Clinical Edge Journal Scan Commentary

Amlitelimab is a monoclonal antibody that targets the OX40 ligand (Weidinger et al). It is predicted to have broad potential therapeutic application for multiple immune diseases, including atopic dermatitis. I'm not looking for that. I've been spoiled by drugs that have narrow therapeutic application (like IL-23 blockade and IL-4/IL-13 blockade) that target a specific disease very effectively with very little in the way of side effects.

The OX40 ligand/receptor interaction may be too important. When I Google "OX40 deficiency," the first thing that pops up is a combined T- and B-cell immunodeficiency associated with possible aggressive, childhood-onset, disseminated, cutaneous, and systemic Kaposi sarcoma. That doesn't mean that such a horrible outcome will come with the level of pharmacologic OX40 blockade that we would try to achieve in our patients. Clinical trials don't show horrible adverse events — so far. I'm in no hurry to find out in my patients whether real-life efficacy in large numbers of people treated for long periods of time matches up with the short-term safety profiles seen in relatively small clinical trial populations.

It might be nice to give patients upadacitinib only as needed, for example for a flare of their atopic dermatitis, then cut down the dose or stop altogether until the next flare. The study by Guttman-Yassky and colleagues found that atopic dermatitis came back quickly when upadacitinib was stopped. However, their study looked at patients with chronically bad atopic dermatitis. If we have a patient who tends to flare only intermittently, it may be that we could use upadacitinib or other systemic treatments on an intermittent basis. I know when it came to my son's mild atopic dermatitis, intermittent use of a little triamcinolone ointment was all that was needed. Yes, I know that's a "reactive," roller-coaster approach. Yes, I know that a "proactive" keep-the-disease-away approach sounds better. But I'm realistic when it comes to patients' adherence behaviors. I think there's a lot to be said for minimizing drug exposure and just using treatments as needed. Guttman-Yassky's work makes me believe that a lot of patients will need continuous treatment to keep their severe disease under control. I'm not convinced that everyone will need continuous treatment to be happy with their treatment.

O'Connor and colleagues found that emollient bathing is associated with later development of atopic dermatitis. They defined emollient bathing as baths with oil or emulsifier-based additives. This study illustrates the importance of randomization in a controlled trial. Because their study was not randomized, we don't know whether the emollient bathing caused atopic dermatitis or whether families that had more dry skin or more family history of atopic dermatitis were more likely to use emollient bathing.

When dupilumab was first approved, I prescribed it to my patients to take every 2 weeks as recommended on the label. I'm not so sure how many patients actually used it that way. I suspect that a lot of them took the medicine less often than recommended, especially when they were doing well. This report by Sánchez-García and colleagues suggests that patients who are doing very well on dupilumab may be able to take the drug less often. That's probably not news to my patients who are already taking the drug less often than I told them to.

I think less frequent dosing may become even more common over time, particularly for drugs that may have more safety risks than dupilumab. Many patients with atopic dermatitis probably don't need to be taking drugs all the time. Patients who tend to have flare-ups but who do very well for a long period of time between flares may only need drugs intermittently. It will be interesting to see if our patients can use oral treatments for atopic dermatitis that way.

Siegfried and colleagues assessed how well dupilumab worked in children with atopic dermatitis in different areas of the body: head and neck, trunk, upper extremities, lower extremities. Dupilumab worked well in all these areas, as expected.

Xu and colleagues did a meta-analysis of studies of dupilumab for atopic dermatitis and concluded, not shockingly, that dupilumab is safe and effective for atopic dermatitis. Okay, I believe that. They further concluded: "More long-term, high-quality, controlled studies in different regions are needed for further verification." I don't think so. I think the evidence is clear already.

Studies that measure the levels of things are generally not particularly helpful. The study by García-Reyes and colleagues studied the levels of serum thymic stromal lymphopoietin (TSLP) in patients with atopic dermatitis. TSLP levels were higher in patients with atopic dermatitis compared with patients without atopic dermatitis. This basically tells us nothing about the role of TSLP in atopic dermatitis. The elevated levels could be causing atopic dermatitis or they could be the body's response to having atopic dermatitis.

To tell whether something is causal we have to look at either genetic studies or studies with specific inhibitors. A specific inhibitor study was done by atopic dermatitis expert Eric Simpson and colleagues.1 This was a randomized, placebo-controlled study in which an anti-TSLP antibody was given to patients with atopic dermatitis. Both the anti-TSLP antibody and placebo groups were permitted to use topical steroids. While the anti-TSLP antibody–treated patients did better than placebo-treated patients, the difference did not achieve statistical significance, probably, I believe, because the placebo-treated patients used more topical steroids. When you want to assess whether a drug for atopic dermatitis is better than placebo, you must be careful about how much topical steroid you let patients in the study use!

Additional Reference

1. Simpson EL, Parnes JR, She D, et al. Tezepelumab, an anti-thymic stromal lymphopoietin monoclonal antibody, in the treatment of moderate to severe atopic dermatitis: A randomized phase 2a clinical trial. J Am Acad Dermatol. 2019;80(4):1013-1021. doi: 10.1016/j.jaad.2018.11.059

Amlitelimab is a monoclonal antibody that targets the OX40 ligand (Weidinger et al). It is predicted to have broad potential therapeutic application for multiple immune diseases, including atopic dermatitis. I'm not looking for that. I've been spoiled by drugs that have narrow therapeutic application (like IL-23 blockade and IL-4/IL-13 blockade) that target a specific disease very effectively with very little in the way of side effects.

The OX40 ligand/receptor interaction may be too important. When I Google "OX40 deficiency," the first thing that pops up is a combined T- and B-cell immunodeficiency associated with possible aggressive, childhood-onset, disseminated, cutaneous, and systemic Kaposi sarcoma. That doesn't mean that such a horrible outcome will come with the level of pharmacologic OX40 blockade that we would try to achieve in our patients. Clinical trials don't show horrible adverse events — so far. I'm in no hurry to find out in my patients whether real-life efficacy in large numbers of people treated for long periods of time matches up with the short-term safety profiles seen in relatively small clinical trial populations.

It might be nice to give patients upadacitinib only as needed, for example for a flare of their atopic dermatitis, then cut down the dose or stop altogether until the next flare. The study by Guttman-Yassky and colleagues found that atopic dermatitis came back quickly when upadacitinib was stopped. However, their study looked at patients with chronically bad atopic dermatitis. If we have a patient who tends to flare only intermittently, it may be that we could use upadacitinib or other systemic treatments on an intermittent basis. I know when it came to my son's mild atopic dermatitis, intermittent use of a little triamcinolone ointment was all that was needed. Yes, I know that's a "reactive," roller-coaster approach. Yes, I know that a "proactive" keep-the-disease-away approach sounds better. But I'm realistic when it comes to patients' adherence behaviors. I think there's a lot to be said for minimizing drug exposure and just using treatments as needed. Guttman-Yassky's work makes me believe that a lot of patients will need continuous treatment to keep their severe disease under control. I'm not convinced that everyone will need continuous treatment to be happy with their treatment.

O'Connor and colleagues found that emollient bathing is associated with later development of atopic dermatitis. They defined emollient bathing as baths with oil or emulsifier-based additives. This study illustrates the importance of randomization in a controlled trial. Because their study was not randomized, we don't know whether the emollient bathing caused atopic dermatitis or whether families that had more dry skin or more family history of atopic dermatitis were more likely to use emollient bathing.

When dupilumab was first approved, I prescribed it to my patients to take every 2 weeks as recommended on the label. I'm not so sure how many patients actually used it that way. I suspect that a lot of them took the medicine less often than recommended, especially when they were doing well. This report by Sánchez-García and colleagues suggests that patients who are doing very well on dupilumab may be able to take the drug less often. That's probably not news to my patients who are already taking the drug less often than I told them to.

I think less frequent dosing may become even more common over time, particularly for drugs that may have more safety risks than dupilumab. Many patients with atopic dermatitis probably don't need to be taking drugs all the time. Patients who tend to have flare-ups but who do very well for a long period of time between flares may only need drugs intermittently. It will be interesting to see if our patients can use oral treatments for atopic dermatitis that way.

Siegfried and colleagues assessed how well dupilumab worked in children with atopic dermatitis in different areas of the body: head and neck, trunk, upper extremities, lower extremities. Dupilumab worked well in all these areas, as expected.

Xu and colleagues did a meta-analysis of studies of dupilumab for atopic dermatitis and concluded, not shockingly, that dupilumab is safe and effective for atopic dermatitis. Okay, I believe that. They further concluded: "More long-term, high-quality, controlled studies in different regions are needed for further verification." I don't think so. I think the evidence is clear already.

Studies that measure the levels of things are generally not particularly helpful. The study by García-Reyes and colleagues studied the levels of serum thymic stromal lymphopoietin (TSLP) in patients with atopic dermatitis. TSLP levels were higher in patients with atopic dermatitis compared with patients without atopic dermatitis. This basically tells us nothing about the role of TSLP in atopic dermatitis. The elevated levels could be causing atopic dermatitis or they could be the body's response to having atopic dermatitis.

To tell whether something is causal we have to look at either genetic studies or studies with specific inhibitors. A specific inhibitor study was done by atopic dermatitis expert Eric Simpson and colleagues.1 This was a randomized, placebo-controlled study in which an anti-TSLP antibody was given to patients with atopic dermatitis. Both the anti-TSLP antibody and placebo groups were permitted to use topical steroids. While the anti-TSLP antibody–treated patients did better than placebo-treated patients, the difference did not achieve statistical significance, probably, I believe, because the placebo-treated patients used more topical steroids. When you want to assess whether a drug for atopic dermatitis is better than placebo, you must be careful about how much topical steroid you let patients in the study use!

Additional Reference

1. Simpson EL, Parnes JR, She D, et al. Tezepelumab, an anti-thymic stromal lymphopoietin monoclonal antibody, in the treatment of moderate to severe atopic dermatitis: A randomized phase 2a clinical trial. J Am Acad Dermatol. 2019;80(4):1013-1021. doi: 10.1016/j.jaad.2018.11.059

Amlitelimab is a monoclonal antibody that targets the OX40 ligand (Weidinger et al). It is predicted to have broad potential therapeutic application for multiple immune diseases, including atopic dermatitis. I'm not looking for that. I've been spoiled by drugs that have narrow therapeutic application (like IL-23 blockade and IL-4/IL-13 blockade) that target a specific disease very effectively with very little in the way of side effects.

The OX40 ligand/receptor interaction may be too important. When I Google "OX40 deficiency," the first thing that pops up is a combined T- and B-cell immunodeficiency associated with possible aggressive, childhood-onset, disseminated, cutaneous, and systemic Kaposi sarcoma. That doesn't mean that such a horrible outcome will come with the level of pharmacologic OX40 blockade that we would try to achieve in our patients. Clinical trials don't show horrible adverse events — so far. I'm in no hurry to find out in my patients whether real-life efficacy in large numbers of people treated for long periods of time matches up with the short-term safety profiles seen in relatively small clinical trial populations.

It might be nice to give patients upadacitinib only as needed, for example for a flare of their atopic dermatitis, then cut down the dose or stop altogether until the next flare. The study by Guttman-Yassky and colleagues found that atopic dermatitis came back quickly when upadacitinib was stopped. However, their study looked at patients with chronically bad atopic dermatitis. If we have a patient who tends to flare only intermittently, it may be that we could use upadacitinib or other systemic treatments on an intermittent basis. I know when it came to my son's mild atopic dermatitis, intermittent use of a little triamcinolone ointment was all that was needed. Yes, I know that's a "reactive," roller-coaster approach. Yes, I know that a "proactive" keep-the-disease-away approach sounds better. But I'm realistic when it comes to patients' adherence behaviors. I think there's a lot to be said for minimizing drug exposure and just using treatments as needed. Guttman-Yassky's work makes me believe that a lot of patients will need continuous treatment to keep their severe disease under control. I'm not convinced that everyone will need continuous treatment to be happy with their treatment.

O'Connor and colleagues found that emollient bathing is associated with later development of atopic dermatitis. They defined emollient bathing as baths with oil or emulsifier-based additives. This study illustrates the importance of randomization in a controlled trial. Because their study was not randomized, we don't know whether the emollient bathing caused atopic dermatitis or whether families that had more dry skin or more family history of atopic dermatitis were more likely to use emollient bathing.

When dupilumab was first approved, I prescribed it to my patients to take every 2 weeks as recommended on the label. I'm not so sure how many patients actually used it that way. I suspect that a lot of them took the medicine less often than recommended, especially when they were doing well. This report by Sánchez-García and colleagues suggests that patients who are doing very well on dupilumab may be able to take the drug less often. That's probably not news to my patients who are already taking the drug less often than I told them to.

I think less frequent dosing may become even more common over time, particularly for drugs that may have more safety risks than dupilumab. Many patients with atopic dermatitis probably don't need to be taking drugs all the time. Patients who tend to have flare-ups but who do very well for a long period of time between flares may only need drugs intermittently. It will be interesting to see if our patients can use oral treatments for atopic dermatitis that way.

Siegfried and colleagues assessed how well dupilumab worked in children with atopic dermatitis in different areas of the body: head and neck, trunk, upper extremities, lower extremities. Dupilumab worked well in all these areas, as expected.

Xu and colleagues did a meta-analysis of studies of dupilumab for atopic dermatitis and concluded, not shockingly, that dupilumab is safe and effective for atopic dermatitis. Okay, I believe that. They further concluded: "More long-term, high-quality, controlled studies in different regions are needed for further verification." I don't think so. I think the evidence is clear already.

Studies that measure the levels of things are generally not particularly helpful. The study by García-Reyes and colleagues studied the levels of serum thymic stromal lymphopoietin (TSLP) in patients with atopic dermatitis. TSLP levels were higher in patients with atopic dermatitis compared with patients without atopic dermatitis. This basically tells us nothing about the role of TSLP in atopic dermatitis. The elevated levels could be causing atopic dermatitis or they could be the body's response to having atopic dermatitis.

To tell whether something is causal we have to look at either genetic studies or studies with specific inhibitors. A specific inhibitor study was done by atopic dermatitis expert Eric Simpson and colleagues.1 This was a randomized, placebo-controlled study in which an anti-TSLP antibody was given to patients with atopic dermatitis. Both the anti-TSLP antibody and placebo groups were permitted to use topical steroids. While the anti-TSLP antibody–treated patients did better than placebo-treated patients, the difference did not achieve statistical significance, probably, I believe, because the placebo-treated patients used more topical steroids. When you want to assess whether a drug for atopic dermatitis is better than placebo, you must be careful about how much topical steroid you let patients in the study use!

Additional Reference

1. Simpson EL, Parnes JR, She D, et al. Tezepelumab, an anti-thymic stromal lymphopoietin monoclonal antibody, in the treatment of moderate to severe atopic dermatitis: A randomized phase 2a clinical trial. J Am Acad Dermatol. 2019;80(4):1013-1021. doi: 10.1016/j.jaad.2018.11.059

Studies have shown that breast cancer survivors have increased rates of age-related conditions, including cardiovascular disease and osteoporosis among others, therefore postulating that the biological aging process may be accelerated in this population.² Among 417 women enrolled in the prospective Sister Study cohort, paired blood samples collected an average of 7.7 years apart compared three epigenetic metrics of biological aging (calculated on the basis of DNA methylation data) between women who were diagnosed and treated for breast cancer (n = 190) vs those who remained breast cancer–free (n = 227) (Kresovich et al). Women diagnosed and treated for breast cancer had higher biological aging metrics than women who were cancer-free at the time of follow-up: PhenoAgeAccel³ (standardized mean difference [β] = 0.13; P = .04), GrimAgeAccel⁴ (β = 0.14; P = .01), and DunedinPACE⁵ (β = 0.37; P < .001). Regarding breast cancer therapies received, the increases in biological aging were most striking for those women who underwent radiation. The effect of cancer treatments, specifically chemotherapy and radiation, on DNA methylation profiles and accelerating the aging process has been demonstrated in prior studies as well.⁶ Future research should strive to improve our understanding of the specific mechanisms underlying these age-related changes, identify ways to affect those which are modifiable, and positively influence long-term cognitive and functional consequences.

The association between cardiometabolic abnormalities, including obesity, hyperinsulinemia, diabetes, hypertension, and dyslipidemia, and an elevated breast cancer risk has been demonstrated in various studies.⁷ Furthermore, dysregulation of obesity-related proteins plays a role in breast cancer development and progression. A study by Xu and colleagues evaluated the temporal relationships and longitudinal associations of body mass index (BMI), cardiometabolic risk score (CRS), and obesity-related protein score (OPS) among 444 healthy women in a breast cancer screening cohort. After adjustment for demographics, lifestyle, and reproductive factors, a 1-kg/m² increase in BMI per year increased CRS in both premenopausal (0.057 unit; P = .025) and postmenopausal women (0.054 unit; P = .033) and increased OPS by 0.588 unit (P = .001) in postmenopausal women. A significant association was also observed between CRS and OPS in postmenopausal women (β = 0.281; P = .034). These results support the importance of weight management and its effect on cardiometabolic and obesity-related parameters in breast cancer prevention. Research focused on lifestyle interventions to modify risk factors and effective implementation of these techniques will contribute to further reducing breast cancer risk.

Additional References

1. García-Albéniz X, Hernán MA, Logan RW, et al. Continuation of annual screening mammography and breast cancer mortality in women older than 70 years. Ann Intern Med. 2020;172(6):381-389. doi: 10.7326/M18-1199
2. Greenlee H, Iribarren C, Rana JS, et al. Risk of cardiovascular disease in women with and without breast cancer: The Pathways Heart Study. J Clin Oncol. 2022;40(15):1647-1658. doi: 10.1200/JCO.21.01736
3. Levine ME, Lu AT, Quach A, et al. An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany NY). 2018;10(4):573-591. doi: 10.18632/aging.101414
4. Lu AT, Quach A, Wilson JG, et al. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging (Albany NY). 2019;11(2):303-327. doi: 10.18632/aging.101684
5. Belsky DW, Caspi A, Corcoran DL, et al. DunedinPACE, a DNA methylation biomarker of the pace of aging. eLife. 2022:11:e73420. doi: 10.7554/eLife.73420
6. Sehl ME, Carroll JE, Horvath S, Bower JE. The acute effects of adjuvant radiation and chemotherapy on peripheral blood epigenetic age in early stage breast cancer patients. NPJ Breast Cancer. 2020;6:23. doi: 10.1038/s41523-020-0161-3
7. Nouri M, Mohsenpour MA, Katsiki N, et al. Effect of serum lipid profile on the risk of breast cancer: Systematic review and meta-analysis of 1,628,871 women. J Clin Med. 2022;11(15):4503. doi: 10.3390/jcm11154503

Studies have shown that breast cancer survivors have increased rates of age-related conditions, including cardiovascular disease and osteoporosis among others, therefore postulating that the biological aging process may be accelerated in this population.² Among 417 women enrolled in the prospective Sister Study cohort, paired blood samples collected an average of 7.7 years apart compared three epigenetic metrics of biological aging (calculated on the basis of DNA methylation data) between women who were diagnosed and treated for breast cancer (n = 190) vs those who remained breast cancer–free (n = 227) (Kresovich et al). Women diagnosed and treated for breast cancer had higher biological aging metrics than women who were cancer-free at the time of follow-up: PhenoAgeAccel³ (standardized mean difference [β] = 0.13; P = .04), GrimAgeAccel⁴ (β = 0.14; P = .01), and DunedinPACE⁵ (β = 0.37; P < .001). Regarding breast cancer therapies received, the increases in biological aging were most striking for those women who underwent radiation. The effect of cancer treatments, specifically chemotherapy and radiation, on DNA methylation profiles and accelerating the aging process has been demonstrated in prior studies as well.⁶ Future research should strive to improve our understanding of the specific mechanisms underlying these age-related changes, identify ways to affect those which are modifiable, and positively influence long-term cognitive and functional consequences.

The association between cardiometabolic abnormalities, including obesity, hyperinsulinemia, diabetes, hypertension, and dyslipidemia, and an elevated breast cancer risk has been demonstrated in various studies.⁷ Furthermore, dysregulation of obesity-related proteins plays a role in breast cancer development and progression. A study by Xu and colleagues evaluated the temporal relationships and longitudinal associations of body mass index (BMI), cardiometabolic risk score (CRS), and obesity-related protein score (OPS) among 444 healthy women in a breast cancer screening cohort. After adjustment for demographics, lifestyle, and reproductive factors, a 1-kg/m² increase in BMI per year increased CRS in both premenopausal (0.057 unit; P = .025) and postmenopausal women (0.054 unit; P = .033) and increased OPS by 0.588 unit (P = .001) in postmenopausal women. A significant association was also observed between CRS and OPS in postmenopausal women (β = 0.281; P = .034). These results support the importance of weight management and its effect on cardiometabolic and obesity-related parameters in breast cancer prevention. Research focused on lifestyle interventions to modify risk factors and effective implementation of these techniques will contribute to further reducing breast cancer risk.

Additional References

1. García-Albéniz X, Hernán MA, Logan RW, et al. Continuation of annual screening mammography and breast cancer mortality in women older than 70 years. Ann Intern Med. 2020;172(6):381-389. doi: 10.7326/M18-1199
2. Greenlee H, Iribarren C, Rana JS, et al. Risk of cardiovascular disease in women with and without breast cancer: The Pathways Heart Study. J Clin Oncol. 2022;40(15):1647-1658. doi: 10.1200/JCO.21.01736
3. Levine ME, Lu AT, Quach A, et al. An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany NY). 2018;10(4):573-591. doi: 10.18632/aging.101414
4. Lu AT, Quach A, Wilson JG, et al. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging (Albany NY). 2019;11(2):303-327. doi: 10.18632/aging.101684
5. Belsky DW, Caspi A, Corcoran DL, et al. DunedinPACE, a DNA methylation biomarker of the pace of aging. eLife. 2022:11:e73420. doi: 10.7554/eLife.73420
6. Sehl ME, Carroll JE, Horvath S, Bower JE. The acute effects of adjuvant radiation and chemotherapy on peripheral blood epigenetic age in early stage breast cancer patients. NPJ Breast Cancer. 2020;6:23. doi: 10.1038/s41523-020-0161-3
7. Nouri M, Mohsenpour MA, Katsiki N, et al. Effect of serum lipid profile on the risk of breast cancer: Systematic review and meta-analysis of 1,628,871 women. J Clin Med. 2022;11(15):4503. doi: 10.3390/jcm11154503

Studies have shown that breast cancer survivors have increased rates of age-related conditions, including cardiovascular disease and osteoporosis among others, therefore postulating that the biological aging process may be accelerated in this population.² Among 417 women enrolled in the prospective Sister Study cohort, paired blood samples collected an average of 7.7 years apart compared three epigenetic metrics of biological aging (calculated on the basis of DNA methylation data) between women who were diagnosed and treated for breast cancer (n = 190) vs those who remained breast cancer–free (n = 227) (Kresovich et al). Women diagnosed and treated for breast cancer had higher biological aging metrics than women who were cancer-free at the time of follow-up: PhenoAgeAccel³ (standardized mean difference [β] = 0.13; P = .04), GrimAgeAccel⁴ (β = 0.14; P = .01), and DunedinPACE⁵ (β = 0.37; P < .001). Regarding breast cancer therapies received, the increases in biological aging were most striking for those women who underwent radiation. The effect of cancer treatments, specifically chemotherapy and radiation, on DNA methylation profiles and accelerating the aging process has been demonstrated in prior studies as well.⁶ Future research should strive to improve our understanding of the specific mechanisms underlying these age-related changes, identify ways to affect those which are modifiable, and positively influence long-term cognitive and functional consequences.

The association between cardiometabolic abnormalities, including obesity, hyperinsulinemia, diabetes, hypertension, and dyslipidemia, and an elevated breast cancer risk has been demonstrated in various studies.⁷ Furthermore, dysregulation of obesity-related proteins plays a role in breast cancer development and progression. A study by Xu and colleagues evaluated the temporal relationships and longitudinal associations of body mass index (BMI), cardiometabolic risk score (CRS), and obesity-related protein score (OPS) among 444 healthy women in a breast cancer screening cohort. After adjustment for demographics, lifestyle, and reproductive factors, a 1-kg/m² increase in BMI per year increased CRS in both premenopausal (0.057 unit; P = .025) and postmenopausal women (0.054 unit; P = .033) and increased OPS by 0.588 unit (P = .001) in postmenopausal women. A significant association was also observed between CRS and OPS in postmenopausal women (β = 0.281; P = .034). These results support the importance of weight management and its effect on cardiometabolic and obesity-related parameters in breast cancer prevention. Research focused on lifestyle interventions to modify risk factors and effective implementation of these techniques will contribute to further reducing breast cancer risk.

Additional References

1. García-Albéniz X, Hernán MA, Logan RW, et al. Continuation of annual screening mammography and breast cancer mortality in women older than 70 years. Ann Intern Med. 2020;172(6):381-389. doi: 10.7326/M18-1199
2. Greenlee H, Iribarren C, Rana JS, et al. Risk of cardiovascular disease in women with and without breast cancer: The Pathways Heart Study. J Clin Oncol. 2022;40(15):1647-1658. doi: 10.1200/JCO.21.01736
3. Levine ME, Lu AT, Quach A, et al. An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany NY). 2018;10(4):573-591. doi: 10.18632/aging.101414
4. Lu AT, Quach A, Wilson JG, et al. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging (Albany NY). 2019;11(2):303-327. doi: 10.18632/aging.101684
5. Belsky DW, Caspi A, Corcoran DL, et al. DunedinPACE, a DNA methylation biomarker of the pace of aging. eLife. 2022:11:e73420. doi: 10.7554/eLife.73420
6. Sehl ME, Carroll JE, Horvath S, Bower JE. The acute effects of adjuvant radiation and chemotherapy on peripheral blood epigenetic age in early stage breast cancer patients. NPJ Breast Cancer. 2020;6:23. doi: 10.1038/s41523-020-0161-3
7. Nouri M, Mohsenpour MA, Katsiki N, et al. Effect of serum lipid profile on the risk of breast cancer: Systematic review and meta-analysis of 1,628,871 women. J Clin Med. 2022;11(15):4503. doi: 10.3390/jcm11154503

The treatment landscape of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) has been transformed over the past decade with the advent of targeted therapies, including Bruton tyrosine kinase (BTK) inhibitors. Covalent BTK inhibitors, which are available in both the frontline and relapsed/refractory settings, include ibrutinib, acalabrutinib, and zanubrutinib.^1-3

BTK inhibitors have also demonstrated activity in higher-risk subgroups, including patients harboring TP53 aberrations. Clinical trials have shown encouraging outcomes of BTK inhibitors in these patients, and real-world studies have demonstrated similar findings.^4-6 Recently, a real-world Italian registry study similarly showed favorable outcomes in 747 patients with CLL carrying 17p- or TP53 or both mutations treated with first-line ibrutinib. in what appears to be the largest real-world analysis of this patient population (Rigolin et al). At 24 months, the median overall survival was not reached; the estimated treatment persistence and survival rates were 63.4% (95% CI 60.0%-67.0%) and 82.6% (95% CI 79.9%-85.4%), respectively. The median time to treatment discontinuation was 37.4 months (95% CI 34.8-42.2 months). Disease progression or death was the reason for discontinuation in 45.8% of patients. Although ibrutinib is not generally the favored BTK inhibitor given an improved safety profile with next-generation options, these data provide real-world estimates for outcomes with BTK inhibitors in this large dataset of high-risk patients.

Although outcomes have improved for patients with CLL or SLL, it is common for resistance to targeted therapy to eventually occur. Noncovalent BTK inhibitors, such as pirtobrutinib, offer a promising approach for this population. The BRUIN trial was a phase 1/2 trial of pirtobrutinib in patients with relapsed/refractory CLL or SLL (Mato et al). A total of 317 patients were treated, including 247 who had previously received a BTK inhibitor. Patients had been treated with a median of three prior lines of therapy and over 40% had been treated with a BCL-2 inhibitor. The overall response rate was 73.3% (95% CI 67.3%-78.7%) and increased to 82.2% (95% CI 76.8%-86.7%) when partial response with lymphocytosis was included. At a 19.4-month median follow-up, the median progression-free survival was 19.6 (95% CI 16.9-22.1) months. The drug was also well-tolerated, with 2.8% of patients discontinuing therapy owing to treatment-related adverse events. Adverse events that can be seen with BTK inhibition, including hypertension, atrial fibrillation or flutter, and bleeding, were rare. This trial demonstrates that CLL/SLL cells can maintain dependency on the B-cell receptor pathway following treatment with a covalent inhibitor and that ongoing BTK inhibition using a novel mechanism is a feasible strategy. The optimal sequencing of pirtobrutinib with other available therapies, including BCL-2 inhibitors, remains unknown.

BTK inhibitors are also active in mantle cell lymphoma (MCL). They are approved for relapsed/refractory disease and are being studied in earlier lines of therapy. Whereas early progression of disease (POD) has been shown to be an important prognostic marker in MCL, the impact of early relapse on outcome specifically after BTK inhibitor initiation is less clear.⁷ A recent multicente retrospective observational study aimed to determine the impact on time-to-POD between rituximab-containing front-line therapy and second-line BTK inhibitor and overall outcomes (Villa et al). This study included 360 adult patients with relapsed or refractory MCL treated with second-line BTK inhibitor. Not surprisingly, the authors found that patients with POD within 24 months of first-line therapy had significantly shorter median progression-free survival (0.45 year vs 2.3 years; P < .001) and overall survival (0.9 year vs 5.5 years P < .001) compared with patients with relapse beyond 24 months. Furthermore, they found that Ki-67 ≥ 30% and Mantle Cell Lymphoma International Prognostic Index (MIPI) were also associated with progression‐free survival and overall survival from the start of a second-line BTK inhibitor, though to a lesser extent than time-to-POD. These variables were subsequently used to determine a second-line BTK MIPI, which can help inform which patients are most likely to benefit from a BTK inhibitor compared with other available options, such as chimeric antigen receptor (CAR) T-cell therapy or a clinical trial strategy.

BTK inhibitors are an important drug class for the treatment of lymphoid cancers and have changed the treatment paradigms in CLL/SLL and MCL. Additional studies evaluating combination strategies, sequencing approaches, time-limited options, and predictors of response are likely to further refine optimization of use in these diseases.

Additional References

1.         Barr PM, Owen C, Robak T, et al. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv. 2022;6:3440-3450. doi:10.1182/bloodadvances.2021006434

2.         Sharman JP, Egyed M, Jurczak W, et al. Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naive chronic lymphocytic leukemia. Leukemia. 2022;36:1171-1175. doi:10.1038/s41375-021-01485-x

3.         Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23:1031-1043. doi:10.1016/S1470-2045(22)00293-5

4.         Ahn IE, Tian X, Wiestner A. Ibrutinib for chronic lymphocytic leukemia with TP53 alterations. N Engl J Med. 2020;383:498-500. doi:10.1056/NEJMc2005943

5.         Allan JN, Shanafelt T, Wiestner A, et al. Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukaemia in patients with TP53 aberrations: a pooled analysis from four clinical trials. Br J Haematol. 2022;196:947-953. doi:10.1111/bjh.17984

6.         Mato AR, Tang B, Azmi S, et al. A clinical practice comparison of patients with chronic lymphocytic leukemia with and without deletion 17p receiving first-line treatment with ibrutinib. Haematologica. 2022;107:2630-2640. doi:10.3324/haematol.2021.280376

7.         Bond DA, Switchenko JM, Villa D, et al. Early relapse identifies MCL patients with inferior survival after intensive or less intensive frontline therapy. Blood Adv. 2021;5:5179-5189. doi:10.1182/bloodadvances.2021004765

The treatment landscape of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) has been transformed over the past decade with the advent of targeted therapies, including Bruton tyrosine kinase (BTK) inhibitors. Covalent BTK inhibitors, which are available in both the frontline and relapsed/refractory settings, include ibrutinib, acalabrutinib, and zanubrutinib.^1-3

BTK inhibitors have also demonstrated activity in higher-risk subgroups, including patients harboring TP53 aberrations. Clinical trials have shown encouraging outcomes of BTK inhibitors in these patients, and real-world studies have demonstrated similar findings.^4-6 Recently, a real-world Italian registry study similarly showed favorable outcomes in 747 patients with CLL carrying 17p- or TP53 or both mutations treated with first-line ibrutinib. in what appears to be the largest real-world analysis of this patient population (Rigolin et al). At 24 months, the median overall survival was not reached; the estimated treatment persistence and survival rates were 63.4% (95% CI 60.0%-67.0%) and 82.6% (95% CI 79.9%-85.4%), respectively. The median time to treatment discontinuation was 37.4 months (95% CI 34.8-42.2 months). Disease progression or death was the reason for discontinuation in 45.8% of patients. Although ibrutinib is not generally the favored BTK inhibitor given an improved safety profile with next-generation options, these data provide real-world estimates for outcomes with BTK inhibitors in this large dataset of high-risk patients.

Although outcomes have improved for patients with CLL or SLL, it is common for resistance to targeted therapy to eventually occur. Noncovalent BTK inhibitors, such as pirtobrutinib, offer a promising approach for this population. The BRUIN trial was a phase 1/2 trial of pirtobrutinib in patients with relapsed/refractory CLL or SLL (Mato et al). A total of 317 patients were treated, including 247 who had previously received a BTK inhibitor. Patients had been treated with a median of three prior lines of therapy and over 40% had been treated with a BCL-2 inhibitor. The overall response rate was 73.3% (95% CI 67.3%-78.7%) and increased to 82.2% (95% CI 76.8%-86.7%) when partial response with lymphocytosis was included. At a 19.4-month median follow-up, the median progression-free survival was 19.6 (95% CI 16.9-22.1) months. The drug was also well-tolerated, with 2.8% of patients discontinuing therapy owing to treatment-related adverse events. Adverse events that can be seen with BTK inhibition, including hypertension, atrial fibrillation or flutter, and bleeding, were rare. This trial demonstrates that CLL/SLL cells can maintain dependency on the B-cell receptor pathway following treatment with a covalent inhibitor and that ongoing BTK inhibition using a novel mechanism is a feasible strategy. The optimal sequencing of pirtobrutinib with other available therapies, including BCL-2 inhibitors, remains unknown.

BTK inhibitors are also active in mantle cell lymphoma (MCL). They are approved for relapsed/refractory disease and are being studied in earlier lines of therapy. Whereas early progression of disease (POD) has been shown to be an important prognostic marker in MCL, the impact of early relapse on outcome specifically after BTK inhibitor initiation is less clear.⁷ A recent multicente retrospective observational study aimed to determine the impact on time-to-POD between rituximab-containing front-line therapy and second-line BTK inhibitor and overall outcomes (Villa et al). This study included 360 adult patients with relapsed or refractory MCL treated with second-line BTK inhibitor. Not surprisingly, the authors found that patients with POD within 24 months of first-line therapy had significantly shorter median progression-free survival (0.45 year vs 2.3 years; P < .001) and overall survival (0.9 year vs 5.5 years P < .001) compared with patients with relapse beyond 24 months. Furthermore, they found that Ki-67 ≥ 30% and Mantle Cell Lymphoma International Prognostic Index (MIPI) were also associated with progression‐free survival and overall survival from the start of a second-line BTK inhibitor, though to a lesser extent than time-to-POD. These variables were subsequently used to determine a second-line BTK MIPI, which can help inform which patients are most likely to benefit from a BTK inhibitor compared with other available options, such as chimeric antigen receptor (CAR) T-cell therapy or a clinical trial strategy.

BTK inhibitors are an important drug class for the treatment of lymphoid cancers and have changed the treatment paradigms in CLL/SLL and MCL. Additional studies evaluating combination strategies, sequencing approaches, time-limited options, and predictors of response are likely to further refine optimization of use in these diseases.

Additional References

1.         Barr PM, Owen C, Robak T, et al. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv. 2022;6:3440-3450. doi:10.1182/bloodadvances.2021006434

2.         Sharman JP, Egyed M, Jurczak W, et al. Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naive chronic lymphocytic leukemia. Leukemia. 2022;36:1171-1175. doi:10.1038/s41375-021-01485-x

3.         Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23:1031-1043. doi:10.1016/S1470-2045(22)00293-5

4.         Ahn IE, Tian X, Wiestner A. Ibrutinib for chronic lymphocytic leukemia with TP53 alterations. N Engl J Med. 2020;383:498-500. doi:10.1056/NEJMc2005943

5.         Allan JN, Shanafelt T, Wiestner A, et al. Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukaemia in patients with TP53 aberrations: a pooled analysis from four clinical trials. Br J Haematol. 2022;196:947-953. doi:10.1111/bjh.17984

6.         Mato AR, Tang B, Azmi S, et al. A clinical practice comparison of patients with chronic lymphocytic leukemia with and without deletion 17p receiving first-line treatment with ibrutinib. Haematologica. 2022;107:2630-2640. doi:10.3324/haematol.2021.280376

7.         Bond DA, Switchenko JM, Villa D, et al. Early relapse identifies MCL patients with inferior survival after intensive or less intensive frontline therapy. Blood Adv. 2021;5:5179-5189. doi:10.1182/bloodadvances.2021004765

The treatment landscape of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) has been transformed over the past decade with the advent of targeted therapies, including Bruton tyrosine kinase (BTK) inhibitors. Covalent BTK inhibitors, which are available in both the frontline and relapsed/refractory settings, include ibrutinib, acalabrutinib, and zanubrutinib.^1-3

BTK inhibitors have also demonstrated activity in higher-risk subgroups, including patients harboring TP53 aberrations. Clinical trials have shown encouraging outcomes of BTK inhibitors in these patients, and real-world studies have demonstrated similar findings.^4-6 Recently, a real-world Italian registry study similarly showed favorable outcomes in 747 patients with CLL carrying 17p- or TP53 or both mutations treated with first-line ibrutinib. in what appears to be the largest real-world analysis of this patient population (Rigolin et al). At 24 months, the median overall survival was not reached; the estimated treatment persistence and survival rates were 63.4% (95% CI 60.0%-67.0%) and 82.6% (95% CI 79.9%-85.4%), respectively. The median time to treatment discontinuation was 37.4 months (95% CI 34.8-42.2 months). Disease progression or death was the reason for discontinuation in 45.8% of patients. Although ibrutinib is not generally the favored BTK inhibitor given an improved safety profile with next-generation options, these data provide real-world estimates for outcomes with BTK inhibitors in this large dataset of high-risk patients.

Although outcomes have improved for patients with CLL or SLL, it is common for resistance to targeted therapy to eventually occur. Noncovalent BTK inhibitors, such as pirtobrutinib, offer a promising approach for this population. The BRUIN trial was a phase 1/2 trial of pirtobrutinib in patients with relapsed/refractory CLL or SLL (Mato et al). A total of 317 patients were treated, including 247 who had previously received a BTK inhibitor. Patients had been treated with a median of three prior lines of therapy and over 40% had been treated with a BCL-2 inhibitor. The overall response rate was 73.3% (95% CI 67.3%-78.7%) and increased to 82.2% (95% CI 76.8%-86.7%) when partial response with lymphocytosis was included. At a 19.4-month median follow-up, the median progression-free survival was 19.6 (95% CI 16.9-22.1) months. The drug was also well-tolerated, with 2.8% of patients discontinuing therapy owing to treatment-related adverse events. Adverse events that can be seen with BTK inhibition, including hypertension, atrial fibrillation or flutter, and bleeding, were rare. This trial demonstrates that CLL/SLL cells can maintain dependency on the B-cell receptor pathway following treatment with a covalent inhibitor and that ongoing BTK inhibition using a novel mechanism is a feasible strategy. The optimal sequencing of pirtobrutinib with other available therapies, including BCL-2 inhibitors, remains unknown.

BTK inhibitors are also active in mantle cell lymphoma (MCL). They are approved for relapsed/refractory disease and are being studied in earlier lines of therapy. Whereas early progression of disease (POD) has been shown to be an important prognostic marker in MCL, the impact of early relapse on outcome specifically after BTK inhibitor initiation is less clear.⁷ A recent multicente retrospective observational study aimed to determine the impact on time-to-POD between rituximab-containing front-line therapy and second-line BTK inhibitor and overall outcomes (Villa et al). This study included 360 adult patients with relapsed or refractory MCL treated with second-line BTK inhibitor. Not surprisingly, the authors found that patients with POD within 24 months of first-line therapy had significantly shorter median progression-free survival (0.45 year vs 2.3 years; P < .001) and overall survival (0.9 year vs 5.5 years P < .001) compared with patients with relapse beyond 24 months. Furthermore, they found that Ki-67 ≥ 30% and Mantle Cell Lymphoma International Prognostic Index (MIPI) were also associated with progression‐free survival and overall survival from the start of a second-line BTK inhibitor, though to a lesser extent than time-to-POD. These variables were subsequently used to determine a second-line BTK MIPI, which can help inform which patients are most likely to benefit from a BTK inhibitor compared with other available options, such as chimeric antigen receptor (CAR) T-cell therapy or a clinical trial strategy.

BTK inhibitors are an important drug class for the treatment of lymphoid cancers and have changed the treatment paradigms in CLL/SLL and MCL. Additional studies evaluating combination strategies, sequencing approaches, time-limited options, and predictors of response are likely to further refine optimization of use in these diseases.

Additional References

1.         Barr PM, Owen C, Robak T, et al. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv. 2022;6:3440-3450. doi:10.1182/bloodadvances.2021006434

2.         Sharman JP, Egyed M, Jurczak W, et al. Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naive chronic lymphocytic leukemia. Leukemia. 2022;36:1171-1175. doi:10.1038/s41375-021-01485-x

3.         Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23:1031-1043. doi:10.1016/S1470-2045(22)00293-5

4.         Ahn IE, Tian X, Wiestner A. Ibrutinib for chronic lymphocytic leukemia with TP53 alterations. N Engl J Med. 2020;383:498-500. doi:10.1056/NEJMc2005943

5.         Allan JN, Shanafelt T, Wiestner A, et al. Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukaemia in patients with TP53 aberrations: a pooled analysis from four clinical trials. Br J Haematol. 2022;196:947-953. doi:10.1111/bjh.17984

6.         Mato AR, Tang B, Azmi S, et al. A clinical practice comparison of patients with chronic lymphocytic leukemia with and without deletion 17p receiving first-line treatment with ibrutinib. Haematologica. 2022;107:2630-2640. doi:10.3324/haematol.2021.280376

7.         Bond DA, Switchenko JM, Villa D, et al. Early relapse identifies MCL patients with inferior survival after intensive or less intensive frontline therapy. Blood Adv. 2021;5:5179-5189. doi:10.1182/bloodadvances.2021004765

Although there are several treatment options for PsA, there have been few head-to-head studies conducted to determine comparative efficacy. Ustekinumab, a biologic agent targeting IL-p40, and therefore both IL-12 and IL-23, has proven efficacy in PsA, but the impression is that this drug is less effective than are TNF inhibitors for the treatment of the peripheral arthritis domain. However, in a prospective, observational study, Gossec and colleagues report that the improvements in patient-reported outcomes were generally comparable between ustekinumab and TNF inhibitor treatments. This study evaluated 437 patients with PsA from the PsABio study who initiated first- to third-line ustekinumab (n = 219) or TNF inhibitors (n = 218) and continued the initial treatment for 3 years. At 3 years, ustekinumab and TNF inhibitors were associated with comparable improvements in the EuroQol-5 dimensions health state visual analog scale scores, Psoriatic Arthritis Impact of Disease 12-item scores, and work productivity, although the improvements were generally greater in the TNF inhibitor–treated group. A randomized trial comparing ustekinumab to TNF inhibitors in PsA is warranted to confirm these findings and inform treatment decisions.

Targeted therapies, such as biologics, are proven to be more efficacious than are conventional therapies; however, only about 60% of patients initiating targeted therapies demonstrate treatment response. Identifying the predictors of treatment response is an active area of research. Linde and colleagues looked at data from 13,369 biologic-naive patients registered with a PsA diagnosis from 13 European registries who initiated a first TNF inhibitor treatment. The study demonstrated that sex, disease duration, C-reactive protein level, age at treatment initiation, and fatigue predicted the achievement of the Disease Activity in Psoriatic Arthritis in 28 joints remission at 6 months.

Could biomarkers help predict response beyond clinical predictors? An interesting study indicates that beta–defensin 2 (BD-2) may serve as a predictive biomarker for clinical response to secukinumab in PsA. BD-2 is an antimicrobial peptide and an important protein in innate immune response. Cardner and colleagues analyzed protein expression data in serum samples from the phase 3 FUTURE 1-5 trials that included 1989 patients with PsA who received secukinumab or placebo. Baseline BD-2 levels were associated with early as well as sustained PsA treatment response to secukinumab, independent of psoriasis severity. BD-2 levels did not predict response to adalimumab in PsA nor was it associated with treatment response to secukinumab in RA. The addition of BD-2 to the clinical prediction model significantly improved the prediction of the 16-week American College of Rheumatology 20 response. Thus, BD-2 seems to be a secukinumab treatment response biomarker and requires further evaluation.

Although there are several treatment options for PsA, there have been few head-to-head studies conducted to determine comparative efficacy. Ustekinumab, a biologic agent targeting IL-p40, and therefore both IL-12 and IL-23, has proven efficacy in PsA, but the impression is that this drug is less effective than are TNF inhibitors for the treatment of the peripheral arthritis domain. However, in a prospective, observational study, Gossec and colleagues report that the improvements in patient-reported outcomes were generally comparable between ustekinumab and TNF inhibitor treatments. This study evaluated 437 patients with PsA from the PsABio study who initiated first- to third-line ustekinumab (n = 219) or TNF inhibitors (n = 218) and continued the initial treatment for 3 years. At 3 years, ustekinumab and TNF inhibitors were associated with comparable improvements in the EuroQol-5 dimensions health state visual analog scale scores, Psoriatic Arthritis Impact of Disease 12-item scores, and work productivity, although the improvements were generally greater in the TNF inhibitor–treated group. A randomized trial comparing ustekinumab to TNF inhibitors in PsA is warranted to confirm these findings and inform treatment decisions.

Targeted therapies, such as biologics, are proven to be more efficacious than are conventional therapies; however, only about 60% of patients initiating targeted therapies demonstrate treatment response. Identifying the predictors of treatment response is an active area of research. Linde and colleagues looked at data from 13,369 biologic-naive patients registered with a PsA diagnosis from 13 European registries who initiated a first TNF inhibitor treatment. The study demonstrated that sex, disease duration, C-reactive protein level, age at treatment initiation, and fatigue predicted the achievement of the Disease Activity in Psoriatic Arthritis in 28 joints remission at 6 months.

Could biomarkers help predict response beyond clinical predictors? An interesting study indicates that beta–defensin 2 (BD-2) may serve as a predictive biomarker for clinical response to secukinumab in PsA. BD-2 is an antimicrobial peptide and an important protein in innate immune response. Cardner and colleagues analyzed protein expression data in serum samples from the phase 3 FUTURE 1-5 trials that included 1989 patients with PsA who received secukinumab or placebo. Baseline BD-2 levels were associated with early as well as sustained PsA treatment response to secukinumab, independent of psoriasis severity. BD-2 levels did not predict response to adalimumab in PsA nor was it associated with treatment response to secukinumab in RA. The addition of BD-2 to the clinical prediction model significantly improved the prediction of the 16-week American College of Rheumatology 20 response. Thus, BD-2 seems to be a secukinumab treatment response biomarker and requires further evaluation.

Although there are several treatment options for PsA, there have been few head-to-head studies conducted to determine comparative efficacy. Ustekinumab, a biologic agent targeting IL-p40, and therefore both IL-12 and IL-23, has proven efficacy in PsA, but the impression is that this drug is less effective than are TNF inhibitors for the treatment of the peripheral arthritis domain. However, in a prospective, observational study, Gossec and colleagues report that the improvements in patient-reported outcomes were generally comparable between ustekinumab and TNF inhibitor treatments. This study evaluated 437 patients with PsA from the PsABio study who initiated first- to third-line ustekinumab (n = 219) or TNF inhibitors (n = 218) and continued the initial treatment for 3 years. At 3 years, ustekinumab and TNF inhibitors were associated with comparable improvements in the EuroQol-5 dimensions health state visual analog scale scores, Psoriatic Arthritis Impact of Disease 12-item scores, and work productivity, although the improvements were generally greater in the TNF inhibitor–treated group. A randomized trial comparing ustekinumab to TNF inhibitors in PsA is warranted to confirm these findings and inform treatment decisions.

Targeted therapies, such as biologics, are proven to be more efficacious than are conventional therapies; however, only about 60% of patients initiating targeted therapies demonstrate treatment response. Identifying the predictors of treatment response is an active area of research. Linde and colleagues looked at data from 13,369 biologic-naive patients registered with a PsA diagnosis from 13 European registries who initiated a first TNF inhibitor treatment. The study demonstrated that sex, disease duration, C-reactive protein level, age at treatment initiation, and fatigue predicted the achievement of the Disease Activity in Psoriatic Arthritis in 28 joints remission at 6 months.

Could biomarkers help predict response beyond clinical predictors? An interesting study indicates that beta–defensin 2 (BD-2) may serve as a predictive biomarker for clinical response to secukinumab in PsA. BD-2 is an antimicrobial peptide and an important protein in innate immune response. Cardner and colleagues analyzed protein expression data in serum samples from the phase 3 FUTURE 1-5 trials that included 1989 patients with PsA who received secukinumab or placebo. Baseline BD-2 levels were associated with early as well as sustained PsA treatment response to secukinumab, independent of psoriasis severity. BD-2 levels did not predict response to adalimumab in PsA nor was it associated with treatment response to secukinumab in RA. The addition of BD-2 to the clinical prediction model significantly improved the prediction of the 16-week American College of Rheumatology 20 response. Thus, BD-2 seems to be a secukinumab treatment response biomarker and requires further evaluation.

The excellent short-term efficacy of the drug was well maintained up to 48 weeks, with only a slight loss of efficacy over time. Abrocitinib is a small molecule. We wouldn't expect a loss of efficacy due to the anti-drug antibodies that we see for large-molecule biologic drugs. I suspect that the slight loss of efficacy over time is a form of tachyphylaxis that is, to my thinking, probably due to poor adherence. Shocking, I know! Patients may not be fully adherent to treatment, even in a clinical trial. I think we should encourage patients to use 7-day pill boxes to aid better long-term adherence and outcomes.

Long-term safety is a critical issue with any new drug, certainly with a Janus kinase (JAK) inhibitor. Reich and colleagues concluded, "The long-term safety profile was manageable and consistent with previous reports." That conclusion seems reasonable to me. The most common side effects were upper respiratory tract infections. There may be a slight signal for increased risk for oral herpes infection, particularly at the higher dose. If this safety profile endures with longer-term data in larger numbers of people, it will be very reassuring.

The study by Wan and colleagues is another extremely well-done, important study by the premier dermatoepidemiology research team at the University of Pennsylvania. The study used an outstanding database from the United Kingdom that encompassed the clinical care experience of hundreds of thousands of children and adults with atopic dermatitis and millions of control patients without atopic dermatitis. With this many patients, the study has tremendous power to detect risk differences between groups.

With all that power, this study’s findings are very reassuring that there is no meaningful overall increased risk for malignancy in children or adults with atopic dermatitis. And while there was a statistically significant increased risk for lymphoma in children with severe atopic dermatitis, that risk is small … very small. Similarly, adults with severe AD had a twofold higher risk for noncutaneous T-cell lymphoma (CTCL), but since non-CTCL is rare, patients with severe AD shouldn't lose any sleep over it..

Simpson and colleagues' study of the effect of dupilumab on Staphylococcus aureus surprised me. Of course, we could expect that S aureus counts would be reduced with dupilumab; as barrier function is restored, surely S aureus counts would go down too. But, fascinatingly, with dupilumab treatment, S aureus counts decreased almost immediately, at both 3 and 7 days, before there was apparent clinical improvement in the skin rash. Simpson and colleagues suggest that the drop in S aureus counts could be due to improvement in immune function when interleukins 4 and 13 are blocked. Whether or not that is true, it is striking how fast S aureus counts improved, long before normal skin barrier function is restored.

Here's a fun fact: Atopic dermatitis is a little less common, about 10% less common, in people born second or later in the birth order. Lisik and colleagues did a meta-analysis of 114 studies and found this marginally lower rate in those born second or later compared with those born first. I'm not sure that there is any clinically meaningful significance to this, but I found it interesting (even though I was born first, and my younger brother had atopic dermatitis).

The excellent short-term efficacy of the drug was well maintained up to 48 weeks, with only a slight loss of efficacy over time. Abrocitinib is a small molecule. We wouldn't expect a loss of efficacy due to the anti-drug antibodies that we see for large-molecule biologic drugs. I suspect that the slight loss of efficacy over time is a form of tachyphylaxis that is, to my thinking, probably due to poor adherence. Shocking, I know! Patients may not be fully adherent to treatment, even in a clinical trial. I think we should encourage patients to use 7-day pill boxes to aid better long-term adherence and outcomes.

Long-term safety is a critical issue with any new drug, certainly with a Janus kinase (JAK) inhibitor. Reich and colleagues concluded, "The long-term safety profile was manageable and consistent with previous reports." That conclusion seems reasonable to me. The most common side effects were upper respiratory tract infections. There may be a slight signal for increased risk for oral herpes infection, particularly at the higher dose. If this safety profile endures with longer-term data in larger numbers of people, it will be very reassuring.

The study by Wan and colleagues is another extremely well-done, important study by the premier dermatoepidemiology research team at the University of Pennsylvania. The study used an outstanding database from the United Kingdom that encompassed the clinical care experience of hundreds of thousands of children and adults with atopic dermatitis and millions of control patients without atopic dermatitis. With this many patients, the study has tremendous power to detect risk differences between groups.

With all that power, this study’s findings are very reassuring that there is no meaningful overall increased risk for malignancy in children or adults with atopic dermatitis. And while there was a statistically significant increased risk for lymphoma in children with severe atopic dermatitis, that risk is small … very small. Similarly, adults with severe AD had a twofold higher risk for noncutaneous T-cell lymphoma (CTCL), but since non-CTCL is rare, patients with severe AD shouldn't lose any sleep over it..

Simpson and colleagues' study of the effect of dupilumab on Staphylococcus aureus surprised me. Of course, we could expect that S aureus counts would be reduced with dupilumab; as barrier function is restored, surely S aureus counts would go down too. But, fascinatingly, with dupilumab treatment, S aureus counts decreased almost immediately, at both 3 and 7 days, before there was apparent clinical improvement in the skin rash. Simpson and colleagues suggest that the drop in S aureus counts could be due to improvement in immune function when interleukins 4 and 13 are blocked. Whether or not that is true, it is striking how fast S aureus counts improved, long before normal skin barrier function is restored.

Here's a fun fact: Atopic dermatitis is a little less common, about 10% less common, in people born second or later in the birth order. Lisik and colleagues did a meta-analysis of 114 studies and found this marginally lower rate in those born second or later compared with those born first. I'm not sure that there is any clinically meaningful significance to this, but I found it interesting (even though I was born first, and my younger brother had atopic dermatitis).

The excellent short-term efficacy of the drug was well maintained up to 48 weeks, with only a slight loss of efficacy over time. Abrocitinib is a small molecule. We wouldn't expect a loss of efficacy due to the anti-drug antibodies that we see for large-molecule biologic drugs. I suspect that the slight loss of efficacy over time is a form of tachyphylaxis that is, to my thinking, probably due to poor adherence. Shocking, I know! Patients may not be fully adherent to treatment, even in a clinical trial. I think we should encourage patients to use 7-day pill boxes to aid better long-term adherence and outcomes.

Long-term safety is a critical issue with any new drug, certainly with a Janus kinase (JAK) inhibitor. Reich and colleagues concluded, "The long-term safety profile was manageable and consistent with previous reports." That conclusion seems reasonable to me. The most common side effects were upper respiratory tract infections. There may be a slight signal for increased risk for oral herpes infection, particularly at the higher dose. If this safety profile endures with longer-term data in larger numbers of people, it will be very reassuring.

The study by Wan and colleagues is another extremely well-done, important study by the premier dermatoepidemiology research team at the University of Pennsylvania. The study used an outstanding database from the United Kingdom that encompassed the clinical care experience of hundreds of thousands of children and adults with atopic dermatitis and millions of control patients without atopic dermatitis. With this many patients, the study has tremendous power to detect risk differences between groups.

With all that power, this study’s findings are very reassuring that there is no meaningful overall increased risk for malignancy in children or adults with atopic dermatitis. And while there was a statistically significant increased risk for lymphoma in children with severe atopic dermatitis, that risk is small … very small. Similarly, adults with severe AD had a twofold higher risk for noncutaneous T-cell lymphoma (CTCL), but since non-CTCL is rare, patients with severe AD shouldn't lose any sleep over it..

Simpson and colleagues' study of the effect of dupilumab on Staphylococcus aureus surprised me. Of course, we could expect that S aureus counts would be reduced with dupilumab; as barrier function is restored, surely S aureus counts would go down too. But, fascinatingly, with dupilumab treatment, S aureus counts decreased almost immediately, at both 3 and 7 days, before there was apparent clinical improvement in the skin rash. Simpson and colleagues suggest that the drop in S aureus counts could be due to improvement in immune function when interleukins 4 and 13 are blocked. Whether or not that is true, it is striking how fast S aureus counts improved, long before normal skin barrier function is restored.

Here's a fun fact: Atopic dermatitis is a little less common, about 10% less common, in people born second or later in the birth order. Lisik and colleagues did a meta-analysis of 114 studies and found this marginally lower rate in those born second or later compared with those born first. I'm not sure that there is any clinically meaningful significance to this, but I found it interesting (even though I was born first, and my younger brother had atopic dermatitis).

Although there are several treatment options for PsA, there have been few head-to-head studies conducted to determine comparative efficacy. Ustekinumab, a biologic agent targeting IL-p40, and therefore both IL-12 and IL-23, has proven efficacy in PsA, but the impression is that this drug is less effective than are TNF inhibitors for the treatment of the peripheral arthritis domain. However, in a prospective, observational study, Gossec and colleagues report that the improvements in patient-reported outcomes were generally comparable between ustekinumab and TNF inhibitor treatments. This study evaluated 437 patients with PsA from the PsABio study who initiated first- to third-line ustekinumab (n = 219) or TNF inhibitors (n = 218) and continued the initial treatment for 3 years. At 3 years, ustekinumab and TNF inhibitors were associated with comparable improvements in the EuroQol-5 dimensions health state visual analog scale scores, Psoriatic Arthritis Impact of Disease 12-item scores, and work productivity, although the improvements were generally greater in the TNF inhibitor–treated group. A randomized trial comparing ustekinumab to TNF inhibitors in PsA is warranted to confirm these findings and inform treatment decisions.

Targeted therapies, such as biologics, are proven to be more efficacious than are conventional therapies; however, only about 60% of patients initiating targeted therapies demonstrate treatment response. Identifying the predictors of treatment response is an active area of research. Linde and colleagues looked at data from 13,369 biologic-naive patients registered with a PsA diagnosis from 13 European registries who initiated a first TNF inhibitor treatment. The study demonstrated that sex, disease duration, C-reactive protein level, age at treatment initiation, and fatigue predicted the achievement of the Disease Activity in Psoriatic Arthritis in 28 joints remission at 6 months.

Could biomarkers help predict response beyond clinical predictors? An interesting study indicates that beta–defensin 2 (BD-2) may serve as a predictive biomarker for clinical response to secukinumab in PsA. BD-2 is an antimicrobial peptide and an important protein in innate immune response. Cardner and colleagues analyzed protein expression data in serum samples from the phase 3 FUTURE 1-5 trials that included 1989 patients with PsA who received secukinumab or placebo. Baseline BD-2 levels were associated with early as well as sustained PsA treatment response to secukinumab, independent of psoriasis severity. BD-2 levels did not predict response to adalimumab in PsA nor was it associated with treatment response to secukinumab in RA. The addition of BD-2 to the clinical prediction model significantly improved the prediction of the 16-week American College of Rheumatology 20 response. Thus, BD-2 seems to be a secukinumab treatment response biomarker and requires further evaluation.

Although there are several treatment options for PsA, there have been few head-to-head studies conducted to determine comparative efficacy. Ustekinumab, a biologic agent targeting IL-p40, and therefore both IL-12 and IL-23, has proven efficacy in PsA, but the impression is that this drug is less effective than are TNF inhibitors for the treatment of the peripheral arthritis domain. However, in a prospective, observational study, Gossec and colleagues report that the improvements in patient-reported outcomes were generally comparable between ustekinumab and TNF inhibitor treatments. This study evaluated 437 patients with PsA from the PsABio study who initiated first- to third-line ustekinumab (n = 219) or TNF inhibitors (n = 218) and continued the initial treatment for 3 years. At 3 years, ustekinumab and TNF inhibitors were associated with comparable improvements in the EuroQol-5 dimensions health state visual analog scale scores, Psoriatic Arthritis Impact of Disease 12-item scores, and work productivity, although the improvements were generally greater in the TNF inhibitor–treated group. A randomized trial comparing ustekinumab to TNF inhibitors in PsA is warranted to confirm these findings and inform treatment decisions.

Targeted therapies, such as biologics, are proven to be more efficacious than are conventional therapies; however, only about 60% of patients initiating targeted therapies demonstrate treatment response. Identifying the predictors of treatment response is an active area of research. Linde and colleagues looked at data from 13,369 biologic-naive patients registered with a PsA diagnosis from 13 European registries who initiated a first TNF inhibitor treatment. The study demonstrated that sex, disease duration, C-reactive protein level, age at treatment initiation, and fatigue predicted the achievement of the Disease Activity in Psoriatic Arthritis in 28 joints remission at 6 months.

Could biomarkers help predict response beyond clinical predictors? An interesting study indicates that beta–defensin 2 (BD-2) may serve as a predictive biomarker for clinical response to secukinumab in PsA. BD-2 is an antimicrobial peptide and an important protein in innate immune response. Cardner and colleagues analyzed protein expression data in serum samples from the phase 3 FUTURE 1-5 trials that included 1989 patients with PsA who received secukinumab or placebo. Baseline BD-2 levels were associated with early as well as sustained PsA treatment response to secukinumab, independent of psoriasis severity. BD-2 levels did not predict response to adalimumab in PsA nor was it associated with treatment response to secukinumab in RA. The addition of BD-2 to the clinical prediction model significantly improved the prediction of the 16-week American College of Rheumatology 20 response. Thus, BD-2 seems to be a secukinumab treatment response biomarker and requires further evaluation.

Although there are several treatment options for PsA, there have been few head-to-head studies conducted to determine comparative efficacy. Ustekinumab, a biologic agent targeting IL-p40, and therefore both IL-12 and IL-23, has proven efficacy in PsA, but the impression is that this drug is less effective than are TNF inhibitors for the treatment of the peripheral arthritis domain. However, in a prospective, observational study, Gossec and colleagues report that the improvements in patient-reported outcomes were generally comparable between ustekinumab and TNF inhibitor treatments. This study evaluated 437 patients with PsA from the PsABio study who initiated first- to third-line ustekinumab (n = 219) or TNF inhibitors (n = 218) and continued the initial treatment for 3 years. At 3 years, ustekinumab and TNF inhibitors were associated with comparable improvements in the EuroQol-5 dimensions health state visual analog scale scores, Psoriatic Arthritis Impact of Disease 12-item scores, and work productivity, although the improvements were generally greater in the TNF inhibitor–treated group. A randomized trial comparing ustekinumab to TNF inhibitors in PsA is warranted to confirm these findings and inform treatment decisions.

Targeted therapies, such as biologics, are proven to be more efficacious than are conventional therapies; however, only about 60% of patients initiating targeted therapies demonstrate treatment response. Identifying the predictors of treatment response is an active area of research. Linde and colleagues looked at data from 13,369 biologic-naive patients registered with a PsA diagnosis from 13 European registries who initiated a first TNF inhibitor treatment. The study demonstrated that sex, disease duration, C-reactive protein level, age at treatment initiation, and fatigue predicted the achievement of the Disease Activity in Psoriatic Arthritis in 28 joints remission at 6 months.

Could biomarkers help predict response beyond clinical predictors? An interesting study indicates that beta–defensin 2 (BD-2) may serve as a predictive biomarker for clinical response to secukinumab in PsA. BD-2 is an antimicrobial peptide and an important protein in innate immune response. Cardner and colleagues analyzed protein expression data in serum samples from the phase 3 FUTURE 1-5 trials that included 1989 patients with PsA who received secukinumab or placebo. Baseline BD-2 levels were associated with early as well as sustained PsA treatment response to secukinumab, independent of psoriasis severity. BD-2 levels did not predict response to adalimumab in PsA nor was it associated with treatment response to secukinumab in RA. The addition of BD-2 to the clinical prediction model significantly improved the prediction of the 16-week American College of Rheumatology 20 response. Thus, BD-2 seems to be a secukinumab treatment response biomarker and requires further evaluation.

With several new biologic (b) disease-modifying antirheumatic drugs (DMARD) and targeted synthetic (ts) DMARD now available for the treatment of rheumatoid arthritis (RA), information regarding their comparative effectiveness would be of interest. Relatively few head-to-head trials have been published, however. Though "real-world" studies have been published to provide some information about comparative effectiveness, Deakin and colleagues used a target trial emulation framework to apply clinical trial methods to real-world data. Using the Australian OPAL registry of bDMARD/tsDMARD-naive patients, they developed a randomized controlled trial protocol of tofacitinib vs adalimumab using an intention-to-treat analysis. Under this framework, there was small reduction of disease activity with tofacitinib vs adalimumab at 3 months and no difference at 9 months. While this framework is conceptually interesting, it may be more meaningful used in side-by-side comparison to a real-world analysis of the same data to evaluate pitfalls and biases in both; otherwise, its utility as a stand-alone analysis of observational data is not fully clear.

Østergaard and colleagues also performed a head-to-head study of several different therapies to address the question of optimal treatment strategies for patients with early RA. Patients with moderate to severe disease activity were randomly assigned to treatment with methotrexate combined with (1) oral glucocorticoid or sulfasalazine, hydroxychloroquine, and intra-articular steroid injections, (2) certolizumab, (3) abatacept, or (4) tocilizumab. Disease activity and radiographic changes were evaluated at 48 weeks. In this study of over 800 patients, treatment with abatacept or certolizumab was associated with improved Clinical Disease Activity Index (CDAI) remission rates compared with the active conventional therapy (group 1), but tocilizumab was not. The overall differences between bDMARD treatment groups were small and thus may not reflect significant differences in effectiveness. Instead, this study challenges the notion of initiating conventional synthetic DMARD (csDMARD) therapy in patients with early RA and stepping up to bDMARD, as initial bDMARD therapy may be of benefit in patients with more active early RA.

Alongside the question of the effectiveness of bMARD and tsDMARD in real-world settings, the appropriate role for long-term low-dose prednisone in the treatment of RA remains unknown. A recent study by Güler-Yüksel and colleagues examined the effects of 5 mg prednisolone daily in addition to standard therapy in patients over 65 years of age with active RA. Due to the potential complications of weight gain and glucose intolerance with long-term glucocorticoids, in addition to low-bone-density issues, their use has generally not been viewed favorably. In this multicenter trial, 449 patients were randomly assigned to receive prednisolone vs placebo in addition to their usual medications over 2 years. Notably, patients in the prednisolone group had an average of 0.9 kg weight gain compared with placebo with 0.4 kg weight loss over 2 years. By the end of 2 years, 29% of patients in the prednisolone group had a weight gain of > 2 kg compared with 18% of patients in the placebo group. Only 57 patients in all underwent body composition analysis, and, interestingly, those in the prednisolone group had small increases in lean body mass compared with fat mass, though these patients were not necessarily representative. The authors suggest, though the study does not prove, that low-dose prednisolone can be protective against sarcopenia, which is associated with older age and "rheumatoid cachexia." The study also did not examine the interaction of glucocorticoid use with diet and exercise. While it is reassuring that patients in this study did not experience major weight gain, it does not appear to be a generalizable finding at this point.

With several new biologic (b) disease-modifying antirheumatic drugs (DMARD) and targeted synthetic (ts) DMARD now available for the treatment of rheumatoid arthritis (RA), information regarding their comparative effectiveness would be of interest. Relatively few head-to-head trials have been published, however. Though "real-world" studies have been published to provide some information about comparative effectiveness, Deakin and colleagues used a target trial emulation framework to apply clinical trial methods to real-world data. Using the Australian OPAL registry of bDMARD/tsDMARD-naive patients, they developed a randomized controlled trial protocol of tofacitinib vs adalimumab using an intention-to-treat analysis. Under this framework, there was small reduction of disease activity with tofacitinib vs adalimumab at 3 months and no difference at 9 months. While this framework is conceptually interesting, it may be more meaningful used in side-by-side comparison to a real-world analysis of the same data to evaluate pitfalls and biases in both; otherwise, its utility as a stand-alone analysis of observational data is not fully clear.

Østergaard and colleagues also performed a head-to-head study of several different therapies to address the question of optimal treatment strategies for patients with early RA. Patients with moderate to severe disease activity were randomly assigned to treatment with methotrexate combined with (1) oral glucocorticoid or sulfasalazine, hydroxychloroquine, and intra-articular steroid injections, (2) certolizumab, (3) abatacept, or (4) tocilizumab. Disease activity and radiographic changes were evaluated at 48 weeks. In this study of over 800 patients, treatment with abatacept or certolizumab was associated with improved Clinical Disease Activity Index (CDAI) remission rates compared with the active conventional therapy (group 1), but tocilizumab was not. The overall differences between bDMARD treatment groups were small and thus may not reflect significant differences in effectiveness. Instead, this study challenges the notion of initiating conventional synthetic DMARD (csDMARD) therapy in patients with early RA and stepping up to bDMARD, as initial bDMARD therapy may be of benefit in patients with more active early RA.

Alongside the question of the effectiveness of bMARD and tsDMARD in real-world settings, the appropriate role for long-term low-dose prednisone in the treatment of RA remains unknown. A recent study by Güler-Yüksel and colleagues examined the effects of 5 mg prednisolone daily in addition to standard therapy in patients over 65 years of age with active RA. Due to the potential complications of weight gain and glucose intolerance with long-term glucocorticoids, in addition to low-bone-density issues, their use has generally not been viewed favorably. In this multicenter trial, 449 patients were randomly assigned to receive prednisolone vs placebo in addition to their usual medications over 2 years. Notably, patients in the prednisolone group had an average of 0.9 kg weight gain compared with placebo with 0.4 kg weight loss over 2 years. By the end of 2 years, 29% of patients in the prednisolone group had a weight gain of > 2 kg compared with 18% of patients in the placebo group. Only 57 patients in all underwent body composition analysis, and, interestingly, those in the prednisolone group had small increases in lean body mass compared with fat mass, though these patients were not necessarily representative. The authors suggest, though the study does not prove, that low-dose prednisolone can be protective against sarcopenia, which is associated with older age and "rheumatoid cachexia." The study also did not examine the interaction of glucocorticoid use with diet and exercise. While it is reassuring that patients in this study did not experience major weight gain, it does not appear to be a generalizable finding at this point.

With several new biologic (b) disease-modifying antirheumatic drugs (DMARD) and targeted synthetic (ts) DMARD now available for the treatment of rheumatoid arthritis (RA), information regarding their comparative effectiveness would be of interest. Relatively few head-to-head trials have been published, however. Though "real-world" studies have been published to provide some information about comparative effectiveness, Deakin and colleagues used a target trial emulation framework to apply clinical trial methods to real-world data. Using the Australian OPAL registry of bDMARD/tsDMARD-naive patients, they developed a randomized controlled trial protocol of tofacitinib vs adalimumab using an intention-to-treat analysis. Under this framework, there was small reduction of disease activity with tofacitinib vs adalimumab at 3 months and no difference at 9 months. While this framework is conceptually interesting, it may be more meaningful used in side-by-side comparison to a real-world analysis of the same data to evaluate pitfalls and biases in both; otherwise, its utility as a stand-alone analysis of observational data is not fully clear.

Østergaard and colleagues also performed a head-to-head study of several different therapies to address the question of optimal treatment strategies for patients with early RA. Patients with moderate to severe disease activity were randomly assigned to treatment with methotrexate combined with (1) oral glucocorticoid or sulfasalazine, hydroxychloroquine, and intra-articular steroid injections, (2) certolizumab, (3) abatacept, or (4) tocilizumab. Disease activity and radiographic changes were evaluated at 48 weeks. In this study of over 800 patients, treatment with abatacept or certolizumab was associated with improved Clinical Disease Activity Index (CDAI) remission rates compared with the active conventional therapy (group 1), but tocilizumab was not. The overall differences between bDMARD treatment groups were small and thus may not reflect significant differences in effectiveness. Instead, this study challenges the notion of initiating conventional synthetic DMARD (csDMARD) therapy in patients with early RA and stepping up to bDMARD, as initial bDMARD therapy may be of benefit in patients with more active early RA.

Alongside the question of the effectiveness of bMARD and tsDMARD in real-world settings, the appropriate role for long-term low-dose prednisone in the treatment of RA remains unknown. A recent study by Güler-Yüksel and colleagues examined the effects of 5 mg prednisolone daily in addition to standard therapy in patients over 65 years of age with active RA. Due to the potential complications of weight gain and glucose intolerance with long-term glucocorticoids, in addition to low-bone-density issues, their use has generally not been viewed favorably. In this multicenter trial, 449 patients were randomly assigned to receive prednisolone vs placebo in addition to their usual medications over 2 years. Notably, patients in the prednisolone group had an average of 0.9 kg weight gain compared with placebo with 0.4 kg weight loss over 2 years. By the end of 2 years, 29% of patients in the prednisolone group had a weight gain of > 2 kg compared with 18% of patients in the placebo group. Only 57 patients in all underwent body composition analysis, and, interestingly, those in the prednisolone group had small increases in lean body mass compared with fat mass, though these patients were not necessarily representative. The authors suggest, though the study does not prove, that low-dose prednisolone can be protective against sarcopenia, which is associated with older age and "rheumatoid cachexia." The study also did not examine the interaction of glucocorticoid use with diet and exercise. While it is reassuring that patients in this study did not experience major weight gain, it does not appear to be a generalizable finding at this point.

Data are limited regarding the effect of interrupting radiation therapy for patients with BC. A retrospective study by Chow and colleagues looked at 35,845 patients with nonmetastatic triple-negative BC from the National Cancer Database who had received external beam radiation therapy as part of the management of their BC. The analysis showed inferior overall survival in patients with a longer duration of radiation treatment (hazard ratio 1.023; 95% CI 1.015-1.031) The more days of interruption, the higher the likelihood of mortality seen. In reference to 0-1 days of interruption, patients with 2-5 interrupted days (hazard ratio 1.069; 95% CI 1.002-1.140), 6-10 interrupted days (hazard ratio 1.239; 95% CI 1.140-1.348), and 11-15 interrupted days (hazard ratio 1.265; 95% CI 1.126-1.431) did worse. These findings should encourage further studies to explore ways to minimize treatment interruptions among patients with BC.

A lack of adherence to adjuvant endocrine therapy has been associated with increased mortality among women with BC. The retrospective study by Zheng and Thomas  included 25,796 older women (> 65 years old) diagnosed with stage I-III hormone receptor–positive BC and looked at associations between adherence to and persistence with adjuvant endocrine therapy and mortality in this cohort. Their findings showed that the risk for all-cause mortality was reduced by 25% in patients with vs without cumulative adherence to endocrine therapy (hazard ratio 0.75; P < .001), although no association was seen with BC-specific mortality. Persistence with endocrine therapy, which was defined as having taken the treatment for ≥ 180 continuous days, was associated with 11% reduction in all-cause mortality and 37% reduction in BC-specific mortality. This study supports prior studies in highlighting the importance of endocrine therapy adherence among women with hormone-positive BC.

Tumor-infiltrating lymphocytes (TIL) are considered significant prognostic markers in patients with BC, although the prognostic effect of TIL in human epidermal growth factor reception 2 (HER2)–low BC has not been identified. A large-cohort, single-institution retrospective analysis by Sun and colleagues investigated the prognostic role of TIL in HER2-low early-stage BC. The analysis included 1763 patients with early-stage BC who underwent surgery, of whom 429 patients were HER2+, 739 were HER2-low, and 595 were HER2-0. No differences in disease-free survival (DFS) were seen between the three cohorts. However, in patients with HER2-low BC, high (>10%) vs low (≤10%) TIL levels were associated with a 53% improvement in DFS overall (hazard ratio 0.47; P = .035), and a 58% improvement in DFS was seen for the hormone receptor–positive/HER2-low cohort (hazard ratio 0.42; P = .032).

Data are limited regarding the effect of interrupting radiation therapy for patients with BC. A retrospective study by Chow and colleagues looked at 35,845 patients with nonmetastatic triple-negative BC from the National Cancer Database who had received external beam radiation therapy as part of the management of their BC. The analysis showed inferior overall survival in patients with a longer duration of radiation treatment (hazard ratio 1.023; 95% CI 1.015-1.031) The more days of interruption, the higher the likelihood of mortality seen. In reference to 0-1 days of interruption, patients with 2-5 interrupted days (hazard ratio 1.069; 95% CI 1.002-1.140), 6-10 interrupted days (hazard ratio 1.239; 95% CI 1.140-1.348), and 11-15 interrupted days (hazard ratio 1.265; 95% CI 1.126-1.431) did worse. These findings should encourage further studies to explore ways to minimize treatment interruptions among patients with BC.

A lack of adherence to adjuvant endocrine therapy has been associated with increased mortality among women with BC. The retrospective study by Zheng and Thomas  included 25,796 older women (> 65 years old) diagnosed with stage I-III hormone receptor–positive BC and looked at associations between adherence to and persistence with adjuvant endocrine therapy and mortality in this cohort. Their findings showed that the risk for all-cause mortality was reduced by 25% in patients with vs without cumulative adherence to endocrine therapy (hazard ratio 0.75; P < .001), although no association was seen with BC-specific mortality. Persistence with endocrine therapy, which was defined as having taken the treatment for ≥ 180 continuous days, was associated with 11% reduction in all-cause mortality and 37% reduction in BC-specific mortality. This study supports prior studies in highlighting the importance of endocrine therapy adherence among women with hormone-positive BC.

Tumor-infiltrating lymphocytes (TIL) are considered significant prognostic markers in patients with BC, although the prognostic effect of TIL in human epidermal growth factor reception 2 (HER2)–low BC has not been identified. A large-cohort, single-institution retrospective analysis by Sun and colleagues investigated the prognostic role of TIL in HER2-low early-stage BC. The analysis included 1763 patients with early-stage BC who underwent surgery, of whom 429 patients were HER2+, 739 were HER2-low, and 595 were HER2-0. No differences in disease-free survival (DFS) were seen between the three cohorts. However, in patients with HER2-low BC, high (>10%) vs low (≤10%) TIL levels were associated with a 53% improvement in DFS overall (hazard ratio 0.47; P = .035), and a 58% improvement in DFS was seen for the hormone receptor–positive/HER2-low cohort (hazard ratio 0.42; P = .032).

Data are limited regarding the effect of interrupting radiation therapy for patients with BC. A retrospective study by Chow and colleagues looked at 35,845 patients with nonmetastatic triple-negative BC from the National Cancer Database who had received external beam radiation therapy as part of the management of their BC. The analysis showed inferior overall survival in patients with a longer duration of radiation treatment (hazard ratio 1.023; 95% CI 1.015-1.031) The more days of interruption, the higher the likelihood of mortality seen. In reference to 0-1 days of interruption, patients with 2-5 interrupted days (hazard ratio 1.069; 95% CI 1.002-1.140), 6-10 interrupted days (hazard ratio 1.239; 95% CI 1.140-1.348), and 11-15 interrupted days (hazard ratio 1.265; 95% CI 1.126-1.431) did worse. These findings should encourage further studies to explore ways to minimize treatment interruptions among patients with BC.

A lack of adherence to adjuvant endocrine therapy has been associated with increased mortality among women with BC. The retrospective study by Zheng and Thomas  included 25,796 older women (> 65 years old) diagnosed with stage I-III hormone receptor–positive BC and looked at associations between adherence to and persistence with adjuvant endocrine therapy and mortality in this cohort. Their findings showed that the risk for all-cause mortality was reduced by 25% in patients with vs without cumulative adherence to endocrine therapy (hazard ratio 0.75; P < .001), although no association was seen with BC-specific mortality. Persistence with endocrine therapy, which was defined as having taken the treatment for ≥ 180 continuous days, was associated with 11% reduction in all-cause mortality and 37% reduction in BC-specific mortality. This study supports prior studies in highlighting the importance of endocrine therapy adherence among women with hormone-positive BC.

Tumor-infiltrating lymphocytes (TIL) are considered significant prognostic markers in patients with BC, although the prognostic effect of TIL in human epidermal growth factor reception 2 (HER2)–low BC has not been identified. A large-cohort, single-institution retrospective analysis by Sun and colleagues investigated the prognostic role of TIL in HER2-low early-stage BC. The analysis included 1763 patients with early-stage BC who underwent surgery, of whom 429 patients were HER2+, 739 were HER2-low, and 595 were HER2-0. No differences in disease-free survival (DFS) were seen between the three cohorts. However, in patients with HER2-low BC, high (>10%) vs low (≤10%) TIL levels were associated with a 53% improvement in DFS overall (hazard ratio 0.47; P = .035), and a 58% improvement in DFS was seen for the hormone receptor–positive/HER2-low cohort (hazard ratio 0.42; P = .032).

The addition of pertuzumab to trastuzumab plus chemotherapy has demonstrated improvement in pathologic complete response (pCR) rates compared with trastuzumab plus chemotherapy in early-stage HER2-positive breast cancer.³ The framework of oncology is built on clinical trials through their rigorous design, enrollment, and synthesis of data; however, real-world studies are an integral component of cancer research because they provide a more representative sample of the general population treated in routine clinical practice. Neopearl was a retrospective, observational, real-world study that evaluated the efficacy and safety of trastuzumab plus chemotherapy with or without pertuzumab among 271 patients with stage II-III HER2-positive breast cancer (Fabbri et al). The addition of pertuzumab led to an increase in pCR rate (49% vs 62%; odds ratio 1.74; P = .032) and improvement in 5-year event-free survival (81% vs 93%; hazard ratio 2.22; P = .041), and the benefit on univariate analysis was restricted to patients with positive axillary nodes. Furthermore, there were no significant differences in adverse events, including cardiac, between the two groups. These results serve to strengthen the available data regarding the clinical efficacy and favorable safety profile of dual HER2-targeted therapy combined with neoadjuvant chemotherapy.

Lifestyle factors, including physical activity and diet, are becoming increasingly recognized as important determinants of various cancer-specific outcomes and overall health. Furthermore, because these are modifiable, there is often motivation on behalf of an individual to change behaviors that can affect their outcome. Adherence to the Mediterranean diet (MD) has been associated with reduced risk for breast cancer development and lower mortality among women with breast cancer.^4,5 Data from a prospective multicenter European cohort including 13,270 breast cancer survivors demonstrated that low compared with medium adherence to a MD before a breast cancer diagnosis was associated with a 13% higher risk for all-cause mortality (hazard ratio 1.13; 95% CI 1.01-1.26). A three-unit increase in the adapted relative MD score was associated with an 8% reduced risk for overall mortality (hazard ratio_3-unit 0.92; 95% CI 0.87-0.97); this result was sustained in the postmenopausal population and strengthened in metastatic disease (Castro-Espin et al). The connection between diet and cancer outcomes is complex, and future research evaluating specific dietary interventions and the underlying biologic pathways by which nutrition exerts its effects will be important to inform our counseling for patients with breast cancer in the survivorship setting.

Additional References

1. Whelan TJ, Olivotto IA, Parulekar WR, et al, for the MA.20 Study Investigators. Regional nodal irradiation in early-stage breast cancer. N Engl J Med. 2015;373:307-16. doi:10.1056/NEJMoa1415340
2. ClinicalTrials.gov. Regional radiotherapy in biomarker low-risk node positive and T3N0 breast cancer (TAILOR RT). National Library of Medicine. Last updated November 23, 2022. https://www.clinicaltrials.gov/study/NCT03488693
3. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): A randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:25-32. doi:10.1016/S1470-2045(11)70336-9
4. Buckland G, Travier N, Cottet V, et al. Adherence to the mediterranean diet and risk of breast cancer in the European prospective investigation into cancer and nutrition cohort study. Int J Cancer. 2013;132:2918-27. doi:10.1002/ijc.27958
5. Haslam DE, John EM, Knight JA, et al. Diet quality and all-cause mortality in women with breast cancer from the Breast Cancer Family Registry. Cancer Epidemiol Biomarkers Prev. 2023;32:678-686. doi:10.1158/1055-9965.EPI-22-1198

The addition of pertuzumab to trastuzumab plus chemotherapy has demonstrated improvement in pathologic complete response (pCR) rates compared with trastuzumab plus chemotherapy in early-stage HER2-positive breast cancer.³ The framework of oncology is built on clinical trials through their rigorous design, enrollment, and synthesis of data; however, real-world studies are an integral component of cancer research because they provide a more representative sample of the general population treated in routine clinical practice. Neopearl was a retrospective, observational, real-world study that evaluated the efficacy and safety of trastuzumab plus chemotherapy with or without pertuzumab among 271 patients with stage II-III HER2-positive breast cancer (Fabbri et al). The addition of pertuzumab led to an increase in pCR rate (49% vs 62%; odds ratio 1.74; P = .032) and improvement in 5-year event-free survival (81% vs 93%; hazard ratio 2.22; P = .041), and the benefit on univariate analysis was restricted to patients with positive axillary nodes. Furthermore, there were no significant differences in adverse events, including cardiac, between the two groups. These results serve to strengthen the available data regarding the clinical efficacy and favorable safety profile of dual HER2-targeted therapy combined with neoadjuvant chemotherapy.

Lifestyle factors, including physical activity and diet, are becoming increasingly recognized as important determinants of various cancer-specific outcomes and overall health. Furthermore, because these are modifiable, there is often motivation on behalf of an individual to change behaviors that can affect their outcome. Adherence to the Mediterranean diet (MD) has been associated with reduced risk for breast cancer development and lower mortality among women with breast cancer.^4,5 Data from a prospective multicenter European cohort including 13,270 breast cancer survivors demonstrated that low compared with medium adherence to a MD before a breast cancer diagnosis was associated with a 13% higher risk for all-cause mortality (hazard ratio 1.13; 95% CI 1.01-1.26). A three-unit increase in the adapted relative MD score was associated with an 8% reduced risk for overall mortality (hazard ratio_3-unit 0.92; 95% CI 0.87-0.97); this result was sustained in the postmenopausal population and strengthened in metastatic disease (Castro-Espin et al). The connection between diet and cancer outcomes is complex, and future research evaluating specific dietary interventions and the underlying biologic pathways by which nutrition exerts its effects will be important to inform our counseling for patients with breast cancer in the survivorship setting.

Additional References

1. Whelan TJ, Olivotto IA, Parulekar WR, et al, for the MA.20 Study Investigators. Regional nodal irradiation in early-stage breast cancer. N Engl J Med. 2015;373:307-16. doi:10.1056/NEJMoa1415340
2. ClinicalTrials.gov. Regional radiotherapy in biomarker low-risk node positive and T3N0 breast cancer (TAILOR RT). National Library of Medicine. Last updated November 23, 2022. https://www.clinicaltrials.gov/study/NCT03488693
3. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): A randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:25-32. doi:10.1016/S1470-2045(11)70336-9
4. Buckland G, Travier N, Cottet V, et al. Adherence to the mediterranean diet and risk of breast cancer in the European prospective investigation into cancer and nutrition cohort study. Int J Cancer. 2013;132:2918-27. doi:10.1002/ijc.27958
5. Haslam DE, John EM, Knight JA, et al. Diet quality and all-cause mortality in women with breast cancer from the Breast Cancer Family Registry. Cancer Epidemiol Biomarkers Prev. 2023;32:678-686. doi:10.1158/1055-9965.EPI-22-1198

The addition of pertuzumab to trastuzumab plus chemotherapy has demonstrated improvement in pathologic complete response (pCR) rates compared with trastuzumab plus chemotherapy in early-stage HER2-positive breast cancer.³ The framework of oncology is built on clinical trials through their rigorous design, enrollment, and synthesis of data; however, real-world studies are an integral component of cancer research because they provide a more representative sample of the general population treated in routine clinical practice. Neopearl was a retrospective, observational, real-world study that evaluated the efficacy and safety of trastuzumab plus chemotherapy with or without pertuzumab among 271 patients with stage II-III HER2-positive breast cancer (Fabbri et al). The addition of pertuzumab led to an increase in pCR rate (49% vs 62%; odds ratio 1.74; P = .032) and improvement in 5-year event-free survival (81% vs 93%; hazard ratio 2.22; P = .041), and the benefit on univariate analysis was restricted to patients with positive axillary nodes. Furthermore, there were no significant differences in adverse events, including cardiac, between the two groups. These results serve to strengthen the available data regarding the clinical efficacy and favorable safety profile of dual HER2-targeted therapy combined with neoadjuvant chemotherapy.

Lifestyle factors, including physical activity and diet, are becoming increasingly recognized as important determinants of various cancer-specific outcomes and overall health. Furthermore, because these are modifiable, there is often motivation on behalf of an individual to change behaviors that can affect their outcome. Adherence to the Mediterranean diet (MD) has been associated with reduced risk for breast cancer development and lower mortality among women with breast cancer.^4,5 Data from a prospective multicenter European cohort including 13,270 breast cancer survivors demonstrated that low compared with medium adherence to a MD before a breast cancer diagnosis was associated with a 13% higher risk for all-cause mortality (hazard ratio 1.13; 95% CI 1.01-1.26). A three-unit increase in the adapted relative MD score was associated with an 8% reduced risk for overall mortality (hazard ratio_3-unit 0.92; 95% CI 0.87-0.97); this result was sustained in the postmenopausal population and strengthened in metastatic disease (Castro-Espin et al). The connection between diet and cancer outcomes is complex, and future research evaluating specific dietary interventions and the underlying biologic pathways by which nutrition exerts its effects will be important to inform our counseling for patients with breast cancer in the survivorship setting.

Additional References

1. Whelan TJ, Olivotto IA, Parulekar WR, et al, for the MA.20 Study Investigators. Regional nodal irradiation in early-stage breast cancer. N Engl J Med. 2015;373:307-16. doi:10.1056/NEJMoa1415340
2. ClinicalTrials.gov. Regional radiotherapy in biomarker low-risk node positive and T3N0 breast cancer (TAILOR RT). National Library of Medicine. Last updated November 23, 2022. https://www.clinicaltrials.gov/study/NCT03488693
3. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): A randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:25-32. doi:10.1016/S1470-2045(11)70336-9
4. Buckland G, Travier N, Cottet V, et al. Adherence to the mediterranean diet and risk of breast cancer in the European prospective investigation into cancer and nutrition cohort study. Int J Cancer. 2013;132:2918-27. doi:10.1002/ijc.27958
5. Haslam DE, John EM, Knight JA, et al. Diet quality and all-cause mortality in women with breast cancer from the Breast Cancer Family Registry. Cancer Epidemiol Biomarkers Prev. 2023;32:678-686. doi:10.1158/1055-9965.EPI-22-1198

Mantle cell lymphoma (MCL) is a rare and often heterogenous subtype of non-Hodgkin lymphoma (NHL). Though patients can experience prolonged remissions after frontline therapy, most patients ultimately relapse. Treatment of relapsed/refractory disease can be challenging, but there have recently been a growing number of therapeutic options in this setting. Covalent Bruton tyrosine kinase (BTK) inhibitors, for example, have demonstrated activity in patients with MCL and are approved by the US Food and Drug Administration (FDA) for relapsed/refractory disease. Chimeric antigen receptor (CAR) T-cell therapy is also an effective option for relapsed/refractory disease, though this is typically available only at select centers and is associated with toxicities, such as cytokine release syndrome and neurologic toxicity.

Recently, a novel BTK inhibitor, pirtobrutinib, has also been studied across NHL, including MCL (Wang et al) Pirtobrutinib is a selective, noncovalent BTK inhibitor with the ability to bind both the C481S-mutant and wild-type BTK. The multicenter, phase 1/2 BRUIN study included 90 patients with MCL who were previously treated with a covalent BTK inhibitor. Patients in the phase 1 portion of the study were treated with oral pirtobrutinib at a dose of 25-300 mg once daily, and patients in the phase 2 study were treated at the recommended dose of 200 mg once daily. The overall response rate was 57.8% (95% CI 46.9%-68.1%), with the complete response rate being 20.0%. At a median follow-up of 12 months, the median duration of response was 21.6 (95% CI 7.5 to not reached) months. Treatment-related adverse events that were grade 3 or higher were not frequent, with neutropenia (8.5%) being the most common. Of note, grade 3 or higher hemorrhage and atrial fibrillation, which can be seen with BTK inhibitors, were rare, occurring in 3.7% and 1.2% of patients, respectively. Based on the results of this study, pirtobrutinib has been approved by the FDA for patients with relapsed/refractory MCL after at least two prior lines of therapy, including a BTK inhibitor. This is an appealing oral option for patients with relapsed disease.

Options for patients with relapsed/refractory large B-cell lymphoma (LBCL) have also significantly increased in recent years. One of the most important advances in this disease has been the use of anti-CD19 CAR T-cell therapy. There are currently three FDA-approved options for patients with relapsed/refractory LBCL who have received at least two prior lines of therapy.^1-3 More recently, axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel) have also been approved for the second line based on the results of the ZUMA-7 and TRANSFORM studies, respectively.^4,5

Longer follow-up of the ZUMA-7 trial continues to confirm the advantage of axi-cel over standard-care therapy for patients with primary refractory or early relapse of disease, now with evidence of an overall survival advantage (Westin et al). The ZUMA-7 trial included 359 adults with LBCL (refractory to or relapsed within 12 months of first-line treatment) who were randomly assigned to receive axi-cel (n = 180) or standard care (n = 179). At a median follow-up of 47.2 mo, patients receiving axi-cel vs standard care had a significantly longer median overall survival (not reached vs 31.1 mo; hazard ratio [HR] 0.73; P = .03) and an absolute improvement in overall survival (8.6 percentage points at 4 years). No new treatment-related deaths were reported since the primary event-free survival analysis. These data confirm that early use of axi-cel is preferred over standard-care therapy with high-dose chemotherapy and autologous stem cell transplantation.

Another important study that was recently published looked at the role of mental health on outcomes in patients with diffuse large B-cell lymphoma (DLBCL) (Kuczmarski et al). Though it is known that mental health disorders can decrease the quality of life of patients with cancer, there is limited information on the survival implications of these issues. A recent retrospective cohort study analyzed the data of 13,244 patients aged 67 years or older with DLBCL from the Surveillance, Epidemiology, and End Results (SEER)–Medicare registry, of which, 2094 patients had depression, anxiety, or both at the time of their DLBCL diagnosis. At a median follow-up of 2.0 years, patients with depression, anxiety, or both vs without any mental disorder had significantly lower 5-year overall survival rates (27.0% vs 37.4%; HR 1.37; 95% CI 1.29-1.44). They also found that those patients with preexisting depression vs without any mental disorder have the worst survival (23.4% vs 38.0%; HR 1.37; P < .0001). Though the mechanism accounting for decreased survival is not clear, the authors postulate that mental health disorders may lead to delays or interruptions in lymphoma-directed therapy. They also note the potential for increased barriers to care in patients with mental health disorders, which may result in nonadherence in this patient population. Regardless, these results highlight the importance of mental health screening and interventions in patients with DLBCL.

Additional References

1. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-Cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531-2544. doi: 10.1056/NEJMoa1707447
    
2. Schuster SJ, Bishop MR, Tam CS, et al; JULIET Investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380:45-56. doi: 10.1056/NEJMoa1804980
    
3. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): A multicentre seamless design study. Lancet. 2020;396:839-852. doi: 10.1016/S0140-6736(20)31366-0
    
4. Locke FL, Miklos DB, Jacobson CA, et al; All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654. doi: 10.1056/NEJMoa2116133
5. Kamdar M, Solomon SR, Arnason J, et al; TRANSFORM Investigators. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): Results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399:2294-2308. doi: 10.1016/S0140-6736(22)00662-6

Mantle cell lymphoma (MCL) is a rare and often heterogenous subtype of non-Hodgkin lymphoma (NHL). Though patients can experience prolonged remissions after frontline therapy, most patients ultimately relapse. Treatment of relapsed/refractory disease can be challenging, but there have recently been a growing number of therapeutic options in this setting. Covalent Bruton tyrosine kinase (BTK) inhibitors, for example, have demonstrated activity in patients with MCL and are approved by the US Food and Drug Administration (FDA) for relapsed/refractory disease. Chimeric antigen receptor (CAR) T-cell therapy is also an effective option for relapsed/refractory disease, though this is typically available only at select centers and is associated with toxicities, such as cytokine release syndrome and neurologic toxicity.

Recently, a novel BTK inhibitor, pirtobrutinib, has also been studied across NHL, including MCL (Wang et al) Pirtobrutinib is a selective, noncovalent BTK inhibitor with the ability to bind both the C481S-mutant and wild-type BTK. The multicenter, phase 1/2 BRUIN study included 90 patients with MCL who were previously treated with a covalent BTK inhibitor. Patients in the phase 1 portion of the study were treated with oral pirtobrutinib at a dose of 25-300 mg once daily, and patients in the phase 2 study were treated at the recommended dose of 200 mg once daily. The overall response rate was 57.8% (95% CI 46.9%-68.1%), with the complete response rate being 20.0%. At a median follow-up of 12 months, the median duration of response was 21.6 (95% CI 7.5 to not reached) months. Treatment-related adverse events that were grade 3 or higher were not frequent, with neutropenia (8.5%) being the most common. Of note, grade 3 or higher hemorrhage and atrial fibrillation, which can be seen with BTK inhibitors, were rare, occurring in 3.7% and 1.2% of patients, respectively. Based on the results of this study, pirtobrutinib has been approved by the FDA for patients with relapsed/refractory MCL after at least two prior lines of therapy, including a BTK inhibitor. This is an appealing oral option for patients with relapsed disease.

Options for patients with relapsed/refractory large B-cell lymphoma (LBCL) have also significantly increased in recent years. One of the most important advances in this disease has been the use of anti-CD19 CAR T-cell therapy. There are currently three FDA-approved options for patients with relapsed/refractory LBCL who have received at least two prior lines of therapy.^1-3 More recently, axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel) have also been approved for the second line based on the results of the ZUMA-7 and TRANSFORM studies, respectively.^4,5

Longer follow-up of the ZUMA-7 trial continues to confirm the advantage of axi-cel over standard-care therapy for patients with primary refractory or early relapse of disease, now with evidence of an overall survival advantage (Westin et al). The ZUMA-7 trial included 359 adults with LBCL (refractory to or relapsed within 12 months of first-line treatment) who were randomly assigned to receive axi-cel (n = 180) or standard care (n = 179). At a median follow-up of 47.2 mo, patients receiving axi-cel vs standard care had a significantly longer median overall survival (not reached vs 31.1 mo; hazard ratio [HR] 0.73; P = .03) and an absolute improvement in overall survival (8.6 percentage points at 4 years). No new treatment-related deaths were reported since the primary event-free survival analysis. These data confirm that early use of axi-cel is preferred over standard-care therapy with high-dose chemotherapy and autologous stem cell transplantation.

Another important study that was recently published looked at the role of mental health on outcomes in patients with diffuse large B-cell lymphoma (DLBCL) (Kuczmarski et al). Though it is known that mental health disorders can decrease the quality of life of patients with cancer, there is limited information on the survival implications of these issues. A recent retrospective cohort study analyzed the data of 13,244 patients aged 67 years or older with DLBCL from the Surveillance, Epidemiology, and End Results (SEER)–Medicare registry, of which, 2094 patients had depression, anxiety, or both at the time of their DLBCL diagnosis. At a median follow-up of 2.0 years, patients with depression, anxiety, or both vs without any mental disorder had significantly lower 5-year overall survival rates (27.0% vs 37.4%; HR 1.37; 95% CI 1.29-1.44). They also found that those patients with preexisting depression vs without any mental disorder have the worst survival (23.4% vs 38.0%; HR 1.37; P < .0001). Though the mechanism accounting for decreased survival is not clear, the authors postulate that mental health disorders may lead to delays or interruptions in lymphoma-directed therapy. They also note the potential for increased barriers to care in patients with mental health disorders, which may result in nonadherence in this patient population. Regardless, these results highlight the importance of mental health screening and interventions in patients with DLBCL.

Additional References

1. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-Cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531-2544. doi: 10.1056/NEJMoa1707447
    
2. Schuster SJ, Bishop MR, Tam CS, et al; JULIET Investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380:45-56. doi: 10.1056/NEJMoa1804980
    
3. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): A multicentre seamless design study. Lancet. 2020;396:839-852. doi: 10.1016/S0140-6736(20)31366-0
    
4. Locke FL, Miklos DB, Jacobson CA, et al; All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654. doi: 10.1056/NEJMoa2116133
5. Kamdar M, Solomon SR, Arnason J, et al; TRANSFORM Investigators. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): Results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399:2294-2308. doi: 10.1016/S0140-6736(22)00662-6

Mantle cell lymphoma (MCL) is a rare and often heterogenous subtype of non-Hodgkin lymphoma (NHL). Though patients can experience prolonged remissions after frontline therapy, most patients ultimately relapse. Treatment of relapsed/refractory disease can be challenging, but there have recently been a growing number of therapeutic options in this setting. Covalent Bruton tyrosine kinase (BTK) inhibitors, for example, have demonstrated activity in patients with MCL and are approved by the US Food and Drug Administration (FDA) for relapsed/refractory disease. Chimeric antigen receptor (CAR) T-cell therapy is also an effective option for relapsed/refractory disease, though this is typically available only at select centers and is associated with toxicities, such as cytokine release syndrome and neurologic toxicity.

Recently, a novel BTK inhibitor, pirtobrutinib, has also been studied across NHL, including MCL (Wang et al) Pirtobrutinib is a selective, noncovalent BTK inhibitor with the ability to bind both the C481S-mutant and wild-type BTK. The multicenter, phase 1/2 BRUIN study included 90 patients with MCL who were previously treated with a covalent BTK inhibitor. Patients in the phase 1 portion of the study were treated with oral pirtobrutinib at a dose of 25-300 mg once daily, and patients in the phase 2 study were treated at the recommended dose of 200 mg once daily. The overall response rate was 57.8% (95% CI 46.9%-68.1%), with the complete response rate being 20.0%. At a median follow-up of 12 months, the median duration of response was 21.6 (95% CI 7.5 to not reached) months. Treatment-related adverse events that were grade 3 or higher were not frequent, with neutropenia (8.5%) being the most common. Of note, grade 3 or higher hemorrhage and atrial fibrillation, which can be seen with BTK inhibitors, were rare, occurring in 3.7% and 1.2% of patients, respectively. Based on the results of this study, pirtobrutinib has been approved by the FDA for patients with relapsed/refractory MCL after at least two prior lines of therapy, including a BTK inhibitor. This is an appealing oral option for patients with relapsed disease.

Options for patients with relapsed/refractory large B-cell lymphoma (LBCL) have also significantly increased in recent years. One of the most important advances in this disease has been the use of anti-CD19 CAR T-cell therapy. There are currently three FDA-approved options for patients with relapsed/refractory LBCL who have received at least two prior lines of therapy.^1-3 More recently, axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel) have also been approved for the second line based on the results of the ZUMA-7 and TRANSFORM studies, respectively.^4,5

Longer follow-up of the ZUMA-7 trial continues to confirm the advantage of axi-cel over standard-care therapy for patients with primary refractory or early relapse of disease, now with evidence of an overall survival advantage (Westin et al). The ZUMA-7 trial included 359 adults with LBCL (refractory to or relapsed within 12 months of first-line treatment) who were randomly assigned to receive axi-cel (n = 180) or standard care (n = 179). At a median follow-up of 47.2 mo, patients receiving axi-cel vs standard care had a significantly longer median overall survival (not reached vs 31.1 mo; hazard ratio [HR] 0.73; P = .03) and an absolute improvement in overall survival (8.6 percentage points at 4 years). No new treatment-related deaths were reported since the primary event-free survival analysis. These data confirm that early use of axi-cel is preferred over standard-care therapy with high-dose chemotherapy and autologous stem cell transplantation.

Another important study that was recently published looked at the role of mental health on outcomes in patients with diffuse large B-cell lymphoma (DLBCL) (Kuczmarski et al). Though it is known that mental health disorders can decrease the quality of life of patients with cancer, there is limited information on the survival implications of these issues. A recent retrospective cohort study analyzed the data of 13,244 patients aged 67 years or older with DLBCL from the Surveillance, Epidemiology, and End Results (SEER)–Medicare registry, of which, 2094 patients had depression, anxiety, or both at the time of their DLBCL diagnosis. At a median follow-up of 2.0 years, patients with depression, anxiety, or both vs without any mental disorder had significantly lower 5-year overall survival rates (27.0% vs 37.4%; HR 1.37; 95% CI 1.29-1.44). They also found that those patients with preexisting depression vs without any mental disorder have the worst survival (23.4% vs 38.0%; HR 1.37; P < .0001). Though the mechanism accounting for decreased survival is not clear, the authors postulate that mental health disorders may lead to delays or interruptions in lymphoma-directed therapy. They also note the potential for increased barriers to care in patients with mental health disorders, which may result in nonadherence in this patient population. Regardless, these results highlight the importance of mental health screening and interventions in patients with DLBCL.

Additional References

1. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-Cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531-2544. doi: 10.1056/NEJMoa1707447
    
2. Schuster SJ, Bishop MR, Tam CS, et al; JULIET Investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380:45-56. doi: 10.1056/NEJMoa1804980
    
3. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): A multicentre seamless design study. Lancet. 2020;396:839-852. doi: 10.1016/S0140-6736(20)31366-0
    
4. Locke FL, Miklos DB, Jacobson CA, et al; All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654. doi: 10.1056/NEJMoa2116133
5. Kamdar M, Solomon SR, Arnason J, et al; TRANSFORM Investigators. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): Results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399:2294-2308. doi: 10.1016/S0140-6736(22)00662-6