Clinical Edge Journal Scan Commentary

Breast cancer in young women presents a unique set of challenges owing to life-stage at the time of diagnosis and treatment. Oncofertility, family planning, and pregnancy are essential issues to address at the time of initial consultation and throughout the survivorship setting. Various studies have provided supportive evidence regarding the safety of pregnancy after breast cancer diagnosis and treatment.³ HR+ breast cancer is associated with its own distinctive considerations related to pregnancy and its timing, including the use of endocrine therapy for 5-10 years, the role of female hormones during pregnancy, and late patterns of recurrence that characterize this subtype. A meta-analysis including eight eligible studies and 3805 women with HR+ early breast cancer investigated the prognostic impact of future pregnancy among these patients (Arecco et al). A total of 1285 women had a pregnancy after breast cancer diagnosis and treatment; there was no difference in disease-free survival (hazard ratio 0.96; 95% CI 0.75-1.24; P = .781) and better overall survival (OS; hazard ratio 0.46; 95% CI 0.27-0.77; P < .005) in those with vs those without subsequent pregnancy. Added to this body of data is the prospective POSITIVE trial, which showed that a temporary pause of endocrine therapy for an attempt at conceiving appears to be safe in young women with early HR+ breast cancer with short-term follow-up.⁴ Future research efforts investigating outcomes after assisted reproductive technologies in this population, those with germline mutations, and extended follow-up of studies, such as POSITIVE, will continue to inform guidance for and management of young women with breast cancer.

Guidelines favor the use of adjuvant chemotherapy for small, node-negative, triple-negative breast cancer (TNBC), specifically T1b and T1c tumors.⁵ However, high-quality data to inform this decision-making are sparse, and it is valuable to consider the magnitude of benefit weighed against possible risks and side effects of treatment, as well as patient comorbidities. A retrospective analysis of the Surveillance, Epidemiology, and End Results (SEER) database including 11,510 patients (3388 with T1b and 8122 with T1c TNBC) evaluated the impact of adjuvant chemotherapy on OS and breast cancer–specific survival (BCSS) (Carbajal-Ochoa et al). The use of adjuvant chemotherapy was associated with improved OS (hazard ratio 0.54; 95% CI 0.47-0.62; P < .001) and BCSS (hazard ratio 0.79; 95% CI 0.63-0.99; P = .043) among T1c TNBC. For those with T1b tumors, adjuvant chemotherapy improved OS (hazard ratio 0.52; 95% CI 0.41-0.68; P < .001) but did not improve BCSS (hazard ratio 0.70; 95% CI 0.45-1.07; P = .10). A better understanding of the molecular drivers implicated in this heterogeneous subtype, and predictors of response and resistance, will aid in identifying those patients who have greater benefit and those who can potentially be spared chemotherapy-related toxicities.

Additional References

1. Anwar SL, Cahyono R, Prabowo D, et al. Metabolic comorbidities and the association with risks of recurrent metastatic disease in breast cancer survivors. BMC Cancer. 2021;21:590. doi: 10.1186/s12885-021-08343-0
2. Sestak I, Distler W, Forbes JF, et al. Effect of body mass index on recurrences in tamoxifen and anastrozole treated women: An exploratory analysis from the ATAC trial. J Clin Oncol. 2010;28:3411-3415. doi: 10.1200/JCO.2009.27.2021
3. Lambertini M, Blondeaux E, Bruzzone M, et al. Pregnancy after breast cancer: A systematic review and meta-analysis. J Clin Oncol. 2021;39:3293-3305. doi: 10.1200/JCO.21.00535
4. Partridge AH, Niman SM, Ruggeri M, et al for the International Breast Cancer Study Group and POSITIVE Trial Collaborators. Interrupting endocrine therapy to attempt pregnancy after breast cancer. N Engl J Med. 2023;388:1645-1656. doi:10.1056/NEJMoa2212856
5. Curigliano G, Burstein HJ, Winer EP, et al. De-escalating and escalating treatments for early-stage breast cancer: The St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017. Ann Oncol. 2017;28:1700-1712. doi:10.1093/annonc/mdx308

Breast cancer in young women presents a unique set of challenges owing to life-stage at the time of diagnosis and treatment. Oncofertility, family planning, and pregnancy are essential issues to address at the time of initial consultation and throughout the survivorship setting. Various studies have provided supportive evidence regarding the safety of pregnancy after breast cancer diagnosis and treatment.³ HR+ breast cancer is associated with its own distinctive considerations related to pregnancy and its timing, including the use of endocrine therapy for 5-10 years, the role of female hormones during pregnancy, and late patterns of recurrence that characterize this subtype. A meta-analysis including eight eligible studies and 3805 women with HR+ early breast cancer investigated the prognostic impact of future pregnancy among these patients (Arecco et al). A total of 1285 women had a pregnancy after breast cancer diagnosis and treatment; there was no difference in disease-free survival (hazard ratio 0.96; 95% CI 0.75-1.24; P = .781) and better overall survival (OS; hazard ratio 0.46; 95% CI 0.27-0.77; P < .005) in those with vs those without subsequent pregnancy. Added to this body of data is the prospective POSITIVE trial, which showed that a temporary pause of endocrine therapy for an attempt at conceiving appears to be safe in young women with early HR+ breast cancer with short-term follow-up.⁴ Future research efforts investigating outcomes after assisted reproductive technologies in this population, those with germline mutations, and extended follow-up of studies, such as POSITIVE, will continue to inform guidance for and management of young women with breast cancer.

Guidelines favor the use of adjuvant chemotherapy for small, node-negative, triple-negative breast cancer (TNBC), specifically T1b and T1c tumors.⁵ However, high-quality data to inform this decision-making are sparse, and it is valuable to consider the magnitude of benefit weighed against possible risks and side effects of treatment, as well as patient comorbidities. A retrospective analysis of the Surveillance, Epidemiology, and End Results (SEER) database including 11,510 patients (3388 with T1b and 8122 with T1c TNBC) evaluated the impact of adjuvant chemotherapy on OS and breast cancer–specific survival (BCSS) (Carbajal-Ochoa et al). The use of adjuvant chemotherapy was associated with improved OS (hazard ratio 0.54; 95% CI 0.47-0.62; P < .001) and BCSS (hazard ratio 0.79; 95% CI 0.63-0.99; P = .043) among T1c TNBC. For those with T1b tumors, adjuvant chemotherapy improved OS (hazard ratio 0.52; 95% CI 0.41-0.68; P < .001) but did not improve BCSS (hazard ratio 0.70; 95% CI 0.45-1.07; P = .10). A better understanding of the molecular drivers implicated in this heterogeneous subtype, and predictors of response and resistance, will aid in identifying those patients who have greater benefit and those who can potentially be spared chemotherapy-related toxicities.

Additional References

1. Anwar SL, Cahyono R, Prabowo D, et al. Metabolic comorbidities and the association with risks of recurrent metastatic disease in breast cancer survivors. BMC Cancer. 2021;21:590. doi: 10.1186/s12885-021-08343-0
2. Sestak I, Distler W, Forbes JF, et al. Effect of body mass index on recurrences in tamoxifen and anastrozole treated women: An exploratory analysis from the ATAC trial. J Clin Oncol. 2010;28:3411-3415. doi: 10.1200/JCO.2009.27.2021
3. Lambertini M, Blondeaux E, Bruzzone M, et al. Pregnancy after breast cancer: A systematic review and meta-analysis. J Clin Oncol. 2021;39:3293-3305. doi: 10.1200/JCO.21.00535
4. Partridge AH, Niman SM, Ruggeri M, et al for the International Breast Cancer Study Group and POSITIVE Trial Collaborators. Interrupting endocrine therapy to attempt pregnancy after breast cancer. N Engl J Med. 2023;388:1645-1656. doi:10.1056/NEJMoa2212856
5. Curigliano G, Burstein HJ, Winer EP, et al. De-escalating and escalating treatments for early-stage breast cancer: The St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017. Ann Oncol. 2017;28:1700-1712. doi:10.1093/annonc/mdx308

Breast cancer in young women presents a unique set of challenges owing to life-stage at the time of diagnosis and treatment. Oncofertility, family planning, and pregnancy are essential issues to address at the time of initial consultation and throughout the survivorship setting. Various studies have provided supportive evidence regarding the safety of pregnancy after breast cancer diagnosis and treatment.³ HR+ breast cancer is associated with its own distinctive considerations related to pregnancy and its timing, including the use of endocrine therapy for 5-10 years, the role of female hormones during pregnancy, and late patterns of recurrence that characterize this subtype. A meta-analysis including eight eligible studies and 3805 women with HR+ early breast cancer investigated the prognostic impact of future pregnancy among these patients (Arecco et al). A total of 1285 women had a pregnancy after breast cancer diagnosis and treatment; there was no difference in disease-free survival (hazard ratio 0.96; 95% CI 0.75-1.24; P = .781) and better overall survival (OS; hazard ratio 0.46; 95% CI 0.27-0.77; P < .005) in those with vs those without subsequent pregnancy. Added to this body of data is the prospective POSITIVE trial, which showed that a temporary pause of endocrine therapy for an attempt at conceiving appears to be safe in young women with early HR+ breast cancer with short-term follow-up.⁴ Future research efforts investigating outcomes after assisted reproductive technologies in this population, those with germline mutations, and extended follow-up of studies, such as POSITIVE, will continue to inform guidance for and management of young women with breast cancer.

Guidelines favor the use of adjuvant chemotherapy for small, node-negative, triple-negative breast cancer (TNBC), specifically T1b and T1c tumors.⁵ However, high-quality data to inform this decision-making are sparse, and it is valuable to consider the magnitude of benefit weighed against possible risks and side effects of treatment, as well as patient comorbidities. A retrospective analysis of the Surveillance, Epidemiology, and End Results (SEER) database including 11,510 patients (3388 with T1b and 8122 with T1c TNBC) evaluated the impact of adjuvant chemotherapy on OS and breast cancer–specific survival (BCSS) (Carbajal-Ochoa et al). The use of adjuvant chemotherapy was associated with improved OS (hazard ratio 0.54; 95% CI 0.47-0.62; P < .001) and BCSS (hazard ratio 0.79; 95% CI 0.63-0.99; P = .043) among T1c TNBC. For those with T1b tumors, adjuvant chemotherapy improved OS (hazard ratio 0.52; 95% CI 0.41-0.68; P < .001) but did not improve BCSS (hazard ratio 0.70; 95% CI 0.45-1.07; P = .10). A better understanding of the molecular drivers implicated in this heterogeneous subtype, and predictors of response and resistance, will aid in identifying those patients who have greater benefit and those who can potentially be spared chemotherapy-related toxicities.

Additional References

1. Anwar SL, Cahyono R, Prabowo D, et al. Metabolic comorbidities and the association with risks of recurrent metastatic disease in breast cancer survivors. BMC Cancer. 2021;21:590. doi: 10.1186/s12885-021-08343-0
2. Sestak I, Distler W, Forbes JF, et al. Effect of body mass index on recurrences in tamoxifen and anastrozole treated women: An exploratory analysis from the ATAC trial. J Clin Oncol. 2010;28:3411-3415. doi: 10.1200/JCO.2009.27.2021
3. Lambertini M, Blondeaux E, Bruzzone M, et al. Pregnancy after breast cancer: A systematic review and meta-analysis. J Clin Oncol. 2021;39:3293-3305. doi: 10.1200/JCO.21.00535
4. Partridge AH, Niman SM, Ruggeri M, et al for the International Breast Cancer Study Group and POSITIVE Trial Collaborators. Interrupting endocrine therapy to attempt pregnancy after breast cancer. N Engl J Med. 2023;388:1645-1656. doi:10.1056/NEJMoa2212856
5. Curigliano G, Burstein HJ, Winer EP, et al. De-escalating and escalating treatments for early-stage breast cancer: The St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017. Ann Oncol. 2017;28:1700-1712. doi:10.1093/annonc/mdx308

Schlösser and colleagues provide a real-world report of 48 patients treated with upadacitinib for atopic dermatitis, many of whom had previously been treated with cyclosporine and dupilumab. The upbeat authors concluded, "Overall, adverse events were mostly well tolerated." Being a cynical, glass-is-half-empty kind of person, I wondered what that meant. Most patients (56%) reported adverse events, the most common being acne (25% of patients treated), nausea (13%), respiratory tract infections (10%), and herpes virus (8%). The herpes virus signal is not just a bit of a concern for me, but it also makes it hard for me to convince patients to take a Janus kinase (JAK) inhibitor, as when I even mention herpes, patients reply, often rather emphatically, "I don't want herpes!" I'll be encouraging patients to get vaccinated for shingles when starting them on JAK inhibitors.

Dupilumab seems to work great in real-life use. In Martinez-Cabriales and colleagues' study of 62 children age < 12 with atopic dermatitis, only four discontinued the treatment. One of these was a nonresponder who took only one injection and had flushing, and one of the other three discontinued because their skin had completely cleared.

When I saw the title of Rand and colleagues' article, "Matching-Adjusted Indirect Comparison of the Long-Term Efficacy Maintenance and Adverse Event Rates of Lebrikizumab Versus Dupilumab in Moderate-to-Severe Atopic Dermatitis," I thought, Oh, this is great — a head-to-head, long-term trial comparing lebrikizumab and dupilumab. I was disappointed to find that this was simply a retrospective analysis of data reported from different studies. The study found little difference in efficacy or safety of the two drugs. Both seem to be excellent medications for atopic dermatitis.

Here's another study (Zhou et al) that reports possible increased risk for a comorbidity (cognitive dysfunction) associated with atopic dermatitis. This study reports that there is an elevated hazard ratio that is statistically significant; the article fails to report what the increased absolute risk is for cognitive dysfunction associated with atopic dermatitis. My guess is that it is small and probably clinically unimportant. The hazard ratio for developing dementia was 1.16. It's hard to know how that translates into absolute risk, but my brilliant friend and former partner, Dr Alan Fleischer, once told me that the odds ratio for smoking and lung cancer is something like 100; the hazard ratio is in the range of 20. On the basis of a hazard ratio of 1.16, I don't think patients with atopic dermatitis need to be any more worried about dementia than those without. (Though, to be honest, I think we can all be worried about developing dementia.)

In this tour de force analysis of 83 trials with over 20,000 participants, Drucker and colleagues determined that high doses of abrocitinib and upadacitinib are more effective than even dupilumab for atopic dermatitis. The standard doses of these JAK inhibitors were similar in efficacy to dupilumab. I think it's safe to say that JAK inhibitors are, at least at their high doses, more effective than dupilumab, but safety remains a critical factor in treatment decision-making. I think JAK inhibitors are a great option for patients who need the most effective treatment or who fail to respond to dupilumab.

The title of the article by Oh and colleagues, "Increased Risk of Renal Malignancy in Patients With Moderate to Severe Atopic Dermatitis," seems like it could terrify patients. The study involved an analysis of an enormous number of people, including tens of thousands with atopic dermatitis and millions of controls. The investigators did find statistically significant differences in the rate of malignancy. The rate of renal cancer was about 1.6 per 10,000 person-years for people without atopic dermatitis or people with mild atopic dermatitis; the rate was about 2.5 per 10,000 people for patients with moderate to severe atopic dermatitis. While the rate of renal cancer was statistically significantly higher in patients with moderate to severe atopic dermatitis (ie, the higher rate was unlikely to be occurring due to chance alone), these patients have very little risk for renal malignancy. The authors' conclusion that regular checkups for renal malignancy are recommended for patients with severe atopic dermatitis seems unnecessary to me.

Schlösser and colleagues provide a real-world report of 48 patients treated with upadacitinib for atopic dermatitis, many of whom had previously been treated with cyclosporine and dupilumab. The upbeat authors concluded, "Overall, adverse events were mostly well tolerated." Being a cynical, glass-is-half-empty kind of person, I wondered what that meant. Most patients (56%) reported adverse events, the most common being acne (25% of patients treated), nausea (13%), respiratory tract infections (10%), and herpes virus (8%). The herpes virus signal is not just a bit of a concern for me, but it also makes it hard for me to convince patients to take a Janus kinase (JAK) inhibitor, as when I even mention herpes, patients reply, often rather emphatically, "I don't want herpes!" I'll be encouraging patients to get vaccinated for shingles when starting them on JAK inhibitors.

Dupilumab seems to work great in real-life use. In Martinez-Cabriales and colleagues' study of 62 children age < 12 with atopic dermatitis, only four discontinued the treatment. One of these was a nonresponder who took only one injection and had flushing, and one of the other three discontinued because their skin had completely cleared.

When I saw the title of Rand and colleagues' article, "Matching-Adjusted Indirect Comparison of the Long-Term Efficacy Maintenance and Adverse Event Rates of Lebrikizumab Versus Dupilumab in Moderate-to-Severe Atopic Dermatitis," I thought, Oh, this is great — a head-to-head, long-term trial comparing lebrikizumab and dupilumab. I was disappointed to find that this was simply a retrospective analysis of data reported from different studies. The study found little difference in efficacy or safety of the two drugs. Both seem to be excellent medications for atopic dermatitis.

Here's another study (Zhou et al) that reports possible increased risk for a comorbidity (cognitive dysfunction) associated with atopic dermatitis. This study reports that there is an elevated hazard ratio that is statistically significant; the article fails to report what the increased absolute risk is for cognitive dysfunction associated with atopic dermatitis. My guess is that it is small and probably clinically unimportant. The hazard ratio for developing dementia was 1.16. It's hard to know how that translates into absolute risk, but my brilliant friend and former partner, Dr Alan Fleischer, once told me that the odds ratio for smoking and lung cancer is something like 100; the hazard ratio is in the range of 20. On the basis of a hazard ratio of 1.16, I don't think patients with atopic dermatitis need to be any more worried about dementia than those without. (Though, to be honest, I think we can all be worried about developing dementia.)

In this tour de force analysis of 83 trials with over 20,000 participants, Drucker and colleagues determined that high doses of abrocitinib and upadacitinib are more effective than even dupilumab for atopic dermatitis. The standard doses of these JAK inhibitors were similar in efficacy to dupilumab. I think it's safe to say that JAK inhibitors are, at least at their high doses, more effective than dupilumab, but safety remains a critical factor in treatment decision-making. I think JAK inhibitors are a great option for patients who need the most effective treatment or who fail to respond to dupilumab.

The title of the article by Oh and colleagues, "Increased Risk of Renal Malignancy in Patients With Moderate to Severe Atopic Dermatitis," seems like it could terrify patients. The study involved an analysis of an enormous number of people, including tens of thousands with atopic dermatitis and millions of controls. The investigators did find statistically significant differences in the rate of malignancy. The rate of renal cancer was about 1.6 per 10,000 person-years for people without atopic dermatitis or people with mild atopic dermatitis; the rate was about 2.5 per 10,000 people for patients with moderate to severe atopic dermatitis. While the rate of renal cancer was statistically significantly higher in patients with moderate to severe atopic dermatitis (ie, the higher rate was unlikely to be occurring due to chance alone), these patients have very little risk for renal malignancy. The authors' conclusion that regular checkups for renal malignancy are recommended for patients with severe atopic dermatitis seems unnecessary to me.

Schlösser and colleagues provide a real-world report of 48 patients treated with upadacitinib for atopic dermatitis, many of whom had previously been treated with cyclosporine and dupilumab. The upbeat authors concluded, "Overall, adverse events were mostly well tolerated." Being a cynical, glass-is-half-empty kind of person, I wondered what that meant. Most patients (56%) reported adverse events, the most common being acne (25% of patients treated), nausea (13%), respiratory tract infections (10%), and herpes virus (8%). The herpes virus signal is not just a bit of a concern for me, but it also makes it hard for me to convince patients to take a Janus kinase (JAK) inhibitor, as when I even mention herpes, patients reply, often rather emphatically, "I don't want herpes!" I'll be encouraging patients to get vaccinated for shingles when starting them on JAK inhibitors.

Dupilumab seems to work great in real-life use. In Martinez-Cabriales and colleagues' study of 62 children age < 12 with atopic dermatitis, only four discontinued the treatment. One of these was a nonresponder who took only one injection and had flushing, and one of the other three discontinued because their skin had completely cleared.

When I saw the title of Rand and colleagues' article, "Matching-Adjusted Indirect Comparison of the Long-Term Efficacy Maintenance and Adverse Event Rates of Lebrikizumab Versus Dupilumab in Moderate-to-Severe Atopic Dermatitis," I thought, Oh, this is great — a head-to-head, long-term trial comparing lebrikizumab and dupilumab. I was disappointed to find that this was simply a retrospective analysis of data reported from different studies. The study found little difference in efficacy or safety of the two drugs. Both seem to be excellent medications for atopic dermatitis.

Here's another study (Zhou et al) that reports possible increased risk for a comorbidity (cognitive dysfunction) associated with atopic dermatitis. This study reports that there is an elevated hazard ratio that is statistically significant; the article fails to report what the increased absolute risk is for cognitive dysfunction associated with atopic dermatitis. My guess is that it is small and probably clinically unimportant. The hazard ratio for developing dementia was 1.16. It's hard to know how that translates into absolute risk, but my brilliant friend and former partner, Dr Alan Fleischer, once told me that the odds ratio for smoking and lung cancer is something like 100; the hazard ratio is in the range of 20. On the basis of a hazard ratio of 1.16, I don't think patients with atopic dermatitis need to be any more worried about dementia than those without. (Though, to be honest, I think we can all be worried about developing dementia.)

In this tour de force analysis of 83 trials with over 20,000 participants, Drucker and colleagues determined that high doses of abrocitinib and upadacitinib are more effective than even dupilumab for atopic dermatitis. The standard doses of these JAK inhibitors were similar in efficacy to dupilumab. I think it's safe to say that JAK inhibitors are, at least at their high doses, more effective than dupilumab, but safety remains a critical factor in treatment decision-making. I think JAK inhibitors are a great option for patients who need the most effective treatment or who fail to respond to dupilumab.

The title of the article by Oh and colleagues, "Increased Risk of Renal Malignancy in Patients With Moderate to Severe Atopic Dermatitis," seems like it could terrify patients. The study involved an analysis of an enormous number of people, including tens of thousands with atopic dermatitis and millions of controls. The investigators did find statistically significant differences in the rate of malignancy. The rate of renal cancer was about 1.6 per 10,000 person-years for people without atopic dermatitis or people with mild atopic dermatitis; the rate was about 2.5 per 10,000 people for patients with moderate to severe atopic dermatitis. While the rate of renal cancer was statistically significantly higher in patients with moderate to severe atopic dermatitis (ie, the higher rate was unlikely to be occurring due to chance alone), these patients have very little risk for renal malignancy. The authors' conclusion that regular checkups for renal malignancy are recommended for patients with severe atopic dermatitis seems unnecessary to me.

The ZUMA-7 and TRANSFORM studies have been practice-changing for the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL). These studies demonstrated an improvement in outcomes with axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel), respectively, as compared with standard-of-care treatment (chemotherapy and autologous stem cell transplantation).^1,2 Patients included in these studies were refractory to their initial therapy or experienced relapse within 12 months and were considered fit for autologous stem cell transplant. It has remained unclear, however, whether patients who are not transplant candidates may also derive benefit and tolerate treatment with chimeric antigen receptor (CAR) T-cell therapy. The PILOT study was a single-arm phase 2 study that demonstrated favorable outcomes with liso-cel in this patient population, thus resulting in the approval of liso-cel by the US Food and Drug Administration for this population.³ Recently, the ALYCATE study similarly examined outcomes in transplant-ineligible patients treated with axi-cel (Houot et al). This phase 2 study included 62 patients with high-risk R/R LBCL who underwent leukapheresis and subsequently received second-line axi-cel. The complete metabolic response rate 3 months after axi-cel infusion was 71.0% (95% CI 58.1%-81.8%). At a median 12-month follow-up, the median progression-free survival was 11.8 months (95% CI 8.4-not reached) whereas median overall survival was not reached. Grade ≥ 3 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 8.1% and 14.5% of patients, respectively. Also of note, patients age ≥ 70 years did not show increased toxicity compared with those age < 70 years, with similar rates of CRS, ICANS, and intensive care unit transfer. This study supports the role of axi-cel in the second-line setting, regardless of transplant eligibility.

Another important study recently published for patients with LBCL examined the role of central nervous system (CNS) prophylaxis (Lewis et al). We know that certain patients with LBCL, including those with a high CNS international prognostic index (IPI) score, double-hit lymphoma, or disease involvement of multiple or certain extranodal sites (ie, breast, testes, adrenals, kidney) can be at increased risk for lymphoma spread to the CNS.⁴ Strategies to reduce this risk have subsequently been developed for these high-risk patients, though consensus regarding who should be treated and how best to treat patients has been consistent. Recently, retrospective data have also called into question whether our current approaches meaningfully reduce this risk. One such study was a multicenter, international, retrospective observational study that included 2418 adults with aggressive LBCL and a high risk for CNS progression who were treated with curative-intent anti-CD20–based chemoimmunotherapy and who did or did not receive high-dose methotrexate (HD-MTX). Patients who did vs did not receive HD-MTX had a significantly lower risk for CNS progression (adjusted 5-year risk difference 1.6%; adjusted hazard ratio [aHR] 0.59; P = .014), but the significance was lost when considering only those patients who achieved a complete response at chemoimmunotherapy completion (adjusted 5-year risk difference 1.4%; aHR 0.74; P = .30). The study was not sufficiently powered to make definitive conclusions for individual risk groups, though there was no obvious reduction in CNS involvement risk in any high-risk subgroup. With an absolute risk reduction of 1.6% with the use of HD-MTX, 63 patients would require treatment to prevent one CNS progression event over 5 years (Lewis et al). Given the absence of prospective, randomized data, these results, though retrospective in nature, call into question the benefit of CNS prophylaxis. The authors suggest that studies evaluating alternative strategies for prophylaxis and tools for early detection of relapse, such as circulating tumor DNA, may be helpful.

Another study worth noting was one exploring Bruton tyrosine kinase (BTK) inhibition in mantle cell lymphoma (MCL). BTK inhibitors, including zanubrutinib, have emerged as effective therapies for patients with R/R disease. A recent pooled analysis included 112 patients from the BGB-3111-AU-003 and BGB-3111-206 clinical trials who had R/R MCL and received second-line (n = 41) or later-line (n = 71) zanubrutinib (Song et al). At a median follow-up of 35.2 months, patients receiving second-line vs later-line zanubrutinib had significantly improved median overall survival (aHR 0.459; P = .044) and numerically longer median progression-free survival (27.8 vs 22.1 months). Adverse events observed in both groups were consistent with the known safety profile of zanubrutinib. These findings were in line with a prior similar pooled study that demonstrated improved outcomes with second-line ibrutinib for patients with MCL as compared with later-line ibrutinib therapy.⁵ This study, however, did not evaluate the impact on CAR T–cell therapy in MCL, which is also an effective treatment option for patients with R/R disease, and how best to sequence with BTK inhibitors.

Additional References

1.       Locke FL, Miklos DB, Jacobson CA, et al, for 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

2.       Kamdar M, Solomon SR, Arnason J, et al, for theTRANSFORM 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

3.       Gordon LI, Liu FF, Braverman J, et al. Lisocabtagene maraleucel for second-line relapsed or refractory large B-cell lymphoma: Patient-reported outcomes from the PILOT study. Haematologica. 2023 (Aug 31). doi: 10.3324/haematol.2023.283162

4.       Schmitz N, Zeynalova S, Nickelsen M, et al. CNS International Prognostic Index: A risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol. 2016;34:3150-3156. doi: 10.1200/JCO.2015.65.6520

5.       Dreyling M, Goy A, Hess G, et al. Long-term outcomes with ibrutinib treatment for patients with relapsed/refractory mantle cell lymphoma: A pooled analysis of 3 clinical trials with nearly 10 years of follow-up. Hemasphere. 2022;6:e712. doi: 10.1097/HS9.0000000000000712

The ZUMA-7 and TRANSFORM studies have been practice-changing for the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL). These studies demonstrated an improvement in outcomes with axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel), respectively, as compared with standard-of-care treatment (chemotherapy and autologous stem cell transplantation).^1,2 Patients included in these studies were refractory to their initial therapy or experienced relapse within 12 months and were considered fit for autologous stem cell transplant. It has remained unclear, however, whether patients who are not transplant candidates may also derive benefit and tolerate treatment with chimeric antigen receptor (CAR) T-cell therapy. The PILOT study was a single-arm phase 2 study that demonstrated favorable outcomes with liso-cel in this patient population, thus resulting in the approval of liso-cel by the US Food and Drug Administration for this population.³ Recently, the ALYCATE study similarly examined outcomes in transplant-ineligible patients treated with axi-cel (Houot et al). This phase 2 study included 62 patients with high-risk R/R LBCL who underwent leukapheresis and subsequently received second-line axi-cel. The complete metabolic response rate 3 months after axi-cel infusion was 71.0% (95% CI 58.1%-81.8%). At a median 12-month follow-up, the median progression-free survival was 11.8 months (95% CI 8.4-not reached) whereas median overall survival was not reached. Grade ≥ 3 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 8.1% and 14.5% of patients, respectively. Also of note, patients age ≥ 70 years did not show increased toxicity compared with those age < 70 years, with similar rates of CRS, ICANS, and intensive care unit transfer. This study supports the role of axi-cel in the second-line setting, regardless of transplant eligibility.

Another important study recently published for patients with LBCL examined the role of central nervous system (CNS) prophylaxis (Lewis et al). We know that certain patients with LBCL, including those with a high CNS international prognostic index (IPI) score, double-hit lymphoma, or disease involvement of multiple or certain extranodal sites (ie, breast, testes, adrenals, kidney) can be at increased risk for lymphoma spread to the CNS.⁴ Strategies to reduce this risk have subsequently been developed for these high-risk patients, though consensus regarding who should be treated and how best to treat patients has been consistent. Recently, retrospective data have also called into question whether our current approaches meaningfully reduce this risk. One such study was a multicenter, international, retrospective observational study that included 2418 adults with aggressive LBCL and a high risk for CNS progression who were treated with curative-intent anti-CD20–based chemoimmunotherapy and who did or did not receive high-dose methotrexate (HD-MTX). Patients who did vs did not receive HD-MTX had a significantly lower risk for CNS progression (adjusted 5-year risk difference 1.6%; adjusted hazard ratio [aHR] 0.59; P = .014), but the significance was lost when considering only those patients who achieved a complete response at chemoimmunotherapy completion (adjusted 5-year risk difference 1.4%; aHR 0.74; P = .30). The study was not sufficiently powered to make definitive conclusions for individual risk groups, though there was no obvious reduction in CNS involvement risk in any high-risk subgroup. With an absolute risk reduction of 1.6% with the use of HD-MTX, 63 patients would require treatment to prevent one CNS progression event over 5 years (Lewis et al). Given the absence of prospective, randomized data, these results, though retrospective in nature, call into question the benefit of CNS prophylaxis. The authors suggest that studies evaluating alternative strategies for prophylaxis and tools for early detection of relapse, such as circulating tumor DNA, may be helpful.

Another study worth noting was one exploring Bruton tyrosine kinase (BTK) inhibition in mantle cell lymphoma (MCL). BTK inhibitors, including zanubrutinib, have emerged as effective therapies for patients with R/R disease. A recent pooled analysis included 112 patients from the BGB-3111-AU-003 and BGB-3111-206 clinical trials who had R/R MCL and received second-line (n = 41) or later-line (n = 71) zanubrutinib (Song et al). At a median follow-up of 35.2 months, patients receiving second-line vs later-line zanubrutinib had significantly improved median overall survival (aHR 0.459; P = .044) and numerically longer median progression-free survival (27.8 vs 22.1 months). Adverse events observed in both groups were consistent with the known safety profile of zanubrutinib. These findings were in line with a prior similar pooled study that demonstrated improved outcomes with second-line ibrutinib for patients with MCL as compared with later-line ibrutinib therapy.⁵ This study, however, did not evaluate the impact on CAR T–cell therapy in MCL, which is also an effective treatment option for patients with R/R disease, and how best to sequence with BTK inhibitors.

Additional References

1.       Locke FL, Miklos DB, Jacobson CA, et al, for 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

2.       Kamdar M, Solomon SR, Arnason J, et al, for theTRANSFORM 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

3.       Gordon LI, Liu FF, Braverman J, et al. Lisocabtagene maraleucel for second-line relapsed or refractory large B-cell lymphoma: Patient-reported outcomes from the PILOT study. Haematologica. 2023 (Aug 31). doi: 10.3324/haematol.2023.283162

4.       Schmitz N, Zeynalova S, Nickelsen M, et al. CNS International Prognostic Index: A risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol. 2016;34:3150-3156. doi: 10.1200/JCO.2015.65.6520

5.       Dreyling M, Goy A, Hess G, et al. Long-term outcomes with ibrutinib treatment for patients with relapsed/refractory mantle cell lymphoma: A pooled analysis of 3 clinical trials with nearly 10 years of follow-up. Hemasphere. 2022;6:e712. doi: 10.1097/HS9.0000000000000712

The ZUMA-7 and TRANSFORM studies have been practice-changing for the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL). These studies demonstrated an improvement in outcomes with axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel), respectively, as compared with standard-of-care treatment (chemotherapy and autologous stem cell transplantation).^1,2 Patients included in these studies were refractory to their initial therapy or experienced relapse within 12 months and were considered fit for autologous stem cell transplant. It has remained unclear, however, whether patients who are not transplant candidates may also derive benefit and tolerate treatment with chimeric antigen receptor (CAR) T-cell therapy. The PILOT study was a single-arm phase 2 study that demonstrated favorable outcomes with liso-cel in this patient population, thus resulting in the approval of liso-cel by the US Food and Drug Administration for this population.³ Recently, the ALYCATE study similarly examined outcomes in transplant-ineligible patients treated with axi-cel (Houot et al). This phase 2 study included 62 patients with high-risk R/R LBCL who underwent leukapheresis and subsequently received second-line axi-cel. The complete metabolic response rate 3 months after axi-cel infusion was 71.0% (95% CI 58.1%-81.8%). At a median 12-month follow-up, the median progression-free survival was 11.8 months (95% CI 8.4-not reached) whereas median overall survival was not reached. Grade ≥ 3 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 8.1% and 14.5% of patients, respectively. Also of note, patients age ≥ 70 years did not show increased toxicity compared with those age < 70 years, with similar rates of CRS, ICANS, and intensive care unit transfer. This study supports the role of axi-cel in the second-line setting, regardless of transplant eligibility.

Another important study recently published for patients with LBCL examined the role of central nervous system (CNS) prophylaxis (Lewis et al). We know that certain patients with LBCL, including those with a high CNS international prognostic index (IPI) score, double-hit lymphoma, or disease involvement of multiple or certain extranodal sites (ie, breast, testes, adrenals, kidney) can be at increased risk for lymphoma spread to the CNS.⁴ Strategies to reduce this risk have subsequently been developed for these high-risk patients, though consensus regarding who should be treated and how best to treat patients has been consistent. Recently, retrospective data have also called into question whether our current approaches meaningfully reduce this risk. One such study was a multicenter, international, retrospective observational study that included 2418 adults with aggressive LBCL and a high risk for CNS progression who were treated with curative-intent anti-CD20–based chemoimmunotherapy and who did or did not receive high-dose methotrexate (HD-MTX). Patients who did vs did not receive HD-MTX had a significantly lower risk for CNS progression (adjusted 5-year risk difference 1.6%; adjusted hazard ratio [aHR] 0.59; P = .014), but the significance was lost when considering only those patients who achieved a complete response at chemoimmunotherapy completion (adjusted 5-year risk difference 1.4%; aHR 0.74; P = .30). The study was not sufficiently powered to make definitive conclusions for individual risk groups, though there was no obvious reduction in CNS involvement risk in any high-risk subgroup. With an absolute risk reduction of 1.6% with the use of HD-MTX, 63 patients would require treatment to prevent one CNS progression event over 5 years (Lewis et al). Given the absence of prospective, randomized data, these results, though retrospective in nature, call into question the benefit of CNS prophylaxis. The authors suggest that studies evaluating alternative strategies for prophylaxis and tools for early detection of relapse, such as circulating tumor DNA, may be helpful.

Another study worth noting was one exploring Bruton tyrosine kinase (BTK) inhibition in mantle cell lymphoma (MCL). BTK inhibitors, including zanubrutinib, have emerged as effective therapies for patients with R/R disease. A recent pooled analysis included 112 patients from the BGB-3111-AU-003 and BGB-3111-206 clinical trials who had R/R MCL and received second-line (n = 41) or later-line (n = 71) zanubrutinib (Song et al). At a median follow-up of 35.2 months, patients receiving second-line vs later-line zanubrutinib had significantly improved median overall survival (aHR 0.459; P = .044) and numerically longer median progression-free survival (27.8 vs 22.1 months). Adverse events observed in both groups were consistent with the known safety profile of zanubrutinib. These findings were in line with a prior similar pooled study that demonstrated improved outcomes with second-line ibrutinib for patients with MCL as compared with later-line ibrutinib therapy.⁵ This study, however, did not evaluate the impact on CAR T–cell therapy in MCL, which is also an effective treatment option for patients with R/R disease, and how best to sequence with BTK inhibitors.

Additional References

1.       Locke FL, Miklos DB, Jacobson CA, et al, for 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

2.       Kamdar M, Solomon SR, Arnason J, et al, for theTRANSFORM 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

3.       Gordon LI, Liu FF, Braverman J, et al. Lisocabtagene maraleucel for second-line relapsed or refractory large B-cell lymphoma: Patient-reported outcomes from the PILOT study. Haematologica. 2023 (Aug 31). doi: 10.3324/haematol.2023.283162

4.       Schmitz N, Zeynalova S, Nickelsen M, et al. CNS International Prognostic Index: A risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol. 2016;34:3150-3156. doi: 10.1200/JCO.2015.65.6520

5.       Dreyling M, Goy A, Hess G, et al. Long-term outcomes with ibrutinib treatment for patients with relapsed/refractory mantle cell lymphoma: A pooled analysis of 3 clinical trials with nearly 10 years of follow-up. Hemasphere. 2022;6:e712. doi: 10.1097/HS9.0000000000000712

Given the frequency of autoimmune conditions in women, the possible effects of estrogen and hormonal therapy exposure over the lifespan on the development of rheumatoid arthritis (RA) has long been of interest. Prior studies have identified a potential increase in RA risk in older women taking estrogen replacement. Hadizadeh and colleagues used the UK Biobank to identify cases of RA among over 236,000 women taking oral contraceptives and over 102,000 women taking hormone replacement therapy. Oral contraceptive use was associated with lower risk for RA (hazard ratio [HR] 0.89), whereas hormone replacement therapy was associated with higher risk for RA (HR 1.16) compared with women who had never used these therapies. Exogenous estrogen exposure may affect the development of RA, but the potential mechanisms (including the effect on systemic inflammation) remain unclear.

Among the multitude of studies on a treat-to-target (T2T) strategy in RA, a recent cluster randomized trial by Bessette and colleagues compared use of abatacept in 284 patients treated by 44 physicians. Patients assigned to both T2T and routine care had significant improvement in RA disease activity (as measured by the Clinical Disease Activity Index) with abatacept, with close to 40% in low disease activity at 12 months. Those treated with routine care experienced significant improvements in RA disease activity at 12 months of abatacept treatment. T2T was associated with slightly higher odds of low disease activity and a shorter time to Simplified Disease Activity Index remission (14 vs 19 months). With T2T being largely accepted as a standard of care on the basis of prior studies, this study raises the question of why little difference was seen between the two groups — perhaps it was related to the use of abatacept. It is unlikely to further change the standard of care to reduce use of disease activity measures.

To better understand refractory or difficult-to-treat (D2T) RA, Jung and colleagues used the KOBIO (KOrean College of Rheumatology BIOlogics) registry to compare characteristics of patients with D2T RA vs those who respond more readily to therapy. Of the 2321 patients included in the study, about 12% (271) had D2T RA. Patients with D2T RA tended to be younger and have longer disease duration, as well as a negative rheumatoid factor (RF); less use of conventional synthetic disease-modifying antirheumatic drugs (csDMARD); and, as expected, higher disease activity measures. Given that about 80% of patients were seropositive for RF and the fact that patients with D2T RA tended to have higher inflammatory markers (erythrocyte sedimentation rate and C-reactive protein), it is not likely that patients were misclassified with RA. The reason why patients with D2T RA had less csDMARD use is not clear, but prior studies have supported early and aggressive use of csDMARD for best outcomes. The study did suggest that patients with D2T RA stayed on Janus kinase (JAK) inhibitor therapy the longest, and perhaps similar studies in future will help outline the best treatment strategy for patients with D2T RA and persistently high disease activity.

Finally, in a post hoc analysis of the ORAL Start trial of the JAK inhibitor tofacitinib vs methotrexate, Ciurea and colleagues looked at paired joint pathology scores (PJPS) — swollen and tender joint counts with left and right pooled — over the course of the 12-month study. Patients receiving tofacitinib had overall improved PJPS, though patients receiving methotrexate had more improvement in the foot. These findings, generally supporting those of the initial study, are unlikely to further change therapy.

Given the frequency of autoimmune conditions in women, the possible effects of estrogen and hormonal therapy exposure over the lifespan on the development of rheumatoid arthritis (RA) has long been of interest. Prior studies have identified a potential increase in RA risk in older women taking estrogen replacement. Hadizadeh and colleagues used the UK Biobank to identify cases of RA among over 236,000 women taking oral contraceptives and over 102,000 women taking hormone replacement therapy. Oral contraceptive use was associated with lower risk for RA (hazard ratio [HR] 0.89), whereas hormone replacement therapy was associated with higher risk for RA (HR 1.16) compared with women who had never used these therapies. Exogenous estrogen exposure may affect the development of RA, but the potential mechanisms (including the effect on systemic inflammation) remain unclear.

Among the multitude of studies on a treat-to-target (T2T) strategy in RA, a recent cluster randomized trial by Bessette and colleagues compared use of abatacept in 284 patients treated by 44 physicians. Patients assigned to both T2T and routine care had significant improvement in RA disease activity (as measured by the Clinical Disease Activity Index) with abatacept, with close to 40% in low disease activity at 12 months. Those treated with routine care experienced significant improvements in RA disease activity at 12 months of abatacept treatment. T2T was associated with slightly higher odds of low disease activity and a shorter time to Simplified Disease Activity Index remission (14 vs 19 months). With T2T being largely accepted as a standard of care on the basis of prior studies, this study raises the question of why little difference was seen between the two groups — perhaps it was related to the use of abatacept. It is unlikely to further change the standard of care to reduce use of disease activity measures.

To better understand refractory or difficult-to-treat (D2T) RA, Jung and colleagues used the KOBIO (KOrean College of Rheumatology BIOlogics) registry to compare characteristics of patients with D2T RA vs those who respond more readily to therapy. Of the 2321 patients included in the study, about 12% (271) had D2T RA. Patients with D2T RA tended to be younger and have longer disease duration, as well as a negative rheumatoid factor (RF); less use of conventional synthetic disease-modifying antirheumatic drugs (csDMARD); and, as expected, higher disease activity measures. Given that about 80% of patients were seropositive for RF and the fact that patients with D2T RA tended to have higher inflammatory markers (erythrocyte sedimentation rate and C-reactive protein), it is not likely that patients were misclassified with RA. The reason why patients with D2T RA had less csDMARD use is not clear, but prior studies have supported early and aggressive use of csDMARD for best outcomes. The study did suggest that patients with D2T RA stayed on Janus kinase (JAK) inhibitor therapy the longest, and perhaps similar studies in future will help outline the best treatment strategy for patients with D2T RA and persistently high disease activity.

Finally, in a post hoc analysis of the ORAL Start trial of the JAK inhibitor tofacitinib vs methotrexate, Ciurea and colleagues looked at paired joint pathology scores (PJPS) — swollen and tender joint counts with left and right pooled — over the course of the 12-month study. Patients receiving tofacitinib had overall improved PJPS, though patients receiving methotrexate had more improvement in the foot. These findings, generally supporting those of the initial study, are unlikely to further change therapy.

Given the frequency of autoimmune conditions in women, the possible effects of estrogen and hormonal therapy exposure over the lifespan on the development of rheumatoid arthritis (RA) has long been of interest. Prior studies have identified a potential increase in RA risk in older women taking estrogen replacement. Hadizadeh and colleagues used the UK Biobank to identify cases of RA among over 236,000 women taking oral contraceptives and over 102,000 women taking hormone replacement therapy. Oral contraceptive use was associated with lower risk for RA (hazard ratio [HR] 0.89), whereas hormone replacement therapy was associated with higher risk for RA (HR 1.16) compared with women who had never used these therapies. Exogenous estrogen exposure may affect the development of RA, but the potential mechanisms (including the effect on systemic inflammation) remain unclear.

Among the multitude of studies on a treat-to-target (T2T) strategy in RA, a recent cluster randomized trial by Bessette and colleagues compared use of abatacept in 284 patients treated by 44 physicians. Patients assigned to both T2T and routine care had significant improvement in RA disease activity (as measured by the Clinical Disease Activity Index) with abatacept, with close to 40% in low disease activity at 12 months. Those treated with routine care experienced significant improvements in RA disease activity at 12 months of abatacept treatment. T2T was associated with slightly higher odds of low disease activity and a shorter time to Simplified Disease Activity Index remission (14 vs 19 months). With T2T being largely accepted as a standard of care on the basis of prior studies, this study raises the question of why little difference was seen between the two groups — perhaps it was related to the use of abatacept. It is unlikely to further change the standard of care to reduce use of disease activity measures.

To better understand refractory or difficult-to-treat (D2T) RA, Jung and colleagues used the KOBIO (KOrean College of Rheumatology BIOlogics) registry to compare characteristics of patients with D2T RA vs those who respond more readily to therapy. Of the 2321 patients included in the study, about 12% (271) had D2T RA. Patients with D2T RA tended to be younger and have longer disease duration, as well as a negative rheumatoid factor (RF); less use of conventional synthetic disease-modifying antirheumatic drugs (csDMARD); and, as expected, higher disease activity measures. Given that about 80% of patients were seropositive for RF and the fact that patients with D2T RA tended to have higher inflammatory markers (erythrocyte sedimentation rate and C-reactive protein), it is not likely that patients were misclassified with RA. The reason why patients with D2T RA had less csDMARD use is not clear, but prior studies have supported early and aggressive use of csDMARD for best outcomes. The study did suggest that patients with D2T RA stayed on Janus kinase (JAK) inhibitor therapy the longest, and perhaps similar studies in future will help outline the best treatment strategy for patients with D2T RA and persistently high disease activity.

Finally, in a post hoc analysis of the ORAL Start trial of the JAK inhibitor tofacitinib vs methotrexate, Ciurea and colleagues looked at paired joint pathology scores (PJPS) — swollen and tender joint counts with left and right pooled — over the course of the 12-month study. Patients receiving tofacitinib had overall improved PJPS, though patients receiving methotrexate had more improvement in the foot. These findings, generally supporting those of the initial study, are unlikely to further change therapy.

In patients with node-positive and locally advanced breast cancer (BC), postmastectomy radiation therapy (PMRT) decreases risk for recurrence and improves survival (Mutter et al). Proton therapy is an attractive newer way to deliver PMRT compared with photon-based methods and allows improved sparing of cardiopulmonary and other normal tissue. The phase 2 MC1631 trial included 82 patients with BC who underwent mastectomy with or without immediate breast reconstruction and who were randomly assigned to receive either conventional fractionated (50 Gy in 25 fractions of 2 Gy) or hypofractionated (40.05 Gy in 15 fractions of 2.67 Gy) proton PMRT. At a median follow-up of 39.3 months, both conventional fractionated and hypofractionated proton PMRT had similar complication rates (15% vs 20%; absolute difference 4.9%; one-sided 95% CI 18.5; P = .27), with most complications occurring in patients with immediate expander or implant-based reconstruction. Noninferiority of the hypofractionation group could not be determined after a median follow-up of 39 months. However, no isolated local regional recurrences in either treatment arm were seen. This study provides the first prospective, randomized data of hypofractionated proton PMRT. Further data are awaited to support this approach. 

In patients with metastatic hormone receptor (HR)–positive, PIK3CA-mutant BC, the combination of fulvestrant with alpelisib improves progression-free survival per the SOLAR-1 study.1 Higher rates of hyperglycemia observed among patients treated with alpelisib have led to alpelisib dose reductions, treatment delays, and discontinuation of the drug. In a retrospective cohort study of 247 patients with metastatic BC who received alpelisib either as standard care (n = 147) or in a clinical trial setting (n = 100), 61.5% of patients developed any-grade hyperglycemia (Shen et al). The rate of hyperglycemia was considerably higher in patients who received alpelisib as part of standard care vs clinical trial (80.3% vs 34.0%). Baseline body mass index ≥ 25 (P = .036) and A1c levels in the prediabetes and diabetes range were significantly associated with the development of any-grade hyperglycemia (P = .036 and P < .001, respectively) and grade 3-4 hyperglycemia (P < .001 for both). A total of 4.5% of patients discontinued alpelisib owing to hyperglycemia, 17% of patients required dose reductions, and in 27% of patients alpelisib was held until resolution of hyperglycemia. This study highlights the importance of the management of comorbidities before alpelisib treatment to ensure lower rates of adverse events. 

Patritumab deruxtecan (HER3-DXd) is a novel HER3-targeted antibody-drug conjugate that is being evaluated in HER3-expressing metastatic BC. The U31402-A-J101 study is a phase 1/2 trial including 182 heavily pretreated patients (median of five prior therapies) with HER3-expressing advanced BC who received HER3-DXd (Krop et al). The objective response rate was 30.1% (95% CI 21.8%-39.4%) in HR-positive, human epidermal growth factor receptor 2 (HER2)–negative BC, 22.6% (95% CI 12.3%-36.2%) in triple-negative BC, and 42.9% (95% CI 17.1%-71.1%) in HER2-positive BC. Although 71.4% of patients reported grade ≥ 3 treatment-emergent adverse events (TEAE), the overall rate of treatment discontinuation due to TEAE was low (9.9%). These findings demonstrate an encouraging efficacy and a manageable safety profile for patritumab deruxtecan in previously treated patients with BC across all subtypes. Further studies are awaited to confirm these findings and whether prior treatment with antibody-drug conjugate will affect the activity of this drug.

A retrospective analysis of a cohort including 149 patients with metastatic BC looked at predictors of prognosis in patients who had brain metastases and underwent stereotactic radiosurgery (Depner et al). The median overall survival was 14.8 months for the entire cohort. Receptor profiles and the presence of extracranial visceral metastases were significant predictors of prognosis. Overall survival outcomes worsened in patients with estrogen receptor (ER)–negative, HER2-negative BC (hazard ratio 2.00; 95% CI 1.09-3.67) but were better in those with ER-positive, HER2-positive BC (hazard ratio 0.43; 95% CI 0.19-0.96). Furthermore, the presence of extracranial visceral metastases was associated with poor survival outcomes (hazard ratio 2.90; 95% CI 1.53-5.50)

Additional Reference
1.    André F et al, for the SOLAR-1 Study Group. Alpelisib for PIK3CA-mutated, hormone receptor–positive advanced breast cancer. N Engl J Med. 2019;380:1929-1940. doi: 10.1056/NEJMoa1813904
 

In patients with node-positive and locally advanced breast cancer (BC), postmastectomy radiation therapy (PMRT) decreases risk for recurrence and improves survival (Mutter et al). Proton therapy is an attractive newer way to deliver PMRT compared with photon-based methods and allows improved sparing of cardiopulmonary and other normal tissue. The phase 2 MC1631 trial included 82 patients with BC who underwent mastectomy with or without immediate breast reconstruction and who were randomly assigned to receive either conventional fractionated (50 Gy in 25 fractions of 2 Gy) or hypofractionated (40.05 Gy in 15 fractions of 2.67 Gy) proton PMRT. At a median follow-up of 39.3 months, both conventional fractionated and hypofractionated proton PMRT had similar complication rates (15% vs 20%; absolute difference 4.9%; one-sided 95% CI 18.5; P = .27), with most complications occurring in patients with immediate expander or implant-based reconstruction. Noninferiority of the hypofractionation group could not be determined after a median follow-up of 39 months. However, no isolated local regional recurrences in either treatment arm were seen. This study provides the first prospective, randomized data of hypofractionated proton PMRT. Further data are awaited to support this approach. 

In patients with metastatic hormone receptor (HR)–positive, PIK3CA-mutant BC, the combination of fulvestrant with alpelisib improves progression-free survival per the SOLAR-1 study.1 Higher rates of hyperglycemia observed among patients treated with alpelisib have led to alpelisib dose reductions, treatment delays, and discontinuation of the drug. In a retrospective cohort study of 247 patients with metastatic BC who received alpelisib either as standard care (n = 147) or in a clinical trial setting (n = 100), 61.5% of patients developed any-grade hyperglycemia (Shen et al). The rate of hyperglycemia was considerably higher in patients who received alpelisib as part of standard care vs clinical trial (80.3% vs 34.0%). Baseline body mass index ≥ 25 (P = .036) and A1c levels in the prediabetes and diabetes range were significantly associated with the development of any-grade hyperglycemia (P = .036 and P < .001, respectively) and grade 3-4 hyperglycemia (P < .001 for both). A total of 4.5% of patients discontinued alpelisib owing to hyperglycemia, 17% of patients required dose reductions, and in 27% of patients alpelisib was held until resolution of hyperglycemia. This study highlights the importance of the management of comorbidities before alpelisib treatment to ensure lower rates of adverse events. 

Patritumab deruxtecan (HER3-DXd) is a novel HER3-targeted antibody-drug conjugate that is being evaluated in HER3-expressing metastatic BC. The U31402-A-J101 study is a phase 1/2 trial including 182 heavily pretreated patients (median of five prior therapies) with HER3-expressing advanced BC who received HER3-DXd (Krop et al). The objective response rate was 30.1% (95% CI 21.8%-39.4%) in HR-positive, human epidermal growth factor receptor 2 (HER2)–negative BC, 22.6% (95% CI 12.3%-36.2%) in triple-negative BC, and 42.9% (95% CI 17.1%-71.1%) in HER2-positive BC. Although 71.4% of patients reported grade ≥ 3 treatment-emergent adverse events (TEAE), the overall rate of treatment discontinuation due to TEAE was low (9.9%). These findings demonstrate an encouraging efficacy and a manageable safety profile for patritumab deruxtecan in previously treated patients with BC across all subtypes. Further studies are awaited to confirm these findings and whether prior treatment with antibody-drug conjugate will affect the activity of this drug.

A retrospective analysis of a cohort including 149 patients with metastatic BC looked at predictors of prognosis in patients who had brain metastases and underwent stereotactic radiosurgery (Depner et al). The median overall survival was 14.8 months for the entire cohort. Receptor profiles and the presence of extracranial visceral metastases were significant predictors of prognosis. Overall survival outcomes worsened in patients with estrogen receptor (ER)–negative, HER2-negative BC (hazard ratio 2.00; 95% CI 1.09-3.67) but were better in those with ER-positive, HER2-positive BC (hazard ratio 0.43; 95% CI 0.19-0.96). Furthermore, the presence of extracranial visceral metastases was associated with poor survival outcomes (hazard ratio 2.90; 95% CI 1.53-5.50)

Additional Reference
1.    André F et al, for the SOLAR-1 Study Group. Alpelisib for PIK3CA-mutated, hormone receptor–positive advanced breast cancer. N Engl J Med. 2019;380:1929-1940. doi: 10.1056/NEJMoa1813904
 

In patients with node-positive and locally advanced breast cancer (BC), postmastectomy radiation therapy (PMRT) decreases risk for recurrence and improves survival (Mutter et al). Proton therapy is an attractive newer way to deliver PMRT compared with photon-based methods and allows improved sparing of cardiopulmonary and other normal tissue. The phase 2 MC1631 trial included 82 patients with BC who underwent mastectomy with or without immediate breast reconstruction and who were randomly assigned to receive either conventional fractionated (50 Gy in 25 fractions of 2 Gy) or hypofractionated (40.05 Gy in 15 fractions of 2.67 Gy) proton PMRT. At a median follow-up of 39.3 months, both conventional fractionated and hypofractionated proton PMRT had similar complication rates (15% vs 20%; absolute difference 4.9%; one-sided 95% CI 18.5; P = .27), with most complications occurring in patients with immediate expander or implant-based reconstruction. Noninferiority of the hypofractionation group could not be determined after a median follow-up of 39 months. However, no isolated local regional recurrences in either treatment arm were seen. This study provides the first prospective, randomized data of hypofractionated proton PMRT. Further data are awaited to support this approach. 

In patients with metastatic hormone receptor (HR)–positive, PIK3CA-mutant BC, the combination of fulvestrant with alpelisib improves progression-free survival per the SOLAR-1 study.1 Higher rates of hyperglycemia observed among patients treated with alpelisib have led to alpelisib dose reductions, treatment delays, and discontinuation of the drug. In a retrospective cohort study of 247 patients with metastatic BC who received alpelisib either as standard care (n = 147) or in a clinical trial setting (n = 100), 61.5% of patients developed any-grade hyperglycemia (Shen et al). The rate of hyperglycemia was considerably higher in patients who received alpelisib as part of standard care vs clinical trial (80.3% vs 34.0%). Baseline body mass index ≥ 25 (P = .036) and A1c levels in the prediabetes and diabetes range were significantly associated with the development of any-grade hyperglycemia (P = .036 and P < .001, respectively) and grade 3-4 hyperglycemia (P < .001 for both). A total of 4.5% of patients discontinued alpelisib owing to hyperglycemia, 17% of patients required dose reductions, and in 27% of patients alpelisib was held until resolution of hyperglycemia. This study highlights the importance of the management of comorbidities before alpelisib treatment to ensure lower rates of adverse events. 

Patritumab deruxtecan (HER3-DXd) is a novel HER3-targeted antibody-drug conjugate that is being evaluated in HER3-expressing metastatic BC. The U31402-A-J101 study is a phase 1/2 trial including 182 heavily pretreated patients (median of five prior therapies) with HER3-expressing advanced BC who received HER3-DXd (Krop et al). The objective response rate was 30.1% (95% CI 21.8%-39.4%) in HR-positive, human epidermal growth factor receptor 2 (HER2)–negative BC, 22.6% (95% CI 12.3%-36.2%) in triple-negative BC, and 42.9% (95% CI 17.1%-71.1%) in HER2-positive BC. Although 71.4% of patients reported grade ≥ 3 treatment-emergent adverse events (TEAE), the overall rate of treatment discontinuation due to TEAE was low (9.9%). These findings demonstrate an encouraging efficacy and a manageable safety profile for patritumab deruxtecan in previously treated patients with BC across all subtypes. Further studies are awaited to confirm these findings and whether prior treatment with antibody-drug conjugate will affect the activity of this drug.

A retrospective analysis of a cohort including 149 patients with metastatic BC looked at predictors of prognosis in patients who had brain metastases and underwent stereotactic radiosurgery (Depner et al). The median overall survival was 14.8 months for the entire cohort. Receptor profiles and the presence of extracranial visceral metastases were significant predictors of prognosis. Overall survival outcomes worsened in patients with estrogen receptor (ER)–negative, HER2-negative BC (hazard ratio 2.00; 95% CI 1.09-3.67) but were better in those with ER-positive, HER2-positive BC (hazard ratio 0.43; 95% CI 0.19-0.96). Furthermore, the presence of extracranial visceral metastases was associated with poor survival outcomes (hazard ratio 2.90; 95% CI 1.53-5.50)

Additional Reference
1.    André F et al, for the SOLAR-1 Study Group. Alpelisib for PIK3CA-mutated, hormone receptor–positive advanced breast cancer. N Engl J Med. 2019;380:1929-1940. doi: 10.1056/NEJMoa1813904
 

Flohr and colleagues present the results of a controlled trial of cyclosporine vs methotrexate for severe atopic dermatitis ("Efficacy and Safety of Ciclosporin Versus Methotrexate in the Treatment of Severe Atopic Dermatitis in Children and Young People"). Cyclosporine worked faster, yet methotrexate was a bit more effective in the long run. Both treatments had considerable side effects; 10% and 14% had serious events with cyclosporine and methotrexate, respectively. My only quibble is with the first word of the abstract background section; the authors call cyclosporine and methotrexate "conventional" systemic drugs for atopic dermatitis. At this point, considering safety and efficacy, I would consider drugs like dupilumab to be the "conventional" systemic treatment for atopic dermatitis.

Wan and colleagues ("Neuropsychiatric Disorders in Adults With Atopic Dermatitis") present an exceptionally well-done study with a huge patient population. The study compared about 600,000 adults with atopic dermatitis vs over 2,000,000 adults without the disease. A sample size like that offers a lot of power to detect very small differences between groups. The researchers report higher rates of anxiety and depression in patients with atopic dermatitis compared to those without. Are those differences clinically meaningfully different? The rates of depression were 14 and 17 cases per 1000 patient-years for those without and those with severe atopic dermatitis, respectively. That's a difference of 3 per 1000 patient-years. So maybe roughly 300 patients with atopic dermatitis would need to be seen to observe one patient with depression due to atopic dermatitis (assuming that the observed differences in rates between those with and those without atopic dermatitis were due to the dermatitis). The authors conclude, "Clinicians should inquire about mental health in patients with AD." I don't think their data support such a conclusion. We'd need to see a cost-effectiveness study to know if that's an intervention that we should do. Given the very small difference between the rates in those with and those without atopic dermatitis, it might be reasonable to conclude that we should inquire about mental health in patients with atopic dermatitis about as much as we should in patients without atopic dermatitis.

Some years ago, there was an over-the-counter topical product for psoriasis based on a banana peel extract. I think it was marketed as "FDA approved" for psoriasis (which was legal to say because the product also contained tar) and as being as effective as topical calcipotriene as published in the Journal of Investigational Dermatology (JID). I went to look for the article; the "publication" was the abstract of a poster presentation. The study followed a very small study population for a short period of time. The study was, I believe, underpowered to detect differences between the banana peel extract and the vitamin D analog. Those data were presented as a poster, the poster abstracts were printed in JID, and, voilà, the product was marketed as being as effective as topical calcipotriene as published in JID.

Sowlati and colleagues ("Efficacy and Tolerability of a Novel Topical Treatment Containing Pea Protein and Xyloglucan in the Management of Atopic Dermatitis in Children") randomly assigned 42 patients to receive either a xyloglucan/pea protein topical therapy or hydrocortisone. The participants were followed for 2 weeks. Both groups improved. We don't know whether they improved more than they would have with moisturizer. This study doesn't make me excited about prescribing the xyloglucan/pea protein topical.

The study by Mohamed and colleagues comparing tacrolimus and hydrocortisone reminds me that we have an effective generic topical anti-inflammatory for our patients with atopic dermatitis. Given the safety of topical tacrolimus, I prefer prescribing the 0.1% ointment for all my patients, though I give the lower concentration, approved for children, if the insurer makes me.

Simpson and colleagues' post hoc analysis of tralokinumab tells us that, with continued use, some patients who don't respond well initially will have greater improvement. But what I'd really like to see is a head-to-head study comparing tralokinumab vs dupilumab. Dupilumab seems to have stronger efficacy based on their reported trial numbers, but a head-to-head trial would give us greater confidence in their relative benefits.

I have trouble getting excited about this study by Cork and colleagues ("Dupilumab Safety and Efficacy in a Phase III Open-Label Extension Trial in Children 6-11 Years of Age With Severe Atopic Dermatitis"). I feel very comfortable with dupilumab already.

Flohr and colleagues present the results of a controlled trial of cyclosporine vs methotrexate for severe atopic dermatitis ("Efficacy and Safety of Ciclosporin Versus Methotrexate in the Treatment of Severe Atopic Dermatitis in Children and Young People"). Cyclosporine worked faster, yet methotrexate was a bit more effective in the long run. Both treatments had considerable side effects; 10% and 14% had serious events with cyclosporine and methotrexate, respectively. My only quibble is with the first word of the abstract background section; the authors call cyclosporine and methotrexate "conventional" systemic drugs for atopic dermatitis. At this point, considering safety and efficacy, I would consider drugs like dupilumab to be the "conventional" systemic treatment for atopic dermatitis.

Wan and colleagues ("Neuropsychiatric Disorders in Adults With Atopic Dermatitis") present an exceptionally well-done study with a huge patient population. The study compared about 600,000 adults with atopic dermatitis vs over 2,000,000 adults without the disease. A sample size like that offers a lot of power to detect very small differences between groups. The researchers report higher rates of anxiety and depression in patients with atopic dermatitis compared to those without. Are those differences clinically meaningfully different? The rates of depression were 14 and 17 cases per 1000 patient-years for those without and those with severe atopic dermatitis, respectively. That's a difference of 3 per 1000 patient-years. So maybe roughly 300 patients with atopic dermatitis would need to be seen to observe one patient with depression due to atopic dermatitis (assuming that the observed differences in rates between those with and those without atopic dermatitis were due to the dermatitis). The authors conclude, "Clinicians should inquire about mental health in patients with AD." I don't think their data support such a conclusion. We'd need to see a cost-effectiveness study to know if that's an intervention that we should do. Given the very small difference between the rates in those with and those without atopic dermatitis, it might be reasonable to conclude that we should inquire about mental health in patients with atopic dermatitis about as much as we should in patients without atopic dermatitis.

Some years ago, there was an over-the-counter topical product for psoriasis based on a banana peel extract. I think it was marketed as "FDA approved" for psoriasis (which was legal to say because the product also contained tar) and as being as effective as topical calcipotriene as published in the Journal of Investigational Dermatology (JID). I went to look for the article; the "publication" was the abstract of a poster presentation. The study followed a very small study population for a short period of time. The study was, I believe, underpowered to detect differences between the banana peel extract and the vitamin D analog. Those data were presented as a poster, the poster abstracts were printed in JID, and, voilà, the product was marketed as being as effective as topical calcipotriene as published in JID.

Sowlati and colleagues ("Efficacy and Tolerability of a Novel Topical Treatment Containing Pea Protein and Xyloglucan in the Management of Atopic Dermatitis in Children") randomly assigned 42 patients to receive either a xyloglucan/pea protein topical therapy or hydrocortisone. The participants were followed for 2 weeks. Both groups improved. We don't know whether they improved more than they would have with moisturizer. This study doesn't make me excited about prescribing the xyloglucan/pea protein topical.

The study by Mohamed and colleagues comparing tacrolimus and hydrocortisone reminds me that we have an effective generic topical anti-inflammatory for our patients with atopic dermatitis. Given the safety of topical tacrolimus, I prefer prescribing the 0.1% ointment for all my patients, though I give the lower concentration, approved for children, if the insurer makes me.

Simpson and colleagues' post hoc analysis of tralokinumab tells us that, with continued use, some patients who don't respond well initially will have greater improvement. But what I'd really like to see is a head-to-head study comparing tralokinumab vs dupilumab. Dupilumab seems to have stronger efficacy based on their reported trial numbers, but a head-to-head trial would give us greater confidence in their relative benefits.

I have trouble getting excited about this study by Cork and colleagues ("Dupilumab Safety and Efficacy in a Phase III Open-Label Extension Trial in Children 6-11 Years of Age With Severe Atopic Dermatitis"). I feel very comfortable with dupilumab already.

Flohr and colleagues present the results of a controlled trial of cyclosporine vs methotrexate for severe atopic dermatitis ("Efficacy and Safety of Ciclosporin Versus Methotrexate in the Treatment of Severe Atopic Dermatitis in Children and Young People"). Cyclosporine worked faster, yet methotrexate was a bit more effective in the long run. Both treatments had considerable side effects; 10% and 14% had serious events with cyclosporine and methotrexate, respectively. My only quibble is with the first word of the abstract background section; the authors call cyclosporine and methotrexate "conventional" systemic drugs for atopic dermatitis. At this point, considering safety and efficacy, I would consider drugs like dupilumab to be the "conventional" systemic treatment for atopic dermatitis.

Wan and colleagues ("Neuropsychiatric Disorders in Adults With Atopic Dermatitis") present an exceptionally well-done study with a huge patient population. The study compared about 600,000 adults with atopic dermatitis vs over 2,000,000 adults without the disease. A sample size like that offers a lot of power to detect very small differences between groups. The researchers report higher rates of anxiety and depression in patients with atopic dermatitis compared to those without. Are those differences clinically meaningfully different? The rates of depression were 14 and 17 cases per 1000 patient-years for those without and those with severe atopic dermatitis, respectively. That's a difference of 3 per 1000 patient-years. So maybe roughly 300 patients with atopic dermatitis would need to be seen to observe one patient with depression due to atopic dermatitis (assuming that the observed differences in rates between those with and those without atopic dermatitis were due to the dermatitis). The authors conclude, "Clinicians should inquire about mental health in patients with AD." I don't think their data support such a conclusion. We'd need to see a cost-effectiveness study to know if that's an intervention that we should do. Given the very small difference between the rates in those with and those without atopic dermatitis, it might be reasonable to conclude that we should inquire about mental health in patients with atopic dermatitis about as much as we should in patients without atopic dermatitis.

Some years ago, there was an over-the-counter topical product for psoriasis based on a banana peel extract. I think it was marketed as "FDA approved" for psoriasis (which was legal to say because the product also contained tar) and as being as effective as topical calcipotriene as published in the Journal of Investigational Dermatology (JID). I went to look for the article; the "publication" was the abstract of a poster presentation. The study followed a very small study population for a short period of time. The study was, I believe, underpowered to detect differences between the banana peel extract and the vitamin D analog. Those data were presented as a poster, the poster abstracts were printed in JID, and, voilà, the product was marketed as being as effective as topical calcipotriene as published in JID.

Sowlati and colleagues ("Efficacy and Tolerability of a Novel Topical Treatment Containing Pea Protein and Xyloglucan in the Management of Atopic Dermatitis in Children") randomly assigned 42 patients to receive either a xyloglucan/pea protein topical therapy or hydrocortisone. The participants were followed for 2 weeks. Both groups improved. We don't know whether they improved more than they would have with moisturizer. This study doesn't make me excited about prescribing the xyloglucan/pea protein topical.

The study by Mohamed and colleagues comparing tacrolimus and hydrocortisone reminds me that we have an effective generic topical anti-inflammatory for our patients with atopic dermatitis. Given the safety of topical tacrolimus, I prefer prescribing the 0.1% ointment for all my patients, though I give the lower concentration, approved for children, if the insurer makes me.

Simpson and colleagues' post hoc analysis of tralokinumab tells us that, with continued use, some patients who don't respond well initially will have greater improvement. But what I'd really like to see is a head-to-head study comparing tralokinumab vs dupilumab. Dupilumab seems to have stronger efficacy based on their reported trial numbers, but a head-to-head trial would give us greater confidence in their relative benefits.

I have trouble getting excited about this study by Cork and colleagues ("Dupilumab Safety and Efficacy in a Phase III Open-Label Extension Trial in Children 6-11 Years of Age With Severe Atopic Dermatitis"). I feel very comfortable with dupilumab already.

Hormone receptor–positive breast cancer is the most common subtype, with established risk factors including exposure to exogenous hormones, reproductive history, and lifestyle components (alcohol intake, obesity). There are also less-recognized environmental influences that may disrupt endocrine pathways and, as a result, affect tumor development. Fine particulate matter (PM_2.5), produced by combustion processes (vehicles, industrial facilities), burning wood, and fires, among other sources, is composed of various airborne pollutants (metals, organic compounds, ammonium, nitrate, ozone, sulfate, etc.). Prior studies evaluating the association of PM_2.5 and breast cancer development have shown mixed results.^3,4 A prospective US cohort study including 196,905 women without a prior history of breast cancer estimated historical annual average PM_2.5 concentrations between 1980 and 1984 (10 years prior to enrollment) (White et al). A total of 15,870 breast cancer cases were identified, and a 10 μg/m³ increase in PM_2.5 was associated with an 8% increase in overall breast cancer incidence (HR 1.08; 95% CI 1.02-1.13). The association was observed for estrogen-receptor (ER)-positive (HR 1.10; 95% CI 1.04-1.17) but not ER-negative tumors. Future studies focusing on historic exposures, investigating geographic differences and the resultant effect on cancer development, are of interest.

HER2CLIMB was a pivotal phase 3 randomized, double-blinded trial that demonstrated significant improvement in survival outcomes with the combination of tucatinib/trastuzumab/capecitabine vs tucatinib/trastuzumab/placebo among patients with previously treated human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer.⁵ Real-world data help inform our daily practice because patients enrolled in clinical trials do not always accurately represent the general population. A retrospective cohort study including 3449 patients with HER2-positive metastatic breast cancer evaluated outcomes with tucatinib in a real-world setting, demonstrating results similar to those seen in HER2CLIMB. Among all patients who received tucatinib (n = 216), median real-world time to treatment discontinuation was 6.5 months (95% CI 5.4-8.8), median real-world time to next treatment (which can serve as a proxy for progression-free survival) was 8.7 months (95% CI 6.8-10.7), and real-world overall survival was 26.6 months (95% CI 20.2–not reached). Median real-world time to treatment discontinuation was 8.1 months (95% CI 5.7-9.5) for patients who received the approved tucatinib triplet combination after one or more HER2-directed regimens in the metastatic setting and 9.4 months (95% CI 6.3-14.1) for those receiving it in the second- or third-line setting (Kaufman et al). These results support the efficacy of tucatinib in a real-world population, suggesting that earlier use (second or third line) may result in better outcomes. Future studies will continue to address the positioning of tucatinib in the treatment algorithm for HER2-positive metastatic breast cancer, including the evaluation of novel combinations.

Additional References

1. Giuliano AE et al. Effect of axillary dissection vs no axillary dissection on 10-year overall survival among women with invasive breast cancer and sentinel node metastasis: The ACOSOG Z0011 (Alliance) randomized clinical trial. JAMA. 2017;318:918-926. doi: 10.1001/jama.2017.11470 
2. Bartels SAL, Donker M, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer: 10-year results of the randomized controlled EORTC 10981-22023 AMAROS Trial. J Clin Oncol. 2023;41:2159-2165. doi: 10.1200/JCO.22.01565
3. Gabet S, Lemarchand C, Guénel P, Slama R. Breast cancer risk in association with atmospheric pollution exposure: A meta-analysis of effect estimates followed by a health impact assessment. Environ Health Perspect. 2021;129:57012. doi: 10.1289/EHP8419
4. Hvidtfeldt UA et al. Breast cancer incidence in relation to long-term low-level exposure to air pollution in the ELAPSE pooled cohort. Cancer Epidemiol Biomarkers Prev. 2023;32:105-113. doi: 10.1158/1055-9965.EPI-22-0720  
5. Murthy RK et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382:597-609. doi:10.1056/NEJMoa1914609

Hormone receptor–positive breast cancer is the most common subtype, with established risk factors including exposure to exogenous hormones, reproductive history, and lifestyle components (alcohol intake, obesity). There are also less-recognized environmental influences that may disrupt endocrine pathways and, as a result, affect tumor development. Fine particulate matter (PM_2.5), produced by combustion processes (vehicles, industrial facilities), burning wood, and fires, among other sources, is composed of various airborne pollutants (metals, organic compounds, ammonium, nitrate, ozone, sulfate, etc.). Prior studies evaluating the association of PM_2.5 and breast cancer development have shown mixed results.^3,4 A prospective US cohort study including 196,905 women without a prior history of breast cancer estimated historical annual average PM_2.5 concentrations between 1980 and 1984 (10 years prior to enrollment) (White et al). A total of 15,870 breast cancer cases were identified, and a 10 μg/m³ increase in PM_2.5 was associated with an 8% increase in overall breast cancer incidence (HR 1.08; 95% CI 1.02-1.13). The association was observed for estrogen-receptor (ER)-positive (HR 1.10; 95% CI 1.04-1.17) but not ER-negative tumors. Future studies focusing on historic exposures, investigating geographic differences and the resultant effect on cancer development, are of interest.

HER2CLIMB was a pivotal phase 3 randomized, double-blinded trial that demonstrated significant improvement in survival outcomes with the combination of tucatinib/trastuzumab/capecitabine vs tucatinib/trastuzumab/placebo among patients with previously treated human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer.⁵ Real-world data help inform our daily practice because patients enrolled in clinical trials do not always accurately represent the general population. A retrospective cohort study including 3449 patients with HER2-positive metastatic breast cancer evaluated outcomes with tucatinib in a real-world setting, demonstrating results similar to those seen in HER2CLIMB. Among all patients who received tucatinib (n = 216), median real-world time to treatment discontinuation was 6.5 months (95% CI 5.4-8.8), median real-world time to next treatment (which can serve as a proxy for progression-free survival) was 8.7 months (95% CI 6.8-10.7), and real-world overall survival was 26.6 months (95% CI 20.2–not reached). Median real-world time to treatment discontinuation was 8.1 months (95% CI 5.7-9.5) for patients who received the approved tucatinib triplet combination after one or more HER2-directed regimens in the metastatic setting and 9.4 months (95% CI 6.3-14.1) for those receiving it in the second- or third-line setting (Kaufman et al). These results support the efficacy of tucatinib in a real-world population, suggesting that earlier use (second or third line) may result in better outcomes. Future studies will continue to address the positioning of tucatinib in the treatment algorithm for HER2-positive metastatic breast cancer, including the evaluation of novel combinations.

Additional References

1. Giuliano AE et al. Effect of axillary dissection vs no axillary dissection on 10-year overall survival among women with invasive breast cancer and sentinel node metastasis: The ACOSOG Z0011 (Alliance) randomized clinical trial. JAMA. 2017;318:918-926. doi: 10.1001/jama.2017.11470 
2. Bartels SAL, Donker M, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer: 10-year results of the randomized controlled EORTC 10981-22023 AMAROS Trial. J Clin Oncol. 2023;41:2159-2165. doi: 10.1200/JCO.22.01565
3. Gabet S, Lemarchand C, Guénel P, Slama R. Breast cancer risk in association with atmospheric pollution exposure: A meta-analysis of effect estimates followed by a health impact assessment. Environ Health Perspect. 2021;129:57012. doi: 10.1289/EHP8419
4. Hvidtfeldt UA et al. Breast cancer incidence in relation to long-term low-level exposure to air pollution in the ELAPSE pooled cohort. Cancer Epidemiol Biomarkers Prev. 2023;32:105-113. doi: 10.1158/1055-9965.EPI-22-0720  
5. Murthy RK et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382:597-609. doi:10.1056/NEJMoa1914609

Hormone receptor–positive breast cancer is the most common subtype, with established risk factors including exposure to exogenous hormones, reproductive history, and lifestyle components (alcohol intake, obesity). There are also less-recognized environmental influences that may disrupt endocrine pathways and, as a result, affect tumor development. Fine particulate matter (PM_2.5), produced by combustion processes (vehicles, industrial facilities), burning wood, and fires, among other sources, is composed of various airborne pollutants (metals, organic compounds, ammonium, nitrate, ozone, sulfate, etc.). Prior studies evaluating the association of PM_2.5 and breast cancer development have shown mixed results.^3,4 A prospective US cohort study including 196,905 women without a prior history of breast cancer estimated historical annual average PM_2.5 concentrations between 1980 and 1984 (10 years prior to enrollment) (White et al). A total of 15,870 breast cancer cases were identified, and a 10 μg/m³ increase in PM_2.5 was associated with an 8% increase in overall breast cancer incidence (HR 1.08; 95% CI 1.02-1.13). The association was observed for estrogen-receptor (ER)-positive (HR 1.10; 95% CI 1.04-1.17) but not ER-negative tumors. Future studies focusing on historic exposures, investigating geographic differences and the resultant effect on cancer development, are of interest.

HER2CLIMB was a pivotal phase 3 randomized, double-blinded trial that demonstrated significant improvement in survival outcomes with the combination of tucatinib/trastuzumab/capecitabine vs tucatinib/trastuzumab/placebo among patients with previously treated human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer.⁵ Real-world data help inform our daily practice because patients enrolled in clinical trials do not always accurately represent the general population. A retrospective cohort study including 3449 patients with HER2-positive metastatic breast cancer evaluated outcomes with tucatinib in a real-world setting, demonstrating results similar to those seen in HER2CLIMB. Among all patients who received tucatinib (n = 216), median real-world time to treatment discontinuation was 6.5 months (95% CI 5.4-8.8), median real-world time to next treatment (which can serve as a proxy for progression-free survival) was 8.7 months (95% CI 6.8-10.7), and real-world overall survival was 26.6 months (95% CI 20.2–not reached). Median real-world time to treatment discontinuation was 8.1 months (95% CI 5.7-9.5) for patients who received the approved tucatinib triplet combination after one or more HER2-directed regimens in the metastatic setting and 9.4 months (95% CI 6.3-14.1) for those receiving it in the second- or third-line setting (Kaufman et al). These results support the efficacy of tucatinib in a real-world population, suggesting that earlier use (second or third line) may result in better outcomes. Future studies will continue to address the positioning of tucatinib in the treatment algorithm for HER2-positive metastatic breast cancer, including the evaluation of novel combinations.

Additional References

1. Giuliano AE et al. Effect of axillary dissection vs no axillary dissection on 10-year overall survival among women with invasive breast cancer and sentinel node metastasis: The ACOSOG Z0011 (Alliance) randomized clinical trial. JAMA. 2017;318:918-926. doi: 10.1001/jama.2017.11470 
2. Bartels SAL, Donker M, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer: 10-year results of the randomized controlled EORTC 10981-22023 AMAROS Trial. J Clin Oncol. 2023;41:2159-2165. doi: 10.1200/JCO.22.01565
3. Gabet S, Lemarchand C, Guénel P, Slama R. Breast cancer risk in association with atmospheric pollution exposure: A meta-analysis of effect estimates followed by a health impact assessment. Environ Health Perspect. 2021;129:57012. doi: 10.1289/EHP8419
4. Hvidtfeldt UA et al. Breast cancer incidence in relation to long-term low-level exposure to air pollution in the ELAPSE pooled cohort. Cancer Epidemiol Biomarkers Prev. 2023;32:105-113. doi: 10.1158/1055-9965.EPI-22-0720  
5. Murthy RK et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382:597-609. doi:10.1056/NEJMoa1914609

There is steady advance in the treatment of PsA. Bimekizumab is a novel monoclonal antibody that, by binding to similar sites on interleukin (IL)-17A and IL-17F, inhibits these cytokines. Ritchlin and colleagues recently reported the 52-week results from the phase 3 BE OPTIMAL study including 852 biological disease-modifying antirheumatic drug (bDMARD)-naive patients with active PsA who were randomly assigned to receive bimekizumab, adalimumab, or placebo. At week 16, 43.9% of patients receiving bimekizumab achieved ≥ 50% improvement in the American College of Rheumatology scores (ACR50), with the response being maintained up to week 52 (54.5%). Among patients who switched from placebo to bimekizumab at week 16, a similar proportion (53.0%) achieved ACR50 at week 52. No new safety signals were observed. Thus, bimekizumab led to sustained improvements in clinical response up to week 52 and probably will soon be available to patients with PsA.

The optimal management of axial PsA continues to be investigated. One major question is whether IL-23 inhibitors, which are not efficacious in axial spondyloarthritis, have efficacy in axial PsA. A post hoc analysis of the DISCOVER-2 study included 246 biologic-naive patients with active PsA and sacroiliitis who were randomly assigned to guselkumab every 4 weeks (Q4W; n = 82), guselkumab every 8 weeks (Q8W; n = 68), or placebo with crossover to guselkumab Q4W at week 24 (n = 96), Mease and colleagues report that at week 24, guselkumab Q4W and Q8W vs placebo showed significantly greater scores in the total Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) as well as Ankylosing Spondylitis Disease Activity Score (ASDAS), with further improvements noted at week 100. Thus, in patients with active PsA and imaging-confirmed sacroiliitis, 100 mg guselkumab Q4W and Q8W yielded clinically meaningful and sustained improvements in axial symptoms through 2 years.

Finally, attention is currently being paid to patients with refractory or difficult-to-treat (D2T) PsA. These patients are generally characterized as having active disease despite treatment with two or more targeted DMARD (tDMARD). Philippoteaux and colleagues have reported results from their retrospective cohort study that included 150 patients with PsA who initiated treatment with tDMARD and were followed for at least 2 years, of whom 49 patients had D2T PsA. They found that peripheral structural damage, axial involvement, and the discontinuation of bDMARD due to poor skin psoriasis control were more prevalent in patients with D2T PsA compared with in non-D2T PsA. Thus, patients with D2T PsA are more likely to have more structural damage. Early diagnosis and treatment to reduce structural damage might reduce the prevalence of D2T PsA.

There is steady advance in the treatment of PsA. Bimekizumab is a novel monoclonal antibody that, by binding to similar sites on interleukin (IL)-17A and IL-17F, inhibits these cytokines. Ritchlin and colleagues recently reported the 52-week results from the phase 3 BE OPTIMAL study including 852 biological disease-modifying antirheumatic drug (bDMARD)-naive patients with active PsA who were randomly assigned to receive bimekizumab, adalimumab, or placebo. At week 16, 43.9% of patients receiving bimekizumab achieved ≥ 50% improvement in the American College of Rheumatology scores (ACR50), with the response being maintained up to week 52 (54.5%). Among patients who switched from placebo to bimekizumab at week 16, a similar proportion (53.0%) achieved ACR50 at week 52. No new safety signals were observed. Thus, bimekizumab led to sustained improvements in clinical response up to week 52 and probably will soon be available to patients with PsA.

The optimal management of axial PsA continues to be investigated. One major question is whether IL-23 inhibitors, which are not efficacious in axial spondyloarthritis, have efficacy in axial PsA. A post hoc analysis of the DISCOVER-2 study included 246 biologic-naive patients with active PsA and sacroiliitis who were randomly assigned to guselkumab every 4 weeks (Q4W; n = 82), guselkumab every 8 weeks (Q8W; n = 68), or placebo with crossover to guselkumab Q4W at week 24 (n = 96), Mease and colleagues report that at week 24, guselkumab Q4W and Q8W vs placebo showed significantly greater scores in the total Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) as well as Ankylosing Spondylitis Disease Activity Score (ASDAS), with further improvements noted at week 100. Thus, in patients with active PsA and imaging-confirmed sacroiliitis, 100 mg guselkumab Q4W and Q8W yielded clinically meaningful and sustained improvements in axial symptoms through 2 years.

Finally, attention is currently being paid to patients with refractory or difficult-to-treat (D2T) PsA. These patients are generally characterized as having active disease despite treatment with two or more targeted DMARD (tDMARD). Philippoteaux and colleagues have reported results from their retrospective cohort study that included 150 patients with PsA who initiated treatment with tDMARD and were followed for at least 2 years, of whom 49 patients had D2T PsA. They found that peripheral structural damage, axial involvement, and the discontinuation of bDMARD due to poor skin psoriasis control were more prevalent in patients with D2T PsA compared with in non-D2T PsA. Thus, patients with D2T PsA are more likely to have more structural damage. Early diagnosis and treatment to reduce structural damage might reduce the prevalence of D2T PsA.

There is steady advance in the treatment of PsA. Bimekizumab is a novel monoclonal antibody that, by binding to similar sites on interleukin (IL)-17A and IL-17F, inhibits these cytokines. Ritchlin and colleagues recently reported the 52-week results from the phase 3 BE OPTIMAL study including 852 biological disease-modifying antirheumatic drug (bDMARD)-naive patients with active PsA who were randomly assigned to receive bimekizumab, adalimumab, or placebo. At week 16, 43.9% of patients receiving bimekizumab achieved ≥ 50% improvement in the American College of Rheumatology scores (ACR50), with the response being maintained up to week 52 (54.5%). Among patients who switched from placebo to bimekizumab at week 16, a similar proportion (53.0%) achieved ACR50 at week 52. No new safety signals were observed. Thus, bimekizumab led to sustained improvements in clinical response up to week 52 and probably will soon be available to patients with PsA.

The optimal management of axial PsA continues to be investigated. One major question is whether IL-23 inhibitors, which are not efficacious in axial spondyloarthritis, have efficacy in axial PsA. A post hoc analysis of the DISCOVER-2 study included 246 biologic-naive patients with active PsA and sacroiliitis who were randomly assigned to guselkumab every 4 weeks (Q4W; n = 82), guselkumab every 8 weeks (Q8W; n = 68), or placebo with crossover to guselkumab Q4W at week 24 (n = 96), Mease and colleagues report that at week 24, guselkumab Q4W and Q8W vs placebo showed significantly greater scores in the total Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) as well as Ankylosing Spondylitis Disease Activity Score (ASDAS), with further improvements noted at week 100. Thus, in patients with active PsA and imaging-confirmed sacroiliitis, 100 mg guselkumab Q4W and Q8W yielded clinically meaningful and sustained improvements in axial symptoms through 2 years.

Finally, attention is currently being paid to patients with refractory or difficult-to-treat (D2T) PsA. These patients are generally characterized as having active disease despite treatment with two or more targeted DMARD (tDMARD). Philippoteaux and colleagues have reported results from their retrospective cohort study that included 150 patients with PsA who initiated treatment with tDMARD and were followed for at least 2 years, of whom 49 patients had D2T PsA. They found that peripheral structural damage, axial involvement, and the discontinuation of bDMARD due to poor skin psoriasis control were more prevalent in patients with D2T PsA compared with in non-D2T PsA. Thus, patients with D2T PsA are more likely to have more structural damage. Early diagnosis and treatment to reduce structural damage might reduce the prevalence of D2T PsA.

It is well known that the best outcomes for patients with rheumatoid arthritis (RA) are achieved with a treat-to-target strategy, but recent research has also focused on tapering therapy, especially biologics, in patients who are in prolonged disease remission without synovitis. In the open-label, randomized, noninferiority ARCTIC REWIND trial, Lillegraven and colleagues looked at the effects of tapering tumor necrosis factor inhibitors (TNFi) in 84 patients at different sites in Norway. Patients who had been in remission for a year or more on stable therapy (including TNFi and conventional synthetic disease-modifying antirheumatic drugs [csDMARD]) were included in the study. Of the 43 randomly assigned to tapering TNFi therapy, nearly two-thirds had a flare in 12 months of follow-up, compared with 5% in the stable TNFi group; thus, noninferiority of tapering TNFi was not supported. This study is small and seems to highlight a greater disparity between the two groups than expected from prior studies. Given the stark difference between the two groups, however, caution is advised in tapering TNFi therapy in patients with RA, even those in "deep remission." This information is reassuring in that most patients who flared had a good response to reinstating TNFi therapy, and it is helpful in counseling patients who prefer to try to reduce their medication burden despite the potential for flare.

The impact of chronic steroid use in RA has also received a lot of scrutiny in recent literature due to possible long-term side effects such as bone loss, hyperglycemia, and accelerated atherosclerotic disease. Palmowski and colleagues conducted a pooled analysis of several European randomized trials comparing the use of low-dose glucocorticoids (< 7.5 mg/d prednisone) vs placebo in combination with targeted therapy for RA. Data from over 1100 patients in five trials were analyzed. Over the course of 2 years, participants in both groups had gained weight, more so in the glucocorticoid group compared with the control group (1.8 kg vs 0.7 kg), with negligible effects on blood pressure. While use of moderate and high doses of glucocorticoids is not advisable for the long term, the use of low doses appears to be tolerable, with relatively minor effects on weight and blood pressure.

Given the chronic nature of RA and increasing incidence with age, comorbidities and multimorbidity (two or more comorbidities) are common in patients with RA. Stevens and colleagues used a national claims database to examine the burden of multimorbidity in people with RA and its association with sex and age in two different age groups (18-50 years and older than 51 years). Over 154,000 patients with RA were matched 1:1 to those without. The risk for multimorbidity was higher in women vs men with RA, though the absolute difference in risk was not large. The magnitude of these differences (between women and men, and between those with and without RA) was more pronounced in the younger age group and, as expected, decreased in the older age group. Of note, men with RA, compared with women with RA, had a higher risk for cardiovascular disease, including hypertension, high cholesterol, coronary artery disease, valvular disease, and heart failure. Women with RA had more psychological, neurologic, and comorbid noninflammatory musculoskeletal conditions, such as chronic lower back pain. These differences stress the need for attention to individualized care to improve patients' quality of life and reduce adverse effects on other areas of health.

It is well known that the best outcomes for patients with rheumatoid arthritis (RA) are achieved with a treat-to-target strategy, but recent research has also focused on tapering therapy, especially biologics, in patients who are in prolonged disease remission without synovitis. In the open-label, randomized, noninferiority ARCTIC REWIND trial, Lillegraven and colleagues looked at the effects of tapering tumor necrosis factor inhibitors (TNFi) in 84 patients at different sites in Norway. Patients who had been in remission for a year or more on stable therapy (including TNFi and conventional synthetic disease-modifying antirheumatic drugs [csDMARD]) were included in the study. Of the 43 randomly assigned to tapering TNFi therapy, nearly two-thirds had a flare in 12 months of follow-up, compared with 5% in the stable TNFi group; thus, noninferiority of tapering TNFi was not supported. This study is small and seems to highlight a greater disparity between the two groups than expected from prior studies. Given the stark difference between the two groups, however, caution is advised in tapering TNFi therapy in patients with RA, even those in "deep remission." This information is reassuring in that most patients who flared had a good response to reinstating TNFi therapy, and it is helpful in counseling patients who prefer to try to reduce their medication burden despite the potential for flare.

The impact of chronic steroid use in RA has also received a lot of scrutiny in recent literature due to possible long-term side effects such as bone loss, hyperglycemia, and accelerated atherosclerotic disease. Palmowski and colleagues conducted a pooled analysis of several European randomized trials comparing the use of low-dose glucocorticoids (< 7.5 mg/d prednisone) vs placebo in combination with targeted therapy for RA. Data from over 1100 patients in five trials were analyzed. Over the course of 2 years, participants in both groups had gained weight, more so in the glucocorticoid group compared with the control group (1.8 kg vs 0.7 kg), with negligible effects on blood pressure. While use of moderate and high doses of glucocorticoids is not advisable for the long term, the use of low doses appears to be tolerable, with relatively minor effects on weight and blood pressure.

Given the chronic nature of RA and increasing incidence with age, comorbidities and multimorbidity (two or more comorbidities) are common in patients with RA. Stevens and colleagues used a national claims database to examine the burden of multimorbidity in people with RA and its association with sex and age in two different age groups (18-50 years and older than 51 years). Over 154,000 patients with RA were matched 1:1 to those without. The risk for multimorbidity was higher in women vs men with RA, though the absolute difference in risk was not large. The magnitude of these differences (between women and men, and between those with and without RA) was more pronounced in the younger age group and, as expected, decreased in the older age group. Of note, men with RA, compared with women with RA, had a higher risk for cardiovascular disease, including hypertension, high cholesterol, coronary artery disease, valvular disease, and heart failure. Women with RA had more psychological, neurologic, and comorbid noninflammatory musculoskeletal conditions, such as chronic lower back pain. These differences stress the need for attention to individualized care to improve patients' quality of life and reduce adverse effects on other areas of health.

It is well known that the best outcomes for patients with rheumatoid arthritis (RA) are achieved with a treat-to-target strategy, but recent research has also focused on tapering therapy, especially biologics, in patients who are in prolonged disease remission without synovitis. In the open-label, randomized, noninferiority ARCTIC REWIND trial, Lillegraven and colleagues looked at the effects of tapering tumor necrosis factor inhibitors (TNFi) in 84 patients at different sites in Norway. Patients who had been in remission for a year or more on stable therapy (including TNFi and conventional synthetic disease-modifying antirheumatic drugs [csDMARD]) were included in the study. Of the 43 randomly assigned to tapering TNFi therapy, nearly two-thirds had a flare in 12 months of follow-up, compared with 5% in the stable TNFi group; thus, noninferiority of tapering TNFi was not supported. This study is small and seems to highlight a greater disparity between the two groups than expected from prior studies. Given the stark difference between the two groups, however, caution is advised in tapering TNFi therapy in patients with RA, even those in "deep remission." This information is reassuring in that most patients who flared had a good response to reinstating TNFi therapy, and it is helpful in counseling patients who prefer to try to reduce their medication burden despite the potential for flare.

The impact of chronic steroid use in RA has also received a lot of scrutiny in recent literature due to possible long-term side effects such as bone loss, hyperglycemia, and accelerated atherosclerotic disease. Palmowski and colleagues conducted a pooled analysis of several European randomized trials comparing the use of low-dose glucocorticoids (< 7.5 mg/d prednisone) vs placebo in combination with targeted therapy for RA. Data from over 1100 patients in five trials were analyzed. Over the course of 2 years, participants in both groups had gained weight, more so in the glucocorticoid group compared with the control group (1.8 kg vs 0.7 kg), with negligible effects on blood pressure. While use of moderate and high doses of glucocorticoids is not advisable for the long term, the use of low doses appears to be tolerable, with relatively minor effects on weight and blood pressure.

Given the chronic nature of RA and increasing incidence with age, comorbidities and multimorbidity (two or more comorbidities) are common in patients with RA. Stevens and colleagues used a national claims database to examine the burden of multimorbidity in people with RA and its association with sex and age in two different age groups (18-50 years and older than 51 years). Over 154,000 patients with RA were matched 1:1 to those without. The risk for multimorbidity was higher in women vs men with RA, though the absolute difference in risk was not large. The magnitude of these differences (between women and men, and between those with and without RA) was more pronounced in the younger age group and, as expected, decreased in the older age group. Of note, men with RA, compared with women with RA, had a higher risk for cardiovascular disease, including hypertension, high cholesterol, coronary artery disease, valvular disease, and heart failure. Women with RA had more psychological, neurologic, and comorbid noninflammatory musculoskeletal conditions, such as chronic lower back pain. These differences stress the need for attention to individualized care to improve patients' quality of life and reduce adverse effects on other areas of health.

The treatment of mantle cell lymphoma (MCL) continues to evolve. In the front-line setting, studies are evaluating the role of novel therapies as well as consolidation with autologous stem cell transplantation. In the relapsed/refractory setting, patients can be considered for treatment with Bruton tyrosine kinase (BTK) inhibitors, other targeted therapies, or chimeric antigen receptor (CAR) T-cell therapy. Other novel therapies, including bispecific antibodies and novel antibody drug conjugates, are being studied as well.

Despite the availability of novel agents, a subset of patients continues to have difficult-to-treat disease and a poor prognosis. Established prognostic tools that aid in identifying high-risk patients include alternations in TP53, high proliferation rates, nonclassic morphology, and the Mantle Cell Lymphoma International Prognostic Index (MIPI) score, which incorporates age, performance status, lactate dehydrogenase levels, and white blood cell count. The Nordic study group recently published a paper which provides additional prognostic information beyond these known variables (Rodrigues et al). They examined MYC expression in a cohort of 251 patients with MCL and structural aberrations in MYC and MYC mRNA levels in a smaller cohort. They found that patients with tumors comprising 20% or more cells with MYC overexpression (MYC^high tumors) vs MYC^low tumors had significantly higher risks for death (adjusted hazard ratio [aHR] 2.03; P = .007) and disease progression (aHR 2.20; P = .04), when adjusted for additional high-risk features. Patients with tumors with concomitant MYC^high expression and TP53/p53 alterations vs MYC^low tumors had a particularly poor prognosis, with significantly increased risks for progression (HR 16.90) and death (HR 7.83) with a median overall survival of only 0.9 years (both P < .001). Though MYC overexpression was rare, this study identified a high-risk group of patients, especially those harboring concurrent TP53 aberrations, that may benefit from novel treatment approaches.

Another study recently aimed to identify patients who are at risk for poor outcomes after treatment with brexucabtagene autoleucel (brexu-cel) infusion. Though brexu-cel is an active therapy for patients with relapsed/refractory MCL, there are known toxicities, including cytokine release syndrome, neurologic toxicity, and hematologic toxicity. Given the potential for prolonged cytopenias and immune suppression, patients are also at risk for severe infections, which currently represent the driving determinant of nonrelapse mortality.¹ The CAR-HEMATOTOX (HT) score was previously found to identify patients who are at increased risk for hematologic toxicity after CAR T-cell therapy in diffuse large B-cell lymphoma.² In the current multicenter observational study, which included 103 patients receiving brexu-cel, the authors reported an association between baseline HT score and outcome in MCL as well. Patients with high (2-7) vs low (0-1) HT scores had significantly longer median duration of severe neutropenia (P < .0001), higher rates of severe infections (P = .001), and lower overall response rates (P = .003). The HT score represented an independent predictor of poor progression-free (aHR 3.7; P < .001) and overall (aHR 5.6; P = .002) survival. This tool may provide a helpful guide when counseling patients on treatment options and allow for more personalized toxicity management.

Despite availability of BTK inhibitors and CAR T-cell therapy for patients with MCL, relapses remain common. As upregulation of phosphoinositide 3-kinase (PI3K) is known to play a critical role in lymphomagenesis, there has been interest in targeting this pathway across lymphoma subtypes. Though PI3K inhibitors have been found to be active agents, they have also been associated with poor tolerability and safety concerns. Parsaclisib is a selective PI3K delta inhibitor that showed encouraging data in the phase 1/2 study in patients with non-Hodgkin lymphoma.³ More recently, the phase 2 CITADEL-205 study, which included adult patients with relapsed or refractory MCL previously treated with one to three systemic therapies, with (n = 53) or without (n = 108) prior BTK inhibitor treatment, was published (Zinazni et al). Patients received 20 mg parsaclisib once daily for 8 weeks followed by either 20 mg parsaclisib once weekly or 2.5 mg parsaclisib once daily. Among BTK inhibitor–naive patients who received parsaclisib once daily, 70.1% (95% CI 58.6%-80.0%) and 15.6% (95% CI 8.3%-25.6%) achieved an objective response and a complete response, respectively, with the median duration of response being 12.1 months (95% CI 9.0 to not evaluable). Responses were not thought to be clinically meaningful in the patients treated with prior BTK inhibitors. Most treatment-emergent adverse events were low grade and manageable by dose interruptions or reductions. A total of 30% of patients required drug discontinuation due to adverse events. Though parsaclisib demonstrated activity in patients with relapsed/refractory MCL, the role of this drug in clinical practice is not clear given the increased use of BTK inhibitors as a preferred second-line therapy and ongoing concerns regarding PI3K inhibitor-related toxicity.

Additional References

1.      Wang Y, Jain P, Locke FL, et al. Brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma in standard-of-care practice: Results from the US Lymphoma CAR T Consortium. J Clin Oncol. 2023;41:2594-2606. doi: 10.1200/JCO.22.01797

2.      Rejeski K, Perez A, Sesques P, et al. CAR-HEMATOTOX: A model for CAR T-cell-related hematologic toxicity in relapsed/refractory large B-cell lymphoma. Blood. 2021;138:2499-2513. doi: 10.1182/blood.2020010543

3.      Forero-Torres A, Ramchandren R, Yacoub A, et al. Parsaclisib, a potent and highly selective PI3Kδ inhibitor, in patients with relapsed or refractory B-cell malignancies. Blood. 2019;133:1742-1752. doi: 10.1182/blood-2018-08-867499

The treatment of mantle cell lymphoma (MCL) continues to evolve. In the front-line setting, studies are evaluating the role of novel therapies as well as consolidation with autologous stem cell transplantation. In the relapsed/refractory setting, patients can be considered for treatment with Bruton tyrosine kinase (BTK) inhibitors, other targeted therapies, or chimeric antigen receptor (CAR) T-cell therapy. Other novel therapies, including bispecific antibodies and novel antibody drug conjugates, are being studied as well.

Despite the availability of novel agents, a subset of patients continues to have difficult-to-treat disease and a poor prognosis. Established prognostic tools that aid in identifying high-risk patients include alternations in TP53, high proliferation rates, nonclassic morphology, and the Mantle Cell Lymphoma International Prognostic Index (MIPI) score, which incorporates age, performance status, lactate dehydrogenase levels, and white blood cell count. The Nordic study group recently published a paper which provides additional prognostic information beyond these known variables (Rodrigues et al). They examined MYC expression in a cohort of 251 patients with MCL and structural aberrations in MYC and MYC mRNA levels in a smaller cohort. They found that patients with tumors comprising 20% or more cells with MYC overexpression (MYC^high tumors) vs MYC^low tumors had significantly higher risks for death (adjusted hazard ratio [aHR] 2.03; P = .007) and disease progression (aHR 2.20; P = .04), when adjusted for additional high-risk features. Patients with tumors with concomitant MYC^high expression and TP53/p53 alterations vs MYC^low tumors had a particularly poor prognosis, with significantly increased risks for progression (HR 16.90) and death (HR 7.83) with a median overall survival of only 0.9 years (both P < .001). Though MYC overexpression was rare, this study identified a high-risk group of patients, especially those harboring concurrent TP53 aberrations, that may benefit from novel treatment approaches.

Another study recently aimed to identify patients who are at risk for poor outcomes after treatment with brexucabtagene autoleucel (brexu-cel) infusion. Though brexu-cel is an active therapy for patients with relapsed/refractory MCL, there are known toxicities, including cytokine release syndrome, neurologic toxicity, and hematologic toxicity. Given the potential for prolonged cytopenias and immune suppression, patients are also at risk for severe infections, which currently represent the driving determinant of nonrelapse mortality.¹ The CAR-HEMATOTOX (HT) score was previously found to identify patients who are at increased risk for hematologic toxicity after CAR T-cell therapy in diffuse large B-cell lymphoma.² In the current multicenter observational study, which included 103 patients receiving brexu-cel, the authors reported an association between baseline HT score and outcome in MCL as well. Patients with high (2-7) vs low (0-1) HT scores had significantly longer median duration of severe neutropenia (P < .0001), higher rates of severe infections (P = .001), and lower overall response rates (P = .003). The HT score represented an independent predictor of poor progression-free (aHR 3.7; P < .001) and overall (aHR 5.6; P = .002) survival. This tool may provide a helpful guide when counseling patients on treatment options and allow for more personalized toxicity management.

Despite availability of BTK inhibitors and CAR T-cell therapy for patients with MCL, relapses remain common. As upregulation of phosphoinositide 3-kinase (PI3K) is known to play a critical role in lymphomagenesis, there has been interest in targeting this pathway across lymphoma subtypes. Though PI3K inhibitors have been found to be active agents, they have also been associated with poor tolerability and safety concerns. Parsaclisib is a selective PI3K delta inhibitor that showed encouraging data in the phase 1/2 study in patients with non-Hodgkin lymphoma.³ More recently, the phase 2 CITADEL-205 study, which included adult patients with relapsed or refractory MCL previously treated with one to three systemic therapies, with (n = 53) or without (n = 108) prior BTK inhibitor treatment, was published (Zinazni et al). Patients received 20 mg parsaclisib once daily for 8 weeks followed by either 20 mg parsaclisib once weekly or 2.5 mg parsaclisib once daily. Among BTK inhibitor–naive patients who received parsaclisib once daily, 70.1% (95% CI 58.6%-80.0%) and 15.6% (95% CI 8.3%-25.6%) achieved an objective response and a complete response, respectively, with the median duration of response being 12.1 months (95% CI 9.0 to not evaluable). Responses were not thought to be clinically meaningful in the patients treated with prior BTK inhibitors. Most treatment-emergent adverse events were low grade and manageable by dose interruptions or reductions. A total of 30% of patients required drug discontinuation due to adverse events. Though parsaclisib demonstrated activity in patients with relapsed/refractory MCL, the role of this drug in clinical practice is not clear given the increased use of BTK inhibitors as a preferred second-line therapy and ongoing concerns regarding PI3K inhibitor-related toxicity.

Additional References

1.      Wang Y, Jain P, Locke FL, et al. Brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma in standard-of-care practice: Results from the US Lymphoma CAR T Consortium. J Clin Oncol. 2023;41:2594-2606. doi: 10.1200/JCO.22.01797

2.      Rejeski K, Perez A, Sesques P, et al. CAR-HEMATOTOX: A model for CAR T-cell-related hematologic toxicity in relapsed/refractory large B-cell lymphoma. Blood. 2021;138:2499-2513. doi: 10.1182/blood.2020010543

3.      Forero-Torres A, Ramchandren R, Yacoub A, et al. Parsaclisib, a potent and highly selective PI3Kδ inhibitor, in patients with relapsed or refractory B-cell malignancies. Blood. 2019;133:1742-1752. doi: 10.1182/blood-2018-08-867499

The treatment of mantle cell lymphoma (MCL) continues to evolve. In the front-line setting, studies are evaluating the role of novel therapies as well as consolidation with autologous stem cell transplantation. In the relapsed/refractory setting, patients can be considered for treatment with Bruton tyrosine kinase (BTK) inhibitors, other targeted therapies, or chimeric antigen receptor (CAR) T-cell therapy. Other novel therapies, including bispecific antibodies and novel antibody drug conjugates, are being studied as well.

Despite the availability of novel agents, a subset of patients continues to have difficult-to-treat disease and a poor prognosis. Established prognostic tools that aid in identifying high-risk patients include alternations in TP53, high proliferation rates, nonclassic morphology, and the Mantle Cell Lymphoma International Prognostic Index (MIPI) score, which incorporates age, performance status, lactate dehydrogenase levels, and white blood cell count. The Nordic study group recently published a paper which provides additional prognostic information beyond these known variables (Rodrigues et al). They examined MYC expression in a cohort of 251 patients with MCL and structural aberrations in MYC and MYC mRNA levels in a smaller cohort. They found that patients with tumors comprising 20% or more cells with MYC overexpression (MYC^high tumors) vs MYC^low tumors had significantly higher risks for death (adjusted hazard ratio [aHR] 2.03; P = .007) and disease progression (aHR 2.20; P = .04), when adjusted for additional high-risk features. Patients with tumors with concomitant MYC^high expression and TP53/p53 alterations vs MYC^low tumors had a particularly poor prognosis, with significantly increased risks for progression (HR 16.90) and death (HR 7.83) with a median overall survival of only 0.9 years (both P < .001). Though MYC overexpression was rare, this study identified a high-risk group of patients, especially those harboring concurrent TP53 aberrations, that may benefit from novel treatment approaches.

Another study recently aimed to identify patients who are at risk for poor outcomes after treatment with brexucabtagene autoleucel (brexu-cel) infusion. Though brexu-cel is an active therapy for patients with relapsed/refractory MCL, there are known toxicities, including cytokine release syndrome, neurologic toxicity, and hematologic toxicity. Given the potential for prolonged cytopenias and immune suppression, patients are also at risk for severe infections, which currently represent the driving determinant of nonrelapse mortality.¹ The CAR-HEMATOTOX (HT) score was previously found to identify patients who are at increased risk for hematologic toxicity after CAR T-cell therapy in diffuse large B-cell lymphoma.² In the current multicenter observational study, which included 103 patients receiving brexu-cel, the authors reported an association between baseline HT score and outcome in MCL as well. Patients with high (2-7) vs low (0-1) HT scores had significantly longer median duration of severe neutropenia (P < .0001), higher rates of severe infections (P = .001), and lower overall response rates (P = .003). The HT score represented an independent predictor of poor progression-free (aHR 3.7; P < .001) and overall (aHR 5.6; P = .002) survival. This tool may provide a helpful guide when counseling patients on treatment options and allow for more personalized toxicity management.

Despite availability of BTK inhibitors and CAR T-cell therapy for patients with MCL, relapses remain common. As upregulation of phosphoinositide 3-kinase (PI3K) is known to play a critical role in lymphomagenesis, there has been interest in targeting this pathway across lymphoma subtypes. Though PI3K inhibitors have been found to be active agents, they have also been associated with poor tolerability and safety concerns. Parsaclisib is a selective PI3K delta inhibitor that showed encouraging data in the phase 1/2 study in patients with non-Hodgkin lymphoma.³ More recently, the phase 2 CITADEL-205 study, which included adult patients with relapsed or refractory MCL previously treated with one to three systemic therapies, with (n = 53) or without (n = 108) prior BTK inhibitor treatment, was published (Zinazni et al). Patients received 20 mg parsaclisib once daily for 8 weeks followed by either 20 mg parsaclisib once weekly or 2.5 mg parsaclisib once daily. Among BTK inhibitor–naive patients who received parsaclisib once daily, 70.1% (95% CI 58.6%-80.0%) and 15.6% (95% CI 8.3%-25.6%) achieved an objective response and a complete response, respectively, with the median duration of response being 12.1 months (95% CI 9.0 to not evaluable). Responses were not thought to be clinically meaningful in the patients treated with prior BTK inhibitors. Most treatment-emergent adverse events were low grade and manageable by dose interruptions or reductions. A total of 30% of patients required drug discontinuation due to adverse events. Though parsaclisib demonstrated activity in patients with relapsed/refractory MCL, the role of this drug in clinical practice is not clear given the increased use of BTK inhibitors as a preferred second-line therapy and ongoing concerns regarding PI3K inhibitor-related toxicity.

Additional References

1.      Wang Y, Jain P, Locke FL, et al. Brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma in standard-of-care practice: Results from the US Lymphoma CAR T Consortium. J Clin Oncol. 2023;41:2594-2606. doi: 10.1200/JCO.22.01797

2.      Rejeski K, Perez A, Sesques P, et al. CAR-HEMATOTOX: A model for CAR T-cell-related hematologic toxicity in relapsed/refractory large B-cell lymphoma. Blood. 2021;138:2499-2513. doi: 10.1182/blood.2020010543

3.      Forero-Torres A, Ramchandren R, Yacoub A, et al. Parsaclisib, a potent and highly selective PI3Kδ inhibitor, in patients with relapsed or refractory B-cell malignancies. Blood. 2019;133:1742-1752. doi: 10.1182/blood-2018-08-867499