Geneology International

Month: February 2022

  • Duke coach Mike Krzyzewski provides an update to his health status

    Duke coach Mike Krzyzewski provides an update to his health status

    Duke mentor Mike Krzyzewski supplied the community with an update on his wellbeing problem soon after he experienced difficulties that prevented him from coaching the second 50 percent of the Blue Devils’ 76–74 victory around Wake Forest on Tuesday.

    Speaking on ESPNU radio with Sean Farnham, Krzyzewski claimed he was feeling “better.”

    “We went through a pretty taxing part of our year with 4 games in eight times, late travel,” Krzyzewski reported. “I continue to prepare the exact way. That day, for Wake, I was not experience that superior. But in the course of the match, all through the first 50 percent, I acquired lightheaded on the bench. I known as [assistant coaches] Jon Scheyer and Chris Carrawell more than and said, ‘I’m not emotion wonderful you guys do extra. Really don’t keep again.’ Then I began feeling a little bit improved through the 50 {fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}, and then as I’m strolling off the court at halftime, it was the very first time I experienced stood up. I definitely thought I could move out.”

  • Celebrities Over 50 Share Their Workout Tips

    Celebrities Over 50 Share Their Workout Tips

    Let’s be authentic: with each individual birthday, it will get a lot easier to be discouraged and compare yourself—and much more pointedly, your physique—to your young self. And although you can make just about every justification in the guide as to why you do not seem or come to feel like you used to, you can find sufficient proof that when it will come to health and fitness, age can just be one more range if you are ready to place in the operate.

    We generally spotlight the education routines of notable men here at MH for our Practice Like films collection, and a lot more frequently than you’d consider, fellas in excess of 50 a long time of age show out even more powerful than the celebs in their twenties.

    “In your fifties, you assume you need to be slowing down. But I’m in all probability in the most effective shape of my daily life at 52,” Frank Grillo formerly advised Men’s Health and fitness.

    We highlighted some of the most critical classes these skilled men (like Lenny Kravitz, Christopher Meloni, Dave Bautista, and Lou Ferrigno) shared in their workout walkthroughs. They all provide as evidence that it actually is doable to be in your very best shape even as you get older. Below are 8 of their very best tips to remain jacked above 50.

    Tip 1: You should not Skip Squats

    Though you could be tempted to place all your focus into your arms, upper body, and shoulders as you sluggish down, you’d be selling you shorter if you skimp on your lessen overall body schooling. Even when you’re past 50, ‘Don’t skip leg day’ however applies.

    “I seriously really like squatting. I’m one of people tall guys, for some rationale I had this advanced when I was youthful, I never ever preferred to be the guy with skinny legs,” claims Dave Bautista. “I like squatting—love it.”

    But 1 of the gains of age is that you can discover to really like new points, like Lenny Kravitz. “I applied to loathe legs. I failed to like it—I was not into that,” he suggests. “But now I am.

    Chris Meloni, whose reduced half is renowned in its possess suitable, also arrived all over to squatting afterwards in everyday living.

    “The squats had been, I am ashamed to say, kind of new to me. I have been doing the job out lots of several years and I constantly shied away. I often did the sleds… every little thing but squats. And the rationale why is that they are seriously challenging,” claims Meloni. “I now am a substantial proponent of squats, and I love them.”

    Suggestion 2: Embrace Struggle Training

    Punching fires up your core muscle tissue, shoulders, and back, and the type of schooling often related with boxing is sure to whip you into wonderful situation if you place your all into the intense exercise sessions. But the sport can have additional profound gains, too.

    “We do the similar point about and about and in excess of all over again so that it is really just a language. It can be my therapy,” Grillo claims about his boxing routine. “It retains my mind relocating, and where the head goes the human body follows. So it keeps my brain healthier, my physique relocating, and retains me nutritious.”

    “Combat instruction is the toughest education I have at any time done. I really don’t think people today recognize how grueling a five-minute spherical is,” claims Bautista, a previous professional wrestler. “To look at these men do a five-moment spherical, I know what they are likely by, and it can be just a little something you have to regard and admire. But I feel combat coaching is just the toughest matter I’ve at any time accomplished in my existence.”

    Tip 3: Do not Be Fearful of Cardio

    You could possibly be a runner—but you don’t have to be. Grillo uses shadowboxing to ramp up his coronary heart charge.

    Bautista does too, but he also works by using machines to get going. “It generally get my cardio in on an Assault bicycle, and with martial arts and boxing,” he claims.

    Tip 4: Train Anyplace and Everywhere you go

    With all your knowledge, you may well get trapped in a behavior of only associating workouts with the health club. Drop that line of thinking—you can get your schooling accomplished any place if you happen to be keen and ready to modify. If you will not have a bench, for instance, you can be like Lenny Kravitz and use a… tropical tree trunk (or far more likely, an ottoman in your residing space). You might even locate that you like the improve of scenery.

    “This is the place I training. I can get an astounding exercise below,” Kravitz mentioned of his tree trunk setup in the Bahamas. “This exercise session is wonderful… I might alternatively be exterior in character than currently being cooped up inside of a gym.”

    Idea 5: Mentality Is Every little thing

    Numerous of these men come across that training assists them to sense pleased with themselves. They wind up with more than just huge muscle tissue.

    “If you can handle your entire body and improve your body, there is certainly no purpose you won’t be able to do nearly anything past this, mainly because people that are not prosperous with their body are not quite thriving in their existence,” says Lou Ferrigno.

    “There’s no policies,” states Grillo. “So never imagine as you get more mature you get slower. You actually can raise the amount you get the job done out, and sense good,”

    “I hit my stride afterwards in existence, and I want to make the most of it to keep younger and nutritious and rejuvenated and almost everything that will make me come to feel excellent about myself, and also carries on my career,” says Bautista. “It is priceless to me.”

    Idea 6: Train for Entire body and Intellect

    “I function out five to 6 days a week,” says Kravitz. “Training retains my brain, human body and spirit the place I can be much more resourceful.”

    “If I had my option I would exercise routine just about every day—sometimes I training twice a working day,” claims Bautista. “It is really not some thing I have to do to remain in shape, it can be a little something I need to do to retain my mind correct.”

    “I possibly practice 4 hrs a working day. Yet again, in your 50s you feel you really should be slowing down…I’ve possibly gotten in the very best condition of my life at 52 a long time previous,” claims Grillo.

    “If I never ever bodybuilded, if I hardly ever weight properly trained, I wouldn’t be where by I am now for the reason that it saved me alive,” says Ferrigno. “It stored a fire in me. It manufactured me incredibly passionate, quite self-aggressive.”

    Tip 7: Take into consideration Producing a Alter to Your Diet plan

    Fish and eggs are both fantastic resources of vital vitamins and minerals.

    Kravitz confirmed off a fridge comprehensive of nothing but vegetables, and he follows a mainly uncooked vegan diet plan.

    Bautista isn’t really that stringent, but he has mainly removed meat from his diet regime. “I minimize out red meat. I minimize out pork in 2010,” he claims. “And about 6, 7 months back I completely cut meat out of my diet. I’m predominantly pant-centered. But I do have fish a few situations a week. And I do consume eggs.”

    Idea 8: Hardly ever Ignore Core Strength—and Determination

    You can prepare your abdominal muscles each day. That normally takes extra than just a passing motivation to your physical fitness plan—you have to acquire in to make the development you want, no make a difference how previous you are.

    “A lot of persons say, ‘You know when I am your age, I want to be in that type of shape’, and I glance at them (and some of them are in their 30s), and I go ‘Well you happen to be not in that form now,” says Grillo. “So what helps make you assume you’re heading to be in that form of form when you’re 50?”

    Want a lot more superstar exercise session routines? Look at out all of our Coach Like movies.

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  • Tips on understanding and preventing heart disease

    Tips on understanding and preventing heart disease

    MIDDLETOWN — February is American Coronary heart Month. In accordance to the American Coronary heart Association, practically half of all adults in the United States are living with cardiovascular ailment, the No. 1 killer of Americans.

    This short article will talk about some key tactics to blocking and running heart disorder.

    The American University of Cardiology and AHA have revealed the pursuing tips advised to stop coronary heart disease.

    These methods incorporate taking a day by day minimal-dose aspirin when encouraged by one’s medical provider protecting blood tension beneath 130/80 and a nutritious cholesterol degree refraining from using tobacco, handling weight and eating plan by like much more fruits, vegetables, healthful fat, nuts, fish, and complete grains controlling blood sugar if diabetic, and participating in 150 minutes of average exercising a week.

    According to Dr. Supriya M. Tigadi, assistant professor of medicine at the Pat and Jim Calhoun Cardiology Center at UConn Wellness, “It is significant to know your numbers. Getting once-a-year tests, examining cholesterol stages, controlling blood tension, and getting approved medicines as directed are quite critical to enable protect against a heart assault or stroke.”

    If your blood tension is higher, it should really be monitored frequently. A food plan lower in salt and limiting alcoholic beverages will help to preserve a healthful blood tension. In addition, replacing animal unwanted fat (purple meat) with plant-based fat is recommended, as very well as restricting refined sugars.


    According to the AHA, cholesterol ranges must be checked concerning ages 9 and 11 and once again in between 17 and 21, additionally every single four a long time following 20. This guideline may perhaps change primarily based on family record. High cholesterol does not discriminate primarily based on age or sexual intercourse. Moreover, those who are not chubby and exercise can continue to have unhealthy cholesterol numbers.

    Even if you’re getting prescription drugs for large blood strain or to regulate cholesterol, it is critical to eat a nutritious very well-balanced diet program, lead an energetic way of living, and keep a wholesome excess weight to decrease chance of heart condition and stroke.

    Dr. Tigadi additional reported girls can have warning indications of coronary heart disorder at a youthful age. Specifically, these who had pre-eclampsia, eclampsia, gestational diabetes, or early menopause are at higher danger of a heart attack. “Education at 30 can prevent coronary heart sickness at 60,” she said.

    In critique, possibility elements for coronary heart disorder and stroke consist of, but are not limited to, getting a spouse and children background of cardiac ailment, smoking, higher blood force, significant cholesterol, diabetic issues, serious kidney disorder and serious inflammatory disorders.

    Speak with your health-related service provider if you have any problems about your coronary heart overall health. Furthermore, the American Coronary heart Association’s website, coronary heart.org, is a terrific source for information on heart sickness which include wholesome dwelling, caregiver assistance, and far more.

    Laura Falt is director of enterprise enhancement for Nationwide Wellbeing Care Associates, CT North. She signifies seven nursing centers in greater Hartford, together with Water’s Edge Heart for Health & Rehabilitation in Middletown. Get hold of her at [email protected].

  • a Focus on Current and Emerging Therapies

    a Focus on Current and Emerging Therapies

    Abstract

    Follicular lymphoma (FL) is the most common indolent lymphoma and is characterized by a relapsing and remitting course. In addition to significant biologic heterogeneity, the clinical trajectory for patients is variable, with some being observed for many years, and others having aggressive disease requiring multiple treatment courses. Unfortunately, FL remains incurable, and continues to cause early mortality. Improved understanding of the genetic and immune biology of FL has led to several FDA-approved therapies in the relapsed and refractory setting, including PI3K inhibitors; immunomodulatory agents; the EZH2 inhibitor, tazemetostat; and anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, axicabtagene ciloleucel. This review outlines the current approach to the diagnosis and treatment of FL with a focus on emerging investigational therapies, including targeted protein inhibitors, antibody-drug conjugates, monoclonal antibodies, bispecific antibodies, and novel combination strategies.

    Key Words: follicular lymphoma; treatment; novel therapies

    Introduction

    Follicular lymphoma (FL) is an incurable B-cell lymphoid neoplasm with significant biological and clinical heterogeneity. As the most common indolent lymphoma and second most common non-Hodgkin lymphoma (NHL), it has a relapsing and remitting course with risk of transformation to aggressive disease.1,2 Most patients present with advanced disease and will eventually
    require treatment for symptomatic disease. Given the range of clinical behaviors, the decision of when to treat is equally important as how to treat, noting that therapeutic goals include meaningful remission, symptom palliation, and prolongation of life.

    While the majority of patients have survival approximating 2 decades, a subset of patients have aggressive disease with poor outcomes.3 Unfortunately, baseline identification of these patients remains challenging. Approximately 20{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} of patients with FL have progressive disease within 2 years of initial chemoimmunotherapy and a 5-year overall survival (OS) of 50{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}.4 Cumulative toxicity from repeated exposure to palliative cytotoxic chemotherapy also contributes to morbidity and mortality. While anti–CD20-based chemoimmunotherapy remains an important standard of care, more rational and biologically driven agents are either approved or in development. In this review, we examine the current approach to the diagnosis and treatment of FL with a focus on targeted therapy and other novel agents.

    Current Standards for Diagnosis

    A diagnosis of FL requires histologic examination of a lymph node biopsy for assessment of nodal architecture and grading.5 FL is characterized by neoplastic germinal center B-cells growing in densely packed follicles with distortion of the normal nodal architecture. Grading depends on the number of centroblasts/high-power field. Grade 1-3a are considered indolent, whereas 3b is more aggressive and clinically approached as diffuse large B-cell lymphoma (DLBCL).6 The classic immunophenotype includes the B-cell antigens CD19, CD20, and CD79a; lymphoid progenitor marker, CD10; and nuclear proteins, BCL-2 and BCL-6. Unlike mantle cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma, it is negative for CD5.

    Molecular Testing

    Cytogenetically, FL is characterized by the translocation t(14;18), which occurs in up to 90{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} of cases, as a result of aberrant V(D)J recombination. This results in BCL-2 protein overexpression and increased cell survival (Figure 1).7 As a hallmark of FL, it is necessary, but alone insufficient, for lymphomagenesis.8-10 An important recent finding is early mutations in genes coding for chromatin modifying proteins.11-13 These ‘epimutations’ are a second hallmark of FL and include: KMT2D (~70-80{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), CREBBP (~65-70{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), EZH2 (~25{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), and EP300 (~14{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}).12,14 These transcriptionally repressive mutations result in increased germinal center proliferation, differentiation block, and immune evasion.15-17 Along with the BCL2 translocation, these mutations are early events occurring in a common progenitor cell.

    Through divergent clonal evolution, other mutations are subsequently acquired including mutations in genes involved in immune modulation (TNFRSF14); JAK-STAT signaling (STAT6, SOCS1); and B-cell receptor–NF-kB signaling (CARD11, TNFAIP3, MYD88).12 While conventional karyotyping and fluorescent in situ hybridization (FISH) for t(14;18) are part of the standard evaluation for FL, genomic sequencing is limited to testing for the EZH2 mutation when tazemetostat is being considered.18 Nonetheless, next-generation sequencing has revealed the diverse mutational landscape of FL and provides insight into disease pathogenesis, as well as opportunities for more precise therapeutic strategies.

    Stratification for Treatment Selection

    The treatment of FL must consider individual parameters and balance the risk of cumulative toxicity versus remission and palliation of symptoms. The conventional approach to FL is clinical observation until there is an indication to treat, typically based on criteria of the Groupe d’Etude des Lymphomes Folliculaires (GELF) or National Comprehensive Cancer Network (NCCN).19,20 There are several prognostic indices in FL including the Follicular Lymphoma International Prognostic Index (FLIPI), FLIPI-2, and m7-FLIPI, but none dictate the timing or type of treatment at an individual patient level.14,21,22

    The m7-FLIPI and gene expression profiling panels include genomic features, but have varied performance and are not validated for clinical practice.23 Staging with positron emission tomography (PET) imaging helps to identify the extent of disease and preferred sites for biopsy when histologic transformation to DLBCL is suspected, as this occurs in up to 15{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} of patients.3 The assumption here is that higher uptake values correspond with more rapid cell turnover and aggressive histology. This is somewhat controversial, and PET alone does not appear to predict histologic transformation.24 Nonetheless, PET imaging does result in disease upstaging in approximately 10{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} to 60{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} of cases, which often has treatment implications.25,26

    Therapy Selection

    First-line Treatment

    For patients with stage I-II disease, there are several options including observation, rituximab (Rituxan), chemoimmunotherapy, or radiation, with the majority of patients having similar excellent long-term survival regardless of initial approach.27 Approximately 70{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} of patients have advanced disease (stage III or IV) at diagnosis.3,28 Asymptomatic patients with low disease burden may be actively monitored. When treatment is indicated for patients with low tumor-burden advanced disease, rituximab monotherapy is often used, given the high overall response rate (ORR; complete remission [CR] plus partial remission [PR]) of 71{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}, low toxicity, and long median time to treatment failure of approximately 4 years, which delays the need for cytotoxic therapy.29

    When selecting initial treatment for patients with high tumor burden and symptomatic advanced FL, there are several considerations regarding the chemotherapy backbone, the anti-CD20 antibody, the use of maintenance strategies, and whether to opt for a nonchemotherapy regimen (Figure 2). Based on the StiL (NCT00991211) and BRIGHT (NCT00877006) trials, bendamustine and rituximab (BR) or rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), are both options with ORR >90{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}.30,31

    BR has become a preferred option based on superior progression-free survival (PFS) over R-CHOP (70 vs 31 months, respectively) and it is also not associated with alopecia, anthracycline-associated cardiotoxicity, vinca alkaloid-associated neuropathy, or steroid-associated risks. R-CHOP may be preferred in cases where occult transformation is suspected, or immune suppression associated with bendamustine is to be avoided. In patients treated with R-CHOP or rituximab with cyclophosphamide, vincristine, and prednisone (R-CVP), maintenance therapy with rituximab every
    8 weeks for 2 years compared with placebo improves PFS, but not OS, based on the PRIMA study (NCT00140582).32

    It is unclear whether this extends to patients treated with BR. In the GALLIUM study (NCT01332968), chemoimmunotherapy with obinutuzumab (Gazyva) versus rituximab improved PFS, with no difference in OS, but did result in high grade 3-5 adverse events, including infusion-related events and infections.33,34 The use of maintenance therapy is controversial, and even more so during the COVID-19 pandemic. Among surveyed physicians who treat indolent lymphomas with a maintenance therapy strategy, 53{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} hold rituximab maintenance to allow for vaccination.35 Lenalidomide (Revlimid)with rituximab is an alternative to chemoimmunotherapy with similar response rates, PFS, and OS to chemoimmunotherapy (R-CHOP, BR, or R-CVP).36 Similar to chemoimmunotherapy, it is a fixed-duration treatment, but with a much longer time frame at 18 months. It remains an option for patients wishing to avoid cytotoxic chemotherapy.

    Relapsed/Refractory Treatment

    There is no standard treatment or sequence of treatments for relapsed/refractory FL (RR-FL), but the number of options is increasing. Approximately 20{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} of patients have early relapse and progression of disease within 24 months (POD24), and these patients have poor outcomes.4 Unfortunately, upfront identification of these patients is not possible, and more effective treatments for these patients are needed. For all patients with RR-FL, a chemoimmunotherapy regimen (BR, R-CHOP, or R-CVP) different from the first-line therapy is an option.

    There is limited data on R-CHOP after BR, but second-line BR in patients with indolent NHL with previous rituximab (39{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) or CHOP (54{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) had an ORR of 82{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} and PFS of 34 months.37 Rituximab monotherapy is also effective for some patients with low tumor burden and previous rituximab-based regimens with an ORR 55{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} to 64{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} and PFS of 14 months.38,39 Obinutuzumab with either bendamustine or CHOP may improve outcomes by overcoming rituximab refractoriness, especially for relapses within 6 to 12 months.40,41 In transplant-eligible patients with chemosensitive disease to first salvage, consolidative autologous stem cell transplantation (auto-SCT) appears to improve long-term survival based on several retrospective analyses.

    Among patients with POD24, auto-SCT has an improved 5-year OS of approximately 77{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} vs 59{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} among those without auto-SCT.42 Similar results were observed for patients undergoing auto-SCT within 1 year of treatment failure, with a 5-year OS of 73{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} compared with 60{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} without auto-SCT.43 It should be noted, however, that the benefit of auto-SCT may simply be due to a favorable response to second-line therapy and randomized studies are needed.

    In the era of increased alternative treatments, the use of auto-SCT has been substantially reduced. The use of allogeneic-SCT, a historical option with curative potential in FL, has also declined. While the preferred therapy for high-risk patients with early relapse has yet to be defined, targeted therapy beyond anti-CD20 monoclonal antibodies has been reshaping the treatment landscape of FL since 2014 (Table 1), with several new trials focusing on this population, including a US Intergroup Study S1608 (NCT03269669).

    Lenalidomide

    Lenalidomide is an immunomodulatory drug with direct cytotoxicity to lymphoma cells via inhibition of the E3 ubiquitin ligase, cereblon, as well as indirect antitumor effects mediated through changes in the tumor microenvironment.44 Lenalidomide with rituximab is an active regimen in rituximab-sensitive relapsed FL, as demonstrated in the AUGMENT trial (NCT01938001) with an ORR of 80{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR 35{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) compared with an ORR of 55{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR 20{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) for rituximab alone.39 The combination had a 2-year OS and median PFS of 95{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} and 39.4 months compared with 86{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} and 13.9 months, respectively, for rituximab alone. The combination had a higher incidence of all grades of infections (63{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} vs 49{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}, respectively), neutropenia (58{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} vs 23{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), and cutaneous reactions (32{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} vs 12{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}). Of the grade 3 or 4 adverse events, a higher incidence of neutropenia (50{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} vs 13{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) was also observed with the combination. This study led to the regulatory approval of lenalidomide with rituximab in patients with RR-FL.

    PI3K Inhibitors

    Inhibition of PI3K signaling has been a largely successful approach, with 4 FDA-approved agents in RR-FL.45 PI3K mediates proximal intracellular B-cell receptor signaling, as well as cell survival signals received from the tumor microenvironment. Idelalisib (δ isoform inhibitor; Zydelig) was the first of these agents to be approved and a major breakthrough in the RR-FL space. The ORR was 57{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR 6{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) with a median duration of response (DOR) of 12.5 months and median PFS of 11 months in very heavily pretreated patients.46 Unfortunately, significant toxicities, including neutropenia, diarrhea, transaminitis, and pneumonia, limited its development. Copanlisib (pan-isoform inhibitor; Aliqopa); duvelisib (δ and γ isoform inhibitor; Copiktra); and umbralisib (δ isoform and CK1 ε inhibitor; Ukoniq) are also approved for RR-FL with comparable efficacy and improved toxicity profiles.47-49 They all have an ORR ranging from 42{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} to 59{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}, median DOR of 10 to 12 months, and median PFS of 9.5 to 11 months. They have regulatory approval for patients with multiply relapsed FL, based on activity in the heavily pretreated setting.

    Tazemetostat

    Approximately 25{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} of patients with FL have a gain of function mutation in the histone methyltransferase protein, EZH2, with consequent increased expression of genes involved in cell proliferation.12,14,50 Although it contributes to lymphomagenesis, EZH2 gene mutations are associated with improved PFS.50 Tazemetostat (Tazverik) is an EZH2 inhibitor that targets this epimutation. It is the first biomarker-directed therapy in FL and has been approved as a third-line option in RR-FL, with an ORR of 69{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} and CR rate of 13{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}.51 With a median follow-up of 22 months, the median PFS was 13.8 months, and median OS was not reached. It also appears to have activity in patients without an EZH2 gene mutation, with ORR of 35{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} and similar median PFS and OS. There were few significant treatment-related adverse events, with 3{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} of patients having grade 3 or 4 myelosuppression and a low discontinuation rate of 8{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}. Its favorable toxicity profile makes it an attractive oral option.

    CAR T-Cell Therapy

    While targeted agents have clinical activity in RR-FL, long-term remission is still lacking and most require prolonged treatment courses. CAR T-cell therapy has revolutionized the treatment of aggressive lymphomas like DLBCL, and is also now an option for RR-FL, although follow-up remains short. Axicabtagene ciloleucel (axi-cel; Yescarta) is an anti-CD19 CAR T-cell
    therapy that received accelerated approval in March 2021 for adult patients with RR-FL (≥ 2 lines of prior therapy) based on the results of the phase 2 study ZUMA-5.52 In a preliminary report of updated results (median follow-up of 31 months), 86 patients with RR-FL had an ORR of 94{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR 79{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), median DOR and PFS of 38.6 months and 39.6 months, respectively, while OS was not reached.53 The incidence of cytokine release syndrome (CRS) and neurotoxicity grade ≥ 3 were 6{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} and 15{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}, respectively.

    The phase 2 ELARA trial (NCT03568461) evaluating tisagenlecleucel (tisa-cel) in patients with RR-FL (≥ 2 lines of prior therapy) had an ORR 86{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR 69{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) without any grade ≥ 3 CRS, and only 3{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} with grade ≥ 3 neurotoxicity.54 At a median follow-up of 16.9 months, the median DOR, PFS, and OS were not reached, but 1-year PFS was 67{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}. The phase 2 TRANSCEND FL trial (NCT04245839) using lisocabtagene maraleucel is ongoing. One of the most crucial challenges is patient selection for CAR T, which remains a costly and
    aggressive approach. Long-term follow-up and real-world data for CAR T-cell therapy from the commercial setting will be important guides influencing patient selection.

    Emerging and Novel Therapies

    Beyond the commercially approved targeted therapies in FL, there are multiple emerging agents that target the biology of FL (Figure 3). These are reviewed briefly in the following section, which also highlights novel investigational use of these treatments in FL (Table 2).

    Antibody-Drug Conjugates

    Antibody-drug conjugates (ADCs) offer an appealing means of antigen-based drug delivery, with several in development. In a phase 2 study in patients with RR-FL, the anti-CD79b ADC, polatuzumab vedotin, (pola; Polivy) was combined with rituximab and resulted in an ORR of 70{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR 45{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) with a 9.4-month DOR.55 The PFS was 15.3 months with a 2-year OS of 88{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}. The most common grade 3-4 adverse events were neutropenia (15{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) and diarrhea (10{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}); however, although no grade 3-4 neuropathy was observed, 40{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} had grade 1-2 neuropathy.

    In preliminary reports of early-phase studies evaluating pola combinations in RR-FL, pola with BR did not improve treatment response.56 Pola with obinutuzumab/lenalidomide had an ORR of 76{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR of 65{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), while pola with obinutuzumab/venetoclax had an ORR of 71{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR of 57{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), and long-term results with updated survival are anticipated.57,58 In a phase 1 study including 14 patients with RR-FL, the anti-CD19 ADC, loncastuximab tesirine (Zynlonta), had an ORR of 79{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR of 65{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), and cytopenias were the most common adverse effect.59

    Checkpoint Inhibitors

    Although checkpoint blockade monotherapy has low response rates in RR-FL, combinations may be more active. A phase 1/2 trial (NCT02631577) using obinutuzumab, atezolizumab (Tecentriq), and lenalidomide (G-atezo-len) in patients with RR-FL reported an ORR of 78{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR of 72{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), median DOR of 38 months, and 2-year PFS of 65{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}.60 Cytopenias were the most common grade ≥ 3 adverse event and occurred in 71{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} of patients. While the majority of toxicities were manageable, the discontinuation rate of any study drug was 29{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}.

    In a preliminary report of pembrolizumab with rituximab in patients with RR-FL (NCT02446457), the ORR was 80{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR of 60{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), and although safe, the benefit of pembrolizumab (Keytruda) over rituximab monotherapy was unclear, as this trial included patients with rituximab-sensitive disease.61 In the frontline phase 2 trial (1st FLOR study; NCT03245021), immune priming with nivolumab (Opdivo), followed by rituximab and nivolumab had an ORR of 92{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR of 54{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), with a favorable toxicity profile.62 Larger studies and a longer follow-up are needed to clarify the role of checkpoint inhibitors as first-line nonchemotherapy options.

    Novel Antibodies and Combinations

    Antibodies with novel targets are also under investigation in FL. The anti-CD47 antibody, magrolimab (Hu5F9-G4), blocks CD47 on lymphoma cells to enhance macrophage-mediated phagocytosis. In a phase 1 study of patients with RR-NHL, which included 7 patients with RR-FL, magrolimab with rituximab resulted in an ORR of 71{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (5/7) and CR rate of 43{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (3/7).63 Although small, these numbers are encouraging, with many patients having rituximab-refractory disease. The phase 2 portion of this study (NCT02953509) is currently recruiting.

    Another trial investigating venetoclax (Venclexta) with obinutuzumab and magrolimab (VENOM) in relapsed/refractory indolent lymphomas is recruiting, and the results are eagerly anticipated (NCT04599634). Tafasitamab (Monjuvi) is an anti-CD19 antibody approved in combination with lenalidomide for relapsed/refractory DLBCL, but has low activity as a monotherapy in FL.64 A phase 3 trial (InMIND) of tafasitamab plus lenalidomide/rituximab versus lenalidomide/rituximab alone in patients with RR-FL or marginal zone lymphoma will determine whether there is a role for tafasitamab in RR-FL (NCT04680052).

    Bispecific Antibodies

    Bispecific antibodies or bispecific T-cell engagers (BiTes) are novel protein constructs with separate B-cell (CD20) and T-cell targeting (CD3) domains. Mosunetuzumab, glofitamab, odronextamab, and epcoritamab are bispecific antibodies being investigated in early-phase RR-FL trials (Table 3), which have shown promising results with ORR ranging from 80{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} to 100{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR from 50{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} to 75{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) in heavily pretreated patients.65-69 Bispecific antibodies provide an off-the-shelf form of T-cell mediated therapy, with the goal of achieving the durable remissions seen with CAR T-cell therapy. Unlike CAR T-cell therapy, they appear to have a lower risk of CRS and neurotoxicity, and favorable responses in patients relapsing after CAR T-cell therapy. The optimal clinical use of bispecific antibodies remains unknown, and trials including novel combinations in FL are ongoing: mosunetuzumab and lenalidomide (NCT04246086); and epcoritamab with lenalidomide/rituximab or BR (NCT04663347).

    BCL2 and Epigenetic Targeting

    While BCL2 translocation and epigenetic dysregulation are both frequent features in FL, the efficacy of existing agents has been modest. The BCL2 inhibitor, venetoclax, had low monotherapy activity in FL with an ORR of 38{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR of 14{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}),70 but combination strategies are in development. A preliminary report of the first trial to combine a Bruton tyrosine kinase (BTK) inhibitor, ibrutinib (Imbruvica), with venetoclax in RR-FL showed an ORR of 83{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR of 33{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) with manageable toxicity (NCT02956382).71 Several frontline trials using venetoclax-based combinations include the following: venetoclax, oral azacitidine (CC-486), and obinutuzumab (NCT04722601); venetoclax, lenalidomide, and obinutuzumab (NCT03980171); and venetoclax, ibrutinib, and obinutuzumab (NCT04450173).

    The phase 2 PrECOG 0403 trial with frontline venetoclax, bendamustine, and obinutuzumab (NCT03113422) for patients with high tumor-burden FL (n = 56) showed an ORR of 93{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR of 73{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), 2-year estimated PFS of 86{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}, and 2-year estimated OS of 94{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} at a median follow-up of 21 months.72 Despite the efficacy, the rate of ≥ grade 3 adverse events was high, at 84{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}, most notably due to tumor lysis, cytopenias, and infections. Unfortunately, this toxicity will preclude its use, but alternative dosing strategies to mitigate adverse effects are being explored. Tazemetostat is also being evaluated in combination with rituximab (NCT04762160), and in combination with lenalidomide and rituximab (NCT04224493).

    Conclusions

    While chemoimmunotherapy, lenalidomide with rituximab, or rituximab alone are standard first or subsequent line options for advanced FL, the treatment choices for RR-FL have evolved over the last several years. Additional agents for multiply relapsed patients include PI3K inhibitors, tazemetostat, and CAR T-cell therapy. Patient selection for CAR T-cell therapy is evolving, and the optimal sequencing with other therapies remains unknown. There are many emerging investigational products, including ADCs, anti-CD47 monoclonal antibodies, bispecific antibodies, checkpoint-based therapy, and novel combination strategies that are being evaluated. Individualized approaches, trial end points with quality-of-life measures, and information to guide sequencing of available regimens and agents are all desperately needed. These efforts, coupled with ongoing discovery in the biology of FL, are imperative to improving outcomes for patients with FL.

    AUTHOR AFFILIATIONS:

    Kirk E. Cahill, MD1; and Sonali M. Smith, MD1

    1Department of Medicine, Section of Hematology/Oncology, University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL.

    Funding: None

    Corresponding author

    Sonali M. Smith, MD; Elwood V. Jensen Professor in Medicine; Chief, Section of Hematology/Oncology; Department of Medicine; The University of Chicago Medicine; 5841 S. Maryland Ave., MC 2115; Chicago, IL 60637; Email: [email protected]

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    47. Dreyling M, Santoro A, Mollica L, et al. Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma. J Clin Oncol. 2017;35(35):3898-3905. doi:10.1200/JCO.2017.75.4648
    48. Flinn IW, Miller CB, Ardeshna KM, et al. DYNAMO: a phase II study of duvelisib (IPI-145) in patients with refractory indolent non-Hodgkin lymphoma. J Clin Oncol. 2019;37(11):912-922. doi:10.1200/JCO.18.00915
    49. Fowler NH, Samaniego F, Jurczak W, et al. Umbralisib, a dual PI3Kdelta/CK1epsilon inhibitor in patients with relapsed or refractory indolent lymphoma. J Clin Oncol. 2021;39(15):1609-1618. doi:10.1200/JCO.20.03433
    50. Huet S, Xerri L, Tesson B, et al. EZH2 alterations in follicular lymphoma: biological and clinical correlations. Blood Cancer J. 2017;7(4):e555. doi:10.1038/bcj.2017.32
    51. Morschhauser F, Tilly H, Chaidos A, et al. Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol. 2020;21(11):1433-1442. doi:10.1016/S1470-2045(20)30441-1
    52. Jacobson C, Chavez JC, Sehgal AR, et al. Primary analysis of ZUMA-5: a phase 2 study of axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). Blood. 2020;136(suppl 1):40-41. doi:10.1182/blood-2020-136834
    53. Neelapu SS, Chavez JC, Sehgal AR, et al. Long-term follow-up analysis of ZUMA-5: a phase 2 study of axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). Blood. 2021;138(suppl 1):93-93. doi:10.1182/blood-2021-148473
    54. Fowler NH, Dickinson M, Dreyling M, et al. Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial. Nat Med. Published online December 17, 2021. doi:10.1038/s41591-021-01622-0
    55. Morschhauser F, Flinn IW, Advani R, et al. Polatuzumab vedotin or pinatuzumab vedotin plus rituximab in patients with relapsed or refractory non-Hodgkin lymphoma: final results from a phase 2 randomised study (ROMULUS). Lancet Haematol. 2019;6(5):e254-e265. doi:10.1016/S2352-3026(19)30026-2
    56. Sehn LH, Kamdar M, Herrera AF, et al. Randomized phase 2 trial of polatuzumab vedotin (pola) with bendamustine and rituximab (BR) in relapsed/refractory (r/r) FL and DLBCL. J Clin Oncol. 2018;36(suppl 15):7507. doi:10.1200/JCO.2018.36.15_suppl.7507
    57. Diefenbach C, Kahl BS, Banerjee L, et al. Polatuzumab vedotin plus obinutuzumab and lenalidomide in patients with relapsed/refractory follicular lymphoma: primary analysis of the full efficacy population in a phase Ib/II trial. Blood. 2019;134(suppl 1):126. doi:10.1182/blood-2019-123669
    58. Bannerji R, Yuen S, Phillips TJ, et al. Polatuzumab vedotin + obinutuzumab + venetoclax in patients with relapsed/refractory (R/R) follicular lymphoma (FL): Primary analysis of a phase 1b/2 trial. J Clin Oncol. 2021;39(suppl 15):7534. doi:10.1200/JCO.2021.39.15_suppl.7534
    59. Hamadani M, Radford J, Carlo-Stella C, et al. Final results of a phase 1 study of loncastuximab tesirine in relapsed/refractory B-cell non-Hodgkin lymphoma. Blood. 2021;137(19):2634-2645. doi:10.1182/blood.2020007512
    60. Morschhauser F, Ghosh N, Lossos IS, et al. Obinutuzumab-atezolizumab-lenalidomide for the treatment of patients with relapsed/refractory follicular lymphoma: final analysis of a Phase Ib/II trial. Blood Cancer J. 2021;11(8):147. doi:10.1038/s41408-021-00539-8
    61. Nastoupil LJ, Westin JR, Fowler NH, et al. Response rates with pembrolizumab in combination with rituximab in patients with relapsed follicular lymphoma: Interim results of an on open-label, phase II study. J Clin Oncol. 2017;35(suppl 15):7519. doi:10.1200/JCO.2017.35.15_suppl.7519
    62. Hawkes EA, Lee ST, Chong G, et al. Immune priming with nivolumab followed by nivolumab and rituximab in first-line treatment of follicular lymphoma: The phase 2 1st FLOR study. J Clin Oncol. 2021;39(suppl 15):7560. doi:10.1200/JCO.2021.39.15_suppl.7560
    63. Advani R, Flinn I, Popplewell L, et al. CD47 Blockade by Hu5F9-G4 and rituximab in non-Hodgkin’s lymphoma. N Engl J Med. 2018;379(18):1711-1721. doi:10.1056/NEJMoa1807315
    64. Jurczak W, Zinzani PL, Gaidano G, et al. Phase IIa study of the CD19 antibody MOR208 in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma. Ann Oncol. 2018;29(5):1266-1272. doi:10.1093/annonc/mdy056
    65. Budde LE, Sehn LH, Matasar MJ, et al. Mosunetuzumab monotherapy is an effective and well-tolerated treatment option for patients with relapsed/refractory (R/R) follicular lymphoma (FL) who have received ≥2 prior lines of therapy: pivotal results from a phase I/II study. Blood. 2021;138(suppl 1):127. doi:10.1182/blood-2021-145872
    66. Morschhauser F, Bishton M, Eyre TA, et al. Mosunetuzumab in combination with lenalidomide has a manageable safety profile and encouraging activity in patients with relapsed/refractory follicular lymphoma: initial results from a phase Ib study. Blood. 2021;138(suppl 1):129. doi:10.1182/blood-2021-145694
    67. Morschhauser F, Carlo-Stella C, Dickinson M, et al. Glofitamab as monotherapy and in combination with obinutuzumab induces high complete response rates in patients (pts) with multiple relapsed or refractory (R/R) follicular lymphoma (FL). Blood. 2021;138(suppl 1):128. doi:10.1182/blood-2021-148778
    68. Hutchings M, Mous R, Clausen MR, et al. Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study. Lancet. 2021;398(10306):1157-1169. doi:10.1016/S0140-6736(21)00889-8
    69. Bannerji R, Allan JN, Arnason JE, et al. Odronextamab (REGN1979), a Human CD20 x CD3 bispecific antibody, induces durable, complete responses in patients with highly refractory B-cell non-Hodgkin lymphoma, including patients refractory to CAR T therapy. Blood. 2020;136(suppl 1):42-43. doi:10.1182/blood-2020-136659
    70. Davids MS, Roberts AW, Seymour JF, et al. Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-hodgkin lymphoma. J Clin Oncol. 2017;35(8):826-833. doi:10.1200/JCO.2016.70.4320
    71. Ujjani CS, Lai C, Leslie LA, et al. Ibrutinib and venetoclax in relapsed and refractory follicular lymphoma. Blood. 2020;136(suppl 1):46-47. doi:10.1182/blood-2020-136219
    72. Portell CA, Jegede O, Wagner-Johnston ND, et al. Phase II study of venetoclax in combination with obinutuzumab and bendamustine in patients with high tumor burden follicular lymphoma as front line therapy (PrECOG 0403). Blood. 2021;138(suppl 1):814. doi:10.1182/blood-2021-145217
  • Taking baby steps toward a healthy lifestyle

    Taking baby steps toward a healthy lifestyle

    It’s simple to let healthful behaviors to fall by the wayside. The fantastic information is, there are small measures that can be taken to support introduce healthy habits into your lifestyle. 

    Little techniques will build on just about every other about time. And if you stick with just 1 routine above a two-week period, you will be properly on your way to generating healthful behavior that persist.

    Below is a tried using-and-real listing of six balanced practices you can include these days that won’t experience like drastic, unmanageable alterations.

    1. Produce down your targets. When you do that, they grow to be additional than just a considered. They become actionable. Generate small wins you can reach. At the time you finish a goal, make confident to rejoice.
    2. Pick a single goal to emphasis on at a time. Let’s confront it, most of us guide fast paced life. Just the believed of including one particular additional to-do to our plates feels stress filled. When you focus on too a lot of changes at 1 time, you can immediately turn out to be overwhelmed and give up.
    3. Maintain a foodstuff journal. This will help if you’re striving to get rid of harmful meals and want to swap them with healthy kinds. Consider it for a week, and genuinely seem at anything you’ve eaten. Then, opt for 1 foods or consume to remove. This is a fantastic way to start off shifting towards a balanced and well balanced eating plan.
    4. Go your overall body. But you do not have to exercising for an hour a day when you begin. In its place, dedicate to moving your body for at minimum five minutes a working day, three days a week. You’ll be surprised at how opting for the stairs as a substitute of the elevator can enable you consider techniques toward wellness. Once you have attained this aim, add compact intervals of added motion. Cardiovascular work out is very important to assist maintain a healthy way of life.
    5. Drink h2o in the early morning. Drinking 8 ounces of h2o as before long as you wake up and along with each individual food is a superior begin. And it will eradicate the prospect of forgetting to drink drinking water throughout the working day when you turn into chaotic. Greater yet, hydration will do wonders for your power and skin.
    6. Lower out just one cigarette for each working day if you smoke. Attempt cutting out one particular a lot more cigarette for each two-7 days period right up until you can give up entirely. Using this slowly can be the variance between entirely kicking the pattern and offering up. 

    It is fantastic to recall that any objective can be damaged down into more compact, far more attainable goals. This assists helps make matters simpler to regulate and apply. The purpose is to make you thriving, so you come to feel empowered to choose extra actions toward a much healthier life style.

    To be related with a major care medical professional who can perform with you to accomplish your well being plans, go to Bayhealth.org/Discover-A-Doc or call 1-866-Bay-Docs.

    Paul Pulchny, DO, is a Bayhealth principal care medical doctor.
  • Oros CBD Gummies Review – What to Know Before Buying!

    Oros CBD Gummies Review – What to Know Before Buying!

    For all those who can just no for a longer period place up with the discomfort of making use of a assortment of chemical-laden medicine to grow to be healthy and conclusion their daily discomforts, the Oros CBD Gummies declare to deliver a multitude of overall health benefits. The principal threats to People in america are chaotic consuming practices and a sedentary life-style.

    The only way to development in this circumstance is to seem for pretty much any therapeutic alternative that tackles widespread clinical problems when having no adverse side effects. Thankfully, the Oros CBD Gummies are below to support with anything. Their components promises to be wholly natural and able of building the most beneficial alterations in the human body.

    The Cannabidiol (CBD) in these gummies will flood the consumer’s procedure and act as regular neurotransmitters, helping in the aid of discomfort and panic reduction, enhanced rest, and the advancement of finish system equilibrium.

    The Oros CBD Gummies contains 25mg of wide-spectrum CBD to help in relieving and eradicating throbbing irritation, as CBD has been discovered to operate extremely proficiently (1, 2) when it arrives to this. This hemp component performs on the entire body to alleviate irritation, which means it addresses the supply of a lot of health difficulties.

    How Do the Oros CBD Gummies Function?

    Cannabinoids are chemical compounds that by natural means come about in the overall body to link with the Endocannabinoid Procedure (ECS) and cannabinoid receptors found throughout the overall body (3). CBD is one of additional than 100 cannabinoids existing in cannabis crops. Further more, CBD is regarded as the most completely researched hemp ingredient, 2nd only to THC.

    Since of the rigid necessities of using GMP rules, the Oros CBD Gummies are unique in good quality, basic safety, and efficacy. They can supply the persistent discomfort aid everyone is hunting for when they have specific health difficulties.

    The ECS in our bodies demands cannabinoids like CBD to function efficiently, is liable for a lot of bodily capabilities, controlling irritation and regulating rest or starvation involved.

    Oros CBD Gummies Feasible Facet Outcomes and Gains

    The 25mg broad-spectrum Oros CBD Gummies are a organic health nutritional supplement that can deliver various health and fitness added benefits. CBD maintains a healthful and favourable mentality, results in psychologically sound responses, and clears the mind of brain fog when made use of as indicated. Irrespective of CBD being normally regarded as 100{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} harmless, there is also the chance that it can result in some disagreeable reactions in unique shoppers.

    The aspect outcomes some might practical experience may perhaps be tiredness or a runny nose. CBD may also result in some issues with particular medications, and a doctor’s information with regards to consuming them really should be required by everyone next therapy for a particular disorder or wellness challenge. Below are a several of the health-related benefits of CBD and of the Oros CBD Gummies.

    Decreased tension – CBD may assistance cope with the stress of a occupied day

    Amplified energy – with the support of character and the dependable force of the hemp plant, from which the CBD in the Oros CBD Gummies is extracted, folks could reside healthily and as energetically as they are entitled to

    Soreness reduction – The capacity to cure a broad range of pains (4) is 1 of CBD’s most thrilling fixes

    Enhanced snooze – When at relaxation, the entire body repairs a large amount of the problems performed throughout the working day. With the aid of the Oros CBD Gummies, people can tumble asleep a lot quicker and stay resting for extended (5)

    Healthy irritation – the CBD in the Oros CBD Gummies can handle and decrease inflammation (6) by powerfully connecting with the ECS’s framework

    Harmony – By utilizing the Oros CBD Gummies all through the day, a human being may possibly expertise a perception of leisure and harmony, claims the product’s formal web site

    ALSO Browse:Eagle Hemp CBD Gummies

    What Do Evaluations on the Oros CBD Gummies Say?

    According to shoppers who left critiques on the Oros CBD Gummies

    • Ted, left a assessment stating the Orso CBD Gummies available effective agony reduction with no any facet consequences.
    • Gerry claims these gummies aided him snooze like a child each individual evening
    • Pam mentions that she no extended needs to use painkillers given that she started using them for her herniated disks.

    And there are a lot more beneficial evaluations on the Oros CBD Gummies formal website from men and women who have tried the product or service and keep on to use it.

    Exactly where to Get the Oros CBD Gummies?

    The Oros CBD Gummies can be obtained on-line and from the formal site, they at the moment charge:

    • One bottle + A person Free at $59.50 per bottle (2-month provide)
    • Two bottles + 1 Free of charge at $53.00 for each bottle (3-thirty day period provide)
    • 3 bottles + Two Free at $39.80 for each bottle (5-thirty day period supply)

    All goods arrive with a 30-working day income-back again ensure that can be claimed by contacting the Oros CBD purchaser guidance 8 am – 9 pm EST Monday – Sunday via:

    • Cellphone Client Aid: 844-203-9923

    Linked:Finest CBD Gummies to Get: Prime CBD Gummies 2022

    Affiliate Disclosure:

    The back links contained in this product or service overview may well result in a smaller commission if you decide to invest in the products advisable at no more expense to you. This goes towards supporting our investigation and editorial workforce and please know we only endorse higher top quality solutions.

    Disclaimer:

    Please comprehend that any information or suggestions revealed in this article are not even remotely a substitute for sound health care information from a certified healthcare provider. Make positive to seek advice from with a specialist medical professional prior to making any purchasing final decision if you use medicines or have worries following the review particulars shared over. Specific final results may well differ as the statements produced about these products have not been evaluated by the Foods and Drug Administration. The efficacy of these merchandise has not been confirmed by Food and drug administration-authorized investigate. These products are not supposed to diagnose, take care of, heal or protect against any disease.