Clinical Edge Journal Scan Commentary

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

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

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

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

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

Additional References

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

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

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

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

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

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

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

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

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

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

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

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

Additional References

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

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

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

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

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

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

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

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

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

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

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

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

Additional References

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Additional References

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

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

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

Additional References

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

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

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

Additional References

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

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

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

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

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

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

Additional References

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

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

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

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

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

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

Additional References

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

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

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

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

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

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

Additional References

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

Despite multiple existing conventional synthetic disease-modifying antirheumatic drug (csDMARD) and biologic DMARD (bDMARD) options, many patients with rheumatoid arthritis (RA) do not respond adequately to treatment. In an exciting development, a recent phase 2 study by Tuttle and colleagues examined a novel treatment approach in RA: stimulation of the programmed cell death protein 1 (PD-1) inhibitor pathway. PD-1 is a checkpoint inhibitor receptor whose activation reflects T-cell activation and may play a role in synovitis and extra-articular inflammation. Blocking PD-1 in cancer therapy has been associated with an increase in inflammatory arthritis. In this 12-week study, RA disease activity was analyzed in patients randomly assigned to two different monthly intravenous doses of peresolimab or placebo. Of note, a large majority of participants were seropositive for rheumatoid factor (RF) or cyclic citrullinated peptide (CCP). Patients receiving the 700-mg dose of peresolimab had a better American College of Rheumatology (ACR) 20 response than did those receiving placebo (71% vs 42%), but not a better ACR50 or ACR70 response; the 300-mg dose was not better than placebo. Although reported adverse events were similar in all three groups, with a short timeframe it would be difficult to address concerns about cancer risk. Though this novel treatment is exciting, a larger and longer-term trial is necessary to address this concern as well as potentially tease out risk factors (including age or other immunosuppression) in this susceptible group.

Two other studies examined use of a much older csDMARD therapy, hydroxychloroquine (HCQ), in Brazilian patients with RA. Bredemeier and colleagues looked at the effects of HCQ on adverse events as well as the persistence of bDMARD/targeted synthetic DMARD (tsDMARD) therapy in over 1300 patients with RA. Using the BiobadaBrasil registry of patients starting their first bDMARD or Janus kinase (JAK) inhibitor, they looked at effects of combination therapy with HCQ during the treatment course of up to six bDMARD or JAK inhibitors. At baseline, patients prescribed antimalarial therapy had shorter RA duration and began treatment earlier, perhaps due to patient or physician preferences regarding starting "milder" antimalarial medication earlier or due to use of "triple therapy" with methotrexate and sulfasalazine. Of interest, patients receiving antimalarial therapy had a lower incidence of adverse events, especially serious infections, but no effect on cardiovascular events was seen despite HCQ's perceived beneficial effects on thrombotic risk and cholesterol profile. Patients receiving HCQ were also more likely to persist in their course of bDMARD or JAK inhibitor therapy, though the effect size seems relatively small. As the focus in this study was on adverse effects, the authors' analysis of the effects on antimalarials on the persistence of therapy was not detailed.

Lin and colleagues also looked at the effects of HCQ in patients with older-onset RA with respect to mortality risk. Using data from the electronic health records of a hospital in Taiwan, mortality-associated risk factors were evaluated in 980 patients with RA diagnosed at >60 years. Male sex, current smoking status, and cancer status were all associated with mortality, whereas HCQ use was associated with reduced mortality (hazard ratio 0.30). In contrast to the registry study mentioned above, patients receiving HCQ had a lower risk for cardiovascular events, hyperlipidemia, diabetes, and chronic kidney disease. Interaction with cancer was less clear due to lower number of patients. Of interest, use of cyclosporine, leflunomide, and a bDMARD was associated with higher mortality risk. The source and true relevance of the potential risk reduction in this study is not clear because of the lack of prospective data, but combined with the information above, this study suggests that the benefits of HCQ use should not be discounted in patients with RA.

Despite multiple existing conventional synthetic disease-modifying antirheumatic drug (csDMARD) and biologic DMARD (bDMARD) options, many patients with rheumatoid arthritis (RA) do not respond adequately to treatment. In an exciting development, a recent phase 2 study by Tuttle and colleagues examined a novel treatment approach in RA: stimulation of the programmed cell death protein 1 (PD-1) inhibitor pathway. PD-1 is a checkpoint inhibitor receptor whose activation reflects T-cell activation and may play a role in synovitis and extra-articular inflammation. Blocking PD-1 in cancer therapy has been associated with an increase in inflammatory arthritis. In this 12-week study, RA disease activity was analyzed in patients randomly assigned to two different monthly intravenous doses of peresolimab or placebo. Of note, a large majority of participants were seropositive for rheumatoid factor (RF) or cyclic citrullinated peptide (CCP). Patients receiving the 700-mg dose of peresolimab had a better American College of Rheumatology (ACR) 20 response than did those receiving placebo (71% vs 42%), but not a better ACR50 or ACR70 response; the 300-mg dose was not better than placebo. Although reported adverse events were similar in all three groups, with a short timeframe it would be difficult to address concerns about cancer risk. Though this novel treatment is exciting, a larger and longer-term trial is necessary to address this concern as well as potentially tease out risk factors (including age or other immunosuppression) in this susceptible group.

Two other studies examined use of a much older csDMARD therapy, hydroxychloroquine (HCQ), in Brazilian patients with RA. Bredemeier and colleagues looked at the effects of HCQ on adverse events as well as the persistence of bDMARD/targeted synthetic DMARD (tsDMARD) therapy in over 1300 patients with RA. Using the BiobadaBrasil registry of patients starting their first bDMARD or Janus kinase (JAK) inhibitor, they looked at effects of combination therapy with HCQ during the treatment course of up to six bDMARD or JAK inhibitors. At baseline, patients prescribed antimalarial therapy had shorter RA duration and began treatment earlier, perhaps due to patient or physician preferences regarding starting "milder" antimalarial medication earlier or due to use of "triple therapy" with methotrexate and sulfasalazine. Of interest, patients receiving antimalarial therapy had a lower incidence of adverse events, especially serious infections, but no effect on cardiovascular events was seen despite HCQ's perceived beneficial effects on thrombotic risk and cholesterol profile. Patients receiving HCQ were also more likely to persist in their course of bDMARD or JAK inhibitor therapy, though the effect size seems relatively small. As the focus in this study was on adverse effects, the authors' analysis of the effects on antimalarials on the persistence of therapy was not detailed.

Lin and colleagues also looked at the effects of HCQ in patients with older-onset RA with respect to mortality risk. Using data from the electronic health records of a hospital in Taiwan, mortality-associated risk factors were evaluated in 980 patients with RA diagnosed at >60 years. Male sex, current smoking status, and cancer status were all associated with mortality, whereas HCQ use was associated with reduced mortality (hazard ratio 0.30). In contrast to the registry study mentioned above, patients receiving HCQ had a lower risk for cardiovascular events, hyperlipidemia, diabetes, and chronic kidney disease. Interaction with cancer was less clear due to lower number of patients. Of interest, use of cyclosporine, leflunomide, and a bDMARD was associated with higher mortality risk. The source and true relevance of the potential risk reduction in this study is not clear because of the lack of prospective data, but combined with the information above, this study suggests that the benefits of HCQ use should not be discounted in patients with RA.

Despite multiple existing conventional synthetic disease-modifying antirheumatic drug (csDMARD) and biologic DMARD (bDMARD) options, many patients with rheumatoid arthritis (RA) do not respond adequately to treatment. In an exciting development, a recent phase 2 study by Tuttle and colleagues examined a novel treatment approach in RA: stimulation of the programmed cell death protein 1 (PD-1) inhibitor pathway. PD-1 is a checkpoint inhibitor receptor whose activation reflects T-cell activation and may play a role in synovitis and extra-articular inflammation. Blocking PD-1 in cancer therapy has been associated with an increase in inflammatory arthritis. In this 12-week study, RA disease activity was analyzed in patients randomly assigned to two different monthly intravenous doses of peresolimab or placebo. Of note, a large majority of participants were seropositive for rheumatoid factor (RF) or cyclic citrullinated peptide (CCP). Patients receiving the 700-mg dose of peresolimab had a better American College of Rheumatology (ACR) 20 response than did those receiving placebo (71% vs 42%), but not a better ACR50 or ACR70 response; the 300-mg dose was not better than placebo. Although reported adverse events were similar in all three groups, with a short timeframe it would be difficult to address concerns about cancer risk. Though this novel treatment is exciting, a larger and longer-term trial is necessary to address this concern as well as potentially tease out risk factors (including age or other immunosuppression) in this susceptible group.

Two other studies examined use of a much older csDMARD therapy, hydroxychloroquine (HCQ), in Brazilian patients with RA. Bredemeier and colleagues looked at the effects of HCQ on adverse events as well as the persistence of bDMARD/targeted synthetic DMARD (tsDMARD) therapy in over 1300 patients with RA. Using the BiobadaBrasil registry of patients starting their first bDMARD or Janus kinase (JAK) inhibitor, they looked at effects of combination therapy with HCQ during the treatment course of up to six bDMARD or JAK inhibitors. At baseline, patients prescribed antimalarial therapy had shorter RA duration and began treatment earlier, perhaps due to patient or physician preferences regarding starting "milder" antimalarial medication earlier or due to use of "triple therapy" with methotrexate and sulfasalazine. Of interest, patients receiving antimalarial therapy had a lower incidence of adverse events, especially serious infections, but no effect on cardiovascular events was seen despite HCQ's perceived beneficial effects on thrombotic risk and cholesterol profile. Patients receiving HCQ were also more likely to persist in their course of bDMARD or JAK inhibitor therapy, though the effect size seems relatively small. As the focus in this study was on adverse effects, the authors' analysis of the effects on antimalarials on the persistence of therapy was not detailed.

Lin and colleagues also looked at the effects of HCQ in patients with older-onset RA with respect to mortality risk. Using data from the electronic health records of a hospital in Taiwan, mortality-associated risk factors were evaluated in 980 patients with RA diagnosed at >60 years. Male sex, current smoking status, and cancer status were all associated with mortality, whereas HCQ use was associated with reduced mortality (hazard ratio 0.30). In contrast to the registry study mentioned above, patients receiving HCQ had a lower risk for cardiovascular events, hyperlipidemia, diabetes, and chronic kidney disease. Interaction with cancer was less clear due to lower number of patients. Of interest, use of cyclosporine, leflunomide, and a bDMARD was associated with higher mortality risk. The source and true relevance of the potential risk reduction in this study is not clear because of the lack of prospective data, but combined with the information above, this study suggests that the benefits of HCQ use should not be discounted in patients with RA.

After a median follow-up of 21.6 mo, the dalpiciclib group demonstrated a significantly longer median progression-free survival (PFS) compared with the placebo group (30.6 mo vs 18.2 mo; stratified hazard ratio [HR] 0.51; 95% CI 0.38-0.69; P < .0001). Overall, the dalpiciclib group demonstrated a manageable safety profile, although a higher percentage of grade 3/4 adverse events was noted with dalpiciclib than with placebo (90% vs 12%), as expected. Overall survival data for this CDK4/6 inhibitor are yet to come. These results suggest that dalpiciclib in combination with endocrine therapy is an alternative treatment for this group of patients, especially in countries where the traditionally approved CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) are not available.

The optimal sequencing of endocrine therapy (ET) after progression on CDK4/6 inhibitor–based therapy remains a challenge. In the phase 2 MAINTAIN trial, 119 patients (all of whom had HR+/HER2- metastatic breast cancer and who progressed on ET and CDK4/6 inhibitors) were randomly assigned to receive a different ET (fulvestrant or exemestane) from the previous ET they had received plus either the CDK4/6 inhibitor ribociclib or placebo. In the study by Kalinksky and colleagues, at a median follow-up of 18.2 mo, a significant improvement in PFS was observed in the switched ET-plus-ribociclib group compared with the switched ET-plus-placebo group (HR 0.57; P = .006). The phase 2 MAINTAIN trial is the first randomized trial to show the benefit of a CDK4/6 inhibitor after progression on another CDK4/6 inhibitor. It is important to note that the majority of patients in the MAINTAIN study previously received palbociclib in the first-line setting, which in recent studies has been demonstrated to be inferior to other CDK4/6 inhibitors. Therefore, it is important to confirm whether this will hold true upon progression from ribociclib or abemaciclib in the first-line setting. In addition, more data are needed to compare this approach with other ET treatment options, such as phosphoinositide 3-kinases inhibitors and oral selective estrogen receptor degraders.

There are several options for adjuvant radiation therapy for early-stage breast cancer. A meta-analysis of 14 randomized controlled trials and six comparative observational studies assessed the efficacy of whole breast irradiation (WBI) compared with partial breast irradiation (PBI) in 17,234 adults with early-stage breast cancer. Results of this meta-analysis showed that PBI was not significantly different from WBI, with similar rates of ipsilateral breast recurrence  at 5 years (relative risk [RR] 1.34; 95% CI 0.83-2.18) and 10 years (RR 1.29; 95% CI 0.87-1.91), although patients undergoing PBI reported fewer acute adverse events  compared with patients undergoing WBI (incidence rate ratio [IRR] 0.53; 95% CI 0.31-0.92) and acute grade ≥2 adverse events (IRR 0.21; 95% CI 0.07-0.62). These findings support using PBI as the adjuvant radiotherapy modality for select patients with favorable-risk early-stage breast cancer.

Another meta-analysis looked at assessing the survival benefit of adding CDK4/6 inhibitors to standard ET in older patients with advanced breast cancer. The study included 10 trials with 1985 older patients with advanced ER+ breast cancer who received ET with or without CDK4/6 inhibitors. The findings showed that adding CDK4/6 inhibitors to ET (letrozole or fulvestrant) significantly reduced the mortality risk by 21% (HR 0.79; 95% CI 0.69-0.91) and progression risk by 41% (HR 0.59; 95% CI 0.51-0.69) in older patients (age ≥ 65 years) with advanced breast cancer. Grade 3-4 neutropenia and diarrhea were similar in older patients. This study supports the use of CDK4/6 inhibitors as a reasonable treatment modality for older patients. More studies dedicated to the geriatric population are needed to help elaborate on the efficacy and tolerability of such agents in this population.

The phase 3 National Surgical Adjuvant Breast and Bowel Project B-42 (NSABP B-42) trial evaluated the role of extended letrozole therapy in postmenopausal breast cancer patients who were disease-free after 5 years of aromatase inhibitor–based therapy. The study included 3966 postmenopausal women with stage I-IIIA HR+ breast cancer who were randomly assigned to receive letrozole or placebo for 5 more years. After a median follow-up of 10.3 years, letrozole significantly improved disease-free survival (10-year absolute benefit 3.4%; HR 0.85; P = .01) compared with placebo, although there were no differences noted in overall survival between the groups (HR 0.97, P = .74). Furthermore, letrozole significantly reduced the breast cancer–free interval (HR 0.75, ,P = .003) and distant recurrence (HR 0.72, P = .01). There were no notable differences in toxicity, particularly rates of osteoporotic fractures and arterial thrombotic events, between the groups. Extended therapy with aromatase inhibitors beyond 5 years can be considered for select patients with early-stage breast cancer. Careful consideration of risks and benefits is needed to make these recommendations. 

After a median follow-up of 21.6 mo, the dalpiciclib group demonstrated a significantly longer median progression-free survival (PFS) compared with the placebo group (30.6 mo vs 18.2 mo; stratified hazard ratio [HR] 0.51; 95% CI 0.38-0.69; P < .0001). Overall, the dalpiciclib group demonstrated a manageable safety profile, although a higher percentage of grade 3/4 adverse events was noted with dalpiciclib than with placebo (90% vs 12%), as expected. Overall survival data for this CDK4/6 inhibitor are yet to come. These results suggest that dalpiciclib in combination with endocrine therapy is an alternative treatment for this group of patients, especially in countries where the traditionally approved CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) are not available.

The optimal sequencing of endocrine therapy (ET) after progression on CDK4/6 inhibitor–based therapy remains a challenge. In the phase 2 MAINTAIN trial, 119 patients (all of whom had HR+/HER2- metastatic breast cancer and who progressed on ET and CDK4/6 inhibitors) were randomly assigned to receive a different ET (fulvestrant or exemestane) from the previous ET they had received plus either the CDK4/6 inhibitor ribociclib or placebo. In the study by Kalinksky and colleagues, at a median follow-up of 18.2 mo, a significant improvement in PFS was observed in the switched ET-plus-ribociclib group compared with the switched ET-plus-placebo group (HR 0.57; P = .006). The phase 2 MAINTAIN trial is the first randomized trial to show the benefit of a CDK4/6 inhibitor after progression on another CDK4/6 inhibitor. It is important to note that the majority of patients in the MAINTAIN study previously received palbociclib in the first-line setting, which in recent studies has been demonstrated to be inferior to other CDK4/6 inhibitors. Therefore, it is important to confirm whether this will hold true upon progression from ribociclib or abemaciclib in the first-line setting. In addition, more data are needed to compare this approach with other ET treatment options, such as phosphoinositide 3-kinases inhibitors and oral selective estrogen receptor degraders.

There are several options for adjuvant radiation therapy for early-stage breast cancer. A meta-analysis of 14 randomized controlled trials and six comparative observational studies assessed the efficacy of whole breast irradiation (WBI) compared with partial breast irradiation (PBI) in 17,234 adults with early-stage breast cancer. Results of this meta-analysis showed that PBI was not significantly different from WBI, with similar rates of ipsilateral breast recurrence  at 5 years (relative risk [RR] 1.34; 95% CI 0.83-2.18) and 10 years (RR 1.29; 95% CI 0.87-1.91), although patients undergoing PBI reported fewer acute adverse events  compared with patients undergoing WBI (incidence rate ratio [IRR] 0.53; 95% CI 0.31-0.92) and acute grade ≥2 adverse events (IRR 0.21; 95% CI 0.07-0.62). These findings support using PBI as the adjuvant radiotherapy modality for select patients with favorable-risk early-stage breast cancer.

Another meta-analysis looked at assessing the survival benefit of adding CDK4/6 inhibitors to standard ET in older patients with advanced breast cancer. The study included 10 trials with 1985 older patients with advanced ER+ breast cancer who received ET with or without CDK4/6 inhibitors. The findings showed that adding CDK4/6 inhibitors to ET (letrozole or fulvestrant) significantly reduced the mortality risk by 21% (HR 0.79; 95% CI 0.69-0.91) and progression risk by 41% (HR 0.59; 95% CI 0.51-0.69) in older patients (age ≥ 65 years) with advanced breast cancer. Grade 3-4 neutropenia and diarrhea were similar in older patients. This study supports the use of CDK4/6 inhibitors as a reasonable treatment modality for older patients. More studies dedicated to the geriatric population are needed to help elaborate on the efficacy and tolerability of such agents in this population.

The phase 3 National Surgical Adjuvant Breast and Bowel Project B-42 (NSABP B-42) trial evaluated the role of extended letrozole therapy in postmenopausal breast cancer patients who were disease-free after 5 years of aromatase inhibitor–based therapy. The study included 3966 postmenopausal women with stage I-IIIA HR+ breast cancer who were randomly assigned to receive letrozole or placebo for 5 more years. After a median follow-up of 10.3 years, letrozole significantly improved disease-free survival (10-year absolute benefit 3.4%; HR 0.85; P = .01) compared with placebo, although there were no differences noted in overall survival between the groups (HR 0.97, P = .74). Furthermore, letrozole significantly reduced the breast cancer–free interval (HR 0.75, ,P = .003) and distant recurrence (HR 0.72, P = .01). There were no notable differences in toxicity, particularly rates of osteoporotic fractures and arterial thrombotic events, between the groups. Extended therapy with aromatase inhibitors beyond 5 years can be considered for select patients with early-stage breast cancer. Careful consideration of risks and benefits is needed to make these recommendations. 

After a median follow-up of 21.6 mo, the dalpiciclib group demonstrated a significantly longer median progression-free survival (PFS) compared with the placebo group (30.6 mo vs 18.2 mo; stratified hazard ratio [HR] 0.51; 95% CI 0.38-0.69; P < .0001). Overall, the dalpiciclib group demonstrated a manageable safety profile, although a higher percentage of grade 3/4 adverse events was noted with dalpiciclib than with placebo (90% vs 12%), as expected. Overall survival data for this CDK4/6 inhibitor are yet to come. These results suggest that dalpiciclib in combination with endocrine therapy is an alternative treatment for this group of patients, especially in countries where the traditionally approved CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) are not available.

The optimal sequencing of endocrine therapy (ET) after progression on CDK4/6 inhibitor–based therapy remains a challenge. In the phase 2 MAINTAIN trial, 119 patients (all of whom had HR+/HER2- metastatic breast cancer and who progressed on ET and CDK4/6 inhibitors) were randomly assigned to receive a different ET (fulvestrant or exemestane) from the previous ET they had received plus either the CDK4/6 inhibitor ribociclib or placebo. In the study by Kalinksky and colleagues, at a median follow-up of 18.2 mo, a significant improvement in PFS was observed in the switched ET-plus-ribociclib group compared with the switched ET-plus-placebo group (HR 0.57; P = .006). The phase 2 MAINTAIN trial is the first randomized trial to show the benefit of a CDK4/6 inhibitor after progression on another CDK4/6 inhibitor. It is important to note that the majority of patients in the MAINTAIN study previously received palbociclib in the first-line setting, which in recent studies has been demonstrated to be inferior to other CDK4/6 inhibitors. Therefore, it is important to confirm whether this will hold true upon progression from ribociclib or abemaciclib in the first-line setting. In addition, more data are needed to compare this approach with other ET treatment options, such as phosphoinositide 3-kinases inhibitors and oral selective estrogen receptor degraders.

There are several options for adjuvant radiation therapy for early-stage breast cancer. A meta-analysis of 14 randomized controlled trials and six comparative observational studies assessed the efficacy of whole breast irradiation (WBI) compared with partial breast irradiation (PBI) in 17,234 adults with early-stage breast cancer. Results of this meta-analysis showed that PBI was not significantly different from WBI, with similar rates of ipsilateral breast recurrence  at 5 years (relative risk [RR] 1.34; 95% CI 0.83-2.18) and 10 years (RR 1.29; 95% CI 0.87-1.91), although patients undergoing PBI reported fewer acute adverse events  compared with patients undergoing WBI (incidence rate ratio [IRR] 0.53; 95% CI 0.31-0.92) and acute grade ≥2 adverse events (IRR 0.21; 95% CI 0.07-0.62). These findings support using PBI as the adjuvant radiotherapy modality for select patients with favorable-risk early-stage breast cancer.

Another meta-analysis looked at assessing the survival benefit of adding CDK4/6 inhibitors to standard ET in older patients with advanced breast cancer. The study included 10 trials with 1985 older patients with advanced ER+ breast cancer who received ET with or without CDK4/6 inhibitors. The findings showed that adding CDK4/6 inhibitors to ET (letrozole or fulvestrant) significantly reduced the mortality risk by 21% (HR 0.79; 95% CI 0.69-0.91) and progression risk by 41% (HR 0.59; 95% CI 0.51-0.69) in older patients (age ≥ 65 years) with advanced breast cancer. Grade 3-4 neutropenia and diarrhea were similar in older patients. This study supports the use of CDK4/6 inhibitors as a reasonable treatment modality for older patients. More studies dedicated to the geriatric population are needed to help elaborate on the efficacy and tolerability of such agents in this population.

The phase 3 National Surgical Adjuvant Breast and Bowel Project B-42 (NSABP B-42) trial evaluated the role of extended letrozole therapy in postmenopausal breast cancer patients who were disease-free after 5 years of aromatase inhibitor–based therapy. The study included 3966 postmenopausal women with stage I-IIIA HR+ breast cancer who were randomly assigned to receive letrozole or placebo for 5 more years. After a median follow-up of 10.3 years, letrozole significantly improved disease-free survival (10-year absolute benefit 3.4%; HR 0.85; P = .01) compared with placebo, although there were no differences noted in overall survival between the groups (HR 0.97, P = .74). Furthermore, letrozole significantly reduced the breast cancer–free interval (HR 0.75, ,P = .003) and distant recurrence (HR 0.72, P = .01). There were no notable differences in toxicity, particularly rates of osteoporotic fractures and arterial thrombotic events, between the groups. Extended therapy with aromatase inhibitors beyond 5 years can be considered for select patients with early-stage breast cancer. Careful consideration of risks and benefits is needed to make these recommendations.