Clinical Edge Journal Scan Commentary

Metastatic triple-negative breast cancer (TNBC) is a heterogeneous, biologically complex subtype, with continuing efforts to identify therapeutic targets. The PI3K/AKT signaling pathway plays a key role in cell proliferation, survival, invasion, and metabolism. In the phase II LOTUS trial (Dent et al) including 124 patients with advanced TNBC (no prior therapy for advanced disease), addition of the oral AKT inhibitor, ipatasertib, to paclitaxel led to a numerical improvement in OS that was not statistically significant. The median OS was 25.8 vs 16.9 months for the ipatasertib-paclitaxel vs placebo-paclitaxel, respectively (HR 0.80, 95% CI 0.50-1.28). Findings from cohort A of the phase III IPATunity130 trial showed that ipatasertib-paclitaxel did not lead to a statistically significant improvement in PFS vs placebo-paclitaxel in patients with PIK3CA/AKT1/PTEN-altered advanced TNBC in the first-line metastatic setting (mPFS 7.4 vs 6.1 months, respectively; HR 1.02, p=0.9237). These findings support further investigation into predictors of response and other molecular markers that may play a role in the diversity of mTNBC. 

Endocrine therapy resistance remains a significant challenge in advanced HR+/HER2- breast cancer, and initial studies with the oral histone deacetylase inhibitor, etinostat, showed promise in this space. Unfortunately, these findings were not upheld in the phase III E2112 trial (Connolly et al), which failed to show an improvement in PFS or OS with exemestane-etinostat (EE) compared to exemestane-placebo (EP) among patients who had progressed on prior non-steroidal AI. Median PFS was 3.3 vs 3.1 months (HR 0.87; p=0.30) and median OS was 23.4 vs 21.7 months (HR 0.99; p=0.94) for the EE vs EP arms, respectively. The combination of an alternative HDAC inhibitor, tucidinostat, has been approved in China in combination with exemestane based on PFS benefit (3.6 months) in the phase III ACE trial. There are notable difference between E2112 and ACE trials, including patient population and design, and importantly OS has not been reported for the latter. The relatively short mPFS and low response rate (5-6%) in E2112 argues for more efficacious therapeutics. There is also value in correlative studies to help further elucidate if there is a role for HDAC inhibitors in this space.

Although adjuvant endocrine therapy has had a significantly beneficial effect on outcomes in early-stage HR+ breast cancer, late recurrences are characteristic of the luminal subtype, and have led to trials investigating extended adjuvant endocrine therapy. The phase III SALSA trial included 3484 women with early HR+ breast cancer who had received 5 years of adjuvant endocrine therapy with randomization to anastrozole for an additional 2 vs 5 years (comparing total of 7 vs 10 years). There was no significant difference in disease-free survival (DFS) at 8 years (73.6% vs 73.9% in the 2 vs 5-year groups, respectively; HR 0.99, p=0.90). Additionally, there was a lower risk of bone fracture in the 2 vs 5-year group (4.7% vs 6.3%; HR 1.35). It is essential to balance modest benefits with toxicities of prolonged AI use, and valuable to identify high-risk patients who may benefit from extended adjuvant endocrine therapy.

References:

Chan A, Moy B, Mansi J, et al; ExteNET Study Group. Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer from the phase III ExteNET trial. Clin Breast Cancer. 2021;21(1):80-91.e7.

von Minckwitz G, Huang CS, Mano MS, et al; KATHERINE Investigators. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628.

Dent R, Kim SB, Oliveira M, et al. Double-blind placebo-controlled randomized phase III trial evaluating first-line ipatasertib combined with paclitaxel for PIK3CA/AKT1/PTEN-altered locally advanced unresectable or metastatic triple-negative breast cancer: primary results from IPATunity130 cohort A. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Oral GS3-04.

Jiang Z, Li W, Hu X, et al. Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(6):806-815.

Mamounas EP, Bandos H, Lembersky BC, et al. Use of letrozole after aromatase inhibitor-based therapy in postmenopausal breast cancer (NRG Oncology/NSABP B-42): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(1):88-99.

Metastatic triple-negative breast cancer (TNBC) is a heterogeneous, biologically complex subtype, with continuing efforts to identify therapeutic targets. The PI3K/AKT signaling pathway plays a key role in cell proliferation, survival, invasion, and metabolism. In the phase II LOTUS trial (Dent et al) including 124 patients with advanced TNBC (no prior therapy for advanced disease), addition of the oral AKT inhibitor, ipatasertib, to paclitaxel led to a numerical improvement in OS that was not statistically significant. The median OS was 25.8 vs 16.9 months for the ipatasertib-paclitaxel vs placebo-paclitaxel, respectively (HR 0.80, 95% CI 0.50-1.28). Findings from cohort A of the phase III IPATunity130 trial showed that ipatasertib-paclitaxel did not lead to a statistically significant improvement in PFS vs placebo-paclitaxel in patients with PIK3CA/AKT1/PTEN-altered advanced TNBC in the first-line metastatic setting (mPFS 7.4 vs 6.1 months, respectively; HR 1.02, p=0.9237). These findings support further investigation into predictors of response and other molecular markers that may play a role in the diversity of mTNBC. 

Endocrine therapy resistance remains a significant challenge in advanced HR+/HER2- breast cancer, and initial studies with the oral histone deacetylase inhibitor, etinostat, showed promise in this space. Unfortunately, these findings were not upheld in the phase III E2112 trial (Connolly et al), which failed to show an improvement in PFS or OS with exemestane-etinostat (EE) compared to exemestane-placebo (EP) among patients who had progressed on prior non-steroidal AI. Median PFS was 3.3 vs 3.1 months (HR 0.87; p=0.30) and median OS was 23.4 vs 21.7 months (HR 0.99; p=0.94) for the EE vs EP arms, respectively. The combination of an alternative HDAC inhibitor, tucidinostat, has been approved in China in combination with exemestane based on PFS benefit (3.6 months) in the phase III ACE trial. There are notable difference between E2112 and ACE trials, including patient population and design, and importantly OS has not been reported for the latter. The relatively short mPFS and low response rate (5-6%) in E2112 argues for more efficacious therapeutics. There is also value in correlative studies to help further elucidate if there is a role for HDAC inhibitors in this space.

Although adjuvant endocrine therapy has had a significantly beneficial effect on outcomes in early-stage HR+ breast cancer, late recurrences are characteristic of the luminal subtype, and have led to trials investigating extended adjuvant endocrine therapy. The phase III SALSA trial included 3484 women with early HR+ breast cancer who had received 5 years of adjuvant endocrine therapy with randomization to anastrozole for an additional 2 vs 5 years (comparing total of 7 vs 10 years). There was no significant difference in disease-free survival (DFS) at 8 years (73.6% vs 73.9% in the 2 vs 5-year groups, respectively; HR 0.99, p=0.90). Additionally, there was a lower risk of bone fracture in the 2 vs 5-year group (4.7% vs 6.3%; HR 1.35). It is essential to balance modest benefits with toxicities of prolonged AI use, and valuable to identify high-risk patients who may benefit from extended adjuvant endocrine therapy.

References:

Chan A, Moy B, Mansi J, et al; ExteNET Study Group. Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer from the phase III ExteNET trial. Clin Breast Cancer. 2021;21(1):80-91.e7.

von Minckwitz G, Huang CS, Mano MS, et al; KATHERINE Investigators. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628.

Dent R, Kim SB, Oliveira M, et al. Double-blind placebo-controlled randomized phase III trial evaluating first-line ipatasertib combined with paclitaxel for PIK3CA/AKT1/PTEN-altered locally advanced unresectable or metastatic triple-negative breast cancer: primary results from IPATunity130 cohort A. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Oral GS3-04.

Jiang Z, Li W, Hu X, et al. Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(6):806-815.

Mamounas EP, Bandos H, Lembersky BC, et al. Use of letrozole after aromatase inhibitor-based therapy in postmenopausal breast cancer (NRG Oncology/NSABP B-42): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(1):88-99.

Metastatic triple-negative breast cancer (TNBC) is a heterogeneous, biologically complex subtype, with continuing efforts to identify therapeutic targets. The PI3K/AKT signaling pathway plays a key role in cell proliferation, survival, invasion, and metabolism. In the phase II LOTUS trial (Dent et al) including 124 patients with advanced TNBC (no prior therapy for advanced disease), addition of the oral AKT inhibitor, ipatasertib, to paclitaxel led to a numerical improvement in OS that was not statistically significant. The median OS was 25.8 vs 16.9 months for the ipatasertib-paclitaxel vs placebo-paclitaxel, respectively (HR 0.80, 95% CI 0.50-1.28). Findings from cohort A of the phase III IPATunity130 trial showed that ipatasertib-paclitaxel did not lead to a statistically significant improvement in PFS vs placebo-paclitaxel in patients with PIK3CA/AKT1/PTEN-altered advanced TNBC in the first-line metastatic setting (mPFS 7.4 vs 6.1 months, respectively; HR 1.02, p=0.9237). These findings support further investigation into predictors of response and other molecular markers that may play a role in the diversity of mTNBC. 

Endocrine therapy resistance remains a significant challenge in advanced HR+/HER2- breast cancer, and initial studies with the oral histone deacetylase inhibitor, etinostat, showed promise in this space. Unfortunately, these findings were not upheld in the phase III E2112 trial (Connolly et al), which failed to show an improvement in PFS or OS with exemestane-etinostat (EE) compared to exemestane-placebo (EP) among patients who had progressed on prior non-steroidal AI. Median PFS was 3.3 vs 3.1 months (HR 0.87; p=0.30) and median OS was 23.4 vs 21.7 months (HR 0.99; p=0.94) for the EE vs EP arms, respectively. The combination of an alternative HDAC inhibitor, tucidinostat, has been approved in China in combination with exemestane based on PFS benefit (3.6 months) in the phase III ACE trial. There are notable difference between E2112 and ACE trials, including patient population and design, and importantly OS has not been reported for the latter. The relatively short mPFS and low response rate (5-6%) in E2112 argues for more efficacious therapeutics. There is also value in correlative studies to help further elucidate if there is a role for HDAC inhibitors in this space.

Although adjuvant endocrine therapy has had a significantly beneficial effect on outcomes in early-stage HR+ breast cancer, late recurrences are characteristic of the luminal subtype, and have led to trials investigating extended adjuvant endocrine therapy. The phase III SALSA trial included 3484 women with early HR+ breast cancer who had received 5 years of adjuvant endocrine therapy with randomization to anastrozole for an additional 2 vs 5 years (comparing total of 7 vs 10 years). There was no significant difference in disease-free survival (DFS) at 8 years (73.6% vs 73.9% in the 2 vs 5-year groups, respectively; HR 0.99, p=0.90). Additionally, there was a lower risk of bone fracture in the 2 vs 5-year group (4.7% vs 6.3%; HR 1.35). It is essential to balance modest benefits with toxicities of prolonged AI use, and valuable to identify high-risk patients who may benefit from extended adjuvant endocrine therapy.

References:

Chan A, Moy B, Mansi J, et al; ExteNET Study Group. Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer from the phase III ExteNET trial. Clin Breast Cancer. 2021;21(1):80-91.e7.

von Minckwitz G, Huang CS, Mano MS, et al; KATHERINE Investigators. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628.

Dent R, Kim SB, Oliveira M, et al. Double-blind placebo-controlled randomized phase III trial evaluating first-line ipatasertib combined with paclitaxel for PIK3CA/AKT1/PTEN-altered locally advanced unresectable or metastatic triple-negative breast cancer: primary results from IPATunity130 cohort A. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Oral GS3-04.

Jiang Z, Li W, Hu X, et al. Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(6):806-815.

Mamounas EP, Bandos H, Lembersky BC, et al. Use of letrozole after aromatase inhibitor-based therapy in postmenopausal breast cancer (NRG Oncology/NSABP B-42): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(1):88-99.

Several recent studies have evaluated that association between psoriasis and known comorbidities including cardiovascular disease, non-alcoholic fatty liver disease (NAFLD), and malignancy. Several recent studies have added to our understanding of the relationship between these conditions.

Using the largest database of hospitalized patients in the United States, Edgen et al found that hospitalization rates for patients with psoriasis are increasing. While the proportion of patients with psoriasis hospitalized with psoriasis as a primary diagnosis decreased about four-fold over a 20-year period (1999-2018), incidence of hospitalizations with any diagnosis of psoriasis has increased. Hospitalized psoriasis patients are increasingly more likely to have other comorbid conditions as during the study period the proportion of hospitalized psoriasis patients with a Charlson Comorbidity Index score of 3 or higher increased from 13.9% to 30.9%. Psoriasis severity, medication use, and reasons for hospitalization were not reported. The authors suggest that screening and management of comorbidities in the outpatient setting may help reduce preventable psoriasis hospitalizations.

Both NAFLD and cardiovascular disease are well-known psoriasis comorbidities, Gonzalez-Cantaro et al studied two cohorts of patients to better define the relationship between these two conditions. In a European cohort of 76 psoriasis patients and 76 control patients, psoriasis patients with NAFLD had a higher prevalence of subclinical atherosclerosis than both psoriasis patients without NAFLD (61% vs 23%) and age, sex, and BMI-matched controls with NAFLD (61% vs 32%). Psoriasis patients were also more likely that control patients to have insulin resistance, higher weight circumference, and dysplipidemia. Among 162 psoriasis patients who underwent PET and coronary CT angiography, higher hepatic FDG uptake (indicating NAFLD) was associated higher atherosclerotic disease burden. Importantly, both the NAFLD and CAD were subclinical in these patients. While the cross-sectional study design precludes any conclusions about causality, physicians should be aware that these two comorbidities are related. Lower waist circumference and greater physical activity were both associated with lower rates of NAFLD among patients with psoriasis, providing some guidance for counseling patients.

Several recent studies have found that cancer rates among patients with psoriasis are higher than what is observed in the general population. The association of psoriasis with lymphohematologic malignancies (LHM) has been controversial. A systematic review and meta-analysis of 25 observational studies including over 2.5 million subjects (Bellinato et al.) found a 1.55-fold increased risk of LHM in patients with moderate to severe psoriasis. Strikingly, the risk of cutaneous T cell lymphoma (CTCL) was increased 6.22-fold, with more severe psoriasis being associated with the highest risk of CTCL. A causal relationship cannot be established from this type of studies, but the authors hypothesize that drugs used to treat psoriasis or the chronic T cell activation caused by active disease may contribute to the risk of LMH. Additionally, psoriasis and CTCL can share clinical features and some cases may be due to misdiagnosis. Interestingly, two psoriasis comorbities, diabetes and obesity, are also associated with an increased risk of LHM.

Early identification and management of comorbidities can help in reducing morbidity and mortality. With so many psoriasis treatments available, understanding how different therapies may impact comorbid conditions is important in helping dermatologists to choose the best therapy for each individual patient.

Several recent studies have evaluated that association between psoriasis and known comorbidities including cardiovascular disease, non-alcoholic fatty liver disease (NAFLD), and malignancy. Several recent studies have added to our understanding of the relationship between these conditions.

Using the largest database of hospitalized patients in the United States, Edgen et al found that hospitalization rates for patients with psoriasis are increasing. While the proportion of patients with psoriasis hospitalized with psoriasis as a primary diagnosis decreased about four-fold over a 20-year period (1999-2018), incidence of hospitalizations with any diagnosis of psoriasis has increased. Hospitalized psoriasis patients are increasingly more likely to have other comorbid conditions as during the study period the proportion of hospitalized psoriasis patients with a Charlson Comorbidity Index score of 3 or higher increased from 13.9% to 30.9%. Psoriasis severity, medication use, and reasons for hospitalization were not reported. The authors suggest that screening and management of comorbidities in the outpatient setting may help reduce preventable psoriasis hospitalizations.

Both NAFLD and cardiovascular disease are well-known psoriasis comorbidities, Gonzalez-Cantaro et al studied two cohorts of patients to better define the relationship between these two conditions. In a European cohort of 76 psoriasis patients and 76 control patients, psoriasis patients with NAFLD had a higher prevalence of subclinical atherosclerosis than both psoriasis patients without NAFLD (61% vs 23%) and age, sex, and BMI-matched controls with NAFLD (61% vs 32%). Psoriasis patients were also more likely that control patients to have insulin resistance, higher weight circumference, and dysplipidemia. Among 162 psoriasis patients who underwent PET and coronary CT angiography, higher hepatic FDG uptake (indicating NAFLD) was associated higher atherosclerotic disease burden. Importantly, both the NAFLD and CAD were subclinical in these patients. While the cross-sectional study design precludes any conclusions about causality, physicians should be aware that these two comorbidities are related. Lower waist circumference and greater physical activity were both associated with lower rates of NAFLD among patients with psoriasis, providing some guidance for counseling patients.

Several recent studies have found that cancer rates among patients with psoriasis are higher than what is observed in the general population. The association of psoriasis with lymphohematologic malignancies (LHM) has been controversial. A systematic review and meta-analysis of 25 observational studies including over 2.5 million subjects (Bellinato et al.) found a 1.55-fold increased risk of LHM in patients with moderate to severe psoriasis. Strikingly, the risk of cutaneous T cell lymphoma (CTCL) was increased 6.22-fold, with more severe psoriasis being associated with the highest risk of CTCL. A causal relationship cannot be established from this type of studies, but the authors hypothesize that drugs used to treat psoriasis or the chronic T cell activation caused by active disease may contribute to the risk of LMH. Additionally, psoriasis and CTCL can share clinical features and some cases may be due to misdiagnosis. Interestingly, two psoriasis comorbities, diabetes and obesity, are also associated with an increased risk of LHM.

Early identification and management of comorbidities can help in reducing morbidity and mortality. With so many psoriasis treatments available, understanding how different therapies may impact comorbid conditions is important in helping dermatologists to choose the best therapy for each individual patient.

Several recent studies have evaluated that association between psoriasis and known comorbidities including cardiovascular disease, non-alcoholic fatty liver disease (NAFLD), and malignancy. Several recent studies have added to our understanding of the relationship between these conditions.

Using the largest database of hospitalized patients in the United States, Edgen et al found that hospitalization rates for patients with psoriasis are increasing. While the proportion of patients with psoriasis hospitalized with psoriasis as a primary diagnosis decreased about four-fold over a 20-year period (1999-2018), incidence of hospitalizations with any diagnosis of psoriasis has increased. Hospitalized psoriasis patients are increasingly more likely to have other comorbid conditions as during the study period the proportion of hospitalized psoriasis patients with a Charlson Comorbidity Index score of 3 or higher increased from 13.9% to 30.9%. Psoriasis severity, medication use, and reasons for hospitalization were not reported. The authors suggest that screening and management of comorbidities in the outpatient setting may help reduce preventable psoriasis hospitalizations.

Both NAFLD and cardiovascular disease are well-known psoriasis comorbidities, Gonzalez-Cantaro et al studied two cohorts of patients to better define the relationship between these two conditions. In a European cohort of 76 psoriasis patients and 76 control patients, psoriasis patients with NAFLD had a higher prevalence of subclinical atherosclerosis than both psoriasis patients without NAFLD (61% vs 23%) and age, sex, and BMI-matched controls with NAFLD (61% vs 32%). Psoriasis patients were also more likely that control patients to have insulin resistance, higher weight circumference, and dysplipidemia. Among 162 psoriasis patients who underwent PET and coronary CT angiography, higher hepatic FDG uptake (indicating NAFLD) was associated higher atherosclerotic disease burden. Importantly, both the NAFLD and CAD were subclinical in these patients. While the cross-sectional study design precludes any conclusions about causality, physicians should be aware that these two comorbidities are related. Lower waist circumference and greater physical activity were both associated with lower rates of NAFLD among patients with psoriasis, providing some guidance for counseling patients.

Several recent studies have found that cancer rates among patients with psoriasis are higher than what is observed in the general population. The association of psoriasis with lymphohematologic malignancies (LHM) has been controversial. A systematic review and meta-analysis of 25 observational studies including over 2.5 million subjects (Bellinato et al.) found a 1.55-fold increased risk of LHM in patients with moderate to severe psoriasis. Strikingly, the risk of cutaneous T cell lymphoma (CTCL) was increased 6.22-fold, with more severe psoriasis being associated with the highest risk of CTCL. A causal relationship cannot be established from this type of studies, but the authors hypothesize that drugs used to treat psoriasis or the chronic T cell activation caused by active disease may contribute to the risk of LMH. Additionally, psoriasis and CTCL can share clinical features and some cases may be due to misdiagnosis. Interestingly, two psoriasis comorbities, diabetes and obesity, are also associated with an increased risk of LHM.

Early identification and management of comorbidities can help in reducing morbidity and mortality. With so many psoriasis treatments available, understanding how different therapies may impact comorbid conditions is important in helping dermatologists to choose the best therapy for each individual patient.

Herpes zoster infection is another well-known complication of RA and its treatment, including glucocorticoid therapy. An increased incidence has recently been noted in people who use JAK inhibitors, though other bDMARDs including TNF inhibitors are also known to increase risk. Redeker et al. compare the incidence of herpes zoster in people with RA using csDMARDs, bDMARDs, and tsDMARDs using a German prospective RA registry. In nearly 14,000 patients, 559 cases of herpes zoster were documented; after adjusting for age, sex, and glucocorticoid use, an increased risk was noted for treatment with monoclonal anti-TNF therapy, B-cell directed therapy, and JAK inhibitors compared to csDMARDs, whereas soluble TNF receptor fusion protein, T cell costimulation modulators and IL-6 inhibitors were not associated with a higher risk of herpes zoster compared with csDMARDs. Unfortunately, zoster vaccination status was not extracted for all patients. The study confirms what we already know with direct risk comparison between different agents and underscores the importance of vaccination in RA patients, especially those being treated with glucocorticoids and tsDMARDs.

Finally, another important consideration in the use of bDMARDs is the increase in cancer risk due to a potential reduction in immunosurveillance. Initial meta-analyses of clinical trials of anti-TNF agents highlighted an early increase in cancer risk, though later studies including meta-analyses and registry studies with longer follow-up durations have been equivocal. Huss et al. examine a Swedish registry of people with RA and no prior history of cancer and found a small increase in cancer-risk in patients with RA compared to the general population (HR 1.2). However, there was no increase in overall cancer incidence in patients treated with TNF inhibitors, rituximab, abatacept, or JAK inhibitors compared to RA patients naïve to bDMARDs and tsDMARDs. Interestingly, urinary tract cancer risk was slightly increased in several treatment groups, though the effect size was small. Considering the generally long duration of follow-up (with the exception of JAK inhibitors), this study is very reassuring regarding long-term risk of cancer of bDMARD use and useful in counseling people with RA on therapeutic risks.

Herpes zoster infection is another well-known complication of RA and its treatment, including glucocorticoid therapy. An increased incidence has recently been noted in people who use JAK inhibitors, though other bDMARDs including TNF inhibitors are also known to increase risk. Redeker et al. compare the incidence of herpes zoster in people with RA using csDMARDs, bDMARDs, and tsDMARDs using a German prospective RA registry. In nearly 14,000 patients, 559 cases of herpes zoster were documented; after adjusting for age, sex, and glucocorticoid use, an increased risk was noted for treatment with monoclonal anti-TNF therapy, B-cell directed therapy, and JAK inhibitors compared to csDMARDs, whereas soluble TNF receptor fusion protein, T cell costimulation modulators and IL-6 inhibitors were not associated with a higher risk of herpes zoster compared with csDMARDs. Unfortunately, zoster vaccination status was not extracted for all patients. The study confirms what we already know with direct risk comparison between different agents and underscores the importance of vaccination in RA patients, especially those being treated with glucocorticoids and tsDMARDs.

Finally, another important consideration in the use of bDMARDs is the increase in cancer risk due to a potential reduction in immunosurveillance. Initial meta-analyses of clinical trials of anti-TNF agents highlighted an early increase in cancer risk, though later studies including meta-analyses and registry studies with longer follow-up durations have been equivocal. Huss et al. examine a Swedish registry of people with RA and no prior history of cancer and found a small increase in cancer-risk in patients with RA compared to the general population (HR 1.2). However, there was no increase in overall cancer incidence in patients treated with TNF inhibitors, rituximab, abatacept, or JAK inhibitors compared to RA patients naïve to bDMARDs and tsDMARDs. Interestingly, urinary tract cancer risk was slightly increased in several treatment groups, though the effect size was small. Considering the generally long duration of follow-up (with the exception of JAK inhibitors), this study is very reassuring regarding long-term risk of cancer of bDMARD use and useful in counseling people with RA on therapeutic risks.

Herpes zoster infection is another well-known complication of RA and its treatment, including glucocorticoid therapy. An increased incidence has recently been noted in people who use JAK inhibitors, though other bDMARDs including TNF inhibitors are also known to increase risk. Redeker et al. compare the incidence of herpes zoster in people with RA using csDMARDs, bDMARDs, and tsDMARDs using a German prospective RA registry. In nearly 14,000 patients, 559 cases of herpes zoster were documented; after adjusting for age, sex, and glucocorticoid use, an increased risk was noted for treatment with monoclonal anti-TNF therapy, B-cell directed therapy, and JAK inhibitors compared to csDMARDs, whereas soluble TNF receptor fusion protein, T cell costimulation modulators and IL-6 inhibitors were not associated with a higher risk of herpes zoster compared with csDMARDs. Unfortunately, zoster vaccination status was not extracted for all patients. The study confirms what we already know with direct risk comparison between different agents and underscores the importance of vaccination in RA patients, especially those being treated with glucocorticoids and tsDMARDs.

Finally, another important consideration in the use of bDMARDs is the increase in cancer risk due to a potential reduction in immunosurveillance. Initial meta-analyses of clinical trials of anti-TNF agents highlighted an early increase in cancer risk, though later studies including meta-analyses and registry studies with longer follow-up durations have been equivocal. Huss et al. examine a Swedish registry of people with RA and no prior history of cancer and found a small increase in cancer-risk in patients with RA compared to the general population (HR 1.2). However, there was no increase in overall cancer incidence in patients treated with TNF inhibitors, rituximab, abatacept, or JAK inhibitors compared to RA patients naïve to bDMARDs and tsDMARDs. Interestingly, urinary tract cancer risk was slightly increased in several treatment groups, though the effect size was small. Considering the generally long duration of follow-up (with the exception of JAK inhibitors), this study is very reassuring regarding long-term risk of cancer of bDMARD use and useful in counseling people with RA on therapeutic risks.

In the study by Sternberg et al, radiographic progression-free survival (rPFS) and safety were compared between patients aged > 70 and younger than age 70 who were enrolled in the CARD study. In the CARD study, patients with metastatic castrate-resistant prostate cancer (mCRPC) were randomized to cabazitaxel versus abiraterone or enzlutamide after having failed previous treatment. Patients aged > 70 who received cabazitaxel had a higher rPFS than those who received abiraterone or enzalutamide. Grade > 3 adverse effects were identified in 58% of patients receiving cabazitaxel versus 49% in those receiving abiraterone or enzalutamide.

In the study by Smith et al., quality of life (QoL) as measured via time to deterioration of patient report outcomes (PRO) was evaluated in patients enrolled on the ARAMIS trial (darolutamide versus placebo in patients with non-metastatic castrate-resistant prostate cancer (nmCRPC). PRO was assessed via surveys as an exploratory endpoint in this study via FACT-P PCS (prostate cancer subscale) and EORTC QLQ-PR25. Overall, the findings were consistent with either an overall improvement in QoL or improvement in urinary and bowel symptoms over time. In a separate study, Fallah et al conducted a pooled analysis of survival and safety outcomes of 3 second generation androgen receptor blockers (apalutamide, darolutamide, and enzalutamide) in men with nmCRPC. They compared results for men age under 80 versus those 80 and above. Metastasis-free survival and overall survival were higher for the treatment groups compared with placebo groups for both age categories. Side effects were slightly higher in the group aged 80 and above.

In summary, quality of life is an endpoint of critical importance to patients. Inclusion of patient reported outcomes as measured via surveys that provide quantitative assessments aid providers in discussing treatment options with patients. In addition, such QoL instruments aid in assessments based on age. Age bias is common in oncology, and the included studies provide further evidence that age alone should not be a reason to adjust treatment recommendations. Inclusion of geriatric assessments into such studies may further aid in determining risks and benefits of particular prostate cancer treatments in future studies

In the study by Sternberg et al, radiographic progression-free survival (rPFS) and safety were compared between patients aged > 70 and younger than age 70 who were enrolled in the CARD study. In the CARD study, patients with metastatic castrate-resistant prostate cancer (mCRPC) were randomized to cabazitaxel versus abiraterone or enzlutamide after having failed previous treatment. Patients aged > 70 who received cabazitaxel had a higher rPFS than those who received abiraterone or enzalutamide. Grade > 3 adverse effects were identified in 58% of patients receiving cabazitaxel versus 49% in those receiving abiraterone or enzalutamide.

In the study by Smith et al., quality of life (QoL) as measured via time to deterioration of patient report outcomes (PRO) was evaluated in patients enrolled on the ARAMIS trial (darolutamide versus placebo in patients with non-metastatic castrate-resistant prostate cancer (nmCRPC). PRO was assessed via surveys as an exploratory endpoint in this study via FACT-P PCS (prostate cancer subscale) and EORTC QLQ-PR25. Overall, the findings were consistent with either an overall improvement in QoL or improvement in urinary and bowel symptoms over time. In a separate study, Fallah et al conducted a pooled analysis of survival and safety outcomes of 3 second generation androgen receptor blockers (apalutamide, darolutamide, and enzalutamide) in men with nmCRPC. They compared results for men age under 80 versus those 80 and above. Metastasis-free survival and overall survival were higher for the treatment groups compared with placebo groups for both age categories. Side effects were slightly higher in the group aged 80 and above.

In summary, quality of life is an endpoint of critical importance to patients. Inclusion of patient reported outcomes as measured via surveys that provide quantitative assessments aid providers in discussing treatment options with patients. In addition, such QoL instruments aid in assessments based on age. Age bias is common in oncology, and the included studies provide further evidence that age alone should not be a reason to adjust treatment recommendations. Inclusion of geriatric assessments into such studies may further aid in determining risks and benefits of particular prostate cancer treatments in future studies

In the study by Sternberg et al, radiographic progression-free survival (rPFS) and safety were compared between patients aged > 70 and younger than age 70 who were enrolled in the CARD study. In the CARD study, patients with metastatic castrate-resistant prostate cancer (mCRPC) were randomized to cabazitaxel versus abiraterone or enzlutamide after having failed previous treatment. Patients aged > 70 who received cabazitaxel had a higher rPFS than those who received abiraterone or enzalutamide. Grade > 3 adverse effects were identified in 58% of patients receiving cabazitaxel versus 49% in those receiving abiraterone or enzalutamide.

In the study by Smith et al., quality of life (QoL) as measured via time to deterioration of patient report outcomes (PRO) was evaluated in patients enrolled on the ARAMIS trial (darolutamide versus placebo in patients with non-metastatic castrate-resistant prostate cancer (nmCRPC). PRO was assessed via surveys as an exploratory endpoint in this study via FACT-P PCS (prostate cancer subscale) and EORTC QLQ-PR25. Overall, the findings were consistent with either an overall improvement in QoL or improvement in urinary and bowel symptoms over time. In a separate study, Fallah et al conducted a pooled analysis of survival and safety outcomes of 3 second generation androgen receptor blockers (apalutamide, darolutamide, and enzalutamide) in men with nmCRPC. They compared results for men age under 80 versus those 80 and above. Metastasis-free survival and overall survival were higher for the treatment groups compared with placebo groups for both age categories. Side effects were slightly higher in the group aged 80 and above.

In summary, quality of life is an endpoint of critical importance to patients. Inclusion of patient reported outcomes as measured via surveys that provide quantitative assessments aid providers in discussing treatment options with patients. In addition, such QoL instruments aid in assessments based on age. Age bias is common in oncology, and the included studies provide further evidence that age alone should not be a reason to adjust treatment recommendations. Inclusion of geriatric assessments into such studies may further aid in determining risks and benefits of particular prostate cancer treatments in future studies

Atopic dermatitis (AD) is a complex disease with varying degrees of itch, pain, eczematous skin lesions and quality of life impact. Research over the past decade uncovered myriad associations of AD with comorbid health disorders. There are well-established associations of AD with atopic comorbidities in children and adults, including asthma, hay fever, food allergies and less commonly eosinophilic esophagitis. AD is also associated with higher rates of mental health disorders, including depression, anxiety and attention deficit (hyperactivity) disorder.

AD patients also have multiple risk factors for hypertension, including chronic sleep deprivation and limitations on physical activity from itch. Yousaf et al conducted a systematic literature review and meta-analysis of 19 studies and found significantly increased likelihood of hypertension in patients with AD compared to healthy controls, particularly moderate-to-severe AD. Though, the odds of hypertension were lower in patients with AD compared to psoriasis.

Sleep disturbances (SD) are also common in AD patients. Manjunath et al conducted a cross-sectional, dermatology practice-based study to examine clinical differences in geriatric vs younger adult AD patients. Geriatric age was not associated with any significant differences of AD severity. However, geriatric AD patients had significantly more nights of SD, particularly trouble staying asleep, and increased fatigue than younger adults. In general, having good sleep hygiene and getting adequate sleep are important for overall health and longevity. SD therefore warrant particular attention in clinical management of AD as they are often modifiable with improved AD control.

Likewise, the myriad comorbidities associated with AD may lead to poorer health outcomes, such as hospitalization. Edigin et al conducted a longitudinal study of 23,410 adults hospitalized in the United States with AD. Hospitalizations rates increased between 1998 and 2018 owing to comorbid health disorders, but not AD itself.

Together, these results highlight the importance of holistic management of AD patients, including atopic and non-atopic comorbidities. However, many questions remain about how and when to best screen for various comorbidities. Generally, more severe AD is one of the strongest predictors of atopic and mental health comorbidities, as well as sleep disturbances and hypertension as shown in the abovementioned studies. Additionally, geriatric AD patients warrant closer monitoring of SD. Of course, screening patients for these comorbidities can take up precious time in a busy clinical practice. Though, it is a worthwhile investment of time and will improve patients’ health outcomes and the quality of care you provide for patients.

Atopic dermatitis (AD) is a complex disease with varying degrees of itch, pain, eczematous skin lesions and quality of life impact. Research over the past decade uncovered myriad associations of AD with comorbid health disorders. There are well-established associations of AD with atopic comorbidities in children and adults, including asthma, hay fever, food allergies and less commonly eosinophilic esophagitis. AD is also associated with higher rates of mental health disorders, including depression, anxiety and attention deficit (hyperactivity) disorder.

AD patients also have multiple risk factors for hypertension, including chronic sleep deprivation and limitations on physical activity from itch. Yousaf et al conducted a systematic literature review and meta-analysis of 19 studies and found significantly increased likelihood of hypertension in patients with AD compared to healthy controls, particularly moderate-to-severe AD. Though, the odds of hypertension were lower in patients with AD compared to psoriasis.

Sleep disturbances (SD) are also common in AD patients. Manjunath et al conducted a cross-sectional, dermatology practice-based study to examine clinical differences in geriatric vs younger adult AD patients. Geriatric age was not associated with any significant differences of AD severity. However, geriatric AD patients had significantly more nights of SD, particularly trouble staying asleep, and increased fatigue than younger adults. In general, having good sleep hygiene and getting adequate sleep are important for overall health and longevity. SD therefore warrant particular attention in clinical management of AD as they are often modifiable with improved AD control.

Likewise, the myriad comorbidities associated with AD may lead to poorer health outcomes, such as hospitalization. Edigin et al conducted a longitudinal study of 23,410 adults hospitalized in the United States with AD. Hospitalizations rates increased between 1998 and 2018 owing to comorbid health disorders, but not AD itself.

Together, these results highlight the importance of holistic management of AD patients, including atopic and non-atopic comorbidities. However, many questions remain about how and when to best screen for various comorbidities. Generally, more severe AD is one of the strongest predictors of atopic and mental health comorbidities, as well as sleep disturbances and hypertension as shown in the abovementioned studies. Additionally, geriatric AD patients warrant closer monitoring of SD. Of course, screening patients for these comorbidities can take up precious time in a busy clinical practice. Though, it is a worthwhile investment of time and will improve patients’ health outcomes and the quality of care you provide for patients.

Atopic dermatitis (AD) is a complex disease with varying degrees of itch, pain, eczematous skin lesions and quality of life impact. Research over the past decade uncovered myriad associations of AD with comorbid health disorders. There are well-established associations of AD with atopic comorbidities in children and adults, including asthma, hay fever, food allergies and less commonly eosinophilic esophagitis. AD is also associated with higher rates of mental health disorders, including depression, anxiety and attention deficit (hyperactivity) disorder.

AD patients also have multiple risk factors for hypertension, including chronic sleep deprivation and limitations on physical activity from itch. Yousaf et al conducted a systematic literature review and meta-analysis of 19 studies and found significantly increased likelihood of hypertension in patients with AD compared to healthy controls, particularly moderate-to-severe AD. Though, the odds of hypertension were lower in patients with AD compared to psoriasis.

Sleep disturbances (SD) are also common in AD patients. Manjunath et al conducted a cross-sectional, dermatology practice-based study to examine clinical differences in geriatric vs younger adult AD patients. Geriatric age was not associated with any significant differences of AD severity. However, geriatric AD patients had significantly more nights of SD, particularly trouble staying asleep, and increased fatigue than younger adults. In general, having good sleep hygiene and getting adequate sleep are important for overall health and longevity. SD therefore warrant particular attention in clinical management of AD as they are often modifiable with improved AD control.

Likewise, the myriad comorbidities associated with AD may lead to poorer health outcomes, such as hospitalization. Edigin et al conducted a longitudinal study of 23,410 adults hospitalized in the United States with AD. Hospitalizations rates increased between 1998 and 2018 owing to comorbid health disorders, but not AD itself.

Together, these results highlight the importance of holistic management of AD patients, including atopic and non-atopic comorbidities. However, many questions remain about how and when to best screen for various comorbidities. Generally, more severe AD is one of the strongest predictors of atopic and mental health comorbidities, as well as sleep disturbances and hypertension as shown in the abovementioned studies. Additionally, geriatric AD patients warrant closer monitoring of SD. Of course, screening patients for these comorbidities can take up precious time in a busy clinical practice. Though, it is a worthwhile investment of time and will improve patients’ health outcomes and the quality of care you provide for patients.

CPX-351 is a liposomal cytarabine and daunorubicin. It was FDA approved in 2017 for the treatment of patients with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC). The approval was based on the results from a randomized trial comparing CPX-351 vs standard 7 +3 chemotherapy in patients older that 65 with t-AML or AML-MRC. The 5-year results from that study were recently published by Lancet et al. At 5 years of follow-up, CPX-351 continued to show benefit in older patients with t-AML or AML-MRC vs standard chemotherapy with cytarabine for 7 days and daunorubicin for 3 days (7+3) . The median OS in favor of CPX-351 vs 7+3 group was maintained (hazard ratio, 0.70; 95% confidence interval [CI], 0.55-0.91). At 5 years, survival estimates were higher for CPX-351 vs 7+3 (18% [95% CI, 12%-25%] vs 8% [95% CI, 4%-13%]). Overall, 5% of deaths in both groups were considered related to the study treatment. Overall, more patients treated with CPX-351 were able to proceed to stem cell transplantation (SCT) compared to those treated with 7 + 3 (35% vs 25%).

The 3-year overall survival from SCT was 56% vs 23% for patients treated with CPX-351 vs 7 +3. Of the responding patients who did not proceed to SCT, only 3 patients were alive at 5 years. Although this data is encouraging, it demonstrates that we have a long way to go to improve the outcome of these patients. In addition, more patients who achieve remission should proceed to SCT in order to improve the survival of this patient population (Lancet JE et al). In terms of supportive care during induction chemotherapy, two published studies this month evaluated two approaches to aiming to decrease the morbidity from infections: prospective monitoring for fungal infections and the use of romyelocel with G-CSF. Prospectively monitoring for fungal infections was performed as an observation study imbedded within a phase 3 Children’s Oncology Group trial (ACCL0933). The study included 471 patients with AML (age, 3 months-30 years) receiving fluconazole (n=235) or caspofungin (n=236).

Twice-weekly surveillance with galactomannan enzyme immunoassay (GM-EIA) and b-D-glucan (BDG) assay were performed in all patients. The negative predictive value was greater than 99% for an individual or combination of GM-EIA and BDG assays. However, true positive results were not observed in any sample collected within 7 days of an invasive aspergillosis/candidiasis diagnosis, resulting in sensitivity and positive predictive value for each test of 0%. This approach was ineffective at detecting invasive fungal diseases (IFDs) in children, adolescents, and young adults with acute myeloid leukemia (AML) receiving antifungal prophylaxis (Fisher BT et al).

A different approach to reduce infection morbidity and mortality during induction chemotherapy is the administration of romyelocel. Myeloid progenitor cells are cells that can produce granulocytes but have no long-term reconstitution capability.  Romyelocel is a cryopreserved product, of MPC manufactured by ex vivo expansion of CD34⁺ hematopoietic stem cells. Romyelocel is capable of producing granulocytes, and thereby may reduce the severity or duration of neutropenic fevers. This phase 2 study included 163 patients with de novo AML receiving induction chemotherapy. Evaluable patients (n=120) were randomly assigned to receive either romyelocel-L plus G-CSF (n=59) or G-CSF monotherapy (n=61). From days 15 to 28, romyelocel-L plus G-CSF vs G-CSF monotherapy significantly reduced the mean duration of febrile episodes (2.36 days vs 3.90 days; P = .02) and incidence of infections (6.8% vs 27.9%; P = .0013). Length of hospitalization was significantly shorter in the romyelocel-L plus G-CSF vs G-CSF monotherapy group (25.5 days vs 28.7 days; P = .002). These results are encouraging, and a phase III trial is suggested by the authors. (Desai PM et al).

Finally, a study by MDACC reported disappointing results with the use of venetoclax in patients with tp53 mutation. Findings are from a retrospective analysis of 238 patients with newly diagnosed TP53-mutated AML treated with either VEN-based (n=58) or non-VEN-based (n=180) therapies. The addition of venetoclax to standard treatment regimens (VEN-based) did not improve clinical outcomes in patients with TP53-mutated acute myeloid leukemia (AML), highlighting the need for novel therapies in this patient population. Overall, there was no significant differences in overall survival (median, 5.7 months vs 6.6 months; P = .4), relapse-free survival (median, 3.5 months vs 4.7 months; P = .43), 4-week mortality (7% vs 10%; P = .5), and 8-week mortality (22% vs 17%; P = .4) in patients receiving VEN-based vs non-VEN-based therapies (Venugopal S et al). Clearly, better therapies are needed for this patient population.

CPX-351 is a liposomal cytarabine and daunorubicin. It was FDA approved in 2017 for the treatment of patients with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC). The approval was based on the results from a randomized trial comparing CPX-351 vs standard 7 +3 chemotherapy in patients older that 65 with t-AML or AML-MRC. The 5-year results from that study were recently published by Lancet et al. At 5 years of follow-up, CPX-351 continued to show benefit in older patients with t-AML or AML-MRC vs standard chemotherapy with cytarabine for 7 days and daunorubicin for 3 days (7+3) . The median OS in favor of CPX-351 vs 7+3 group was maintained (hazard ratio, 0.70; 95% confidence interval [CI], 0.55-0.91). At 5 years, survival estimates were higher for CPX-351 vs 7+3 (18% [95% CI, 12%-25%] vs 8% [95% CI, 4%-13%]). Overall, 5% of deaths in both groups were considered related to the study treatment. Overall, more patients treated with CPX-351 were able to proceed to stem cell transplantation (SCT) compared to those treated with 7 + 3 (35% vs 25%).

The 3-year overall survival from SCT was 56% vs 23% for patients treated with CPX-351 vs 7 +3. Of the responding patients who did not proceed to SCT, only 3 patients were alive at 5 years. Although this data is encouraging, it demonstrates that we have a long way to go to improve the outcome of these patients. In addition, more patients who achieve remission should proceed to SCT in order to improve the survival of this patient population (Lancet JE et al). In terms of supportive care during induction chemotherapy, two published studies this month evaluated two approaches to aiming to decrease the morbidity from infections: prospective monitoring for fungal infections and the use of romyelocel with G-CSF. Prospectively monitoring for fungal infections was performed as an observation study imbedded within a phase 3 Children’s Oncology Group trial (ACCL0933). The study included 471 patients with AML (age, 3 months-30 years) receiving fluconazole (n=235) or caspofungin (n=236).

Twice-weekly surveillance with galactomannan enzyme immunoassay (GM-EIA) and b-D-glucan (BDG) assay were performed in all patients. The negative predictive value was greater than 99% for an individual or combination of GM-EIA and BDG assays. However, true positive results were not observed in any sample collected within 7 days of an invasive aspergillosis/candidiasis diagnosis, resulting in sensitivity and positive predictive value for each test of 0%. This approach was ineffective at detecting invasive fungal diseases (IFDs) in children, adolescents, and young adults with acute myeloid leukemia (AML) receiving antifungal prophylaxis (Fisher BT et al).

A different approach to reduce infection morbidity and mortality during induction chemotherapy is the administration of romyelocel. Myeloid progenitor cells are cells that can produce granulocytes but have no long-term reconstitution capability.  Romyelocel is a cryopreserved product, of MPC manufactured by ex vivo expansion of CD34⁺ hematopoietic stem cells. Romyelocel is capable of producing granulocytes, and thereby may reduce the severity or duration of neutropenic fevers. This phase 2 study included 163 patients with de novo AML receiving induction chemotherapy. Evaluable patients (n=120) were randomly assigned to receive either romyelocel-L plus G-CSF (n=59) or G-CSF monotherapy (n=61). From days 15 to 28, romyelocel-L plus G-CSF vs G-CSF monotherapy significantly reduced the mean duration of febrile episodes (2.36 days vs 3.90 days; P = .02) and incidence of infections (6.8% vs 27.9%; P = .0013). Length of hospitalization was significantly shorter in the romyelocel-L plus G-CSF vs G-CSF monotherapy group (25.5 days vs 28.7 days; P = .002). These results are encouraging, and a phase III trial is suggested by the authors. (Desai PM et al).

Finally, a study by MDACC reported disappointing results with the use of venetoclax in patients with tp53 mutation. Findings are from a retrospective analysis of 238 patients with newly diagnosed TP53-mutated AML treated with either VEN-based (n=58) or non-VEN-based (n=180) therapies. The addition of venetoclax to standard treatment regimens (VEN-based) did not improve clinical outcomes in patients with TP53-mutated acute myeloid leukemia (AML), highlighting the need for novel therapies in this patient population. Overall, there was no significant differences in overall survival (median, 5.7 months vs 6.6 months; P = .4), relapse-free survival (median, 3.5 months vs 4.7 months; P = .43), 4-week mortality (7% vs 10%; P = .5), and 8-week mortality (22% vs 17%; P = .4) in patients receiving VEN-based vs non-VEN-based therapies (Venugopal S et al). Clearly, better therapies are needed for this patient population.

CPX-351 is a liposomal cytarabine and daunorubicin. It was FDA approved in 2017 for the treatment of patients with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC). The approval was based on the results from a randomized trial comparing CPX-351 vs standard 7 +3 chemotherapy in patients older that 65 with t-AML or AML-MRC. The 5-year results from that study were recently published by Lancet et al. At 5 years of follow-up, CPX-351 continued to show benefit in older patients with t-AML or AML-MRC vs standard chemotherapy with cytarabine for 7 days and daunorubicin for 3 days (7+3) . The median OS in favor of CPX-351 vs 7+3 group was maintained (hazard ratio, 0.70; 95% confidence interval [CI], 0.55-0.91). At 5 years, survival estimates were higher for CPX-351 vs 7+3 (18% [95% CI, 12%-25%] vs 8% [95% CI, 4%-13%]). Overall, 5% of deaths in both groups were considered related to the study treatment. Overall, more patients treated with CPX-351 were able to proceed to stem cell transplantation (SCT) compared to those treated with 7 + 3 (35% vs 25%).

The 3-year overall survival from SCT was 56% vs 23% for patients treated with CPX-351 vs 7 +3. Of the responding patients who did not proceed to SCT, only 3 patients were alive at 5 years. Although this data is encouraging, it demonstrates that we have a long way to go to improve the outcome of these patients. In addition, more patients who achieve remission should proceed to SCT in order to improve the survival of this patient population (Lancet JE et al). In terms of supportive care during induction chemotherapy, two published studies this month evaluated two approaches to aiming to decrease the morbidity from infections: prospective monitoring for fungal infections and the use of romyelocel with G-CSF. Prospectively monitoring for fungal infections was performed as an observation study imbedded within a phase 3 Children’s Oncology Group trial (ACCL0933). The study included 471 patients with AML (age, 3 months-30 years) receiving fluconazole (n=235) or caspofungin (n=236).

Twice-weekly surveillance with galactomannan enzyme immunoassay (GM-EIA) and b-D-glucan (BDG) assay were performed in all patients. The negative predictive value was greater than 99% for an individual or combination of GM-EIA and BDG assays. However, true positive results were not observed in any sample collected within 7 days of an invasive aspergillosis/candidiasis diagnosis, resulting in sensitivity and positive predictive value for each test of 0%. This approach was ineffective at detecting invasive fungal diseases (IFDs) in children, adolescents, and young adults with acute myeloid leukemia (AML) receiving antifungal prophylaxis (Fisher BT et al).

A different approach to reduce infection morbidity and mortality during induction chemotherapy is the administration of romyelocel. Myeloid progenitor cells are cells that can produce granulocytes but have no long-term reconstitution capability.  Romyelocel is a cryopreserved product, of MPC manufactured by ex vivo expansion of CD34⁺ hematopoietic stem cells. Romyelocel is capable of producing granulocytes, and thereby may reduce the severity or duration of neutropenic fevers. This phase 2 study included 163 patients with de novo AML receiving induction chemotherapy. Evaluable patients (n=120) were randomly assigned to receive either romyelocel-L plus G-CSF (n=59) or G-CSF monotherapy (n=61). From days 15 to 28, romyelocel-L plus G-CSF vs G-CSF monotherapy significantly reduced the mean duration of febrile episodes (2.36 days vs 3.90 days; P = .02) and incidence of infections (6.8% vs 27.9%; P = .0013). Length of hospitalization was significantly shorter in the romyelocel-L plus G-CSF vs G-CSF monotherapy group (25.5 days vs 28.7 days; P = .002). These results are encouraging, and a phase III trial is suggested by the authors. (Desai PM et al).

Finally, a study by MDACC reported disappointing results with the use of venetoclax in patients with tp53 mutation. Findings are from a retrospective analysis of 238 patients with newly diagnosed TP53-mutated AML treated with either VEN-based (n=58) or non-VEN-based (n=180) therapies. The addition of venetoclax to standard treatment regimens (VEN-based) did not improve clinical outcomes in patients with TP53-mutated acute myeloid leukemia (AML), highlighting the need for novel therapies in this patient population. Overall, there was no significant differences in overall survival (median, 5.7 months vs 6.6 months; P = .4), relapse-free survival (median, 3.5 months vs 4.7 months; P = .43), 4-week mortality (7% vs 10%; P = .5), and 8-week mortality (22% vs 17%; P = .4) in patients receiving VEN-based vs non-VEN-based therapies (Venugopal S et al). Clearly, better therapies are needed for this patient population.

Program death-ligand 1 (PD-L1) inhibition suppresses tumor activity via modulation of immune and tumor cell interaction. TNBC is characterized by higher PD-L1 expression and increased immune infiltration, compared to other subtypes. In the randomized, phase 3 IMpassion130 trial, among 902 patients who were treatment naïve in the metastatic TNBC setting, an exploratory analysis in the PD-L1-positive population demonstrated a clinically meaningful OS benefit with atezolizumab + nab-paclitaxel compared to placebo + nab-paclitaxel (25.4 vs 17.9 months; HR 0.67) (Emens et al). Additionally, the phase 3 KEYNOTE-355 trial demonstrated PFS benefit among patients with mTNBC with combined positive score (CPS) ≥10 with pembrolizumab + chemotherapy (nab-paclitaxel, paclitaxel or gemcitabine/carboplatin) versus placebo + chemotherapy (mPFS 9.7 vs 5.6 months; HR 0.65, 95% CI 0.49-0.86). These results are in contrast to the phase 3 IMpassion131 trial which found no statistically significant difference in PFS or OS among 651 patients with mTNBC randomized to atezolizumab + paclitaxel vs placebo + paclitaxel (PD-L1-positive population: PFS 6.0 vs 5.7 months, HR 0.82, 95% CI 0.60-1.12; OS 22.1 vs 28.3 months, HR 1.11, 95% CI 0.76-1.62) (Miles et al). The reasons underlying these differences remain unclear and warrant further investigation. Some thoughts raised include lack of information on BRCA status (which may serve as prognostic factor) in IMpassion131, concomitant use of steroids with paclitaxel, and allowance of sufficient long-term follow-up for generation of events. Regardless, these studies suggest chemotherapy backbone is relevant and the regimens utilized in IMpassion130 and KEYNOTE-355 have gained FDA approval in the first-line mTNBC setting.

The phase 3 CLEOPATRA trial has established the regimen of docetaxel + trastuzumab + pertuzumab as standard of care in the first-line setting for metastatic HER2-positive breast cancer with an OS benefit of 16 months compared to docetaxel + trastuzumab + placebo (57.1 vs 40.8 months; HR 0.69, 95% CI 0.58-0.82) with over 8 years of follow-up. PERUSE was a single-arm phase 3b study that investigated the safety and efficacy of trastuzumab + pertuzumab combined with various taxanes (docetaxel, paclitaxel or nab-paclitaxel) among 1426 patients with HER2+ mBC (Miles et al). In the overall population at follow-up of 5.7 years, median PFS and OS were 20.7 and 65.3 months, respectively, and were similar regardless of taxane backbone. Docetaxel was associated with higher incidences of neutropenia and febrile neutropenia. These results support consideration of an alternative taxane combined with trastuzumab + pertuzumab in this setting (for example paclitaxel) in patients who may not be ideal candidates for docetaxel.

In the second-line treatment setting for HER2+ mBC with prior exposure to trastuzumab and taxane, the phase 3 EMILIA study showed improvement in OS with T-DM1 vs capecitabine + lapatinib (mOS 29.9 vs 25.9 months, HR 0.75, 95% CI 0.64-0.88). Ethier et al explored real-world application and outcomes associated with pertuzumab and T-DM1 in the first- and second-line settings respectively, in a population-based, retrospective cohort study in Ontario, Canada. In the pertuzumab cohort, median OS and time on treatment were 43 and 4 months, respectively. In the T-DM1 cohort, median OS and time on treatment were 15 months and 4 months, respectively. Additionally, patients in the T-DM1 cohort who were pertuzumab-naïve appeared to do better, potentially suggesting less responsiveness to subsequent HER2-targeted treatment in the real world setting among those who received prior pertuzumab. Findings from this population study demonstrate inferior outcomes when compared to the pivotal CLEOPATRA and EMILIA trials, and highlight a gap between clinical trial and real-world observations (described by authors as efficacy-effectiveness gap). Potential etiologies for these differences include patient factors, prior therapies and delivery of care models, and convey the importance of recognizing this gap exists and optimizing any modifiable factors as trial data and novel therapies are applied to routine clinical practice.

References:

Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res. 2014;2(4):361-70.

Cortes J, Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396(10265):1817-1828.

Swain SM, Miles D, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(4):519-530.

Diéras V, Miles D, Verma S, et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(6):732-742.

Program death-ligand 1 (PD-L1) inhibition suppresses tumor activity via modulation of immune and tumor cell interaction. TNBC is characterized by higher PD-L1 expression and increased immune infiltration, compared to other subtypes. In the randomized, phase 3 IMpassion130 trial, among 902 patients who were treatment naïve in the metastatic TNBC setting, an exploratory analysis in the PD-L1-positive population demonstrated a clinically meaningful OS benefit with atezolizumab + nab-paclitaxel compared to placebo + nab-paclitaxel (25.4 vs 17.9 months; HR 0.67) (Emens et al). Additionally, the phase 3 KEYNOTE-355 trial demonstrated PFS benefit among patients with mTNBC with combined positive score (CPS) ≥10 with pembrolizumab + chemotherapy (nab-paclitaxel, paclitaxel or gemcitabine/carboplatin) versus placebo + chemotherapy (mPFS 9.7 vs 5.6 months; HR 0.65, 95% CI 0.49-0.86). These results are in contrast to the phase 3 IMpassion131 trial which found no statistically significant difference in PFS or OS among 651 patients with mTNBC randomized to atezolizumab + paclitaxel vs placebo + paclitaxel (PD-L1-positive population: PFS 6.0 vs 5.7 months, HR 0.82, 95% CI 0.60-1.12; OS 22.1 vs 28.3 months, HR 1.11, 95% CI 0.76-1.62) (Miles et al). The reasons underlying these differences remain unclear and warrant further investigation. Some thoughts raised include lack of information on BRCA status (which may serve as prognostic factor) in IMpassion131, concomitant use of steroids with paclitaxel, and allowance of sufficient long-term follow-up for generation of events. Regardless, these studies suggest chemotherapy backbone is relevant and the regimens utilized in IMpassion130 and KEYNOTE-355 have gained FDA approval in the first-line mTNBC setting.

The phase 3 CLEOPATRA trial has established the regimen of docetaxel + trastuzumab + pertuzumab as standard of care in the first-line setting for metastatic HER2-positive breast cancer with an OS benefit of 16 months compared to docetaxel + trastuzumab + placebo (57.1 vs 40.8 months; HR 0.69, 95% CI 0.58-0.82) with over 8 years of follow-up. PERUSE was a single-arm phase 3b study that investigated the safety and efficacy of trastuzumab + pertuzumab combined with various taxanes (docetaxel, paclitaxel or nab-paclitaxel) among 1426 patients with HER2+ mBC (Miles et al). In the overall population at follow-up of 5.7 years, median PFS and OS were 20.7 and 65.3 months, respectively, and were similar regardless of taxane backbone. Docetaxel was associated with higher incidences of neutropenia and febrile neutropenia. These results support consideration of an alternative taxane combined with trastuzumab + pertuzumab in this setting (for example paclitaxel) in patients who may not be ideal candidates for docetaxel.

In the second-line treatment setting for HER2+ mBC with prior exposure to trastuzumab and taxane, the phase 3 EMILIA study showed improvement in OS with T-DM1 vs capecitabine + lapatinib (mOS 29.9 vs 25.9 months, HR 0.75, 95% CI 0.64-0.88). Ethier et al explored real-world application and outcomes associated with pertuzumab and T-DM1 in the first- and second-line settings respectively, in a population-based, retrospective cohort study in Ontario, Canada. In the pertuzumab cohort, median OS and time on treatment were 43 and 4 months, respectively. In the T-DM1 cohort, median OS and time on treatment were 15 months and 4 months, respectively. Additionally, patients in the T-DM1 cohort who were pertuzumab-naïve appeared to do better, potentially suggesting less responsiveness to subsequent HER2-targeted treatment in the real world setting among those who received prior pertuzumab. Findings from this population study demonstrate inferior outcomes when compared to the pivotal CLEOPATRA and EMILIA trials, and highlight a gap between clinical trial and real-world observations (described by authors as efficacy-effectiveness gap). Potential etiologies for these differences include patient factors, prior therapies and delivery of care models, and convey the importance of recognizing this gap exists and optimizing any modifiable factors as trial data and novel therapies are applied to routine clinical practice.

References:

Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res. 2014;2(4):361-70.

Cortes J, Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396(10265):1817-1828.

Swain SM, Miles D, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(4):519-530.

Diéras V, Miles D, Verma S, et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(6):732-742.

Program death-ligand 1 (PD-L1) inhibition suppresses tumor activity via modulation of immune and tumor cell interaction. TNBC is characterized by higher PD-L1 expression and increased immune infiltration, compared to other subtypes. In the randomized, phase 3 IMpassion130 trial, among 902 patients who were treatment naïve in the metastatic TNBC setting, an exploratory analysis in the PD-L1-positive population demonstrated a clinically meaningful OS benefit with atezolizumab + nab-paclitaxel compared to placebo + nab-paclitaxel (25.4 vs 17.9 months; HR 0.67) (Emens et al). Additionally, the phase 3 KEYNOTE-355 trial demonstrated PFS benefit among patients with mTNBC with combined positive score (CPS) ≥10 with pembrolizumab + chemotherapy (nab-paclitaxel, paclitaxel or gemcitabine/carboplatin) versus placebo + chemotherapy (mPFS 9.7 vs 5.6 months; HR 0.65, 95% CI 0.49-0.86). These results are in contrast to the phase 3 IMpassion131 trial which found no statistically significant difference in PFS or OS among 651 patients with mTNBC randomized to atezolizumab + paclitaxel vs placebo + paclitaxel (PD-L1-positive population: PFS 6.0 vs 5.7 months, HR 0.82, 95% CI 0.60-1.12; OS 22.1 vs 28.3 months, HR 1.11, 95% CI 0.76-1.62) (Miles et al). The reasons underlying these differences remain unclear and warrant further investigation. Some thoughts raised include lack of information on BRCA status (which may serve as prognostic factor) in IMpassion131, concomitant use of steroids with paclitaxel, and allowance of sufficient long-term follow-up for generation of events. Regardless, these studies suggest chemotherapy backbone is relevant and the regimens utilized in IMpassion130 and KEYNOTE-355 have gained FDA approval in the first-line mTNBC setting.

The phase 3 CLEOPATRA trial has established the regimen of docetaxel + trastuzumab + pertuzumab as standard of care in the first-line setting for metastatic HER2-positive breast cancer with an OS benefit of 16 months compared to docetaxel + trastuzumab + placebo (57.1 vs 40.8 months; HR 0.69, 95% CI 0.58-0.82) with over 8 years of follow-up. PERUSE was a single-arm phase 3b study that investigated the safety and efficacy of trastuzumab + pertuzumab combined with various taxanes (docetaxel, paclitaxel or nab-paclitaxel) among 1426 patients with HER2+ mBC (Miles et al). In the overall population at follow-up of 5.7 years, median PFS and OS were 20.7 and 65.3 months, respectively, and were similar regardless of taxane backbone. Docetaxel was associated with higher incidences of neutropenia and febrile neutropenia. These results support consideration of an alternative taxane combined with trastuzumab + pertuzumab in this setting (for example paclitaxel) in patients who may not be ideal candidates for docetaxel.

In the second-line treatment setting for HER2+ mBC with prior exposure to trastuzumab and taxane, the phase 3 EMILIA study showed improvement in OS with T-DM1 vs capecitabine + lapatinib (mOS 29.9 vs 25.9 months, HR 0.75, 95% CI 0.64-0.88). Ethier et al explored real-world application and outcomes associated with pertuzumab and T-DM1 in the first- and second-line settings respectively, in a population-based, retrospective cohort study in Ontario, Canada. In the pertuzumab cohort, median OS and time on treatment were 43 and 4 months, respectively. In the T-DM1 cohort, median OS and time on treatment were 15 months and 4 months, respectively. Additionally, patients in the T-DM1 cohort who were pertuzumab-naïve appeared to do better, potentially suggesting less responsiveness to subsequent HER2-targeted treatment in the real world setting among those who received prior pertuzumab. Findings from this population study demonstrate inferior outcomes when compared to the pivotal CLEOPATRA and EMILIA trials, and highlight a gap between clinical trial and real-world observations (described by authors as efficacy-effectiveness gap). Potential etiologies for these differences include patient factors, prior therapies and delivery of care models, and convey the importance of recognizing this gap exists and optimizing any modifiable factors as trial data and novel therapies are applied to routine clinical practice.

References:

Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res. 2014;2(4):361-70.

Cortes J, Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396(10265):1817-1828.

Swain SM, Miles D, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(4):519-530.

Diéras V, Miles D, Verma S, et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(6):732-742.

The seroconversion was highest in patients with CML with 75% and observed in 5/6 (83%) of CML patients receiving imatinib that compare favorably to the total group with 58% of seroconversions. Interestingly patients treated with pegylated interferon also had a a high response with 88% (7/8).

Another recent publication by Harrington et al Br J Hem 2021, Jun 3 ahead or print, confirmed and extending the previous data by evaluating humoral and cellular immune responses after a first injection of BNT162b2 vaccine in 16 patients with CML. 87.5% patients have a seroconversion and 93.3% developed a T cell response. These responses are seen in contrast to patients with lymphoid hematological malignancies where the responses have been significantly lower.

The main goal of the treatment for chronic phase CML is to stop the progression to more advanced phased of the disease such as blast phase, where treatments are limited and there are no consensus in the treatment approach. In a recent publication by Saxena et al. J Hematol Oncol. 2021 Jun 15 the authors reported the outcomes of patients with BP-CML treated with different regimens that include a combination therapy of tyrosine kinase inhibitor (TKI) with intensive chemotherapy (IC) or hypomethylating agent (HMA) as well as  TKI or IC alone. Response rates were similar between patients treated with IC + TKI and HMA + TKI. When compared to treatment with TKI alone, treatment with IC/HMA + TKI was superior (CRi 57.5% vs 33.9%), as well as higher complete cytogenetic response rate (45% vs 10.7%) and more patients proceeding to ASCT (32.5% vs 10.7%). The results were even better when using a second generation TKI in combination with IC or HMA with a favorable EFS and OS compared to TKI alone.

The seroconversion was highest in patients with CML with 75% and observed in 5/6 (83%) of CML patients receiving imatinib that compare favorably to the total group with 58% of seroconversions. Interestingly patients treated with pegylated interferon also had a a high response with 88% (7/8).

Another recent publication by Harrington et al Br J Hem 2021, Jun 3 ahead or print, confirmed and extending the previous data by evaluating humoral and cellular immune responses after a first injection of BNT162b2 vaccine in 16 patients with CML. 87.5% patients have a seroconversion and 93.3% developed a T cell response. These responses are seen in contrast to patients with lymphoid hematological malignancies where the responses have been significantly lower.

The main goal of the treatment for chronic phase CML is to stop the progression to more advanced phased of the disease such as blast phase, where treatments are limited and there are no consensus in the treatment approach. In a recent publication by Saxena et al. J Hematol Oncol. 2021 Jun 15 the authors reported the outcomes of patients with BP-CML treated with different regimens that include a combination therapy of tyrosine kinase inhibitor (TKI) with intensive chemotherapy (IC) or hypomethylating agent (HMA) as well as  TKI or IC alone. Response rates were similar between patients treated with IC + TKI and HMA + TKI. When compared to treatment with TKI alone, treatment with IC/HMA + TKI was superior (CRi 57.5% vs 33.9%), as well as higher complete cytogenetic response rate (45% vs 10.7%) and more patients proceeding to ASCT (32.5% vs 10.7%). The results were even better when using a second generation TKI in combination with IC or HMA with a favorable EFS and OS compared to TKI alone.

The seroconversion was highest in patients with CML with 75% and observed in 5/6 (83%) of CML patients receiving imatinib that compare favorably to the total group with 58% of seroconversions. Interestingly patients treated with pegylated interferon also had a a high response with 88% (7/8).

Another recent publication by Harrington et al Br J Hem 2021, Jun 3 ahead or print, confirmed and extending the previous data by evaluating humoral and cellular immune responses after a first injection of BNT162b2 vaccine in 16 patients with CML. 87.5% patients have a seroconversion and 93.3% developed a T cell response. These responses are seen in contrast to patients with lymphoid hematological malignancies where the responses have been significantly lower.

The main goal of the treatment for chronic phase CML is to stop the progression to more advanced phased of the disease such as blast phase, where treatments are limited and there are no consensus in the treatment approach. In a recent publication by Saxena et al. J Hematol Oncol. 2021 Jun 15 the authors reported the outcomes of patients with BP-CML treated with different regimens that include a combination therapy of tyrosine kinase inhibitor (TKI) with intensive chemotherapy (IC) or hypomethylating agent (HMA) as well as  TKI or IC alone. Response rates were similar between patients treated with IC + TKI and HMA + TKI. When compared to treatment with TKI alone, treatment with IC/HMA + TKI was superior (CRi 57.5% vs 33.9%), as well as higher complete cytogenetic response rate (45% vs 10.7%) and more patients proceeding to ASCT (32.5% vs 10.7%). The results were even better when using a second generation TKI in combination with IC or HMA with a favorable EFS and OS compared to TKI alone.

Atopic Dermatitis (AD) is complex with heterogeneous symptoms (e.g. skin-pain, sleep disturbance), signs (e.g. lichenification, prurigo nodules, follicular accentuation), and longitudinal course (intermittent, persistent). These disparate signs and symptoms should be addressed in optimize disease control.

Multiple extracellular cytokines are upregulated in skin of AD patients, including interleukins 4, 5, 13, 22, 31 and thymic stromal lymphopoietin, all of which signal intracellularly through Janus Kinase (JAK)-Signal Transducer and Activator of Transcription (STAT) pathways. Differential cytokine expression is proposed to underlie clinical variability. It may be necessary to inhibit signaling of multiple cytokines to achieve adequate control of AD.

Dupilumab is currently the only biologic treatment approved in the United States for moderate-severe AD. Dupilumab revolutionized AD management. However, there remain unmet needs, including the need for faster and more potent efficacy, and oral treatment options. Recently, oral JAK-inhibitors were investigated as treatments for moderate-severe AD. Multiple JAK-inhibitors demonstrated strong and rapid efficacy across multiple clinician-reported and patient-reported outcomes.

• Miao et al. recently conducted a meta-analysis of 10 randomized controlled trials and found that patients receiving JAK inhibitors showed significantly higher efficacy for eczema area and severity index (EASI) and Numeric Rating Scale (NRS)-itch scores and similar rates of adverse-events.
• Kim et al. pooled data from 3 randomized controlled trials of abrocitinib and found significantly higher proportions of clinically meaningful responses for itch in patients receiving abrocitinib 200 mg and 100 mg vs placebo as early as week 2 which continued through week 12.
• Lio et al. performed a post-hoc analysis of a phase 3 study of conducted in North America and found significant improvements for itch severity and sleep disturbance in patients treated with baricitinib 1 mg and 2 mg vs placebo. In particular, patients who achieved improvement of itch or sleep disturbance compared to those who did not were more likely to report having no impact on quality of life impact and improved work productivity.

This new therapeutic class will be an important addition to our therapeutic armamentarium and has potential to transform the AD treatment landscape.

• Many patients prefer taking pills over injections.
• Rapid-onset of efficacy for JAK-inhibitors will certainly be appreciated by patients, especially when trying to control tough flares. It may even guide clinical decision-making. Patients who have a good clinical response to JAK-inhibitors tend to do so within 4-8 weeks. By 8 weeks, if patients have no clinical response, they are likely not going to respond and may benefit from switching to alternative therapies.
• JAK-inhibitors can have robust efficacy, with higher doses of upadacitinib and abrocritinib showing greater efficacy than dupilumab at 12-16 weeks. This makes them attractive options to consider in patients who previously failed dupilumab.
• On the other hand, JAK-inhibitors have laboratory monitoring requirements, including complete blood count, comprehensive metabolic panel, lipid panel, etc.
• JAK-inhibitors warrant adverse-event monitoring for headache, nausea, acne, herpesvirus infections, risk of venous thromboembolism, etc.

Future research is needed to identify patient subsets who will benefit most from JAK-inhibitor therapy and where to position these agents in treatment guidelines.

Atopic Dermatitis (AD) is complex with heterogeneous symptoms (e.g. skin-pain, sleep disturbance), signs (e.g. lichenification, prurigo nodules, follicular accentuation), and longitudinal course (intermittent, persistent). These disparate signs and symptoms should be addressed in optimize disease control.

Multiple extracellular cytokines are upregulated in skin of AD patients, including interleukins 4, 5, 13, 22, 31 and thymic stromal lymphopoietin, all of which signal intracellularly through Janus Kinase (JAK)-Signal Transducer and Activator of Transcription (STAT) pathways. Differential cytokine expression is proposed to underlie clinical variability. It may be necessary to inhibit signaling of multiple cytokines to achieve adequate control of AD.

Dupilumab is currently the only biologic treatment approved in the United States for moderate-severe AD. Dupilumab revolutionized AD management. However, there remain unmet needs, including the need for faster and more potent efficacy, and oral treatment options. Recently, oral JAK-inhibitors were investigated as treatments for moderate-severe AD. Multiple JAK-inhibitors demonstrated strong and rapid efficacy across multiple clinician-reported and patient-reported outcomes.

• Miao et al. recently conducted a meta-analysis of 10 randomized controlled trials and found that patients receiving JAK inhibitors showed significantly higher efficacy for eczema area and severity index (EASI) and Numeric Rating Scale (NRS)-itch scores and similar rates of adverse-events.
• Kim et al. pooled data from 3 randomized controlled trials of abrocitinib and found significantly higher proportions of clinically meaningful responses for itch in patients receiving abrocitinib 200 mg and 100 mg vs placebo as early as week 2 which continued through week 12.
• Lio et al. performed a post-hoc analysis of a phase 3 study of conducted in North America and found significant improvements for itch severity and sleep disturbance in patients treated with baricitinib 1 mg and 2 mg vs placebo. In particular, patients who achieved improvement of itch or sleep disturbance compared to those who did not were more likely to report having no impact on quality of life impact and improved work productivity.

This new therapeutic class will be an important addition to our therapeutic armamentarium and has potential to transform the AD treatment landscape.

• Many patients prefer taking pills over injections.
• Rapid-onset of efficacy for JAK-inhibitors will certainly be appreciated by patients, especially when trying to control tough flares. It may even guide clinical decision-making. Patients who have a good clinical response to JAK-inhibitors tend to do so within 4-8 weeks. By 8 weeks, if patients have no clinical response, they are likely not going to respond and may benefit from switching to alternative therapies.
• JAK-inhibitors can have robust efficacy, with higher doses of upadacitinib and abrocritinib showing greater efficacy than dupilumab at 12-16 weeks. This makes them attractive options to consider in patients who previously failed dupilumab.
• On the other hand, JAK-inhibitors have laboratory monitoring requirements, including complete blood count, comprehensive metabolic panel, lipid panel, etc.
• JAK-inhibitors warrant adverse-event monitoring for headache, nausea, acne, herpesvirus infections, risk of venous thromboembolism, etc.

Future research is needed to identify patient subsets who will benefit most from JAK-inhibitor therapy and where to position these agents in treatment guidelines.

Atopic Dermatitis (AD) is complex with heterogeneous symptoms (e.g. skin-pain, sleep disturbance), signs (e.g. lichenification, prurigo nodules, follicular accentuation), and longitudinal course (intermittent, persistent). These disparate signs and symptoms should be addressed in optimize disease control.

Multiple extracellular cytokines are upregulated in skin of AD patients, including interleukins 4, 5, 13, 22, 31 and thymic stromal lymphopoietin, all of which signal intracellularly through Janus Kinase (JAK)-Signal Transducer and Activator of Transcription (STAT) pathways. Differential cytokine expression is proposed to underlie clinical variability. It may be necessary to inhibit signaling of multiple cytokines to achieve adequate control of AD.

Dupilumab is currently the only biologic treatment approved in the United States for moderate-severe AD. Dupilumab revolutionized AD management. However, there remain unmet needs, including the need for faster and more potent efficacy, and oral treatment options. Recently, oral JAK-inhibitors were investigated as treatments for moderate-severe AD. Multiple JAK-inhibitors demonstrated strong and rapid efficacy across multiple clinician-reported and patient-reported outcomes.

• Miao et al. recently conducted a meta-analysis of 10 randomized controlled trials and found that patients receiving JAK inhibitors showed significantly higher efficacy for eczema area and severity index (EASI) and Numeric Rating Scale (NRS)-itch scores and similar rates of adverse-events.
• Kim et al. pooled data from 3 randomized controlled trials of abrocitinib and found significantly higher proportions of clinically meaningful responses for itch in patients receiving abrocitinib 200 mg and 100 mg vs placebo as early as week 2 which continued through week 12.
• Lio et al. performed a post-hoc analysis of a phase 3 study of conducted in North America and found significant improvements for itch severity and sleep disturbance in patients treated with baricitinib 1 mg and 2 mg vs placebo. In particular, patients who achieved improvement of itch or sleep disturbance compared to those who did not were more likely to report having no impact on quality of life impact and improved work productivity.

This new therapeutic class will be an important addition to our therapeutic armamentarium and has potential to transform the AD treatment landscape.

• Many patients prefer taking pills over injections.
• Rapid-onset of efficacy for JAK-inhibitors will certainly be appreciated by patients, especially when trying to control tough flares. It may even guide clinical decision-making. Patients who have a good clinical response to JAK-inhibitors tend to do so within 4-8 weeks. By 8 weeks, if patients have no clinical response, they are likely not going to respond and may benefit from switching to alternative therapies.
• JAK-inhibitors can have robust efficacy, with higher doses of upadacitinib and abrocritinib showing greater efficacy than dupilumab at 12-16 weeks. This makes them attractive options to consider in patients who previously failed dupilumab.
• On the other hand, JAK-inhibitors have laboratory monitoring requirements, including complete blood count, comprehensive metabolic panel, lipid panel, etc.
• JAK-inhibitors warrant adverse-event monitoring for headache, nausea, acne, herpesvirus infections, risk of venous thromboembolism, etc.

Future research is needed to identify patient subsets who will benefit most from JAK-inhibitor therapy and where to position these agents in treatment guidelines.

Rana et al published a cost-effectiveness analysis in the British Journal of Obstetrics and Gynecology that evaluated the cost-effectiveness of uterine artery embolization (UAE) and myomectomy for women with symptomatic uterine fibroids wishing to avoid hysterectomy. The analysis was conducted along the FEMME randomized control trial, that examined the quality of life of menstruating women with symptomatic fibroids experience after treatment with UAE or myomectomy. Over a 2-year time period, UAE was associated with higher mean costs and lower quality-adjusted life years compared with myomectomy. Similar results were observed over the 4-year time period. The authors concluded that myomectomy is a cost-effective option for the treatment of uterine fibroids.

A third study by Moor et al evaluated the impact of herpes simplex type 2 (HSV-2) infection on incidence and growth of ultrasound-diagnosed uterine fibroids in a large group of African American women. As reproductive tract infections have long been suspected as risk factors for fibroid development, this is a key study. In this prospective study analyzing data from the Study of Environment, Lifestyle and a large cohort of 25-35 year-old African American women with uterine fibroids were monitored by ultrasound over a 5-year period. A key finding was that fibroid HSV-2 positive status was not associated with fibroid incidence.

Rana et al published a cost-effectiveness analysis in the British Journal of Obstetrics and Gynecology that evaluated the cost-effectiveness of uterine artery embolization (UAE) and myomectomy for women with symptomatic uterine fibroids wishing to avoid hysterectomy. The analysis was conducted along the FEMME randomized control trial, that examined the quality of life of menstruating women with symptomatic fibroids experience after treatment with UAE or myomectomy. Over a 2-year time period, UAE was associated with higher mean costs and lower quality-adjusted life years compared with myomectomy. Similar results were observed over the 4-year time period. The authors concluded that myomectomy is a cost-effective option for the treatment of uterine fibroids.

A third study by Moor et al evaluated the impact of herpes simplex type 2 (HSV-2) infection on incidence and growth of ultrasound-diagnosed uterine fibroids in a large group of African American women. As reproductive tract infections have long been suspected as risk factors for fibroid development, this is a key study. In this prospective study analyzing data from the Study of Environment, Lifestyle and a large cohort of 25-35 year-old African American women with uterine fibroids were monitored by ultrasound over a 5-year period. A key finding was that fibroid HSV-2 positive status was not associated with fibroid incidence.

Rana et al published a cost-effectiveness analysis in the British Journal of Obstetrics and Gynecology that evaluated the cost-effectiveness of uterine artery embolization (UAE) and myomectomy for women with symptomatic uterine fibroids wishing to avoid hysterectomy. The analysis was conducted along the FEMME randomized control trial, that examined the quality of life of menstruating women with symptomatic fibroids experience after treatment with UAE or myomectomy. Over a 2-year time period, UAE was associated with higher mean costs and lower quality-adjusted life years compared with myomectomy. Similar results were observed over the 4-year time period. The authors concluded that myomectomy is a cost-effective option for the treatment of uterine fibroids.

A third study by Moor et al evaluated the impact of herpes simplex type 2 (HSV-2) infection on incidence and growth of ultrasound-diagnosed uterine fibroids in a large group of African American women. As reproductive tract infections have long been suspected as risk factors for fibroid development, this is a key study. In this prospective study analyzing data from the Study of Environment, Lifestyle and a large cohort of 25-35 year-old African American women with uterine fibroids were monitored by ultrasound over a 5-year period. A key finding was that fibroid HSV-2 positive status was not associated with fibroid incidence.