Clinical Edge Journal Scan

Emerging data have helped to elucidate the real world experience of regorafenib vs trifluridine/tipiracil in the third-line setting. In a single-institution retrospective study, Patel and colleagues evaluated 126 patients who received trifluridine/tipiracil and 95 patients who received regorafenib. There were higher response and disease control rates seen with trifluridine/tipiracil, although median overall survival was similar (7.5 vs 7.1 months). These findings are limited by the single-institution, retrospective and non-randomized nature of the study. Also, the better-tolerated ReDOS dose-escalation schema for regorafenib was not utilized in this study, and it would be interesting to see how this novel dosing strategy compares to trifluridine/tipiracil in the real world setting.

Immunotherapy with anti-programmed death 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) monoclonal antibodies has proven to be very effective in the rare group of patients with mCRC harboring deficiencies in mismatch repair, but has unfortunately largely fallen short for the vast majority of patients with mismatch repair proficient cancers. Martinelli et al. looked at adding avelumab, and anti-PD-L1 antibody, to cetuximab in an effort to rechallenge patients with RAS wild-type disease to anti-EGFR therapy in the single-arm phase 2 CAVE trial. 77 patients were treated and the median overall survival was an impressive 11.6 months, increasing to 17.3 months in patients with circulating tumor DNA (ctDNA) that was wild-type for both RAS and BRAF. This study suggests that rechallenging with anti-EGFR therapy can be effective in a ctDNA-selected population and that immunotherapy may have a role to play in this setting, although these findings would need to be confirmed in a larger, randomized phase 3 trial.

Finally, the COVID-19 pandemic has upended medical care, including oncology care. Thierry and co-workers evaluated the effect on the pandemic lockdown in France by looking at the baseline levels of ctDNA in 80 patients with newly diagnosed mCRC presenting pre-lockdown vs. post-lockdown. They showed that median ctDNA was much higher post-lockdown (119.2 vs 17.3 ng/mL), implying that delays in diagnosis related to the pandemic led to more advanced mCRC, at least in terms of ctDNA level. This study adds to the growing literature demonstrating that COVID-19 will continue to have effects on cancer care and cancer-related mortality for years to come.

Emerging data have helped to elucidate the real world experience of regorafenib vs trifluridine/tipiracil in the third-line setting. In a single-institution retrospective study, Patel and colleagues evaluated 126 patients who received trifluridine/tipiracil and 95 patients who received regorafenib. There were higher response and disease control rates seen with trifluridine/tipiracil, although median overall survival was similar (7.5 vs 7.1 months). These findings are limited by the single-institution, retrospective and non-randomized nature of the study. Also, the better-tolerated ReDOS dose-escalation schema for regorafenib was not utilized in this study, and it would be interesting to see how this novel dosing strategy compares to trifluridine/tipiracil in the real world setting.

Immunotherapy with anti-programmed death 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) monoclonal antibodies has proven to be very effective in the rare group of patients with mCRC harboring deficiencies in mismatch repair, but has unfortunately largely fallen short for the vast majority of patients with mismatch repair proficient cancers. Martinelli et al. looked at adding avelumab, and anti-PD-L1 antibody, to cetuximab in an effort to rechallenge patients with RAS wild-type disease to anti-EGFR therapy in the single-arm phase 2 CAVE trial. 77 patients were treated and the median overall survival was an impressive 11.6 months, increasing to 17.3 months in patients with circulating tumor DNA (ctDNA) that was wild-type for both RAS and BRAF. This study suggests that rechallenging with anti-EGFR therapy can be effective in a ctDNA-selected population and that immunotherapy may have a role to play in this setting, although these findings would need to be confirmed in a larger, randomized phase 3 trial.

Finally, the COVID-19 pandemic has upended medical care, including oncology care. Thierry and co-workers evaluated the effect on the pandemic lockdown in France by looking at the baseline levels of ctDNA in 80 patients with newly diagnosed mCRC presenting pre-lockdown vs. post-lockdown. They showed that median ctDNA was much higher post-lockdown (119.2 vs 17.3 ng/mL), implying that delays in diagnosis related to the pandemic led to more advanced mCRC, at least in terms of ctDNA level. This study adds to the growing literature demonstrating that COVID-19 will continue to have effects on cancer care and cancer-related mortality for years to come.

Emerging data have helped to elucidate the real world experience of regorafenib vs trifluridine/tipiracil in the third-line setting. In a single-institution retrospective study, Patel and colleagues evaluated 126 patients who received trifluridine/tipiracil and 95 patients who received regorafenib. There were higher response and disease control rates seen with trifluridine/tipiracil, although median overall survival was similar (7.5 vs 7.1 months). These findings are limited by the single-institution, retrospective and non-randomized nature of the study. Also, the better-tolerated ReDOS dose-escalation schema for regorafenib was not utilized in this study, and it would be interesting to see how this novel dosing strategy compares to trifluridine/tipiracil in the real world setting.

Immunotherapy with anti-programmed death 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) monoclonal antibodies has proven to be very effective in the rare group of patients with mCRC harboring deficiencies in mismatch repair, but has unfortunately largely fallen short for the vast majority of patients with mismatch repair proficient cancers. Martinelli et al. looked at adding avelumab, and anti-PD-L1 antibody, to cetuximab in an effort to rechallenge patients with RAS wild-type disease to anti-EGFR therapy in the single-arm phase 2 CAVE trial. 77 patients were treated and the median overall survival was an impressive 11.6 months, increasing to 17.3 months in patients with circulating tumor DNA (ctDNA) that was wild-type for both RAS and BRAF. This study suggests that rechallenging with anti-EGFR therapy can be effective in a ctDNA-selected population and that immunotherapy may have a role to play in this setting, although these findings would need to be confirmed in a larger, randomized phase 3 trial.

Finally, the COVID-19 pandemic has upended medical care, including oncology care. Thierry and co-workers evaluated the effect on the pandemic lockdown in France by looking at the baseline levels of ctDNA in 80 patients with newly diagnosed mCRC presenting pre-lockdown vs. post-lockdown. They showed that median ctDNA was much higher post-lockdown (119.2 vs 17.3 ng/mL), implying that delays in diagnosis related to the pandemic led to more advanced mCRC, at least in terms of ctDNA level. This study adds to the growing literature demonstrating that COVID-19 will continue to have effects on cancer care and cancer-related mortality for years to come.

A second study also evaluated the growth uterine fibroids during a different time during a woman’s lifespan - pregnancy. While it’s commonly thought that fibroids grow during pregnancy, a prospective cross-sectional study in the International Journal of Gynecology & Obstetrics (Tian et al) evaluated 394 women with uterine fibroids and found that growth depended on gestational age. In this group, ultrasound examinations were conducted to measure the size of uterine fibroids during weeks 6–7, 11–14, 22–24 and 28–34 of pregnancy and before delivery. The study team found that uterine fibroid size commonly increased before 22–24 weeks of pregnancy with the fastest growth occurring before 11–14 weeks gestation. Later in pregnancy, from 22–24 weeks to the date of delivery, uterine fibroid size remained unchanged.

Lin et al published a large-scale nationwide cohort study in PLoS One that evaluated whether women with uterine fibroids were at increased risk of developing endometriosis. Overall, 31,239 women with uterine fibroids were matched to 124, 956 control participants and followed for 14 years. Compared to controls, patients with uterine fibroids were at a higher risk of developing endometriosis (adjusted hazard ratio [aHR] 6.44, P < 0.05). Other conditions associated with a higher risk of endometriosis included history of tubo-ovarian infection (aHR 2.86, P = 0.01), endometritis (aHR 1.14, P < 0.001), infertility (aHR 1.26, P < 0.001) and allergic diseases (aHR, 1.11, P < .001). Similarly, having both uterine fibroids and infertility significantly increased the risk of endometriosis (aHR 6.95; P < 0.001).

A second study also evaluated the growth uterine fibroids during a different time during a woman’s lifespan - pregnancy. While it’s commonly thought that fibroids grow during pregnancy, a prospective cross-sectional study in the International Journal of Gynecology & Obstetrics (Tian et al) evaluated 394 women with uterine fibroids and found that growth depended on gestational age. In this group, ultrasound examinations were conducted to measure the size of uterine fibroids during weeks 6–7, 11–14, 22–24 and 28–34 of pregnancy and before delivery. The study team found that uterine fibroid size commonly increased before 22–24 weeks of pregnancy with the fastest growth occurring before 11–14 weeks gestation. Later in pregnancy, from 22–24 weeks to the date of delivery, uterine fibroid size remained unchanged.

Lin et al published a large-scale nationwide cohort study in PLoS One that evaluated whether women with uterine fibroids were at increased risk of developing endometriosis. Overall, 31,239 women with uterine fibroids were matched to 124, 956 control participants and followed for 14 years. Compared to controls, patients with uterine fibroids were at a higher risk of developing endometriosis (adjusted hazard ratio [aHR] 6.44, P < 0.05). Other conditions associated with a higher risk of endometriosis included history of tubo-ovarian infection (aHR 2.86, P = 0.01), endometritis (aHR 1.14, P < 0.001), infertility (aHR 1.26, P < 0.001) and allergic diseases (aHR, 1.11, P < .001). Similarly, having both uterine fibroids and infertility significantly increased the risk of endometriosis (aHR 6.95; P < 0.001).

A second study also evaluated the growth uterine fibroids during a different time during a woman’s lifespan - pregnancy. While it’s commonly thought that fibroids grow during pregnancy, a prospective cross-sectional study in the International Journal of Gynecology & Obstetrics (Tian et al) evaluated 394 women with uterine fibroids and found that growth depended on gestational age. In this group, ultrasound examinations were conducted to measure the size of uterine fibroids during weeks 6–7, 11–14, 22–24 and 28–34 of pregnancy and before delivery. The study team found that uterine fibroid size commonly increased before 22–24 weeks of pregnancy with the fastest growth occurring before 11–14 weeks gestation. Later in pregnancy, from 22–24 weeks to the date of delivery, uterine fibroid size remained unchanged.

Lin et al published a large-scale nationwide cohort study in PLoS One that evaluated whether women with uterine fibroids were at increased risk of developing endometriosis. Overall, 31,239 women with uterine fibroids were matched to 124, 956 control participants and followed for 14 years. Compared to controls, patients with uterine fibroids were at a higher risk of developing endometriosis (adjusted hazard ratio [aHR] 6.44, P < 0.05). Other conditions associated with a higher risk of endometriosis included history of tubo-ovarian infection (aHR 2.86, P = 0.01), endometritis (aHR 1.14, P < 0.001), infertility (aHR 1.26, P < 0.001) and allergic diseases (aHR, 1.11, P < .001). Similarly, having both uterine fibroids and infertility significantly increased the risk of endometriosis (aHR 6.95; P < 0.001).

Ponatinib is most likely the most powerful tyrosine kinase inhibitor (TKI) approved for the relapsed or refractory chronic myeloid leukemia (CML) after two lines of therapy. In the original PACE study, ponatinib showed deep and durable responses, but arterial occlusive events (AOE) emerged as notable adverse events. Post hoc analyses indicated that AOEs were dose dependent and recommendations to lower the dose from 45 mg to 30 mg after achieving complete cytogenic response (CCR) and to 15 mg after achieving major molecular response (MMR) were used in an attempt to minimize the cardiovascular toxicities. The question remained regarding the optimal dose of ponatinib in terms of efficacy and toxicity. Cortes et al (Blood 2021 Aug 18.) reported the results of the OPTIC trial where patients with chronic phase CML (CP-CML), resistant/intolerant to at least 2 prior BCR-ABL1 TKIs or with a BCR-ABL1T315I mutation, were randomized 1:1:1 to receive 3 different doses of ponatinib daily (45, 30, or 15 mg). Patients who received 45 mg or 30 mg daily reduced their dose to 15 mg upon achievement of response (BCR-ABL1^IS transcript levels ≤1%). The primary endpoint (BCR-ABL1^IS transcript levels ≤1%) was achieved at 12 months in 44.1%, 29.0%, and 23.1% in the 3 cohorts, respectively. Independently confirmed grade 3/4 treatment-emergent AOEs occurred in 5, 5, and 3 patients in the 3 cohorts, respectively. In conclusion, the optimal benefit:risk outcomes occurred with the 45 mg starting dose reduced to 15 mg upon achievement of response.

New drugs with alternative mechanisms of action are always welcome for the treatment of resistant or intolerant CP-CML. Asciminib is a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor with the potential to overcome resistance or intolerance to approved TKIs. Rea et al (Blood 2021 Aug 18) reported the results of the ASCEMBL trial that compare 40 mg twice daily asciminib vs. bosutinib in patients with CP-CML refractory to >2 previous lines of therapy. The rates of MMR at week 24 in patients receiving asciminib and bosutinib were 25.5% and 13.2%, respectively (difference 12.2%; P = .029). The bosutinib arm, compared to the asciminib arm, had a more frequent occurrence of grade 3 or higher adverse events (AE; 60.5% vs. 50.6%) and AEs leading to treatment discontinuation (21.1% vs. 5.8%). This will be another important alternative for CP-CML patients failing 2 lines of therapy; however, it is still unclear if the drug may be superior to ponatinib in the same setting.

In the new era of COVID-19, patients with hematologic malignancies are at an increased risk of SARS-CoV-2 disease (COVID-19) and an adverse outcome. However, is unclear if this can be seen across the board in all type of hematologic malignancies, as a low mortality rate has been described in patients with CP-CML, suggesting that TKIs may have a protective role against severe COVID-19. Bonifacio et al (Cancer Med 2021 Aug 31) conducted a cross-sectional study of 564 consecutive patients with CML who were tested for anti-SARS-CoV-2 IgG/IgM antibodies at their first outpatient visit between May and early November 2020 in 5 hematologic centers representative of 3 Italian regions. Interestingly, the serological prevalence of SARS-CoV-2 infection in patients with CML after the first pandemic wave was similar to that in the general population. The data confirm mild SARS-CoV-2 infection in patients with CML and suggest that patients with CML succeed to mount an antibody response after exposure to SARS-CoV-2 similar to the general population.

Ponatinib is most likely the most powerful tyrosine kinase inhibitor (TKI) approved for the relapsed or refractory chronic myeloid leukemia (CML) after two lines of therapy. In the original PACE study, ponatinib showed deep and durable responses, but arterial occlusive events (AOE) emerged as notable adverse events. Post hoc analyses indicated that AOEs were dose dependent and recommendations to lower the dose from 45 mg to 30 mg after achieving complete cytogenic response (CCR) and to 15 mg after achieving major molecular response (MMR) were used in an attempt to minimize the cardiovascular toxicities. The question remained regarding the optimal dose of ponatinib in terms of efficacy and toxicity. Cortes et al (Blood 2021 Aug 18.) reported the results of the OPTIC trial where patients with chronic phase CML (CP-CML), resistant/intolerant to at least 2 prior BCR-ABL1 TKIs or with a BCR-ABL1T315I mutation, were randomized 1:1:1 to receive 3 different doses of ponatinib daily (45, 30, or 15 mg). Patients who received 45 mg or 30 mg daily reduced their dose to 15 mg upon achievement of response (BCR-ABL1^IS transcript levels ≤1%). The primary endpoint (BCR-ABL1^IS transcript levels ≤1%) was achieved at 12 months in 44.1%, 29.0%, and 23.1% in the 3 cohorts, respectively. Independently confirmed grade 3/4 treatment-emergent AOEs occurred in 5, 5, and 3 patients in the 3 cohorts, respectively. In conclusion, the optimal benefit:risk outcomes occurred with the 45 mg starting dose reduced to 15 mg upon achievement of response.

New drugs with alternative mechanisms of action are always welcome for the treatment of resistant or intolerant CP-CML. Asciminib is a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor with the potential to overcome resistance or intolerance to approved TKIs. Rea et al (Blood 2021 Aug 18) reported the results of the ASCEMBL trial that compare 40 mg twice daily asciminib vs. bosutinib in patients with CP-CML refractory to >2 previous lines of therapy. The rates of MMR at week 24 in patients receiving asciminib and bosutinib were 25.5% and 13.2%, respectively (difference 12.2%; P = .029). The bosutinib arm, compared to the asciminib arm, had a more frequent occurrence of grade 3 or higher adverse events (AE; 60.5% vs. 50.6%) and AEs leading to treatment discontinuation (21.1% vs. 5.8%). This will be another important alternative for CP-CML patients failing 2 lines of therapy; however, it is still unclear if the drug may be superior to ponatinib in the same setting.

In the new era of COVID-19, patients with hematologic malignancies are at an increased risk of SARS-CoV-2 disease (COVID-19) and an adverse outcome. However, is unclear if this can be seen across the board in all type of hematologic malignancies, as a low mortality rate has been described in patients with CP-CML, suggesting that TKIs may have a protective role against severe COVID-19. Bonifacio et al (Cancer Med 2021 Aug 31) conducted a cross-sectional study of 564 consecutive patients with CML who were tested for anti-SARS-CoV-2 IgG/IgM antibodies at their first outpatient visit between May and early November 2020 in 5 hematologic centers representative of 3 Italian regions. Interestingly, the serological prevalence of SARS-CoV-2 infection in patients with CML after the first pandemic wave was similar to that in the general population. The data confirm mild SARS-CoV-2 infection in patients with CML and suggest that patients with CML succeed to mount an antibody response after exposure to SARS-CoV-2 similar to the general population.

Ponatinib is most likely the most powerful tyrosine kinase inhibitor (TKI) approved for the relapsed or refractory chronic myeloid leukemia (CML) after two lines of therapy. In the original PACE study, ponatinib showed deep and durable responses, but arterial occlusive events (AOE) emerged as notable adverse events. Post hoc analyses indicated that AOEs were dose dependent and recommendations to lower the dose from 45 mg to 30 mg after achieving complete cytogenic response (CCR) and to 15 mg after achieving major molecular response (MMR) were used in an attempt to minimize the cardiovascular toxicities. The question remained regarding the optimal dose of ponatinib in terms of efficacy and toxicity. Cortes et al (Blood 2021 Aug 18.) reported the results of the OPTIC trial where patients with chronic phase CML (CP-CML), resistant/intolerant to at least 2 prior BCR-ABL1 TKIs or with a BCR-ABL1T315I mutation, were randomized 1:1:1 to receive 3 different doses of ponatinib daily (45, 30, or 15 mg). Patients who received 45 mg or 30 mg daily reduced their dose to 15 mg upon achievement of response (BCR-ABL1^IS transcript levels ≤1%). The primary endpoint (BCR-ABL1^IS transcript levels ≤1%) was achieved at 12 months in 44.1%, 29.0%, and 23.1% in the 3 cohorts, respectively. Independently confirmed grade 3/4 treatment-emergent AOEs occurred in 5, 5, and 3 patients in the 3 cohorts, respectively. In conclusion, the optimal benefit:risk outcomes occurred with the 45 mg starting dose reduced to 15 mg upon achievement of response.

New drugs with alternative mechanisms of action are always welcome for the treatment of resistant or intolerant CP-CML. Asciminib is a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor with the potential to overcome resistance or intolerance to approved TKIs. Rea et al (Blood 2021 Aug 18) reported the results of the ASCEMBL trial that compare 40 mg twice daily asciminib vs. bosutinib in patients with CP-CML refractory to >2 previous lines of therapy. The rates of MMR at week 24 in patients receiving asciminib and bosutinib were 25.5% and 13.2%, respectively (difference 12.2%; P = .029). The bosutinib arm, compared to the asciminib arm, had a more frequent occurrence of grade 3 or higher adverse events (AE; 60.5% vs. 50.6%) and AEs leading to treatment discontinuation (21.1% vs. 5.8%). This will be another important alternative for CP-CML patients failing 2 lines of therapy; however, it is still unclear if the drug may be superior to ponatinib in the same setting.

In the new era of COVID-19, patients with hematologic malignancies are at an increased risk of SARS-CoV-2 disease (COVID-19) and an adverse outcome. However, is unclear if this can be seen across the board in all type of hematologic malignancies, as a low mortality rate has been described in patients with CP-CML, suggesting that TKIs may have a protective role against severe COVID-19. Bonifacio et al (Cancer Med 2021 Aug 31) conducted a cross-sectional study of 564 consecutive patients with CML who were tested for anti-SARS-CoV-2 IgG/IgM antibodies at their first outpatient visit between May and early November 2020 in 5 hematologic centers representative of 3 Italian regions. Interestingly, the serological prevalence of SARS-CoV-2 infection in patients with CML after the first pandemic wave was similar to that in the general population. The data confirm mild SARS-CoV-2 infection in patients with CML and suggest that patients with CML succeed to mount an antibody response after exposure to SARS-CoV-2 similar to the general population.

Marconi et al report out the results of the COV-Barrier study, a phase 3 randomized placebo controlled (RCT) trial with baricitinib, a JAK-STAT pathway inhibitor generally used to suppress proinflammatory cytokine production and systemic inflammation in rheumatoid arthritis, in hospitalized COVID-19 patients. The 1525 participants equally divided between placebo and baricitinib in an intention to treat analysis, were recruited from 12 countries, and most were on systemic corticosteroids (79.3%) and about one fifth received the antiviral, remdesivir. The study did not show a difference in the primary outcome (a composite of progression to more severe disease including need for high flow oxygen, non-invasive or invasive mechanical ventilation or death by 28 days), but did note a 5% absolute reduction in mortality at 28 days. Based on this results, Baricitinib may have a role similar role in the care of COVID-19 patients as tocilizumab (an IL-6 inhibitor) when given in combination with steroids, but may be used in the care of patients earlier in their disease including those on high flow or noninvasive oxygen as well as those requiring invasive mechanical ventilation, compared to tocilizumab, which is currently preferred by many clinicians in those on more intensive respiratory support and within 24-48 hours of ICU admission.  Like other immunomodulators, there is a concern for increased secondary infections with the use of this therapy, but JAK inhibitors also carry a risk for increase in venous thromboembolic events. Interestingly, in this trial, there was no difference in the incidence of either of these adverse effects between the placebo and treatment groups.

The results of a phase 3 RCT with Canakinumab, an anti-interleukin-1B monoclonal antibody, on the other hand, did not show a benefit in primary outcome of survival without need for mechanical ventilation day 3 to day 29, or recovery time, in hospitalized patients who had elevated C-reactive protein and ferritin but were not yet intubated. Canakinumab was evaluated because IL-1B has been identified as one of the signature elevated cytokines in a maladaptive immune response to SARS-CoV-2 infection and because had shown some promise in small and retrospective studies. 

Lastly, on the prevention side, a study of Regeneron’s anti-SARS-CoV-2 monoclonal antibody cocktail (casirivimab and imdevimab) was evaluated in a double blind placebo controlled RCT in prevention of development of symptomatic SARS-CoV-2 infection within 28 days among household contacts who did not have prior immunity. In the study, 1.5% of those who received the monoclonal therapy subcutaneously versus 7.8% of those who received placebo met the primary endpoint. Additionally, those who received the therapy and were symptomatic, resolved their symptoms two weeks earlier. The real-world utility of the results, however, maybe limited to specific groups, given that need for early identification of contacts, the need to access medical facility for administration, as well as the cost of the drug. There may be a role in high risk and immunocompromised contacts who do not develop adequate immune response to vaccination.

Marconi et al report out the results of the COV-Barrier study, a phase 3 randomized placebo controlled (RCT) trial with baricitinib, a JAK-STAT pathway inhibitor generally used to suppress proinflammatory cytokine production and systemic inflammation in rheumatoid arthritis, in hospitalized COVID-19 patients. The 1525 participants equally divided between placebo and baricitinib in an intention to treat analysis, were recruited from 12 countries, and most were on systemic corticosteroids (79.3%) and about one fifth received the antiviral, remdesivir. The study did not show a difference in the primary outcome (a composite of progression to more severe disease including need for high flow oxygen, non-invasive or invasive mechanical ventilation or death by 28 days), but did note a 5% absolute reduction in mortality at 28 days. Based on this results, Baricitinib may have a role similar role in the care of COVID-19 patients as tocilizumab (an IL-6 inhibitor) when given in combination with steroids, but may be used in the care of patients earlier in their disease including those on high flow or noninvasive oxygen as well as those requiring invasive mechanical ventilation, compared to tocilizumab, which is currently preferred by many clinicians in those on more intensive respiratory support and within 24-48 hours of ICU admission.  Like other immunomodulators, there is a concern for increased secondary infections with the use of this therapy, but JAK inhibitors also carry a risk for increase in venous thromboembolic events. Interestingly, in this trial, there was no difference in the incidence of either of these adverse effects between the placebo and treatment groups.

The results of a phase 3 RCT with Canakinumab, an anti-interleukin-1B monoclonal antibody, on the other hand, did not show a benefit in primary outcome of survival without need for mechanical ventilation day 3 to day 29, or recovery time, in hospitalized patients who had elevated C-reactive protein and ferritin but were not yet intubated. Canakinumab was evaluated because IL-1B has been identified as one of the signature elevated cytokines in a maladaptive immune response to SARS-CoV-2 infection and because had shown some promise in small and retrospective studies. 

Lastly, on the prevention side, a study of Regeneron’s anti-SARS-CoV-2 monoclonal antibody cocktail (casirivimab and imdevimab) was evaluated in a double blind placebo controlled RCT in prevention of development of symptomatic SARS-CoV-2 infection within 28 days among household contacts who did not have prior immunity. In the study, 1.5% of those who received the monoclonal therapy subcutaneously versus 7.8% of those who received placebo met the primary endpoint. Additionally, those who received the therapy and were symptomatic, resolved their symptoms two weeks earlier. The real-world utility of the results, however, maybe limited to specific groups, given that need for early identification of contacts, the need to access medical facility for administration, as well as the cost of the drug. There may be a role in high risk and immunocompromised contacts who do not develop adequate immune response to vaccination.

Marconi et al report out the results of the COV-Barrier study, a phase 3 randomized placebo controlled (RCT) trial with baricitinib, a JAK-STAT pathway inhibitor generally used to suppress proinflammatory cytokine production and systemic inflammation in rheumatoid arthritis, in hospitalized COVID-19 patients. The 1525 participants equally divided between placebo and baricitinib in an intention to treat analysis, were recruited from 12 countries, and most were on systemic corticosteroids (79.3%) and about one fifth received the antiviral, remdesivir. The study did not show a difference in the primary outcome (a composite of progression to more severe disease including need for high flow oxygen, non-invasive or invasive mechanical ventilation or death by 28 days), but did note a 5% absolute reduction in mortality at 28 days. Based on this results, Baricitinib may have a role similar role in the care of COVID-19 patients as tocilizumab (an IL-6 inhibitor) when given in combination with steroids, but may be used in the care of patients earlier in their disease including those on high flow or noninvasive oxygen as well as those requiring invasive mechanical ventilation, compared to tocilizumab, which is currently preferred by many clinicians in those on more intensive respiratory support and within 24-48 hours of ICU admission.  Like other immunomodulators, there is a concern for increased secondary infections with the use of this therapy, but JAK inhibitors also carry a risk for increase in venous thromboembolic events. Interestingly, in this trial, there was no difference in the incidence of either of these adverse effects between the placebo and treatment groups.

The results of a phase 3 RCT with Canakinumab, an anti-interleukin-1B monoclonal antibody, on the other hand, did not show a benefit in primary outcome of survival without need for mechanical ventilation day 3 to day 29, or recovery time, in hospitalized patients who had elevated C-reactive protein and ferritin but were not yet intubated. Canakinumab was evaluated because IL-1B has been identified as one of the signature elevated cytokines in a maladaptive immune response to SARS-CoV-2 infection and because had shown some promise in small and retrospective studies. 

Lastly, on the prevention side, a study of Regeneron’s anti-SARS-CoV-2 monoclonal antibody cocktail (casirivimab and imdevimab) was evaluated in a double blind placebo controlled RCT in prevention of development of symptomatic SARS-CoV-2 infection within 28 days among household contacts who did not have prior immunity. In the study, 1.5% of those who received the monoclonal therapy subcutaneously versus 7.8% of those who received placebo met the primary endpoint. Additionally, those who received the therapy and were symptomatic, resolved their symptoms two weeks earlier. The real-world utility of the results, however, maybe limited to specific groups, given that need for early identification of contacts, the need to access medical facility for administration, as well as the cost of the drug. There may be a role in high risk and immunocompromised contacts who do not develop adequate immune response to vaccination.

Topical and oral Janus Kinase (JAK)-inhibitors are important new additions to the therapeutic armamentarium of atopic dermatitis (AD). I recently addressed some important treatment considerations regarding the JAK-inhibitors. In just two short months, there have already been a number of important new publications on JAK-inhibitors in AD that provide crucial data to guide treatment decisions.

Topical ruxolitinib 1.5% cream (a JAK1/2 inhibitor) was just approved by United States Food and Drug Administration for the treatment of mild-moderate AD. Clinicians always want to know about the comparative effectiveness of new agents compared to already approved agents. A previous phase 2B randomized controlled trial (RCT) compared multiple doses of ruxolitinib cream with a vehicle control and triamcinolone 0.1% cream active comparator¹. Topical ruxolitinib 1.5% cream was significantly more effective than vehicle and numerically more effective than triamcinolone 0.1% cream.

Zhang et al. recently conducted a network meta-analysis of 10 RCT for topical JAK and phosphodiesterase E4 (PDE4)-inhibitors, mostly with mild-to-moderate AD. All included JAK inhibitors showed higher Investigators Global Assessment (IGA) response vs. vehicle, with ruxolitinib 1.5% once daily showing similar efficacy as tofacitinib 2% and delgocitinib 3% twice daily. Whereas, topical tacrolimus 0.1% and hydrocortisone butyrate 0.1% twice a day were not more effective than vehicle at achieving IGA response. These results suggest that topical ruxolitinib and other JAK-inhibitors are more effective at clearing AD lesions than currently used topical therapies.

There has been a recent flurry of publications regarding the efficacy and safety of abrocitinib (an oral, once daily, JAK1 inhibitor) in moderate-severe atopic dermatitis.

• Eichenfield et al. published the results of the JADE TEEN study ², a phase 3 RCT of abrocitinib in adolescents. Abrocitinib 200 mg and 100 mg resulted in significant improvements of IGA, Eczema Area and Severity Index, and itch scores, etc. over a 12-week treatment period compared to placebo. These results support the efficacy of abrocitinib in adolescents with moderate-severe AD.
• Simpson et al. published the results from an integrated safety analysis of pooled data from 5 short-term and 1 long-term extension study of abrocitinib therapy ³. Abrocitinib 200 mg and 100 mg doses were well-tolerated during 12-week placebo controlled trials, with nausea, headache, and acne being the most common adverse-events. The incidence of different adverse-events did not consistently increase over time. However, there were some rare events reported for venous thromboembolism and deaths. These results indicate an overall good safety profile for abrocitinib, but proper patient and dose selection should be carefully considered.
• Additionally, strategies should be employed to potentially minimize risk of adverse-events. One such approach is flexible dosing in order to maintain long-term disease control using the lowest amount of medicine needed. Blauvelt et al. published findings from the JADE REGIMEN study ⁴. Patients who responded to 12 weeks of abrocitinib 200 mg open-label monotherapy were randomly assigned to abrocitinib 200 mg, abrocitinib 100 mg, or placebo maintenance therapy for 40-weeks. Flares occurred least commonly in patients maintained on abrocitinib 200 mg (18.9%), followed by abrocitinib 100 mg (42.6%), and most commonly for placebo (80.9%). These results indicate that a large subset of patients who achieve clinical response with abrocitinib 200 mg could be maintained on a lower dose of 100 mg and in some cases may even be able to have a drug holiday without flaring. While similar studies were not performed for other oral JAK-inhibitors, it may be that lower maintenance dosing may also be feasible and effective for other oral JAK-inhibitors. Future research is needed to identify patient subsets who will most likely maintain clinical response with lower maintenance dosing of oral JAK-inhibitors.

1. Kim BS, Howell MD, Sun K, et al. Treatment of atopic dermatitis with ruxolitinib cream (JAK1/JAK2 inhibitor) or triamcinolone cream. The Journal of allergy and clinical immunology. 2020;145(2):572-582.
2. Eichenfield LF, Flohr C, Sidbury R, et al. Efficacy and Safety of Abrocitinib in Combination With Topical Therapy in Adolescents With Moderate-to-Severe Atopic Dermatitis: The JADE TEEN Randomized Clinical Trial. JAMA dermatology. 2021.
3. Simpson EL, Silverberg JI, Nosbaum A, et al. Integrated Safety Analysis of Abrocitinib for the Treatment of Moderate-to-Severe Atopic Dermatitis From the Phase II and Phase III Clinical Trial Program. American journal of clinical dermatology. 2021;22(5):693-707.
4. Blauvelt A, Silverberg JI, Lynde CW, et al. Abrocitinib induction, randomized withdrawal, and retreatment in patients with moderate-to-severe atopic dermatitis: Results from the JAK1 Atopic Dermatitis Efficacy and Safety (JADE) REGIMEN phase 3 trial. Journal of the American Academy of Dermatology.

Topical and oral Janus Kinase (JAK)-inhibitors are important new additions to the therapeutic armamentarium of atopic dermatitis (AD). I recently addressed some important treatment considerations regarding the JAK-inhibitors. In just two short months, there have already been a number of important new publications on JAK-inhibitors in AD that provide crucial data to guide treatment decisions.

Topical ruxolitinib 1.5% cream (a JAK1/2 inhibitor) was just approved by United States Food and Drug Administration for the treatment of mild-moderate AD. Clinicians always want to know about the comparative effectiveness of new agents compared to already approved agents. A previous phase 2B randomized controlled trial (RCT) compared multiple doses of ruxolitinib cream with a vehicle control and triamcinolone 0.1% cream active comparator¹. Topical ruxolitinib 1.5% cream was significantly more effective than vehicle and numerically more effective than triamcinolone 0.1% cream.

Zhang et al. recently conducted a network meta-analysis of 10 RCT for topical JAK and phosphodiesterase E4 (PDE4)-inhibitors, mostly with mild-to-moderate AD. All included JAK inhibitors showed higher Investigators Global Assessment (IGA) response vs. vehicle, with ruxolitinib 1.5% once daily showing similar efficacy as tofacitinib 2% and delgocitinib 3% twice daily. Whereas, topical tacrolimus 0.1% and hydrocortisone butyrate 0.1% twice a day were not more effective than vehicle at achieving IGA response. These results suggest that topical ruxolitinib and other JAK-inhibitors are more effective at clearing AD lesions than currently used topical therapies.

There has been a recent flurry of publications regarding the efficacy and safety of abrocitinib (an oral, once daily, JAK1 inhibitor) in moderate-severe atopic dermatitis.

• Eichenfield et al. published the results of the JADE TEEN study ², a phase 3 RCT of abrocitinib in adolescents. Abrocitinib 200 mg and 100 mg resulted in significant improvements of IGA, Eczema Area and Severity Index, and itch scores, etc. over a 12-week treatment period compared to placebo. These results support the efficacy of abrocitinib in adolescents with moderate-severe AD.
• Simpson et al. published the results from an integrated safety analysis of pooled data from 5 short-term and 1 long-term extension study of abrocitinib therapy ³. Abrocitinib 200 mg and 100 mg doses were well-tolerated during 12-week placebo controlled trials, with nausea, headache, and acne being the most common adverse-events. The incidence of different adverse-events did not consistently increase over time. However, there were some rare events reported for venous thromboembolism and deaths. These results indicate an overall good safety profile for abrocitinib, but proper patient and dose selection should be carefully considered.
• Additionally, strategies should be employed to potentially minimize risk of adverse-events. One such approach is flexible dosing in order to maintain long-term disease control using the lowest amount of medicine needed. Blauvelt et al. published findings from the JADE REGIMEN study ⁴. Patients who responded to 12 weeks of abrocitinib 200 mg open-label monotherapy were randomly assigned to abrocitinib 200 mg, abrocitinib 100 mg, or placebo maintenance therapy for 40-weeks. Flares occurred least commonly in patients maintained on abrocitinib 200 mg (18.9%), followed by abrocitinib 100 mg (42.6%), and most commonly for placebo (80.9%). These results indicate that a large subset of patients who achieve clinical response with abrocitinib 200 mg could be maintained on a lower dose of 100 mg and in some cases may even be able to have a drug holiday without flaring. While similar studies were not performed for other oral JAK-inhibitors, it may be that lower maintenance dosing may also be feasible and effective for other oral JAK-inhibitors. Future research is needed to identify patient subsets who will most likely maintain clinical response with lower maintenance dosing of oral JAK-inhibitors.

1. Kim BS, Howell MD, Sun K, et al. Treatment of atopic dermatitis with ruxolitinib cream (JAK1/JAK2 inhibitor) or triamcinolone cream. The Journal of allergy and clinical immunology. 2020;145(2):572-582.
2. Eichenfield LF, Flohr C, Sidbury R, et al. Efficacy and Safety of Abrocitinib in Combination With Topical Therapy in Adolescents With Moderate-to-Severe Atopic Dermatitis: The JADE TEEN Randomized Clinical Trial. JAMA dermatology. 2021.
3. Simpson EL, Silverberg JI, Nosbaum A, et al. Integrated Safety Analysis of Abrocitinib for the Treatment of Moderate-to-Severe Atopic Dermatitis From the Phase II and Phase III Clinical Trial Program. American journal of clinical dermatology. 2021;22(5):693-707.
4. Blauvelt A, Silverberg JI, Lynde CW, et al. Abrocitinib induction, randomized withdrawal, and retreatment in patients with moderate-to-severe atopic dermatitis: Results from the JAK1 Atopic Dermatitis Efficacy and Safety (JADE) REGIMEN phase 3 trial. Journal of the American Academy of Dermatology.

Topical and oral Janus Kinase (JAK)-inhibitors are important new additions to the therapeutic armamentarium of atopic dermatitis (AD). I recently addressed some important treatment considerations regarding the JAK-inhibitors. In just two short months, there have already been a number of important new publications on JAK-inhibitors in AD that provide crucial data to guide treatment decisions.

Topical ruxolitinib 1.5% cream (a JAK1/2 inhibitor) was just approved by United States Food and Drug Administration for the treatment of mild-moderate AD. Clinicians always want to know about the comparative effectiveness of new agents compared to already approved agents. A previous phase 2B randomized controlled trial (RCT) compared multiple doses of ruxolitinib cream with a vehicle control and triamcinolone 0.1% cream active comparator¹. Topical ruxolitinib 1.5% cream was significantly more effective than vehicle and numerically more effective than triamcinolone 0.1% cream.

Zhang et al. recently conducted a network meta-analysis of 10 RCT for topical JAK and phosphodiesterase E4 (PDE4)-inhibitors, mostly with mild-to-moderate AD. All included JAK inhibitors showed higher Investigators Global Assessment (IGA) response vs. vehicle, with ruxolitinib 1.5% once daily showing similar efficacy as tofacitinib 2% and delgocitinib 3% twice daily. Whereas, topical tacrolimus 0.1% and hydrocortisone butyrate 0.1% twice a day were not more effective than vehicle at achieving IGA response. These results suggest that topical ruxolitinib and other JAK-inhibitors are more effective at clearing AD lesions than currently used topical therapies.

There has been a recent flurry of publications regarding the efficacy and safety of abrocitinib (an oral, once daily, JAK1 inhibitor) in moderate-severe atopic dermatitis.

• Eichenfield et al. published the results of the JADE TEEN study ², a phase 3 RCT of abrocitinib in adolescents. Abrocitinib 200 mg and 100 mg resulted in significant improvements of IGA, Eczema Area and Severity Index, and itch scores, etc. over a 12-week treatment period compared to placebo. These results support the efficacy of abrocitinib in adolescents with moderate-severe AD.
• Simpson et al. published the results from an integrated safety analysis of pooled data from 5 short-term and 1 long-term extension study of abrocitinib therapy ³. Abrocitinib 200 mg and 100 mg doses were well-tolerated during 12-week placebo controlled trials, with nausea, headache, and acne being the most common adverse-events. The incidence of different adverse-events did not consistently increase over time. However, there were some rare events reported for venous thromboembolism and deaths. These results indicate an overall good safety profile for abrocitinib, but proper patient and dose selection should be carefully considered.
• Additionally, strategies should be employed to potentially minimize risk of adverse-events. One such approach is flexible dosing in order to maintain long-term disease control using the lowest amount of medicine needed. Blauvelt et al. published findings from the JADE REGIMEN study ⁴. Patients who responded to 12 weeks of abrocitinib 200 mg open-label monotherapy were randomly assigned to abrocitinib 200 mg, abrocitinib 100 mg, or placebo maintenance therapy for 40-weeks. Flares occurred least commonly in patients maintained on abrocitinib 200 mg (18.9%), followed by abrocitinib 100 mg (42.6%), and most commonly for placebo (80.9%). These results indicate that a large subset of patients who achieve clinical response with abrocitinib 200 mg could be maintained on a lower dose of 100 mg and in some cases may even be able to have a drug holiday without flaring. While similar studies were not performed for other oral JAK-inhibitors, it may be that lower maintenance dosing may also be feasible and effective for other oral JAK-inhibitors. Future research is needed to identify patient subsets who will most likely maintain clinical response with lower maintenance dosing of oral JAK-inhibitors.

1. Kim BS, Howell MD, Sun K, et al. Treatment of atopic dermatitis with ruxolitinib cream (JAK1/JAK2 inhibitor) or triamcinolone cream. The Journal of allergy and clinical immunology. 2020;145(2):572-582.
2. Eichenfield LF, Flohr C, Sidbury R, et al. Efficacy and Safety of Abrocitinib in Combination With Topical Therapy in Adolescents With Moderate-to-Severe Atopic Dermatitis: The JADE TEEN Randomized Clinical Trial. JAMA dermatology. 2021.
3. Simpson EL, Silverberg JI, Nosbaum A, et al. Integrated Safety Analysis of Abrocitinib for the Treatment of Moderate-to-Severe Atopic Dermatitis From the Phase II and Phase III Clinical Trial Program. American journal of clinical dermatology. 2021;22(5):693-707.
4. Blauvelt A, Silverberg JI, Lynde CW, et al. Abrocitinib induction, randomized withdrawal, and retreatment in patients with moderate-to-severe atopic dermatitis: Results from the JAK1 Atopic Dermatitis Efficacy and Safety (JADE) REGIMEN phase 3 trial. Journal of the American Academy of Dermatology.

High-potency topical steroids such as clobetasol are commonly used as first-line treatment for psoriasis. A recent study (Sidgiddi S et al. Dermatol Ther (Heidelb). 2021 Aug 28) compared the efficacy and safety of clobetasol 0.05% vs. 0.025% cream.  Patients were randomized to receive either clobetasol 0.05% cream or one of two different formulations of clobetasol 0.025% cream twice a day for two weeks. PGA success rates (clear or almost clear skin) were higher with the 0.025% formulations (38.9% and 36.8%) than with the 0.05% cream (30.8%). Safety also appeared to be better or comparable with the 0.025% formulation as measured by the proportion of patients with an abnormal ACTH stimulation test (20.7% and 17.2% in the 0.025% group compared with 30.0% in the 0.05% group). Due to the small study size (88 subjects) these differences did not reach statistical significance, although they suggest that high efficacy and perhaps better safety (reduced hypothalamic–pituitary–adrenal axis suppression) can be achieved with lower concentration formulations of clobetasol cream.

The oral phosphodiesterase 4 inhibitor apremilast is FDA-approved to treat psoriasis and psoriatic arthritis and recent studies have shown that it is more effective than placebo in treating patients with mild-moderate psoriasis and scalp psoriasis. A recent prospective cohort study followed 45 adult patients with plaque and nail psoriasis with a fingernail Nail Psoriasis Severity Index (NAPSI) score of 12 or more treated with apremilast 30 mg twice daily for 52 weeks (Muñoz-Santos C et al. J Dermatol. 2021 Aug 12). The primary endpoint, the percentage of patients with a Nail Assessment in Psoriasis and Psoriatic Arthritis-Patient Benefit Index of 2 or more at week 52, was achieved in 52% of patients. A median improvement of 53% in fingernail NAPSI score and a mean reduction in nail pain of 68% were observed at week 52.  These findings show that apremilast can be useful in improving the quality-of-life impairment caused by nail psoriasis.

Traditional systemic therapies such as methotrexate and acitretin are cost-effective options for many psoriasis patients. The association of psoriasis with other comorbid conditions, particularly cardiovascular disease, has raised awareness of the importance of considering how therapies impact not just skin disease but also the risk posed by these psoriasis-associated comorbidities. A large Taiwanese retrospective cohort study compared patients treated with methotrexate (13,777) or acitretin (6,020) and found that in comparison to those treated with acitretin, patients treated with methotrexate were at lower risk of experiencing adverse cardiovascular outcomes, including ischemic heart disease and stroke, (adjusted hazard ratio [aHR], 0.84; 95% confidence interval [CI], 0.76-0.94) and had a lower risk of all-cause mortality (aHR, 0.75; 95% CI, 0.66-0.85).

Many disease and patient factors must be considered when choosing the right therapy for a patient. These studies provide valuable information to incorporate into this process and highlight the utility of topical and oral therapies for psoriasis.

High-potency topical steroids such as clobetasol are commonly used as first-line treatment for psoriasis. A recent study (Sidgiddi S et al. Dermatol Ther (Heidelb). 2021 Aug 28) compared the efficacy and safety of clobetasol 0.05% vs. 0.025% cream.  Patients were randomized to receive either clobetasol 0.05% cream or one of two different formulations of clobetasol 0.025% cream twice a day for two weeks. PGA success rates (clear or almost clear skin) were higher with the 0.025% formulations (38.9% and 36.8%) than with the 0.05% cream (30.8%). Safety also appeared to be better or comparable with the 0.025% formulation as measured by the proportion of patients with an abnormal ACTH stimulation test (20.7% and 17.2% in the 0.025% group compared with 30.0% in the 0.05% group). Due to the small study size (88 subjects) these differences did not reach statistical significance, although they suggest that high efficacy and perhaps better safety (reduced hypothalamic–pituitary–adrenal axis suppression) can be achieved with lower concentration formulations of clobetasol cream.

The oral phosphodiesterase 4 inhibitor apremilast is FDA-approved to treat psoriasis and psoriatic arthritis and recent studies have shown that it is more effective than placebo in treating patients with mild-moderate psoriasis and scalp psoriasis. A recent prospective cohort study followed 45 adult patients with plaque and nail psoriasis with a fingernail Nail Psoriasis Severity Index (NAPSI) score of 12 or more treated with apremilast 30 mg twice daily for 52 weeks (Muñoz-Santos C et al. J Dermatol. 2021 Aug 12). The primary endpoint, the percentage of patients with a Nail Assessment in Psoriasis and Psoriatic Arthritis-Patient Benefit Index of 2 or more at week 52, was achieved in 52% of patients. A median improvement of 53% in fingernail NAPSI score and a mean reduction in nail pain of 68% were observed at week 52.  These findings show that apremilast can be useful in improving the quality-of-life impairment caused by nail psoriasis.

Traditional systemic therapies such as methotrexate and acitretin are cost-effective options for many psoriasis patients. The association of psoriasis with other comorbid conditions, particularly cardiovascular disease, has raised awareness of the importance of considering how therapies impact not just skin disease but also the risk posed by these psoriasis-associated comorbidities. A large Taiwanese retrospective cohort study compared patients treated with methotrexate (13,777) or acitretin (6,020) and found that in comparison to those treated with acitretin, patients treated with methotrexate were at lower risk of experiencing adverse cardiovascular outcomes, including ischemic heart disease and stroke, (adjusted hazard ratio [aHR], 0.84; 95% confidence interval [CI], 0.76-0.94) and had a lower risk of all-cause mortality (aHR, 0.75; 95% CI, 0.66-0.85).

Many disease and patient factors must be considered when choosing the right therapy for a patient. These studies provide valuable information to incorporate into this process and highlight the utility of topical and oral therapies for psoriasis.

High-potency topical steroids such as clobetasol are commonly used as first-line treatment for psoriasis. A recent study (Sidgiddi S et al. Dermatol Ther (Heidelb). 2021 Aug 28) compared the efficacy and safety of clobetasol 0.05% vs. 0.025% cream.  Patients were randomized to receive either clobetasol 0.05% cream or one of two different formulations of clobetasol 0.025% cream twice a day for two weeks. PGA success rates (clear or almost clear skin) were higher with the 0.025% formulations (38.9% and 36.8%) than with the 0.05% cream (30.8%). Safety also appeared to be better or comparable with the 0.025% formulation as measured by the proportion of patients with an abnormal ACTH stimulation test (20.7% and 17.2% in the 0.025% group compared with 30.0% in the 0.05% group). Due to the small study size (88 subjects) these differences did not reach statistical significance, although they suggest that high efficacy and perhaps better safety (reduced hypothalamic–pituitary–adrenal axis suppression) can be achieved with lower concentration formulations of clobetasol cream.

The oral phosphodiesterase 4 inhibitor apremilast is FDA-approved to treat psoriasis and psoriatic arthritis and recent studies have shown that it is more effective than placebo in treating patients with mild-moderate psoriasis and scalp psoriasis. A recent prospective cohort study followed 45 adult patients with plaque and nail psoriasis with a fingernail Nail Psoriasis Severity Index (NAPSI) score of 12 or more treated with apremilast 30 mg twice daily for 52 weeks (Muñoz-Santos C et al. J Dermatol. 2021 Aug 12). The primary endpoint, the percentage of patients with a Nail Assessment in Psoriasis and Psoriatic Arthritis-Patient Benefit Index of 2 or more at week 52, was achieved in 52% of patients. A median improvement of 53% in fingernail NAPSI score and a mean reduction in nail pain of 68% were observed at week 52.  These findings show that apremilast can be useful in improving the quality-of-life impairment caused by nail psoriasis.

Traditional systemic therapies such as methotrexate and acitretin are cost-effective options for many psoriasis patients. The association of psoriasis with other comorbid conditions, particularly cardiovascular disease, has raised awareness of the importance of considering how therapies impact not just skin disease but also the risk posed by these psoriasis-associated comorbidities. A large Taiwanese retrospective cohort study compared patients treated with methotrexate (13,777) or acitretin (6,020) and found that in comparison to those treated with acitretin, patients treated with methotrexate were at lower risk of experiencing adverse cardiovascular outcomes, including ischemic heart disease and stroke, (adjusted hazard ratio [aHR], 0.84; 95% confidence interval [CI], 0.76-0.94) and had a lower risk of all-cause mortality (aHR, 0.75; 95% CI, 0.66-0.85).

Many disease and patient factors must be considered when choosing the right therapy for a patient. These studies provide valuable information to incorporate into this process and highlight the utility of topical and oral therapies for psoriasis.

This month a couple of studies evaluated the role of enasidenib and gemtuzumab in the therapy of patients with AML using clinical and non-clinical trial data. In a propensity score-matching (PSM) analysis, was enasidenib associated with better outcomes compared to standard of care (SoC). The study included adult patients with relapsed/refractory (R/R) AML with an isocitrate dehydrogenase 2 (IDH2) mutation ineligible for hematopoietic stem cell transplantation (HSCT) treated with enasidenib (n = 195) from the AG221 C-001 trial or SoC therapies (n = 78) from the French Chart Review study. The SoC regimens included azacytidine, decitabine, cytarabine containing regimens, and others. Enasidenib was associated with superior overall survival (OS) (hazard ratio [HR] 0.67; 95% CI 0.47-0.97) compared to SoC therapies in patients with R/R AML with IDH2 mutation who were ineligible for HSCT. The median OS was 9.26 months vs. 4.76 months for enasidenib and SoC respectively. The results of this study are not surprising given the data seen in clinical trials. Although not evaluated in this study, the quality of life for patients receiving enasidenib is better when compared to SoC regimens, such as 7 +3 (cytarabine + idarubicin). Other than the limitations of a PSM study, which are well acknowledged by the authors, the main weakness is this study did not include venetoclax in the SoC regimen. It remains unclear whether using venetoclax in the R/R setting in patients with IDH2 mutations would lead to similar outcomes.

The benefit of gemtuzumab ozogamicin (GO) was demonstrated again in a metanalysis that included 15 randomized controlled trials and 15 retrospective studies that compared GO (n = 4,768) with non-GO (n = 6,466) therapies in 11,234 patients with AML (n = 11,105) and high-risk myelodysplastic syndrome (MDS) (n = 129). GO showed superior survival outcomes in patients with AML or high-risk MDS than non-GO therapy, but higher doses increased the risk for early death. GO vs. non-GO arm showed improved overall survival (HR 0.86; P = .003), event-free survival (HR 0.86; P = .015), and relapse-free survival (HR 0.83; P = .001). However, GO vs. non-GO was associated with an increased risk for early death at a dose of ≥6 mg/m² (relative risk [RR] 2.01; P = .005), hepatic-related adverse effects (RR 1.29; P = .02), and bleeding (RR 1.13; P = .018). Finally, a study by the Polish adult leukemia group demonstrated the safety and efficacy of a low dose cytarabine + cladribine regimen. Treatment consisted of 5 mg/m² cladribine intravenously on day 1-5 (in the first cycle) and on days 1 to 3 (in the second cycle) combined with low dose cytarabine (40 mg) subcutaneously once daily on days 1–10. Patients may continue on low dose cytarabine after that if they have achieved at least a partial remission. Rates of overall response and 56-day mortality were 54.0% and 20.5%, respectively. The median overall survival was 6.9 months (95% CI 4.9-9.6) and superior in patients who achieved an objective response (HR 0.04; P < .0001) or partial remission (HR 0.31; P = .0002) compared to nonresponders.

In addition to the better therapies in the last decade, allogeneic hematopoietic stem cell transplantation (allo-HSCT) outcomes have also improved. In a retrospective analysis from the Japanese nationwide transplantation registry the outcomes of patients transplanted with unrelated cord blood (UCB) and Haplo transplant between 2007 to 2014 were worse when compared to patients who had a transplant between 2015 and 2018. For patients who had transplants between 2015 and 2018, the 3-year overall survival of mismatched unrelated donor (MMUD), unrelated cord blood (UCB), and Haplo groups were 60%, 66%, and 63%, respectively (P = .693). The rates of nonrelapse mortality (P = .147), relapse (P = .075), and graft-vs. host disease-free/relapse-free survival (P = .365) were also similar between the 3 groups. For patients with transplant between 2007 to 2014 the 3 year overall survival was 60%, 54%, and 47% for MMUD, UCB, and Haplo transplants respectively. Newer, better drugs, better tolerated regimens, and improved transplant outcomes were the result: many small gains lead to large improvements.

This month a couple of studies evaluated the role of enasidenib and gemtuzumab in the therapy of patients with AML using clinical and non-clinical trial data. In a propensity score-matching (PSM) analysis, was enasidenib associated with better outcomes compared to standard of care (SoC). The study included adult patients with relapsed/refractory (R/R) AML with an isocitrate dehydrogenase 2 (IDH2) mutation ineligible for hematopoietic stem cell transplantation (HSCT) treated with enasidenib (n = 195) from the AG221 C-001 trial or SoC therapies (n = 78) from the French Chart Review study. The SoC regimens included azacytidine, decitabine, cytarabine containing regimens, and others. Enasidenib was associated with superior overall survival (OS) (hazard ratio [HR] 0.67; 95% CI 0.47-0.97) compared to SoC therapies in patients with R/R AML with IDH2 mutation who were ineligible for HSCT. The median OS was 9.26 months vs. 4.76 months for enasidenib and SoC respectively. The results of this study are not surprising given the data seen in clinical trials. Although not evaluated in this study, the quality of life for patients receiving enasidenib is better when compared to SoC regimens, such as 7 +3 (cytarabine + idarubicin). Other than the limitations of a PSM study, which are well acknowledged by the authors, the main weakness is this study did not include venetoclax in the SoC regimen. It remains unclear whether using venetoclax in the R/R setting in patients with IDH2 mutations would lead to similar outcomes.

The benefit of gemtuzumab ozogamicin (GO) was demonstrated again in a metanalysis that included 15 randomized controlled trials and 15 retrospective studies that compared GO (n = 4,768) with non-GO (n = 6,466) therapies in 11,234 patients with AML (n = 11,105) and high-risk myelodysplastic syndrome (MDS) (n = 129). GO showed superior survival outcomes in patients with AML or high-risk MDS than non-GO therapy, but higher doses increased the risk for early death. GO vs. non-GO arm showed improved overall survival (HR 0.86; P = .003), event-free survival (HR 0.86; P = .015), and relapse-free survival (HR 0.83; P = .001). However, GO vs. non-GO was associated with an increased risk for early death at a dose of ≥6 mg/m² (relative risk [RR] 2.01; P = .005), hepatic-related adverse effects (RR 1.29; P = .02), and bleeding (RR 1.13; P = .018). Finally, a study by the Polish adult leukemia group demonstrated the safety and efficacy of a low dose cytarabine + cladribine regimen. Treatment consisted of 5 mg/m² cladribine intravenously on day 1-5 (in the first cycle) and on days 1 to 3 (in the second cycle) combined with low dose cytarabine (40 mg) subcutaneously once daily on days 1–10. Patients may continue on low dose cytarabine after that if they have achieved at least a partial remission. Rates of overall response and 56-day mortality were 54.0% and 20.5%, respectively. The median overall survival was 6.9 months (95% CI 4.9-9.6) and superior in patients who achieved an objective response (HR 0.04; P < .0001) or partial remission (HR 0.31; P = .0002) compared to nonresponders.

In addition to the better therapies in the last decade, allogeneic hematopoietic stem cell transplantation (allo-HSCT) outcomes have also improved. In a retrospective analysis from the Japanese nationwide transplantation registry the outcomes of patients transplanted with unrelated cord blood (UCB) and Haplo transplant between 2007 to 2014 were worse when compared to patients who had a transplant between 2015 and 2018. For patients who had transplants between 2015 and 2018, the 3-year overall survival of mismatched unrelated donor (MMUD), unrelated cord blood (UCB), and Haplo groups were 60%, 66%, and 63%, respectively (P = .693). The rates of nonrelapse mortality (P = .147), relapse (P = .075), and graft-vs. host disease-free/relapse-free survival (P = .365) were also similar between the 3 groups. For patients with transplant between 2007 to 2014 the 3 year overall survival was 60%, 54%, and 47% for MMUD, UCB, and Haplo transplants respectively. Newer, better drugs, better tolerated regimens, and improved transplant outcomes were the result: many small gains lead to large improvements.

This month a couple of studies evaluated the role of enasidenib and gemtuzumab in the therapy of patients with AML using clinical and non-clinical trial data. In a propensity score-matching (PSM) analysis, was enasidenib associated with better outcomes compared to standard of care (SoC). The study included adult patients with relapsed/refractory (R/R) AML with an isocitrate dehydrogenase 2 (IDH2) mutation ineligible for hematopoietic stem cell transplantation (HSCT) treated with enasidenib (n = 195) from the AG221 C-001 trial or SoC therapies (n = 78) from the French Chart Review study. The SoC regimens included azacytidine, decitabine, cytarabine containing regimens, and others. Enasidenib was associated with superior overall survival (OS) (hazard ratio [HR] 0.67; 95% CI 0.47-0.97) compared to SoC therapies in patients with R/R AML with IDH2 mutation who were ineligible for HSCT. The median OS was 9.26 months vs. 4.76 months for enasidenib and SoC respectively. The results of this study are not surprising given the data seen in clinical trials. Although not evaluated in this study, the quality of life for patients receiving enasidenib is better when compared to SoC regimens, such as 7 +3 (cytarabine + idarubicin). Other than the limitations of a PSM study, which are well acknowledged by the authors, the main weakness is this study did not include venetoclax in the SoC regimen. It remains unclear whether using venetoclax in the R/R setting in patients with IDH2 mutations would lead to similar outcomes.

The benefit of gemtuzumab ozogamicin (GO) was demonstrated again in a metanalysis that included 15 randomized controlled trials and 15 retrospective studies that compared GO (n = 4,768) with non-GO (n = 6,466) therapies in 11,234 patients with AML (n = 11,105) and high-risk myelodysplastic syndrome (MDS) (n = 129). GO showed superior survival outcomes in patients with AML or high-risk MDS than non-GO therapy, but higher doses increased the risk for early death. GO vs. non-GO arm showed improved overall survival (HR 0.86; P = .003), event-free survival (HR 0.86; P = .015), and relapse-free survival (HR 0.83; P = .001). However, GO vs. non-GO was associated with an increased risk for early death at a dose of ≥6 mg/m² (relative risk [RR] 2.01; P = .005), hepatic-related adverse effects (RR 1.29; P = .02), and bleeding (RR 1.13; P = .018). Finally, a study by the Polish adult leukemia group demonstrated the safety and efficacy of a low dose cytarabine + cladribine regimen. Treatment consisted of 5 mg/m² cladribine intravenously on day 1-5 (in the first cycle) and on days 1 to 3 (in the second cycle) combined with low dose cytarabine (40 mg) subcutaneously once daily on days 1–10. Patients may continue on low dose cytarabine after that if they have achieved at least a partial remission. Rates of overall response and 56-day mortality were 54.0% and 20.5%, respectively. The median overall survival was 6.9 months (95% CI 4.9-9.6) and superior in patients who achieved an objective response (HR 0.04; P < .0001) or partial remission (HR 0.31; P = .0002) compared to nonresponders.

In addition to the better therapies in the last decade, allogeneic hematopoietic stem cell transplantation (allo-HSCT) outcomes have also improved. In a retrospective analysis from the Japanese nationwide transplantation registry the outcomes of patients transplanted with unrelated cord blood (UCB) and Haplo transplant between 2007 to 2014 were worse when compared to patients who had a transplant between 2015 and 2018. For patients who had transplants between 2015 and 2018, the 3-year overall survival of mismatched unrelated donor (MMUD), unrelated cord blood (UCB), and Haplo groups were 60%, 66%, and 63%, respectively (P = .693). The rates of nonrelapse mortality (P = .147), relapse (P = .075), and graft-vs. host disease-free/relapse-free survival (P = .365) were also similar between the 3 groups. For patients with transplant between 2007 to 2014 the 3 year overall survival was 60%, 54%, and 47% for MMUD, UCB, and Haplo transplants respectively. Newer, better drugs, better tolerated regimens, and improved transplant outcomes were the result: many small gains lead to large improvements.

Key clinical point: A meta-analysis has identified 10 key risk factors for mortality in hospitalized patients with COVID-19.

Major finding: The significant mortality-related risk factors in hospitalized patients with COVID-19 included older age, male sex, smoking, obesity, cardiovascular disease, diabetes, hypertension, chronic obstructive pulmonary disease, acute kidney injury, and elevated D-dimer levels.

Study details: The data come from a meta-analysis of 42 studies involving 423,117 patients with COVID-19.

Disclosures: The study did not receive any funding. The authors declared no conflict of interests.

Source: Dessie ZG et al. BMC Infect Dis. 2021 Aug 21. doi: 10.1186/s12879-021-06536-3.

Key clinical point: A meta-analysis has identified 10 key risk factors for mortality in hospitalized patients with COVID-19.

Major finding: The significant mortality-related risk factors in hospitalized patients with COVID-19 included older age, male sex, smoking, obesity, cardiovascular disease, diabetes, hypertension, chronic obstructive pulmonary disease, acute kidney injury, and elevated D-dimer levels.

Study details: The data come from a meta-analysis of 42 studies involving 423,117 patients with COVID-19.

Disclosures: The study did not receive any funding. The authors declared no conflict of interests.

Source: Dessie ZG et al. BMC Infect Dis. 2021 Aug 21. doi: 10.1186/s12879-021-06536-3.

Key clinical point: A meta-analysis has identified 10 key risk factors for mortality in hospitalized patients with COVID-19.

Major finding: The significant mortality-related risk factors in hospitalized patients with COVID-19 included older age, male sex, smoking, obesity, cardiovascular disease, diabetes, hypertension, chronic obstructive pulmonary disease, acute kidney injury, and elevated D-dimer levels.

Study details: The data come from a meta-analysis of 42 studies involving 423,117 patients with COVID-19.

Disclosures: The study did not receive any funding. The authors declared no conflict of interests.

Source: Dessie ZG et al. BMC Infect Dis. 2021 Aug 21. doi: 10.1186/s12879-021-06536-3.

Key clinical point: A single subcutaneous dose of the antibody cocktail REGEN-COV (casirivimab plus imdevimab) is effective in preventing symptomatic and asymptomatic infection in household contacts of COVID-19-positive individuals.

Major finding: The antibody cocktail group developed fewer symptomatic SARS-CoV-2 infections than the placebo group (relative risk reduction, 81.4%). The antibody cocktail effectively prevented symptomatic and asymptomatic infections overall (relative risk reduction, 66.4%).

Study details: In a randomized, double-blind, placebo-controlled trial, unaffected household members (age, 12 years or older) of individuals testing positive for SARS-CoV-2 received either the antibody cocktail (n=753) or placebo (n=752).

Disclosures: The study was funded by Regeneron Pharmaceuticals, F. Hoffmann-LaRoche, and the National Institutes of Health. Several authors were employees and/or stockholders of Regeneron Pharmaceuticals.

Source: O'Brien MP et al. N Engl J Med. 2021 Aug 4. doi: 10.1056/NEJMoa2109682.

Key clinical point: A single subcutaneous dose of the antibody cocktail REGEN-COV (casirivimab plus imdevimab) is effective in preventing symptomatic and asymptomatic infection in household contacts of COVID-19-positive individuals.

Major finding: The antibody cocktail group developed fewer symptomatic SARS-CoV-2 infections than the placebo group (relative risk reduction, 81.4%). The antibody cocktail effectively prevented symptomatic and asymptomatic infections overall (relative risk reduction, 66.4%).

Study details: In a randomized, double-blind, placebo-controlled trial, unaffected household members (age, 12 years or older) of individuals testing positive for SARS-CoV-2 received either the antibody cocktail (n=753) or placebo (n=752).

Disclosures: The study was funded by Regeneron Pharmaceuticals, F. Hoffmann-LaRoche, and the National Institutes of Health. Several authors were employees and/or stockholders of Regeneron Pharmaceuticals.

Source: O'Brien MP et al. N Engl J Med. 2021 Aug 4. doi: 10.1056/NEJMoa2109682.

Key clinical point: A single subcutaneous dose of the antibody cocktail REGEN-COV (casirivimab plus imdevimab) is effective in preventing symptomatic and asymptomatic infection in household contacts of COVID-19-positive individuals.

Major finding: The antibody cocktail group developed fewer symptomatic SARS-CoV-2 infections than the placebo group (relative risk reduction, 81.4%). The antibody cocktail effectively prevented symptomatic and asymptomatic infections overall (relative risk reduction, 66.4%).

Study details: In a randomized, double-blind, placebo-controlled trial, unaffected household members (age, 12 years or older) of individuals testing positive for SARS-CoV-2 received either the antibody cocktail (n=753) or placebo (n=752).

Disclosures: The study was funded by Regeneron Pharmaceuticals, F. Hoffmann-LaRoche, and the National Institutes of Health. Several authors were employees and/or stockholders of Regeneron Pharmaceuticals.

Source: O'Brien MP et al. N Engl J Med. 2021 Aug 4. doi: 10.1056/NEJMoa2109682.

Key clinical point: Dapagliflozin does not improve COVID-19 hospitalization outcomes for patients with cardiometabolic risk factors.

Major finding: Dapagliflozin vs placebo failed to meet the primary composite outcome of organ dysfunction or all-cause death (hazard ratio, 0.80; 95% confidence interval, 0.58-1.10). There was no difference in the rates of new/worsened organ dysfunction, deaths, or clinical improvement between the groups.

Study details: In the DARE-19 phase 3 trial, patients were randomly assigned to receive either dapagliflozin (n=625) or placebo (n=625).

Disclosures: The study was funded by AstraZeneca. R Esterline, J Oscarsson, SB Gasparyan, J Buenconsejo, AM Langkilde, and P Ambery are employees and stockholders of AstraZeneca. M Aboudara, E Akin, WKS Barroso, ADM Feitosa, CRH Filho, A Fonseca, K Gosch, RA Gordon, CP Jaeger, LN Maia, DDF Moia, JRL Soto, F Tang, SL Windsor, O Mukhtar, V Chopra, RVP Soares, V Garla, PE Leaes, FS Silveira, and M Pursley declared no conflict of interests. The remaining authors disclosed relationships with pharmaceutical companies and/or research institutions.

Source: Kosiborod MN et al. Lancet Diabetes Endocrinol. 2021 Jul 21. doi: 10.1016/S2213-8587(21)00180-7.

Key clinical point: Dapagliflozin does not improve COVID-19 hospitalization outcomes for patients with cardiometabolic risk factors.

Major finding: Dapagliflozin vs placebo failed to meet the primary composite outcome of organ dysfunction or all-cause death (hazard ratio, 0.80; 95% confidence interval, 0.58-1.10). There was no difference in the rates of new/worsened organ dysfunction, deaths, or clinical improvement between the groups.

Study details: In the DARE-19 phase 3 trial, patients were randomly assigned to receive either dapagliflozin (n=625) or placebo (n=625).

Disclosures: The study was funded by AstraZeneca. R Esterline, J Oscarsson, SB Gasparyan, J Buenconsejo, AM Langkilde, and P Ambery are employees and stockholders of AstraZeneca. M Aboudara, E Akin, WKS Barroso, ADM Feitosa, CRH Filho, A Fonseca, K Gosch, RA Gordon, CP Jaeger, LN Maia, DDF Moia, JRL Soto, F Tang, SL Windsor, O Mukhtar, V Chopra, RVP Soares, V Garla, PE Leaes, FS Silveira, and M Pursley declared no conflict of interests. The remaining authors disclosed relationships with pharmaceutical companies and/or research institutions.

Source: Kosiborod MN et al. Lancet Diabetes Endocrinol. 2021 Jul 21. doi: 10.1016/S2213-8587(21)00180-7.

Key clinical point: Dapagliflozin does not improve COVID-19 hospitalization outcomes for patients with cardiometabolic risk factors.

Major finding: Dapagliflozin vs placebo failed to meet the primary composite outcome of organ dysfunction or all-cause death (hazard ratio, 0.80; 95% confidence interval, 0.58-1.10). There was no difference in the rates of new/worsened organ dysfunction, deaths, or clinical improvement between the groups.

Study details: In the DARE-19 phase 3 trial, patients were randomly assigned to receive either dapagliflozin (n=625) or placebo (n=625).

Disclosures: The study was funded by AstraZeneca. R Esterline, J Oscarsson, SB Gasparyan, J Buenconsejo, AM Langkilde, and P Ambery are employees and stockholders of AstraZeneca. M Aboudara, E Akin, WKS Barroso, ADM Feitosa, CRH Filho, A Fonseca, K Gosch, RA Gordon, CP Jaeger, LN Maia, DDF Moia, JRL Soto, F Tang, SL Windsor, O Mukhtar, V Chopra, RVP Soares, V Garla, PE Leaes, FS Silveira, and M Pursley declared no conflict of interests. The remaining authors disclosed relationships with pharmaceutical companies and/or research institutions.

Source: Kosiborod MN et al. Lancet Diabetes Endocrinol. 2021 Jul 21. doi: 10.1016/S2213-8587(21)00180-7.