inside a PFA generator that has these really strong pulsed currents that are uncommon in most other power supplies, you have to select just the right type of capacitor for it,” Friedrichs continued. “Every electronic component that goes into the power supply superficially looks very easy, but to actually get it to work, there’s all sorts of tricks that are not obvious.” PFA generators and catheters create energy fields that can open temporary or permanent holes in the walls of targeted heart cells through a process called electroporation without heat or damage to nearby nerves. A PFA procedure for AFib can be completed hours faster than the same procedure with RF, while it has less risk of damaging surrounding tissue because it’s nonthermal. “If you were to look at the outputs of these PFA systems, a typical specification could be 2,000 volts and 100 or 200 amps,” Friedrichs said. “You’d say, ‘Oh my gosh, that’s 200 kilowatts of power. Are we going to vaporize the patient when we connect this to them?’ But it turns out that the duty cycle is very short, like 1% or 2% on time, so the average power delivered to the patient is a watt or two at most. It’s not a thermal effect. But to design a power supply that’s capable of supporting those instantaneous high voltages and those instantaneous high currents. That’s actually a technical challenge.” “Because of those really high instantaneous voltages and currents, there is consideration for how do you, for example, route cables within a box, because high currents flowing through cables create magnetic fields, they interact with other components,” Friedrichs continued. “So the tolerances and the design controls that you need to go through to ensure that you get a consistent repeatable result are significant and probably not obvious.” The right recipe for PFA With RF ablation, there’s generally only one variable to control when a thermal catheter is in the heart: time. “We don’t want to create steam in the heart, so we set the temperature just below 100°C, just below boiling. Then it’s just a matter of time, because time and temperature together is what damages tissue. But that’s also the reason why these are long procedures,” Friedrichs said. Time is just one variable with PFA, and the pulses are generally measured in microseconds or milliseconds. “With PFA we have literally an infinite number of permutations of the variables,” Friedrichs said. “We have the pulse amplitude, we have the pulse width, we have the spacing between the pulses, we have the number of pulses, we have the polarity of the pulses, often there will just be arbitrary delays between different pulses, there’s recipes that have different amplitudes of pulses. Those are the parameters that vary — and that’s just on the generator, and then we connect it to a catheter and the catheter’s geometry can vary as well. We have not only an infinite space of variables that can be tuned to this, but then it’s also really hard to measure which of those given recipes is effective.” While the voltage is generally thousands of volts, the more important measure is volts per centimeter: field strength, which can be modified by changing the spacing between electrodes on the catheter. The amplitude of the pulses is “probably the strongest lever in getting the tissue selectivity that we want,” Friedrichs said, referring to PFA’s ability to ablate only heart muscle cells while sparing nearby nerves in the esophagus. “But then also it’s the width of the pulse,” he continued. “We’re applying a pulse that has an amplitude and a duration. We have a delay time before we deliver the next pulse in the sequence, and that can be different than the pulse width. Then there’s the number of pulses we apply. The pulses don’t all have to be the same polarity — for instance, we can have positive pulses, then we can have a negative pulse, or we could have two positive pulses and then a lower amplitude but longer negative pulse. And so all those combinations become an infinite number of permutations.” The timing of pulses can help counteract muscle stimulation, one of PFA’s potential side effects. That could trigger a heart contraction (or systole) or cause a patient to cough, which in turn could cause trauma if they’re on a ventilator. “The difference is between a heart defibrillator and one of these systems [is] timing,” Friedrichs said. “Can we rely on software to get the timing correct 100% of the time, or do we think that there’s a one in a million chance that the software might crash while we’re delivering the therapy to this patient?” To avoid that risk of a crash, a device developer might instead write code on a field programmable gate array (FPGA) or implement the control in purely discrete analog circuitry. “Good partitions between software and hardware enable confidence and safety,” McCabe said. And while PFA catheters are usually larger than RF ablation catheters — meaning more risk for accidental mechanical damage within the heart — PFA’s nonthermal and tissue-selective therapy is a big step forward in safety. “Even if the only thing that PFA gives us is safety against accidentally burning the esophagus — which is, to begin with a rare situation, maybe a one-in-1000 type of situation — even that is valuable enough to make this wholesale change in this multi-billion-dollar market,” Friedrichs said. Designing PFA systems for flexibility “We have so many variables, and we don’t have a good understanding of which variables are important,” Friedrichs said. “… When you compare it to legacy technologies like RF ablation, RF ablation has a lot less concern about process control in production of equipment, because we can actually measure what’s happening in the tissue. We literally have a temperature sensor in the tissue and we can measure that it’s being effective, and the variation back in the generator, it almost doesn’t matter. But with PFA, we don’t have the ability to detect that in the tissue. And then we also don’t have the ability to assess efficacy in real-time. So we’re really relying entirely on the recipe of how the pulse generator was built to be consistent and to give the same thing for every patient.” In the design phase, that requires flexibility to dial in the appropriate dose titration for effective therapy, said McCabe. “Unless you’re fortunate enough to work at one of the places that has already cracked it and have their own proprietary methods for treating, more than likely you’re at the beginning of that journey and you want to be able to dial in and alter the different parameters of your pulse,” McCabe said. “You’ve got kind of two sides of the same coin here: you need a lot of flexibility, and then you need to transition to be able to also lock down consistently and repeatedly once you’ve nailed it.” Because there aren’t a lot of electronics operating with similar parameters as PFA generators, device designers may need to consider customized components. “One of the challenges we face on all surgical energy systems is that we have to electrically isolate the patient from mains power for safety,” Friedrichs said. “Components like transformers, digital isolators and isolated power supplies don’t exist specifically for this type of system. That requires us to be very creative and either design our own or adapt something on the market to fit these unique requirements.” The future of PFA While PFA in its current form is generating excitement for its speed and safety, one issue on safety regulators’ radar is bubble formation inside the heart during treatment. Bubbles — like those created by boiling blood above 100°C with thermal ablation — create a risk of embolism, and PFA system developers such as Abbott have discussed the risks with the FDA. “There’s other mechanisms by which you could have bubbles,” Friedrichs said. “You’ve got voltage in a ionic solution — you can create electrolysis, separating ions and create chemical reaction products that way. It’s also possible to have very, very localized heating because these electrodes may have sharp edges, and so you could have hotspots there. I think the science is unsettled as to how significant of an issue this could be. But it’s unavoidable.” Friedrichs said he’s interested to see how PFA will develop in the years ahead. While thermal fields are very difficult to model computationally, the equations for electric fields are simple. “You can imagine a future where we are able to analytically plan out what kind of energy dosage we want to give a patient because right now, it’s more or less, ‘You have this disease, you are getting this dose.’ It’s not patient specific, it’s not titrated to the extent of their disease,” Friedrichs said. “But in the future, you can imagine that we would be able to actually come up with a patient-specific energy prescription and deliver it just for that patient’s disease. And that’s unique to electric fields.”

The supplemental Biologics License Application for Abecma in this indication remains under review with the FDA; Abecma has been approved in Japan and Switzerland and received a positive CHMP Opinion by the European Medicines Agency based on KarMMa-3 PRINCETON, N.J. & CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Bristol Myers Squibb Company (NYSE: BMY) and 2seventy bio, Inc. (Nasdaq: TSVT) today announced that the U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) voted positively (8-3) that Abecma (idecabtagene vicleucel) demonstrated a favorable benefit/risk pro patients with triple-class exposed relapsed or refractory multiple myeloma based on results from the pivotal Phase 3 KarMMa-3 study, including the key secondary endpoint of overall survival. The recommendation from the ODAC will be considered by the FDA during its ongoing review of the supplemental Biologics License Application (sBLA) for Abecma for this patient population. The FDA has not yet assigned a new target action date for review of the sBLA. “We are extremely pleased with the positive outcome of the ODAC meeting, which recognizes the favorable benefit/risk pro Abecma, and based on results from the KarMMa-3 study, we are confident in the significant clinical benefit that Abecma delivers for patients with triple-class exposed relapsed or refractory multiple myeloma, an incurable disease with no clear effective standard of care in earlier lines of therapy,” said Anne Kerber, senior vice president, head of Late Clinical Development, Hematology, Oncology and Cell Therapy, Bristol Myers Squibb. “We look forward to working with the FDA as it completes review of our sBLA in order to bring this potentially transformative therapy to more patients in need.” “The favorable and supportive outcome of the ODAC meeting brings us another step closer to expanding the benefits of Abecma to myeloma patients earlier in their treatment course,” said Anna Truppel-Hartmann, senior vice president, Clinical Research and Development, 2seventy bio. “We believe in the strength of the KarMMa-3 data and remain committed to increasing treatment options and improving outcomes for patients living with multiple myeloma.” The positive vote from the ODAC followed discussion of the interim overall survival data from the KarMMa-3 study which was presented at the 2023 American Society of Hematology (ASH) Annual Meeting and Exposition in December 2023. “With patients becoming triple-class exposed earlier in the multiple myeloma treatment paradigm, it is critical that new treatment options with the potential to improve long-term outcomes are available as early as possible,” said Sagar Lonial, MD, FACP, professor and chair, Department of Hematology & Medical Oncology, Emory University School of Medicine, chief medical officer, Winship Cancer Institute of Emory University. “We are thankful that today’s ODAC vote recognizes this unmet need and helps to advance ide-cel, a novel treatment option with demonstrated clinically meaningful benefit, for patients with triple-class exposed relapsed or refractory multiple myeloma.” Abecma was recently approved in Japan and Switzerland for patients with relapsed and/or refractory multiple myeloma who have received at least two prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody based on the KarMMa-3 study, making it the first CAR T cell therapy to receive regulatory approval for use in earlier lines of therapy for patients with relapsed or refractory multiple myeloma. Abecma also received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) for the extension of indication to include the treatment of patients with triple-class exposed relapsed and refractory multiple myeloma after at least two prior therapies, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody and have demonstrated disease progression on the last therapy. About Abecma Abecma is a CAR T cell therapy that recognizes and binds to the B-cell maturation antigen (BCMA) on the surface of multiple myeloma cells leading to CAR T cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells. Abecma is the first-in-class BCMA-directed CAR T cell immunotherapy approved by the U.S. FDA for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Please see the Important Safety Information section below, including Boxed WARNINGS for Abecma regarding CRS, neurologic toxicities, Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome and Prolonged Cytopenia. Abecma is being jointly developed and commercialized in the U.S. as part of a Co-Development, Co-Promotion, and Profit Share Agreement between Bristol Myers Squibb and 2seventy bio. Abecma is also approved in the European Union, Switzerland, Japan, the United Kingdom and Israel for adult patients with triple-class exposed relapsed or refractory multiple myeloma after three to four or more prior lines of therapy. Bristol Myers Squibb assumes sole responsibility for Abecma drug product manufacturing and commercialization outside of the U.S. The companies’ broad clinical development program for Abecma includes ongoing and planned clinical studies (KarMMa-2, KarMMa-9) for patients with multiple myeloma. For more information visit clinicaltrials.gov. U.S. Important Safety Information BOXED WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, AND PROLONGED CYTOPENIA Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients following treatment with ABECMA. Do not administer ABECMA to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids. Neurologic Toxicities, which may be severe or life-threatening, occurred following treatment with ABECMA, including concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with ABECMA. Provide supportive care and/or corticosteroids as needed. Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS) including fatal and life-threatening reactions, occurred in patients following treatment with ABECMA. HLH/MAS can occur with CRS or neurologic toxicities. Prolonged Cytopenia with bleeding and infection, including fatal outcomes following stem cell transplantation for hematopoietic recovery, occurred following treatment with ABECMA. ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS. WARNINGS AND PRECAUTIONS: Cytokine Release Syndrome (CRS): CRS, including fatal or life-threatening reactions, occurred following treatment with ABECMA in 85% (108/127) of patients. Grade 3 or higher CRS occurred in 9% (12/127) of patients, with Grade 5 CRS reported in one (0.8%) patient. The median time to onset of CRS, any grade, was 1 day (range: 1 - 23 days) and the median duration of CRS was 7 days (range: 1 - 63 days). The most common manifestations included pyrexia, hypotension, tachycardia, chills, hypoxia, fatigue, and headache. Grade 3 or higher events that may be associated with CRS include hypotension, hypoxia, hyperbilirubinemia, hypofibrinogenemia, acute respiratory distress syndrome (ARDS), atrial fibrillation, hepatocellular injury, metabolic acidosis, pulmonary edema, multiple organ dysfunction syndrome, and HLH/MAS. Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. CRS has been reported to be associated with findings of HLH/MAS, and the physiology of the syndromes may overlap. In patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate for evidence of HLH/MAS. Fifty four percent (68/127) of patients received tocilizumab (single dose: 35%; more than 1 dose: 18%). Overall, 15% (19/127) of patients received at least 1 dose of corticosteroids for treatment of CRS. All patients that received corticosteroids for CRS received tocilizumab. Ensure that a minimum of 2 doses of tocilizumab are available prior to infusion of ABECMA. Monitor patients at least daily for 7 days following ABECMA infusion at the REMS-certified healthcare facility for signs or symptoms of CRS and monitor patients for signs or symptoms of CRS for at least 4 weeks after ABECMA infusion. At the first sign of CRS, institute treatment with supportive care, tocilizumab and/or corticosteroids as indicated. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. Neurologic Toxicities: Neurologic toxicities, which may be severe or life-threatening, occurred following treatment with ABECMA in 28% (36/127) of patients receiving ABECMA, including Grade 3 in 4% (5/127) of patients. One patient had ongoing Grade 2 neurotoxicity at the time of death. Two patients had ongoing Grade 1 tremor at the time of data cutoff. The median time to onset of neurotoxicity was 2 days (range: 1 - 42 days). CAR T cell-associated neurotoxicity resolved in 92% (33/36) of patients with a median time to resolution of 5 days (range: 1 - 61 days). The median duration of neurotoxicity was 6 days (range: 1 - 578) in all patients including 3 patients with ongoing neurotoxicity. Thirty-four patients with neurotoxicity had CRS with onset in 3 patients before, 29 patients during, and 2 patients after CRS. The most frequently reported manifestations of CAR T cell-associated neurotoxicity include encephalopathy, tremor, aphasia, and delirium. Grade 4 neurotoxicity and cerebral edema in 1 patient, Grade 3 myelitis, and Grade 3 parkinsonism have been reported with ABECMA in another study in multiple myeloma. Monitor patients at least daily for 7 days following ABECMA infusion at the REMS-certified healthcare facility for signs or symptoms of neurologic toxicities and monitor patients for signs or symptoms of neurologic toxicities for at least 4 weeks after ABECMA infusion and treat promptly. Rule out other causes of neurologic symptoms. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed. Counsel patients to seek immediate medical attention should signs or symptoms occur at any time. Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS): HLH/MAS occurred in 4% (5/127) of patients receiving ABECMA. One patient developed fatal multi-organ HLH/MAS with CRS and another patient developed fatal bronchopulmonary aspergillosis with contributory HLH/MAS. Three cases of Grade 2 HLH/MAS resolved. All events of HLH/MAS had onset within 10 days of receiving ABECMA with a median onset of 7 days (range: 4 - 9 days) and occurred in the setting of ongoing or worsening CRS. Two patients with HLH/MAS had overlapping neurotoxicity. The manifestations of HLH/MAS include hypotension, hypoxia, multiple organ dysfunction, renal dysfunction, and cytopenia. HLH/MAS is a potentially life-threatening condition with a high mortality rate if not recognized early and treated. Treatment of HLH/MAS should be administered per institutional guidelines. ABECMA REMS: Due to the risk of CRS and neurologic toxicities, ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS. Further information is available at or 1-888-423-5436. Hypersensitivity Reactions: Allergic reactions may occur with the infusion of ABECMA. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO) in ABECMA. Infections: ABECMA should not be administered to patients with active infections or inflammatory disorders. Severe, life-threatening, or fatal infections occurred in patients after ABECMA infusion. Infections (all grades) occurred in 70% of patients. Grade 3 or 4 infections occurred in 23% of patients. Overall, 4 patients had Grade 5 infections (3%); 2 patients (1.6%) had Grade 5 events of pneumonia, 1 patient (0.8%) had Grade 5 bronchopulmonary aspergillosis, and 1 patient (0.8%) had cytomegalovirus (CMV) pneumonia associated with Pneumocystis jirovecii. Monitor patients for signs and symptoms of infection before and after ABECMA infusion and treat appropriately. Administer prophylactic, pre-emptive, and/or therapeutic antimicrobials according to standard institutional guidelines. Febrile neutropenia was observed in 16% (20/127) of patients after ABECMA infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care. Viral Reactivation: CMV infection resulting in pneumonia and death has occurred following ABECMA administration. Monitor and treat for CMV reactivation in accordance with clinical guidelines. 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 plasma cells. Perform screening for CMV, HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV) in accordance with clinical guidelines before collection of cells for manufacturing. Prolonged Cytopenias: In the clinical study, 41% of patients (52/127) experienced prolonged Grade 3 or 4 neutropenia and 49% (62/127) experienced prolonged Grade 3 or 4 thrombocytopenia that had not resolved by Month 1 following ABECMA infusion. In 83% (43/52) of patients who recovered from Grade 3 or 4 neutropenia after Month 1, the median time to recovery from ABECMA infusion was 1.9 months. In 65% (40/62) of patients who recovered from Grade 3 or 4 thrombocytopenia, the median time to recovery was 2.1 months. Three patients underwent stem cell therapy for hematopoietic reconstitution due to prolonged cytopenia. Two of the three patients died from complications of prolonged cytopenia. Monitor blood counts prior to and after ABECMA infusion. Manage cytopenia with myeloid growth factor and blood product transfusion support. Hypogammaglobulinemia: Hypogammaglobulinemia was reported as an adverse event in 21% (27/127) of patients; laboratory IgG levels fell below 500 mg/dl after infusion in 25% (32/127) of patients treated with ABECMA. Monitor immunoglobulin levels after treatment with ABECMA and administer IVIG for IgG <400 mg/dl. Manage appropriately per local institutional guidelines, including infection precautions and antibiotic or antiviral prophylaxis. The safety of immunization with live viral vaccines during or after ABECMA treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during ABECMA treatment, and until immune recovery following treatment with ABECMA. Secondary Malignancies: Patients treated with ABECMA may develop secondary malignancies. Monitor life-long for secondary malignancies. If a secondary malignancy occurs, contact Bristol-Myers Squibb at 1-888-805-4555 to obtain instructions on patient samples to collect for testing of secondary malignancy of T cell origin. Effects on Ability to Drive and Operate Machinery: Due to the potential for neurologic events, patients receiving ABECMA are at risk for altered or decreased consciousness or coordination in the 8 weeks following ABECMA infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period. Adverse Reactions: The most common nonlaboratory adverse reactions include CRS, infections – pathogen unspecified, fatigue, musculoskeletal pain, hypogammaglobulinemia, diarrhea, upper respiratory tract infection, nausea, viral infections, encephalopathy, edema, pyrexia, cough, headache, and decreased appetite. Please see full Prescribing Information, including Boxed WARNINGS and Medication Guide. Bristol Myers Squibb: Creating a Better Future for People with Cancer Bristol Myers Squibb is inspired by a single vision — transforming patients’ lives through science. The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine and, through innovative digital platforms, are turning data into insights that sharpen their focus. Deep understanding of causal human biology, cutting-edge capabilities and differentiated research platforms uniquely position the company to approach cancer from every angle. Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. As a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future. Learn more about the science behind cell therapy and ongoing research at Bristol Myers Squibb here. About Bristol Myers Squibb Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube, Facebook and Instagram. About 2seventy bio Our name, 2seventy bio, reflects why we do what we do - TIME. Cancer rips time away, and our goal is to work at the maximum speed of translating human thought into action – 270 miles per hour – to give the people we serve more time. With a deep understanding of the human body’s immune response to tumor cells and how to translate cell therapies into practice, we’re applying this knowledge to deliver the first FDA-approved CAR T cell therapy for multiple myeloma. We are focused on delivering therapies that are designed with the goal to “think” smarter and faster than the disease. Importantly, we remain focused on accomplishing these goals by staying genuine and authentic to our “why” and keeping our people and culture top of mind every day. For more information, visit . Follow 2seventy bio on social media: Twitter and LinkedIn. 2seventy bio is a trademark of 2seventy bio, Inc. Bristol Myers Squibb Cautionary Statement Regarding Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, that future study results may not be consistent with the results to date, that Abecma® (idecabtagene vicleucel) may not receive regulatory approval for the additional indication described in this release in the currently anticipated timeline or at all, that any marketing approvals, if granted, may have significant limitations on their use, and, if approved, whether such product candidate for such additional indication described in this release will be commercially successful. No forward-looking statement can be guaranteed. It should also be noted that acceptance of the sBLA does not change the standards for FDA approval, that validation by the EMA of the application does not change the standards for EMA approval, and that acceptance of the sNDA does not change the standards for Japan’s Ministry of Health, Labour and Welfare approval. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2023, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. 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These risks, assumptions, uncertainties and other factors include, among others, the possibility that Abecma may not receive FDA approval for the indication described in this release in the currently anticipated timeline or at all, that any marketing approvals, if granted, may have significant limitations on their use, that future study results may not be consistent with the results to date, that Abecma may not be commercially successful and that collaboration with Bristol Myers Squibb may not continue or be successful. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect 2seventy bio’s business, particularly those identified in the risk factors discussion in 2seventy bio’s Annual Report on Form 10-K, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. 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MEMPHIS, Tenn. , March 14, 2024 /PRNewswire/ -- Methodist Le Bonheur Healthcare is proud to announce it is the first healthcare system in Tennessee to offer the Medtronic PulseSelect™ Pulsed Field Ablation (PFA) technology to patients suffering from atrial fibrillation (AF). It's also one of the first 25 sites to roll out this procedure in the United States. "Pulsed Field Ablation is a paradigm-shifting technology," said Dr. Yehoshua Levine, division chief of cardiac electrophysiology at Methodist Le Bonheur Healthcare who performed the first PFA at Methodist University Hospital. "This type of development happens probably once every 15 years and it's a complete change in the way we perform ablation." AFib is the most common type of treated heart arrhythmia, and it affects more than 59 million people around the world. An arrhythmia is when a heart beats irregularly or too fast or too slow. Currently, traditional ablations are conducted by heating heart tissue or freezing it. With PFA, this technique only takes minutes to target a specific area of the heart tissue to resolve arrhythmia. Ablation is now even more efficient because the same procedure is reduced to seconds by using electrical pulses to target heart tissue. This efficiency means less time that a patient is under anesthesia and leads to faster recovery. "PFA allows us to deliver timely treatment to more patients when they need help the most," said Dr. James Litzow, cardiac electrophysiologist with Methodist Le Bonheur Germantown Hospital. "Being the first health system in the Memphis-area to use this technology demonstrates our steadfast commitment to innovation for the benefit of our patients." Across the MLH system, the cardiovascular team at Methodist University Hospital conducted the first PFA for the healthcare system on March 11 with Methodist Le Bonheur Germantown Hospital's cardiovascular team conducting its first PFA on March 12. About Methodist Le Bonheur Healthcare Based in Memphis, Tennessee, Methodist Le Bonheur Healthcare has been caring for patients and families regardless of their ability to pay for more than 100 years. Guided by roots in the United Methodist Church and founded in 1918 to help meet the growing need for quality healthcare in the greater Memphis area, MLH has grown from one hospital into a comprehensive healthcare system with 13,000 Associates supporting six hospitals, including nationally ranked Le Bonheur Children's Hospital, ambulatory surgery centers, outpatient facilities, a hospice residence and physician and specialty practices serving communities across the Mid-South. From transplants and advanced heart procedures to expert neurology services and compassionate cancer care, Methodist Le Bonheur Healthcare offers clinical expertise with a focus on improving every life we touch. SOURCE Methodist Le Bonheur Healthcare