Clinical Edge Journal Scan Commentary

Most research published on psoriatic arthritis (PsA) in the month of June 2021 were related to treatment. Conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and anti-tumour necrosis factor (TNF) remain the most used drugs to treat PsA worldwide. However, the benefits of combining csDMARDs and anti-TNF therapies have been less well studied. Lindström et al studied this question using data from 15,332 patients with PsA from 13 European countries participating in the EuroSpA collaboration who initiated a first anti-TNF treatment in 2006–2017.  Sixty-two percent of the patients were on combined therapy, while 38% were no anti-TNF monotherapy. Overall, combined treatment was associated with better remission rates, pooled odds ratio (OR) 1.25 (1.12–1.41). Methotrexate (MTX) comedication was associated with improved rates of remission with adalimumab (OR 1.45 [1.23–1.72]) and infliximab (OR 1.55 [1.21–1.98]) and improved drug retention with infliximab. No effect of comedication could be demonstrated for etanercept. Thus, in clinical practice there may be an advantage to combine MTX with infliximab or adalimumab.

Biosimilars provide similar efficacy and safety to originator biologics at lower cost. Many jurisdictions are mandating nonmedical switch from a biologic to a biosimilar but concerns about such administrative switches remain among patients and physicians. Giunta et al report their observations in patients undergoing nonmedical switch from originator adalimumab to biosimilar adalimumab (ABP 501/ adalimumab-atto). In this retrospective study of 94 patients, 46 of whom underwent nonmedical switch from originator adalimumab to ABP 501, they found no significant differences in PASI or DAS-28 ESR at before and after switch in patients undergoing nonmedical switch from adalimumab originator to ABP 501. This study, although small and observational, adds to the growing body of literature on the effectiveness and safety of biosimilars including nonmedical switching.

About newer therapies, Mease et al reported the 52-week results of the phase 2b trial with tildrakizumab (an anti-IL23 biologic) in PsA. In this study, 391 patients with PsA who were randomly assigned to tildrakizumab 200 mg every 4 weeks (Q4W), tildrakizumab 200 mg, 100 mg, or 20 mg every 12 weeks or placebo Q4W. At week 24, the proportion of patients achieving at least 20% improvement in the American College of Rheumatology response was significantly higher for any dose of tildrakizumab vs placebo (71.4%-79.5% vs 50.6%; all P ≤.0125). However, improvement in dactylitis and enthesitis was not observed. No new safety signals were observed through W52. Tildrakizumab may be another option for the management of PsA but requires further evaluation in phase 3 trials.

About gender differences, Prior-Español et al using the Spanish BIOBADASER III registry demonstrated that women with PsA were at greater risk of discontinuing DMARDs because of both lack of efficacy and adverse events. Finally, Ferguson et al reported results from a prospective, open label study of adults receiving apremilast 30 mg as part of routine care for psoriatic disease. They show that in addition to reduction in disease activity, apremilast treatment was significantly associated with a mean weight loss of 2.2 kg and a mean body mass index decrease of 0.8 kg/m² (both P < .001). Improvement in disease activity did not correlate with weight change.

Most research published on psoriatic arthritis (PsA) in the month of June 2021 were related to treatment. Conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and anti-tumour necrosis factor (TNF) remain the most used drugs to treat PsA worldwide. However, the benefits of combining csDMARDs and anti-TNF therapies have been less well studied. Lindström et al studied this question using data from 15,332 patients with PsA from 13 European countries participating in the EuroSpA collaboration who initiated a first anti-TNF treatment in 2006–2017.  Sixty-two percent of the patients were on combined therapy, while 38% were no anti-TNF monotherapy. Overall, combined treatment was associated with better remission rates, pooled odds ratio (OR) 1.25 (1.12–1.41). Methotrexate (MTX) comedication was associated with improved rates of remission with adalimumab (OR 1.45 [1.23–1.72]) and infliximab (OR 1.55 [1.21–1.98]) and improved drug retention with infliximab. No effect of comedication could be demonstrated for etanercept. Thus, in clinical practice there may be an advantage to combine MTX with infliximab or adalimumab.

Biosimilars provide similar efficacy and safety to originator biologics at lower cost. Many jurisdictions are mandating nonmedical switch from a biologic to a biosimilar but concerns about such administrative switches remain among patients and physicians. Giunta et al report their observations in patients undergoing nonmedical switch from originator adalimumab to biosimilar adalimumab (ABP 501/ adalimumab-atto). In this retrospective study of 94 patients, 46 of whom underwent nonmedical switch from originator adalimumab to ABP 501, they found no significant differences in PASI or DAS-28 ESR at before and after switch in patients undergoing nonmedical switch from adalimumab originator to ABP 501. This study, although small and observational, adds to the growing body of literature on the effectiveness and safety of biosimilars including nonmedical switching.

About newer therapies, Mease et al reported the 52-week results of the phase 2b trial with tildrakizumab (an anti-IL23 biologic) in PsA. In this study, 391 patients with PsA who were randomly assigned to tildrakizumab 200 mg every 4 weeks (Q4W), tildrakizumab 200 mg, 100 mg, or 20 mg every 12 weeks or placebo Q4W. At week 24, the proportion of patients achieving at least 20% improvement in the American College of Rheumatology response was significantly higher for any dose of tildrakizumab vs placebo (71.4%-79.5% vs 50.6%; all P ≤.0125). However, improvement in dactylitis and enthesitis was not observed. No new safety signals were observed through W52. Tildrakizumab may be another option for the management of PsA but requires further evaluation in phase 3 trials.

About gender differences, Prior-Español et al using the Spanish BIOBADASER III registry demonstrated that women with PsA were at greater risk of discontinuing DMARDs because of both lack of efficacy and adverse events. Finally, Ferguson et al reported results from a prospective, open label study of adults receiving apremilast 30 mg as part of routine care for psoriatic disease. They show that in addition to reduction in disease activity, apremilast treatment was significantly associated with a mean weight loss of 2.2 kg and a mean body mass index decrease of 0.8 kg/m² (both P < .001). Improvement in disease activity did not correlate with weight change.

Most research published on psoriatic arthritis (PsA) in the month of June 2021 were related to treatment. Conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and anti-tumour necrosis factor (TNF) remain the most used drugs to treat PsA worldwide. However, the benefits of combining csDMARDs and anti-TNF therapies have been less well studied. Lindström et al studied this question using data from 15,332 patients with PsA from 13 European countries participating in the EuroSpA collaboration who initiated a first anti-TNF treatment in 2006–2017.  Sixty-two percent of the patients were on combined therapy, while 38% were no anti-TNF monotherapy. Overall, combined treatment was associated with better remission rates, pooled odds ratio (OR) 1.25 (1.12–1.41). Methotrexate (MTX) comedication was associated with improved rates of remission with adalimumab (OR 1.45 [1.23–1.72]) and infliximab (OR 1.55 [1.21–1.98]) and improved drug retention with infliximab. No effect of comedication could be demonstrated for etanercept. Thus, in clinical practice there may be an advantage to combine MTX with infliximab or adalimumab.

Biosimilars provide similar efficacy and safety to originator biologics at lower cost. Many jurisdictions are mandating nonmedical switch from a biologic to a biosimilar but concerns about such administrative switches remain among patients and physicians. Giunta et al report their observations in patients undergoing nonmedical switch from originator adalimumab to biosimilar adalimumab (ABP 501/ adalimumab-atto). In this retrospective study of 94 patients, 46 of whom underwent nonmedical switch from originator adalimumab to ABP 501, they found no significant differences in PASI or DAS-28 ESR at before and after switch in patients undergoing nonmedical switch from adalimumab originator to ABP 501. This study, although small and observational, adds to the growing body of literature on the effectiveness and safety of biosimilars including nonmedical switching.

About newer therapies, Mease et al reported the 52-week results of the phase 2b trial with tildrakizumab (an anti-IL23 biologic) in PsA. In this study, 391 patients with PsA who were randomly assigned to tildrakizumab 200 mg every 4 weeks (Q4W), tildrakizumab 200 mg, 100 mg, or 20 mg every 12 weeks or placebo Q4W. At week 24, the proportion of patients achieving at least 20% improvement in the American College of Rheumatology response was significantly higher for any dose of tildrakizumab vs placebo (71.4%-79.5% vs 50.6%; all P ≤.0125). However, improvement in dactylitis and enthesitis was not observed. No new safety signals were observed through W52. Tildrakizumab may be another option for the management of PsA but requires further evaluation in phase 3 trials.

About gender differences, Prior-Español et al using the Spanish BIOBADASER III registry demonstrated that women with PsA were at greater risk of discontinuing DMARDs because of both lack of efficacy and adverse events. Finally, Ferguson et al reported results from a prospective, open label study of adults receiving apremilast 30 mg as part of routine care for psoriatic disease. They show that in addition to reduction in disease activity, apremilast treatment was significantly associated with a mean weight loss of 2.2 kg and a mean body mass index decrease of 0.8 kg/m² (both P < .001). Improvement in disease activity did not correlate with weight change.

Measurable residual disease (MRD) in acute myeloid leukemia (AML) is both predictive and prognostic. However, the best time and method to define its prognostic role remains unclear. This month, 2 papers evaluate the role of MRD testing at different time points during therapy.

The first paper by Tsai et al studied MRD by next-generation sequencing (NGS) after induction and consolidation. The second paper by Kim et al evaluated the role of NGS MRD before and after allogeneic hematopoietic cell transplantation (allo-HCT).

The study by Tsai et al was a retrospective study that analyzed 1005 bone marrow samples serially collected at diagnosis, the first CR after induction chemotherapy (MRD^1st), and after the first consolidation (MRD^2nd) chemotherapy from 335 patients with de novo AML. Patients with antecedent cytopenia, hematologic diseases, and therapy-related AML (t-AML) were excluded. Patients who achieved complete remission with incomplete hematologic recovery (CRi) or had DNMT3A, TET2, and ASXL1 (DTA) only mutations were not included in the analysis. Multiple previous studies have demonstrated that persistence of DTA only mutations have no prognostic impact. Patients with positive MRD^1st (MRD^1st-)but negative MRD^2nd (MRD^2nd-)had good prognosis similar to those with negative MRD at both time points (cumulative incidence of relapse (CIR), P = .140; relapse-free survival (RFS), P = .231; overall survival (OS), P = .188). The median OS for patients with MRD^1st-MRD2^nd- (n = 147), and MRD^1st+MRD^2nd- (n = 60) was not reached compared to 3.1 years for patients with MRD^1st+MRD^2nd+ (n = 75). Only 9 patients progressed from MRD^1st- to MRD^2nd+ and their median survival was 3.6 years.

In the study by Kim et al utilizing NGS pre- and postHCT, the detection of MRD using NGS had a prognostic value before and 1 month after allo-HCT. This study included 146 patients with AML who underwent allo-HCT in complete remission between 2013 and 2018. The OS was 82%, 64%, and 44% for patients who were MRD negative both pre and post HCT, MRD+ then MRD- after alloHCT and MRD+ both pre- and postHCT respectively. In this study, myeloablative conditioning (MAC) pre allo-HCT did not overcome the negative prognostic value of MRD+ disease prior to allo-HCT. This is in contradiction to the BMT CTN0901 where MAC did overcome the negative prognostic impact of MRD+ disease prior to alloHCT. The authors suggest that this difference could be due to the limited number of genes assessed in the BMT CTN0901 study. Both of those studies demonstrate that achieving NGS MRD negativity either with chemotherapy consolidation or alloHCT leads to better outcome and can be used as a meaningful endpoint in AML studies.

Another completely different direction to improve patient outcomes is the evaluation of the gut microbiota. Several studies have demonstrated the negative impact of disturbed gut microbiota on several outcomes in patients with AML receiving intensive chemotherapy. A study by Malard et al demonstrated that autologous fecal microbiota transfer (AFMT) was safe and effective for gut microbiota restoration in patients with AML receiving intensive chemotherapy and antibiotics. After AFMT treatment, α-diversity indices returned to their initial median levels (Shannon index, P = .70; Inverse Simpson index, P = .90) and the b-diversity index showed the restoration of microbial communities, particularly for Lachnospiraceae and Ruminococcaceae families. Gut microbiota composition was preserved even after consolidation chemotherapy with high-dose cytarabine. No serious adverse events were reported, and only 3 patients experienced transient gastrointestinal symptoms. This approach may be considered in the future to improve the outcome of patients or allogeneic stool transfer is another option currently being studied. Clearly gut microbiota have an effect on outcome, and future studies will demonstrate the best and safest way to reconstitute gut microbiota in patients with hematological malignancies.

Measurable residual disease (MRD) in acute myeloid leukemia (AML) is both predictive and prognostic. However, the best time and method to define its prognostic role remains unclear. This month, 2 papers evaluate the role of MRD testing at different time points during therapy.

The first paper by Tsai et al studied MRD by next-generation sequencing (NGS) after induction and consolidation. The second paper by Kim et al evaluated the role of NGS MRD before and after allogeneic hematopoietic cell transplantation (allo-HCT).

The study by Tsai et al was a retrospective study that analyzed 1005 bone marrow samples serially collected at diagnosis, the first CR after induction chemotherapy (MRD^1st), and after the first consolidation (MRD^2nd) chemotherapy from 335 patients with de novo AML. Patients with antecedent cytopenia, hematologic diseases, and therapy-related AML (t-AML) were excluded. Patients who achieved complete remission with incomplete hematologic recovery (CRi) or had DNMT3A, TET2, and ASXL1 (DTA) only mutations were not included in the analysis. Multiple previous studies have demonstrated that persistence of DTA only mutations have no prognostic impact. Patients with positive MRD^1st (MRD^1st-)but negative MRD^2nd (MRD^2nd-)had good prognosis similar to those with negative MRD at both time points (cumulative incidence of relapse (CIR), P = .140; relapse-free survival (RFS), P = .231; overall survival (OS), P = .188). The median OS for patients with MRD^1st-MRD2^nd- (n = 147), and MRD^1st+MRD^2nd- (n = 60) was not reached compared to 3.1 years for patients with MRD^1st+MRD^2nd+ (n = 75). Only 9 patients progressed from MRD^1st- to MRD^2nd+ and their median survival was 3.6 years.

In the study by Kim et al utilizing NGS pre- and postHCT, the detection of MRD using NGS had a prognostic value before and 1 month after allo-HCT. This study included 146 patients with AML who underwent allo-HCT in complete remission between 2013 and 2018. The OS was 82%, 64%, and 44% for patients who were MRD negative both pre and post HCT, MRD+ then MRD- after alloHCT and MRD+ both pre- and postHCT respectively. In this study, myeloablative conditioning (MAC) pre allo-HCT did not overcome the negative prognostic value of MRD+ disease prior to allo-HCT. This is in contradiction to the BMT CTN0901 where MAC did overcome the negative prognostic impact of MRD+ disease prior to alloHCT. The authors suggest that this difference could be due to the limited number of genes assessed in the BMT CTN0901 study. Both of those studies demonstrate that achieving NGS MRD negativity either with chemotherapy consolidation or alloHCT leads to better outcome and can be used as a meaningful endpoint in AML studies.

Another completely different direction to improve patient outcomes is the evaluation of the gut microbiota. Several studies have demonstrated the negative impact of disturbed gut microbiota on several outcomes in patients with AML receiving intensive chemotherapy. A study by Malard et al demonstrated that autologous fecal microbiota transfer (AFMT) was safe and effective for gut microbiota restoration in patients with AML receiving intensive chemotherapy and antibiotics. After AFMT treatment, α-diversity indices returned to their initial median levels (Shannon index, P = .70; Inverse Simpson index, P = .90) and the b-diversity index showed the restoration of microbial communities, particularly for Lachnospiraceae and Ruminococcaceae families. Gut microbiota composition was preserved even after consolidation chemotherapy with high-dose cytarabine. No serious adverse events were reported, and only 3 patients experienced transient gastrointestinal symptoms. This approach may be considered in the future to improve the outcome of patients or allogeneic stool transfer is another option currently being studied. Clearly gut microbiota have an effect on outcome, and future studies will demonstrate the best and safest way to reconstitute gut microbiota in patients with hematological malignancies.

Measurable residual disease (MRD) in acute myeloid leukemia (AML) is both predictive and prognostic. However, the best time and method to define its prognostic role remains unclear. This month, 2 papers evaluate the role of MRD testing at different time points during therapy.

The first paper by Tsai et al studied MRD by next-generation sequencing (NGS) after induction and consolidation. The second paper by Kim et al evaluated the role of NGS MRD before and after allogeneic hematopoietic cell transplantation (allo-HCT).

The study by Tsai et al was a retrospective study that analyzed 1005 bone marrow samples serially collected at diagnosis, the first CR after induction chemotherapy (MRD^1st), and after the first consolidation (MRD^2nd) chemotherapy from 335 patients with de novo AML. Patients with antecedent cytopenia, hematologic diseases, and therapy-related AML (t-AML) were excluded. Patients who achieved complete remission with incomplete hematologic recovery (CRi) or had DNMT3A, TET2, and ASXL1 (DTA) only mutations were not included in the analysis. Multiple previous studies have demonstrated that persistence of DTA only mutations have no prognostic impact. Patients with positive MRD^1st (MRD^1st-)but negative MRD^2nd (MRD^2nd-)had good prognosis similar to those with negative MRD at both time points (cumulative incidence of relapse (CIR), P = .140; relapse-free survival (RFS), P = .231; overall survival (OS), P = .188). The median OS for patients with MRD^1st-MRD2^nd- (n = 147), and MRD^1st+MRD^2nd- (n = 60) was not reached compared to 3.1 years for patients with MRD^1st+MRD^2nd+ (n = 75). Only 9 patients progressed from MRD^1st- to MRD^2nd+ and their median survival was 3.6 years.

In the study by Kim et al utilizing NGS pre- and postHCT, the detection of MRD using NGS had a prognostic value before and 1 month after allo-HCT. This study included 146 patients with AML who underwent allo-HCT in complete remission between 2013 and 2018. The OS was 82%, 64%, and 44% for patients who were MRD negative both pre and post HCT, MRD+ then MRD- after alloHCT and MRD+ both pre- and postHCT respectively. In this study, myeloablative conditioning (MAC) pre allo-HCT did not overcome the negative prognostic value of MRD+ disease prior to allo-HCT. This is in contradiction to the BMT CTN0901 where MAC did overcome the negative prognostic impact of MRD+ disease prior to alloHCT. The authors suggest that this difference could be due to the limited number of genes assessed in the BMT CTN0901 study. Both of those studies demonstrate that achieving NGS MRD negativity either with chemotherapy consolidation or alloHCT leads to better outcome and can be used as a meaningful endpoint in AML studies.

Another completely different direction to improve patient outcomes is the evaluation of the gut microbiota. Several studies have demonstrated the negative impact of disturbed gut microbiota on several outcomes in patients with AML receiving intensive chemotherapy. A study by Malard et al demonstrated that autologous fecal microbiota transfer (AFMT) was safe and effective for gut microbiota restoration in patients with AML receiving intensive chemotherapy and antibiotics. After AFMT treatment, α-diversity indices returned to their initial median levels (Shannon index, P = .70; Inverse Simpson index, P = .90) and the b-diversity index showed the restoration of microbial communities, particularly for Lachnospiraceae and Ruminococcaceae families. Gut microbiota composition was preserved even after consolidation chemotherapy with high-dose cytarabine. No serious adverse events were reported, and only 3 patients experienced transient gastrointestinal symptoms. This approach may be considered in the future to improve the outcome of patients or allogeneic stool transfer is another option currently being studied. Clearly gut microbiota have an effect on outcome, and future studies will demonstrate the best and safest way to reconstitute gut microbiota in patients with hematological malignancies.

Treatment of prostate cancer presents significant challenges with respect to balancing efficacy and side effects of treatments. Thus, quality of life endpoints are included in studies of patients with prostate cancer to better understand and counsel patients with this heterogenous disease. In the 3 studies discussed here, functional or quality of life outcomes were included in the analyses.

            In the first study, Hagens et al evaluated the effects of postoperative complications of robot-assisted radical prostatectomy on the health-related quality of life (HRQoL) as measured via surveys and assessment of functional outcomes. While no significant association between HRQoL at 6 months and complications postoperatively were identified, there was an association between functional outcomes and HRQoL at 6 months identified. Thus, future studies designed to identify more optimal patient selection or improved surgical techniques may benefit patients.

            Studies have suggested that androgen deprivation therapy (ADT) may be associated with decreased cognitive function. However, other studies suggested that ADT via luteinizing hormone releasing hormone (LHRH) agonists or antagonists may actually have a protective effect against decreased cognitive function due to low gonadotropin exposure. Andela et al conducted a systematic review based on this hypothesis. Of the 31 studies included in the review, 16 demonstrated that ADT was not associated with decreased cognitive function, while 11 studies did support this association and 4 studies were inconclusive. Therefore, no definitive conclusions can be made based on this review, and further randomized studies are needed.

            Radiation to the prostate may affect the rectum with sometimes significant effects. Hydrogel spacers injected between the prostate and rectum have been evaluated in patients with conventional radiation previously with evidence of benefit, but the benefits for patients undergoing stereotactic body radiotherapy (SBRT) are unknown. Ogita et al conducted a phase II single-arm study designed to evaluate the effects of a hydrogel spacer on gastrointestinal toxicity within 3 months of SBRT. Physician-assessed toxicity was not reduced, but patient reported toxicity was improved compared with historical controls. While this study does not support routine use in the setting of prostate SBRT, it does suggest that future larger randomized studies are worth consideration.

Treatment of prostate cancer presents significant challenges with respect to balancing efficacy and side effects of treatments. Thus, quality of life endpoints are included in studies of patients with prostate cancer to better understand and counsel patients with this heterogenous disease. In the 3 studies discussed here, functional or quality of life outcomes were included in the analyses.

            In the first study, Hagens et al evaluated the effects of postoperative complications of robot-assisted radical prostatectomy on the health-related quality of life (HRQoL) as measured via surveys and assessment of functional outcomes. While no significant association between HRQoL at 6 months and complications postoperatively were identified, there was an association between functional outcomes and HRQoL at 6 months identified. Thus, future studies designed to identify more optimal patient selection or improved surgical techniques may benefit patients.

            Studies have suggested that androgen deprivation therapy (ADT) may be associated with decreased cognitive function. However, other studies suggested that ADT via luteinizing hormone releasing hormone (LHRH) agonists or antagonists may actually have a protective effect against decreased cognitive function due to low gonadotropin exposure. Andela et al conducted a systematic review based on this hypothesis. Of the 31 studies included in the review, 16 demonstrated that ADT was not associated with decreased cognitive function, while 11 studies did support this association and 4 studies were inconclusive. Therefore, no definitive conclusions can be made based on this review, and further randomized studies are needed.

            Radiation to the prostate may affect the rectum with sometimes significant effects. Hydrogel spacers injected between the prostate and rectum have been evaluated in patients with conventional radiation previously with evidence of benefit, but the benefits for patients undergoing stereotactic body radiotherapy (SBRT) are unknown. Ogita et al conducted a phase II single-arm study designed to evaluate the effects of a hydrogel spacer on gastrointestinal toxicity within 3 months of SBRT. Physician-assessed toxicity was not reduced, but patient reported toxicity was improved compared with historical controls. While this study does not support routine use in the setting of prostate SBRT, it does suggest that future larger randomized studies are worth consideration.

Treatment of prostate cancer presents significant challenges with respect to balancing efficacy and side effects of treatments. Thus, quality of life endpoints are included in studies of patients with prostate cancer to better understand and counsel patients with this heterogenous disease. In the 3 studies discussed here, functional or quality of life outcomes were included in the analyses.

            In the first study, Hagens et al evaluated the effects of postoperative complications of robot-assisted radical prostatectomy on the health-related quality of life (HRQoL) as measured via surveys and assessment of functional outcomes. While no significant association between HRQoL at 6 months and complications postoperatively were identified, there was an association between functional outcomes and HRQoL at 6 months identified. Thus, future studies designed to identify more optimal patient selection or improved surgical techniques may benefit patients.

            Studies have suggested that androgen deprivation therapy (ADT) may be associated with decreased cognitive function. However, other studies suggested that ADT via luteinizing hormone releasing hormone (LHRH) agonists or antagonists may actually have a protective effect against decreased cognitive function due to low gonadotropin exposure. Andela et al conducted a systematic review based on this hypothesis. Of the 31 studies included in the review, 16 demonstrated that ADT was not associated with decreased cognitive function, while 11 studies did support this association and 4 studies were inconclusive. Therefore, no definitive conclusions can be made based on this review, and further randomized studies are needed.

            Radiation to the prostate may affect the rectum with sometimes significant effects. Hydrogel spacers injected between the prostate and rectum have been evaluated in patients with conventional radiation previously with evidence of benefit, but the benefits for patients undergoing stereotactic body radiotherapy (SBRT) are unknown. Ogita et al conducted a phase II single-arm study designed to evaluate the effects of a hydrogel spacer on gastrointestinal toxicity within 3 months of SBRT. Physician-assessed toxicity was not reduced, but patient reported toxicity was improved compared with historical controls. While this study does not support routine use in the setting of prostate SBRT, it does suggest that future larger randomized studies are worth consideration.

The role of adjuvant olaparib was investigated in the phase 3 OlympiA trial, which included 1,836 patients with high-risk HER2-negative gBRCAm early breast cancer who received local treatment and adjuvant or neoadjuvant chemotherapy. One year of adjuvant olaparib was associated with a significant improvement in invasive disease-free survival (hazard ratio [HR] 0.58, P < .001) and distant disease-free survival (HR 0.57, P < .001). The 3-year invasive disease-free survival (iDFS) was 85.9% in the olaparib group and 77.1% in the placebo group (absolute benefit of 8.8%), and 3-year distant disease-free survival (dDFS) was 87.5% and 80.4%, respectively (difference of 7.1%). These results are considered practice changing and lead to questions regarding the expansion of germline testing in early stage breast cancer. Furthermore, PARP inhibitors have shown exciting results in the neoadjuvant setting. Among 61 patients with gBRCAm HER2-negative early breast cancer, neoadjuvant talazoparib produced a pathologic complete response (pCR) in 49.2%, and there may be a subgroup of patients for whom this approach is relevant.

The presence of residual disease after neoadjuvant chemotherapy has prognostic implications and can help tailor adjuvant treatment recommendations. The CREATE-X trial has established the role of adjuvant capecitabine for patients with triple-negative breast cancer with residual disease after pre-operative chemotherapy. The phase 3 EA1131 trial randomized 415 patients with stage II-III triple-negative breast cancer and residual disease post-neoadjuvant chemotherapy to platinum agent or capecitabine. There was no significant difference in 3-year iDFS (42% for platinum vs 49% for capecitabine; HR 1.06, 95% CI 0.62-1.81), and higher hematologic toxicity and dose reductions in the platinum arm. These data support the continued use of capecitabine in this population, and the high event rate highlights the need for more effective therapies in this setting.

The majority of patients with HR+/HER2- MBC will receive a CDK 4/6 inhibitor at some point during their treatment course. In an updated analysis of the phase 3 MONALEESA-3 trial which included postmenopausal patients with HR+HER2- MBC, with median follow-up of 56.3 months, ribociclib plus fulvestrant continued to show an overall survival (OS) benefit of greater than 1 year compared with fulvestrant alone (median OS 53.7 months vs 41.5 months in the ribociclib vs placebo arm, respectively; HR 0.726, 95% CI 0.59-0.90). Additionally, extended follow-up of the PALOMA-3 trial demonstrated OS benefit with palbociclib plus fulvestrant compared to fulvestrant alone in patients with HR+/HER2- MBC; at median follow-up of 73.3 months, median OS was 34.8 months in the palbociclib arm vs 28.0 months in the placebo arm (HR 0.81, P = .0221). Sequencing of other targeted therapies (such as PI3K inhibitors), predictors of CDK 4/6 inhibitor response in different intrinsic subtypes, and the role of CDK 4/6 inhibitor use beyond progression are areas where further research is warranted.

References:

Robson M, Im SA, Senkus E, et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med. 2017;377(6):523-533.

Litton JK, Beck JT, Jones JM, et al. Neoadjuvant talazoparib in patients with germline BRCA1/2 (gBRCA1/2) mutation-positive, early HER2-negative breast cancer (BC): Results of a phase 2 study. J Clin Oncol 39, 2021 (suppl 15; abstr 505).

Symmans WF, Wei C, Gould R, et al. Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype. J Clin Oncol. 2017;35:1049-1060.

Masuda N, Lee SJ, Ohtani S, et al. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med. 2017;376:2147-2159.

Cristofanilli M, Rugo H, Im SA, et al. Overall survival (OS) with palbociclib (PAL) + fulvestrant (FUL) in women with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC): Updated analyses from PALOMA-3. J Clin Oncol. 2021; 39:15_suppl, 1000-1000.

The role of adjuvant olaparib was investigated in the phase 3 OlympiA trial, which included 1,836 patients with high-risk HER2-negative gBRCAm early breast cancer who received local treatment and adjuvant or neoadjuvant chemotherapy. One year of adjuvant olaparib was associated with a significant improvement in invasive disease-free survival (hazard ratio [HR] 0.58, P < .001) and distant disease-free survival (HR 0.57, P < .001). The 3-year invasive disease-free survival (iDFS) was 85.9% in the olaparib group and 77.1% in the placebo group (absolute benefit of 8.8%), and 3-year distant disease-free survival (dDFS) was 87.5% and 80.4%, respectively (difference of 7.1%). These results are considered practice changing and lead to questions regarding the expansion of germline testing in early stage breast cancer. Furthermore, PARP inhibitors have shown exciting results in the neoadjuvant setting. Among 61 patients with gBRCAm HER2-negative early breast cancer, neoadjuvant talazoparib produced a pathologic complete response (pCR) in 49.2%, and there may be a subgroup of patients for whom this approach is relevant.

The presence of residual disease after neoadjuvant chemotherapy has prognostic implications and can help tailor adjuvant treatment recommendations. The CREATE-X trial has established the role of adjuvant capecitabine for patients with triple-negative breast cancer with residual disease after pre-operative chemotherapy. The phase 3 EA1131 trial randomized 415 patients with stage II-III triple-negative breast cancer and residual disease post-neoadjuvant chemotherapy to platinum agent or capecitabine. There was no significant difference in 3-year iDFS (42% for platinum vs 49% for capecitabine; HR 1.06, 95% CI 0.62-1.81), and higher hematologic toxicity and dose reductions in the platinum arm. These data support the continued use of capecitabine in this population, and the high event rate highlights the need for more effective therapies in this setting.

The majority of patients with HR+/HER2- MBC will receive a CDK 4/6 inhibitor at some point during their treatment course. In an updated analysis of the phase 3 MONALEESA-3 trial which included postmenopausal patients with HR+HER2- MBC, with median follow-up of 56.3 months, ribociclib plus fulvestrant continued to show an overall survival (OS) benefit of greater than 1 year compared with fulvestrant alone (median OS 53.7 months vs 41.5 months in the ribociclib vs placebo arm, respectively; HR 0.726, 95% CI 0.59-0.90). Additionally, extended follow-up of the PALOMA-3 trial demonstrated OS benefit with palbociclib plus fulvestrant compared to fulvestrant alone in patients with HR+/HER2- MBC; at median follow-up of 73.3 months, median OS was 34.8 months in the palbociclib arm vs 28.0 months in the placebo arm (HR 0.81, P = .0221). Sequencing of other targeted therapies (such as PI3K inhibitors), predictors of CDK 4/6 inhibitor response in different intrinsic subtypes, and the role of CDK 4/6 inhibitor use beyond progression are areas where further research is warranted.

References:

Robson M, Im SA, Senkus E, et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med. 2017;377(6):523-533.

Litton JK, Beck JT, Jones JM, et al. Neoadjuvant talazoparib in patients with germline BRCA1/2 (gBRCA1/2) mutation-positive, early HER2-negative breast cancer (BC): Results of a phase 2 study. J Clin Oncol 39, 2021 (suppl 15; abstr 505).

Symmans WF, Wei C, Gould R, et al. Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype. J Clin Oncol. 2017;35:1049-1060.

Masuda N, Lee SJ, Ohtani S, et al. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med. 2017;376:2147-2159.

Cristofanilli M, Rugo H, Im SA, et al. Overall survival (OS) with palbociclib (PAL) + fulvestrant (FUL) in women with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC): Updated analyses from PALOMA-3. J Clin Oncol. 2021; 39:15_suppl, 1000-1000.

The role of adjuvant olaparib was investigated in the phase 3 OlympiA trial, which included 1,836 patients with high-risk HER2-negative gBRCAm early breast cancer who received local treatment and adjuvant or neoadjuvant chemotherapy. One year of adjuvant olaparib was associated with a significant improvement in invasive disease-free survival (hazard ratio [HR] 0.58, P < .001) and distant disease-free survival (HR 0.57, P < .001). The 3-year invasive disease-free survival (iDFS) was 85.9% in the olaparib group and 77.1% in the placebo group (absolute benefit of 8.8%), and 3-year distant disease-free survival (dDFS) was 87.5% and 80.4%, respectively (difference of 7.1%). These results are considered practice changing and lead to questions regarding the expansion of germline testing in early stage breast cancer. Furthermore, PARP inhibitors have shown exciting results in the neoadjuvant setting. Among 61 patients with gBRCAm HER2-negative early breast cancer, neoadjuvant talazoparib produced a pathologic complete response (pCR) in 49.2%, and there may be a subgroup of patients for whom this approach is relevant.

The presence of residual disease after neoadjuvant chemotherapy has prognostic implications and can help tailor adjuvant treatment recommendations. The CREATE-X trial has established the role of adjuvant capecitabine for patients with triple-negative breast cancer with residual disease after pre-operative chemotherapy. The phase 3 EA1131 trial randomized 415 patients with stage II-III triple-negative breast cancer and residual disease post-neoadjuvant chemotherapy to platinum agent or capecitabine. There was no significant difference in 3-year iDFS (42% for platinum vs 49% for capecitabine; HR 1.06, 95% CI 0.62-1.81), and higher hematologic toxicity and dose reductions in the platinum arm. These data support the continued use of capecitabine in this population, and the high event rate highlights the need for more effective therapies in this setting.

The majority of patients with HR+/HER2- MBC will receive a CDK 4/6 inhibitor at some point during their treatment course. In an updated analysis of the phase 3 MONALEESA-3 trial which included postmenopausal patients with HR+HER2- MBC, with median follow-up of 56.3 months, ribociclib plus fulvestrant continued to show an overall survival (OS) benefit of greater than 1 year compared with fulvestrant alone (median OS 53.7 months vs 41.5 months in the ribociclib vs placebo arm, respectively; HR 0.726, 95% CI 0.59-0.90). Additionally, extended follow-up of the PALOMA-3 trial demonstrated OS benefit with palbociclib plus fulvestrant compared to fulvestrant alone in patients with HR+/HER2- MBC; at median follow-up of 73.3 months, median OS was 34.8 months in the palbociclib arm vs 28.0 months in the placebo arm (HR 0.81, P = .0221). Sequencing of other targeted therapies (such as PI3K inhibitors), predictors of CDK 4/6 inhibitor response in different intrinsic subtypes, and the role of CDK 4/6 inhibitor use beyond progression are areas where further research is warranted.

References:

Robson M, Im SA, Senkus E, et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med. 2017;377(6):523-533.

Litton JK, Beck JT, Jones JM, et al. Neoadjuvant talazoparib in patients with germline BRCA1/2 (gBRCA1/2) mutation-positive, early HER2-negative breast cancer (BC): Results of a phase 2 study. J Clin Oncol 39, 2021 (suppl 15; abstr 505).

Symmans WF, Wei C, Gould R, et al. Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype. J Clin Oncol. 2017;35:1049-1060.

Masuda N, Lee SJ, Ohtani S, et al. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med. 2017;376:2147-2159.

Cristofanilli M, Rugo H, Im SA, et al. Overall survival (OS) with palbociclib (PAL) + fulvestrant (FUL) in women with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC): Updated analyses from PALOMA-3. J Clin Oncol. 2021; 39:15_suppl, 1000-1000.

In the approach to treatment of patients with rheumatoid arthritis (RA), methotrexate monotherapy is often followed by addition of a biologic disease modifying anti-rheumatic drugs (bDMARDs) for best disease outcomes. Combination DMARDs therapy with methotrexate, hydroxychloroquine, and sulfasalazine (triple therapy) has been proposed as an alternative to biologic therapy. Combination methotrexate and leflunomide is not as frequently addressed in the literature, perhaps due in part to concerns about hepatotoxicity. Bredemeier et al address safety concerns regarding combination methotrexate and leflunomide in the treatment of patients with RA. In this multicenter Brazilian registry study, they compared adverse events (including infection) among patients receiving bDMARDs or JAK inhibitors. Patients treated with combination methotrexate and leflunomide had comparable rates of adverse effects as patients treated with either medication alone; infectious and serious adverse events were fewer compared to patients treated with bDMARDs or JAK inhibitors. Given this reassuring information, further study of the efficacy and durability of combination methotrexate and leflunomide therapy would be helpful to firmly establish its place in treatment of RA, especially among newer biologic choices.

Tofacitinib and tocilizumab, for example, have been under investigation for safety and efficacy, alone and in combination with conventional synthetic DMARDs (csDMARDs). Prior studies have suggested that tofacitinib is more effective in bDMARD-naïve patients than patients who have had inadequate efficacy with one or more bDMARDs. In this multicenter Japanese cohort study, Mori et al examine RA outcomes in new users of tofacitinib and tocilizumab. Clinical disease activity index (CDAI) responses and remission rates were significantly better among bDMARD-naïve patients receiving tofacitinib compared to those receiving tocilizumab; interestingly, this difference was not seen in patients who had previously received bDMARDs. Interpretation of these results is somewhat hampered by the use of the lower every-other-week tocilizimab injection dose, but they still raise the question as to whether timing and sequence of biologics can affect future response to therapy.

The role of conventional DMARDs has also been questioned in the converse role: tapering of therapy. Lillegraven et al compare tapering of csDMARDs to continuing therapy in this randomized multicenter Norwegian study. The possibility of biologic tapering in RA has previously been addressed with some evidence of success in the form of reduced frequency of administration. Unfortunately, despite being in stable remission, patients assigned to reduce csDMARDs to half-dose had more flares than those continuing therapy, suggesting that reducing csDMARDs to half-dose in RA patients in remission may not be easily accomplished. Whether this changes in patients with prolonged or “deep” remission is as yet unknown.

Finally, with all of these options for tailored therapy, how does our treatment of early RA fare? Combe et al report the 10-year outcomes of a French early RA cohort (ESPOIR), including patients with RA for <6 months recruited from 2003-2005. 521 patients were followed; at year 10, half were in DAS28 remission, and 14% in drug-free remission. Compared to outcomes from an earlier community- based study, patients in the ESPOIR cohort have better outcomes, possibly due to more aggressive treatment for RA, use of bDMARDs, or perhaps even earlier identification of patients for treatment. Due to the sizeable proportion of patients in drug-free remission, the impact of stringency of entry criteria should be considered, and a comparison to a later cohort with patients identified using 2019 ACR/EULAR criteria would be of great interest.

In the approach to treatment of patients with rheumatoid arthritis (RA), methotrexate monotherapy is often followed by addition of a biologic disease modifying anti-rheumatic drugs (bDMARDs) for best disease outcomes. Combination DMARDs therapy with methotrexate, hydroxychloroquine, and sulfasalazine (triple therapy) has been proposed as an alternative to biologic therapy. Combination methotrexate and leflunomide is not as frequently addressed in the literature, perhaps due in part to concerns about hepatotoxicity. Bredemeier et al address safety concerns regarding combination methotrexate and leflunomide in the treatment of patients with RA. In this multicenter Brazilian registry study, they compared adverse events (including infection) among patients receiving bDMARDs or JAK inhibitors. Patients treated with combination methotrexate and leflunomide had comparable rates of adverse effects as patients treated with either medication alone; infectious and serious adverse events were fewer compared to patients treated with bDMARDs or JAK inhibitors. Given this reassuring information, further study of the efficacy and durability of combination methotrexate and leflunomide therapy would be helpful to firmly establish its place in treatment of RA, especially among newer biologic choices.

Tofacitinib and tocilizumab, for example, have been under investigation for safety and efficacy, alone and in combination with conventional synthetic DMARDs (csDMARDs). Prior studies have suggested that tofacitinib is more effective in bDMARD-naïve patients than patients who have had inadequate efficacy with one or more bDMARDs. In this multicenter Japanese cohort study, Mori et al examine RA outcomes in new users of tofacitinib and tocilizumab. Clinical disease activity index (CDAI) responses and remission rates were significantly better among bDMARD-naïve patients receiving tofacitinib compared to those receiving tocilizumab; interestingly, this difference was not seen in patients who had previously received bDMARDs. Interpretation of these results is somewhat hampered by the use of the lower every-other-week tocilizimab injection dose, but they still raise the question as to whether timing and sequence of biologics can affect future response to therapy.

The role of conventional DMARDs has also been questioned in the converse role: tapering of therapy. Lillegraven et al compare tapering of csDMARDs to continuing therapy in this randomized multicenter Norwegian study. The possibility of biologic tapering in RA has previously been addressed with some evidence of success in the form of reduced frequency of administration. Unfortunately, despite being in stable remission, patients assigned to reduce csDMARDs to half-dose had more flares than those continuing therapy, suggesting that reducing csDMARDs to half-dose in RA patients in remission may not be easily accomplished. Whether this changes in patients with prolonged or “deep” remission is as yet unknown.

Finally, with all of these options for tailored therapy, how does our treatment of early RA fare? Combe et al report the 10-year outcomes of a French early RA cohort (ESPOIR), including patients with RA for <6 months recruited from 2003-2005. 521 patients were followed; at year 10, half were in DAS28 remission, and 14% in drug-free remission. Compared to outcomes from an earlier community- based study, patients in the ESPOIR cohort have better outcomes, possibly due to more aggressive treatment for RA, use of bDMARDs, or perhaps even earlier identification of patients for treatment. Due to the sizeable proportion of patients in drug-free remission, the impact of stringency of entry criteria should be considered, and a comparison to a later cohort with patients identified using 2019 ACR/EULAR criteria would be of great interest.

In the approach to treatment of patients with rheumatoid arthritis (RA), methotrexate monotherapy is often followed by addition of a biologic disease modifying anti-rheumatic drugs (bDMARDs) for best disease outcomes. Combination DMARDs therapy with methotrexate, hydroxychloroquine, and sulfasalazine (triple therapy) has been proposed as an alternative to biologic therapy. Combination methotrexate and leflunomide is not as frequently addressed in the literature, perhaps due in part to concerns about hepatotoxicity. Bredemeier et al address safety concerns regarding combination methotrexate and leflunomide in the treatment of patients with RA. In this multicenter Brazilian registry study, they compared adverse events (including infection) among patients receiving bDMARDs or JAK inhibitors. Patients treated with combination methotrexate and leflunomide had comparable rates of adverse effects as patients treated with either medication alone; infectious and serious adverse events were fewer compared to patients treated with bDMARDs or JAK inhibitors. Given this reassuring information, further study of the efficacy and durability of combination methotrexate and leflunomide therapy would be helpful to firmly establish its place in treatment of RA, especially among newer biologic choices.

Tofacitinib and tocilizumab, for example, have been under investigation for safety and efficacy, alone and in combination with conventional synthetic DMARDs (csDMARDs). Prior studies have suggested that tofacitinib is more effective in bDMARD-naïve patients than patients who have had inadequate efficacy with one or more bDMARDs. In this multicenter Japanese cohort study, Mori et al examine RA outcomes in new users of tofacitinib and tocilizumab. Clinical disease activity index (CDAI) responses and remission rates were significantly better among bDMARD-naïve patients receiving tofacitinib compared to those receiving tocilizumab; interestingly, this difference was not seen in patients who had previously received bDMARDs. Interpretation of these results is somewhat hampered by the use of the lower every-other-week tocilizimab injection dose, but they still raise the question as to whether timing and sequence of biologics can affect future response to therapy.

The role of conventional DMARDs has also been questioned in the converse role: tapering of therapy. Lillegraven et al compare tapering of csDMARDs to continuing therapy in this randomized multicenter Norwegian study. The possibility of biologic tapering in RA has previously been addressed with some evidence of success in the form of reduced frequency of administration. Unfortunately, despite being in stable remission, patients assigned to reduce csDMARDs to half-dose had more flares than those continuing therapy, suggesting that reducing csDMARDs to half-dose in RA patients in remission may not be easily accomplished. Whether this changes in patients with prolonged or “deep” remission is as yet unknown.

Finally, with all of these options for tailored therapy, how does our treatment of early RA fare? Combe et al report the 10-year outcomes of a French early RA cohort (ESPOIR), including patients with RA for <6 months recruited from 2003-2005. 521 patients were followed; at year 10, half were in DAS28 remission, and 14% in drug-free remission. Compared to outcomes from an earlier community- based study, patients in the ESPOIR cohort have better outcomes, possibly due to more aggressive treatment for RA, use of bDMARDs, or perhaps even earlier identification of patients for treatment. Due to the sizeable proportion of patients in drug-free remission, the impact of stringency of entry criteria should be considered, and a comparison to a later cohort with patients identified using 2019 ACR/EULAR criteria would be of great interest.

Several studies published this month have shed some more light on the treatment and prognosis of certain molecular subgroups such as FLT3, spliceasome mutations and IDH mutation. A study from MD Anderson Cancer Center (MDACC) demonstrated the efficacy of FLT33 inhibitors in the treatment of patients with very low allelic burden. Patients who recived both a FMS-like tyrosine kinase inhibitor (FLT3i) during induction and an allogeneic HCT at time of first remission had better 5 year overall survival (OS) (100%) than those who received neither (27%). The 5-year OS rate among patients who did not receive FLT3i-based induction but underwent allo-SCT in CR1 was 71%. None of the patients who received a FLT3i had detectable FLT3 at time of relapse, compared to 67% for those who did not. The main weakness of the study is the small number of patients (total of 50 patients). This study however does provide some provocative data regarding the validity of the FLT3 allelic ratio in decisions regarding treatment and prognosis. The results of this study need to be validated in a larger cohort of patients.

A study by Lachowiez et al, further refined the prognostic significance of spliceosome mutations in patients treated with ven + HMA. Of the 119 patients, 39 had spliceosome mutations. The overall response and prognosis was not different between patients with and without spliceosome mutations. However, SRSF2 was associated with IDH2 mutation and the median OS was not reached vs, patient with U2AF1 who had a higher association with RAS mutations (OS 8 months). The prognostic role of standard cytotoxic chemotherapy in improving the outcome of patients with an IDH mutation was studied by the group. In a re-evaluation of the randomized trial comparing the addition of fludarabine or cladrbaine to standard 7 +3, 50 patients with an IDH mutation were evaluated. Patients with an IDH mutation who received cladribine. IDH2 mutation had a positive impact on OS in patients treated with DAC regimen (54% vs. 33%; P = .0087) but not in those treated with daunorubicin+cytarabine (DA; 21% vs. 23%; P = .22) regimen. Moreover, DAC induction was independently associated with a reduced risk for death when the observations were censored at allogeneic hematopoietic stem cell transplant (hazard ratio, 0.21; P = .02).

Although hypomethylating agents + venetoclax (HMA +ven) have shown efficacy in multiple patient subgroups, the outcome of patients with post-MPN acute myeloid leukemia (AML) remains poor even with HMA + ven. In a retrospective study, 31 patients with post MPN AML were treated with HMA + ven. The overall survival for patients with relapsed post MPN AML was 3 months with none of the 9 patients achieving a CR/CRi. As for the patients with previously untreated post MPN-AML, the median survival was still poor at 8 months with 43% achieving CR/CRi. This study highlights the large unmet need in this patient population. In comparison, in a retrospective study by Piccini et al, of the 47 patients with relapsed/refractory (R/R) AML treated with venetoclax based regimens the composite CR rate was 55%. These outcomes are similar to other studies of venetoclax based regimens in patients with R/R AML. 

In a retrospective study from the European Society for Blood and Marrow Transplantation (EBMT) registry, the outcomes of patients receiving mismatched unrelated donor (MMUD) with post transplant cyclophosphamide (PTCy) had better outcomes compared to patients receiving cord blood transplantation (CBT). The 2 year leukemia free survival (LFS) for CBT vs MMUD was 42.8% vs 60.5% and OS was 46.85 vs 62.8%. This retrospective study demonstrated that PTCy can improve the outcomes of patients receiving of MMUD (Dholaria B et al. J Hematol Oncol. 2021 May).

Several studies published this month have shed some more light on the treatment and prognosis of certain molecular subgroups such as FLT3, spliceasome mutations and IDH mutation. A study from MD Anderson Cancer Center (MDACC) demonstrated the efficacy of FLT33 inhibitors in the treatment of patients with very low allelic burden. Patients who recived both a FMS-like tyrosine kinase inhibitor (FLT3i) during induction and an allogeneic HCT at time of first remission had better 5 year overall survival (OS) (100%) than those who received neither (27%). The 5-year OS rate among patients who did not receive FLT3i-based induction but underwent allo-SCT in CR1 was 71%. None of the patients who received a FLT3i had detectable FLT3 at time of relapse, compared to 67% for those who did not. The main weakness of the study is the small number of patients (total of 50 patients). This study however does provide some provocative data regarding the validity of the FLT3 allelic ratio in decisions regarding treatment and prognosis. The results of this study need to be validated in a larger cohort of patients.

A study by Lachowiez et al, further refined the prognostic significance of spliceosome mutations in patients treated with ven + HMA. Of the 119 patients, 39 had spliceosome mutations. The overall response and prognosis was not different between patients with and without spliceosome mutations. However, SRSF2 was associated with IDH2 mutation and the median OS was not reached vs, patient with U2AF1 who had a higher association with RAS mutations (OS 8 months). The prognostic role of standard cytotoxic chemotherapy in improving the outcome of patients with an IDH mutation was studied by the group. In a re-evaluation of the randomized trial comparing the addition of fludarabine or cladrbaine to standard 7 +3, 50 patients with an IDH mutation were evaluated. Patients with an IDH mutation who received cladribine. IDH2 mutation had a positive impact on OS in patients treated with DAC regimen (54% vs. 33%; P = .0087) but not in those treated with daunorubicin+cytarabine (DA; 21% vs. 23%; P = .22) regimen. Moreover, DAC induction was independently associated with a reduced risk for death when the observations were censored at allogeneic hematopoietic stem cell transplant (hazard ratio, 0.21; P = .02).

Although hypomethylating agents + venetoclax (HMA +ven) have shown efficacy in multiple patient subgroups, the outcome of patients with post-MPN acute myeloid leukemia (AML) remains poor even with HMA + ven. In a retrospective study, 31 patients with post MPN AML were treated with HMA + ven. The overall survival for patients with relapsed post MPN AML was 3 months with none of the 9 patients achieving a CR/CRi. As for the patients with previously untreated post MPN-AML, the median survival was still poor at 8 months with 43% achieving CR/CRi. This study highlights the large unmet need in this patient population. In comparison, in a retrospective study by Piccini et al, of the 47 patients with relapsed/refractory (R/R) AML treated with venetoclax based regimens the composite CR rate was 55%. These outcomes are similar to other studies of venetoclax based regimens in patients with R/R AML. 

In a retrospective study from the European Society for Blood and Marrow Transplantation (EBMT) registry, the outcomes of patients receiving mismatched unrelated donor (MMUD) with post transplant cyclophosphamide (PTCy) had better outcomes compared to patients receiving cord blood transplantation (CBT). The 2 year leukemia free survival (LFS) for CBT vs MMUD was 42.8% vs 60.5% and OS was 46.85 vs 62.8%. This retrospective study demonstrated that PTCy can improve the outcomes of patients receiving of MMUD (Dholaria B et al. J Hematol Oncol. 2021 May).

Several studies published this month have shed some more light on the treatment and prognosis of certain molecular subgroups such as FLT3, spliceasome mutations and IDH mutation. A study from MD Anderson Cancer Center (MDACC) demonstrated the efficacy of FLT33 inhibitors in the treatment of patients with very low allelic burden. Patients who recived both a FMS-like tyrosine kinase inhibitor (FLT3i) during induction and an allogeneic HCT at time of first remission had better 5 year overall survival (OS) (100%) than those who received neither (27%). The 5-year OS rate among patients who did not receive FLT3i-based induction but underwent allo-SCT in CR1 was 71%. None of the patients who received a FLT3i had detectable FLT3 at time of relapse, compared to 67% for those who did not. The main weakness of the study is the small number of patients (total of 50 patients). This study however does provide some provocative data regarding the validity of the FLT3 allelic ratio in decisions regarding treatment and prognosis. The results of this study need to be validated in a larger cohort of patients.

A study by Lachowiez et al, further refined the prognostic significance of spliceosome mutations in patients treated with ven + HMA. Of the 119 patients, 39 had spliceosome mutations. The overall response and prognosis was not different between patients with and without spliceosome mutations. However, SRSF2 was associated with IDH2 mutation and the median OS was not reached vs, patient with U2AF1 who had a higher association with RAS mutations (OS 8 months). The prognostic role of standard cytotoxic chemotherapy in improving the outcome of patients with an IDH mutation was studied by the group. In a re-evaluation of the randomized trial comparing the addition of fludarabine or cladrbaine to standard 7 +3, 50 patients with an IDH mutation were evaluated. Patients with an IDH mutation who received cladribine. IDH2 mutation had a positive impact on OS in patients treated with DAC regimen (54% vs. 33%; P = .0087) but not in those treated with daunorubicin+cytarabine (DA; 21% vs. 23%; P = .22) regimen. Moreover, DAC induction was independently associated with a reduced risk for death when the observations were censored at allogeneic hematopoietic stem cell transplant (hazard ratio, 0.21; P = .02).

Although hypomethylating agents + venetoclax (HMA +ven) have shown efficacy in multiple patient subgroups, the outcome of patients with post-MPN acute myeloid leukemia (AML) remains poor even with HMA + ven. In a retrospective study, 31 patients with post MPN AML were treated with HMA + ven. The overall survival for patients with relapsed post MPN AML was 3 months with none of the 9 patients achieving a CR/CRi. As for the patients with previously untreated post MPN-AML, the median survival was still poor at 8 months with 43% achieving CR/CRi. This study highlights the large unmet need in this patient population. In comparison, in a retrospective study by Piccini et al, of the 47 patients with relapsed/refractory (R/R) AML treated with venetoclax based regimens the composite CR rate was 55%. These outcomes are similar to other studies of venetoclax based regimens in patients with R/R AML. 

In a retrospective study from the European Society for Blood and Marrow Transplantation (EBMT) registry, the outcomes of patients receiving mismatched unrelated donor (MMUD) with post transplant cyclophosphamide (PTCy) had better outcomes compared to patients receiving cord blood transplantation (CBT). The 2 year leukemia free survival (LFS) for CBT vs MMUD was 42.8% vs 60.5% and OS was 46.85 vs 62.8%. This retrospective study demonstrated that PTCy can improve the outcomes of patients receiving of MMUD (Dholaria B et al. J Hematol Oncol. 2021 May).

In a comprehensive and detailed analysis, Ochi et al evaluated the genetic alterations in 136 blast crisis (BC) and 148 chronic phase (CP) samples from 216 patients with chronic myeloid leukemia (CML) by exome and targeted sequencing. The number of genetic alterations increased during CP to BC progression with a mean of 5.3 nonsynonymous single-nucleotide variants acquired. One or more genetic abnormalities are found in 126 (92.6%) out of the 136 BC patients. As expected, the lineage of the BC and prior use of tyrosine kinase inhibitors (TKIs) correlate with distinct molecular profiles. TKIs markedly suppressed the number of genetic alterations increase during the transition from CP to BC. Notably, genetic alterations such AXL1 mutations complex CNAs, i(17q), and +21, rather than clinical variables, contribute to a better prediction of BC prognosis in early therapy with TKI in CP.

Switching to a second generation TKI with the goal of obtaining a deeper response and therefore a chance for treatment-free remission (TFR), is an option for certain patients and has been investigated in a few trials. ENEStop may be the most popular and Hughes et al had updated the 5 years follow up in a recent publication. The study includes patients with chronic-phase chronic myeloid leukemia (CML-CP)  who achieved sustained deep molecular response only after switching from imatinib to nilotinib and TFR was attempted by 126 patients following 1 year of nilotinib consolidation phase. At 5 years, the rate of successful TFR and overall survival was 42.9% and 95.9%, respectively. Of 59 patients reinitiating nilotinib, 98.3% of patients regained major molecular response. Overall, AEs increased in nilotinib reinitiation vs. consolidation phase including cardiovascular (CV) adverse events (AEs) as patients had a long duration of exposure for nilotinib.

After several publications and recommendations by NCCN and ELN, the optimal cut-off values of the duration of MR4 and deeper responses remain unresolved. Kim et al reported a large study of 131 patients enrolled into the Canadian TKI discontinuation study and evaluated the molecular relapse-free survival (mRFS) at 12 months after imatinib discontinuation. Based on this analysis they propose 6 years with imatinib treatment duration as the shortest imatinib duration- a superior success versus less than 6 years (61.8% vs. 36.0%; P = .01). Also a MR4 duration of 4.5 years or longer vs. less than 4.5 years (64.2% vs. 41.9%; P = .003) was associated with a superior molecular relapse-free survival at 12 months after imatinib discontinuation.

Fatigue is a common complain of patients taking TKI and has been well reported as adverse effects in most of the CML trials. However, when evaluating fatigue, it is always difficult to understand if there are additional factors that can contribute to it. Hyland et al investigated if the use of cognitive behavioral therapy for targeted-therapy related fatigue (CBT-TTF) targeting fatigue perpetuating factors change over time. By delivering CBT via FaceTime or wait list control in CML patients with moderate or severe fatigue, they were able to see an improvement in TKI-related fatigue in CML patients through changes in behavior (sleep, activity patterns) and cognitions about fatigue and cancer.

In a comprehensive and detailed analysis, Ochi et al evaluated the genetic alterations in 136 blast crisis (BC) and 148 chronic phase (CP) samples from 216 patients with chronic myeloid leukemia (CML) by exome and targeted sequencing. The number of genetic alterations increased during CP to BC progression with a mean of 5.3 nonsynonymous single-nucleotide variants acquired. One or more genetic abnormalities are found in 126 (92.6%) out of the 136 BC patients. As expected, the lineage of the BC and prior use of tyrosine kinase inhibitors (TKIs) correlate with distinct molecular profiles. TKIs markedly suppressed the number of genetic alterations increase during the transition from CP to BC. Notably, genetic alterations such AXL1 mutations complex CNAs, i(17q), and +21, rather than clinical variables, contribute to a better prediction of BC prognosis in early therapy with TKI in CP.

Switching to a second generation TKI with the goal of obtaining a deeper response and therefore a chance for treatment-free remission (TFR), is an option for certain patients and has been investigated in a few trials. ENEStop may be the most popular and Hughes et al had updated the 5 years follow up in a recent publication. The study includes patients with chronic-phase chronic myeloid leukemia (CML-CP)  who achieved sustained deep molecular response only after switching from imatinib to nilotinib and TFR was attempted by 126 patients following 1 year of nilotinib consolidation phase. At 5 years, the rate of successful TFR and overall survival was 42.9% and 95.9%, respectively. Of 59 patients reinitiating nilotinib, 98.3% of patients regained major molecular response. Overall, AEs increased in nilotinib reinitiation vs. consolidation phase including cardiovascular (CV) adverse events (AEs) as patients had a long duration of exposure for nilotinib.

After several publications and recommendations by NCCN and ELN, the optimal cut-off values of the duration of MR4 and deeper responses remain unresolved. Kim et al reported a large study of 131 patients enrolled into the Canadian TKI discontinuation study and evaluated the molecular relapse-free survival (mRFS) at 12 months after imatinib discontinuation. Based on this analysis they propose 6 years with imatinib treatment duration as the shortest imatinib duration- a superior success versus less than 6 years (61.8% vs. 36.0%; P = .01). Also a MR4 duration of 4.5 years or longer vs. less than 4.5 years (64.2% vs. 41.9%; P = .003) was associated with a superior molecular relapse-free survival at 12 months after imatinib discontinuation.

Fatigue is a common complain of patients taking TKI and has been well reported as adverse effects in most of the CML trials. However, when evaluating fatigue, it is always difficult to understand if there are additional factors that can contribute to it. Hyland et al investigated if the use of cognitive behavioral therapy for targeted-therapy related fatigue (CBT-TTF) targeting fatigue perpetuating factors change over time. By delivering CBT via FaceTime or wait list control in CML patients with moderate or severe fatigue, they were able to see an improvement in TKI-related fatigue in CML patients through changes in behavior (sleep, activity patterns) and cognitions about fatigue and cancer.

In a comprehensive and detailed analysis, Ochi et al evaluated the genetic alterations in 136 blast crisis (BC) and 148 chronic phase (CP) samples from 216 patients with chronic myeloid leukemia (CML) by exome and targeted sequencing. The number of genetic alterations increased during CP to BC progression with a mean of 5.3 nonsynonymous single-nucleotide variants acquired. One or more genetic abnormalities are found in 126 (92.6%) out of the 136 BC patients. As expected, the lineage of the BC and prior use of tyrosine kinase inhibitors (TKIs) correlate with distinct molecular profiles. TKIs markedly suppressed the number of genetic alterations increase during the transition from CP to BC. Notably, genetic alterations such AXL1 mutations complex CNAs, i(17q), and +21, rather than clinical variables, contribute to a better prediction of BC prognosis in early therapy with TKI in CP.

Switching to a second generation TKI with the goal of obtaining a deeper response and therefore a chance for treatment-free remission (TFR), is an option for certain patients and has been investigated in a few trials. ENEStop may be the most popular and Hughes et al had updated the 5 years follow up in a recent publication. The study includes patients with chronic-phase chronic myeloid leukemia (CML-CP)  who achieved sustained deep molecular response only after switching from imatinib to nilotinib and TFR was attempted by 126 patients following 1 year of nilotinib consolidation phase. At 5 years, the rate of successful TFR and overall survival was 42.9% and 95.9%, respectively. Of 59 patients reinitiating nilotinib, 98.3% of patients regained major molecular response. Overall, AEs increased in nilotinib reinitiation vs. consolidation phase including cardiovascular (CV) adverse events (AEs) as patients had a long duration of exposure for nilotinib.

After several publications and recommendations by NCCN and ELN, the optimal cut-off values of the duration of MR4 and deeper responses remain unresolved. Kim et al reported a large study of 131 patients enrolled into the Canadian TKI discontinuation study and evaluated the molecular relapse-free survival (mRFS) at 12 months after imatinib discontinuation. Based on this analysis they propose 6 years with imatinib treatment duration as the shortest imatinib duration- a superior success versus less than 6 years (61.8% vs. 36.0%; P = .01). Also a MR4 duration of 4.5 years or longer vs. less than 4.5 years (64.2% vs. 41.9%; P = .003) was associated with a superior molecular relapse-free survival at 12 months after imatinib discontinuation.

Fatigue is a common complain of patients taking TKI and has been well reported as adverse effects in most of the CML trials. However, when evaluating fatigue, it is always difficult to understand if there are additional factors that can contribute to it. Hyland et al investigated if the use of cognitive behavioral therapy for targeted-therapy related fatigue (CBT-TTF) targeting fatigue perpetuating factors change over time. By delivering CBT via FaceTime or wait list control in CML patients with moderate or severe fatigue, they were able to see an improvement in TKI-related fatigue in CML patients through changes in behavior (sleep, activity patterns) and cognitions about fatigue and cancer.

Allogeneic stem cell transplantation (SCT) remains the only potential curable option for patients with myelodysplastic syndromes (MDS). While MDS mainly occurs in older patients, MDS does occur in younger patients and prior studies have suggested better overall survival (OS) for younger patients undergoing allogeneic SCT.  Shimomura et al (BMT 2021) analyzed the outcome of 645 patients aged 16-39 years old who received allogeneic SCT in Japan. In this multicenter retrospective analysis, 3 year OS was 71%. In the cohort, 37% of patients had either intermediate-2 or high risk by IPSS, 41% had active disease prior to SCT, and 10% had secondary MDS.  In a multivariate analysis, active disease status, poor cytogenetic risk, and transplant other than from related donor were associated with poor 3 year OS. Cumulative 3 year relapse was 11% and 3 year non-relapse mortality was 19%, which is lower than those of older patients with MDS which ranges from 30-40%. Limitations from this analysis are lack of genetic mutation data, as well as lack of incorporation of prior MDS directed therapy with outcome analysis, however this analysis from a large retrospective cohort provides valuable information regarding outcome in young patients with MDS.

Use of melphalan in multiple myeloma is associated with increased risk of developing MDS and acute myeloid leukemia (AML).  Jonsdottir et al (European Journal of Hematology) reported results of a large population-based study using the Swedish cancer registry to determine relationship of exposure to melphalan treatment for multiple myeloma and development of subsequent MDS and AML. Out of 26,627 patients with multiple myeloma in the Swedish cancer registry, 0.5% (124) patients developed subsequent MDS or AML. The median time from multiple myeloma diagnosis to MDS or AML diagnosis was 3.8 years. There was about threefold higher cumulative exposure to melphalan among those who developed MDS or AML compared to those who did not develop MDS or AML (OR=2.8, 95% CI 1.7-5.2, P < 0.001). There was no difference among the groups in exposure and dosing of radiation therapy, cumulative dose of cyclophosphamide, or doxorubicine. This large population-based study confirms the association between melphalan therapy and development of MDS/AML.

Febrile neutropenia is a common complication for neutropenic patients undergoing therapy. Patients who develop febrile neutropenia are treated with empiric broad-spectrum antibiotics, however there is conflicting recommended duration of antimicrobial treatment in absence of evidence of bacterial infection. The Infectious Disease Society of America recommends antibiotic treatment until marrow recovery, while the European Conference of Infections in Leukemia guidelines suggest consideration of discontinuation after 72 hours if the patient is hemodynamically stable and afebrile for 48 hours. Schauwvlieghe et al (EClinical Medicine 2021) compared the outcome of MDS and AML patients with febrile neutropenia during induction chemotherapy receiving a shortened 3 day empiric antibiotic therapy in absence of documented infection to those receiving antibiotics until neutrophil recovery in a retrospective comparative cohort study in two hospitals in the HOVON network. The shorted antibiotic group received a median of 9 days of antibiotics, compared to 19 days. The primary endpoint was the rate of serious medical complications; there was no statistical difference between the two groups (12.5% for shortened antibiotics vs 8.9% for prolonged antibiotics, P = 0.17).  There was no difference in serious medical complications when adjusting for age, AML risk, non-pulmonary HCT-CI score, and year of admission. There was also no significant difference in infection-related 30-day mortality among the two groups. This study suggests that for patients who develop febrile neutropenia while receiving induction chemotherapy, it may be safe to consider stopping antibiotics after 3 days in absence of infection. A prospective trial should be considered to further evaluate the safety of shortened antibiotic course.

Allogeneic stem cell transplantation (SCT) remains the only potential curable option for patients with myelodysplastic syndromes (MDS). While MDS mainly occurs in older patients, MDS does occur in younger patients and prior studies have suggested better overall survival (OS) for younger patients undergoing allogeneic SCT.  Shimomura et al (BMT 2021) analyzed the outcome of 645 patients aged 16-39 years old who received allogeneic SCT in Japan. In this multicenter retrospective analysis, 3 year OS was 71%. In the cohort, 37% of patients had either intermediate-2 or high risk by IPSS, 41% had active disease prior to SCT, and 10% had secondary MDS.  In a multivariate analysis, active disease status, poor cytogenetic risk, and transplant other than from related donor were associated with poor 3 year OS. Cumulative 3 year relapse was 11% and 3 year non-relapse mortality was 19%, which is lower than those of older patients with MDS which ranges from 30-40%. Limitations from this analysis are lack of genetic mutation data, as well as lack of incorporation of prior MDS directed therapy with outcome analysis, however this analysis from a large retrospective cohort provides valuable information regarding outcome in young patients with MDS.

Use of melphalan in multiple myeloma is associated with increased risk of developing MDS and acute myeloid leukemia (AML).  Jonsdottir et al (European Journal of Hematology) reported results of a large population-based study using the Swedish cancer registry to determine relationship of exposure to melphalan treatment for multiple myeloma and development of subsequent MDS and AML. Out of 26,627 patients with multiple myeloma in the Swedish cancer registry, 0.5% (124) patients developed subsequent MDS or AML. The median time from multiple myeloma diagnosis to MDS or AML diagnosis was 3.8 years. There was about threefold higher cumulative exposure to melphalan among those who developed MDS or AML compared to those who did not develop MDS or AML (OR=2.8, 95% CI 1.7-5.2, P < 0.001). There was no difference among the groups in exposure and dosing of radiation therapy, cumulative dose of cyclophosphamide, or doxorubicine. This large population-based study confirms the association between melphalan therapy and development of MDS/AML.

Febrile neutropenia is a common complication for neutropenic patients undergoing therapy. Patients who develop febrile neutropenia are treated with empiric broad-spectrum antibiotics, however there is conflicting recommended duration of antimicrobial treatment in absence of evidence of bacterial infection. The Infectious Disease Society of America recommends antibiotic treatment until marrow recovery, while the European Conference of Infections in Leukemia guidelines suggest consideration of discontinuation after 72 hours if the patient is hemodynamically stable and afebrile for 48 hours. Schauwvlieghe et al (EClinical Medicine 2021) compared the outcome of MDS and AML patients with febrile neutropenia during induction chemotherapy receiving a shortened 3 day empiric antibiotic therapy in absence of documented infection to those receiving antibiotics until neutrophil recovery in a retrospective comparative cohort study in two hospitals in the HOVON network. The shorted antibiotic group received a median of 9 days of antibiotics, compared to 19 days. The primary endpoint was the rate of serious medical complications; there was no statistical difference between the two groups (12.5% for shortened antibiotics vs 8.9% for prolonged antibiotics, P = 0.17).  There was no difference in serious medical complications when adjusting for age, AML risk, non-pulmonary HCT-CI score, and year of admission. There was also no significant difference in infection-related 30-day mortality among the two groups. This study suggests that for patients who develop febrile neutropenia while receiving induction chemotherapy, it may be safe to consider stopping antibiotics after 3 days in absence of infection. A prospective trial should be considered to further evaluate the safety of shortened antibiotic course.

Allogeneic stem cell transplantation (SCT) remains the only potential curable option for patients with myelodysplastic syndromes (MDS). While MDS mainly occurs in older patients, MDS does occur in younger patients and prior studies have suggested better overall survival (OS) for younger patients undergoing allogeneic SCT.  Shimomura et al (BMT 2021) analyzed the outcome of 645 patients aged 16-39 years old who received allogeneic SCT in Japan. In this multicenter retrospective analysis, 3 year OS was 71%. In the cohort, 37% of patients had either intermediate-2 or high risk by IPSS, 41% had active disease prior to SCT, and 10% had secondary MDS.  In a multivariate analysis, active disease status, poor cytogenetic risk, and transplant other than from related donor were associated with poor 3 year OS. Cumulative 3 year relapse was 11% and 3 year non-relapse mortality was 19%, which is lower than those of older patients with MDS which ranges from 30-40%. Limitations from this analysis are lack of genetic mutation data, as well as lack of incorporation of prior MDS directed therapy with outcome analysis, however this analysis from a large retrospective cohort provides valuable information regarding outcome in young patients with MDS.

Use of melphalan in multiple myeloma is associated with increased risk of developing MDS and acute myeloid leukemia (AML).  Jonsdottir et al (European Journal of Hematology) reported results of a large population-based study using the Swedish cancer registry to determine relationship of exposure to melphalan treatment for multiple myeloma and development of subsequent MDS and AML. Out of 26,627 patients with multiple myeloma in the Swedish cancer registry, 0.5% (124) patients developed subsequent MDS or AML. The median time from multiple myeloma diagnosis to MDS or AML diagnosis was 3.8 years. There was about threefold higher cumulative exposure to melphalan among those who developed MDS or AML compared to those who did not develop MDS or AML (OR=2.8, 95% CI 1.7-5.2, P < 0.001). There was no difference among the groups in exposure and dosing of radiation therapy, cumulative dose of cyclophosphamide, or doxorubicine. This large population-based study confirms the association between melphalan therapy and development of MDS/AML.

Febrile neutropenia is a common complication for neutropenic patients undergoing therapy. Patients who develop febrile neutropenia are treated with empiric broad-spectrum antibiotics, however there is conflicting recommended duration of antimicrobial treatment in absence of evidence of bacterial infection. The Infectious Disease Society of America recommends antibiotic treatment until marrow recovery, while the European Conference of Infections in Leukemia guidelines suggest consideration of discontinuation after 72 hours if the patient is hemodynamically stable and afebrile for 48 hours. Schauwvlieghe et al (EClinical Medicine 2021) compared the outcome of MDS and AML patients with febrile neutropenia during induction chemotherapy receiving a shortened 3 day empiric antibiotic therapy in absence of documented infection to those receiving antibiotics until neutrophil recovery in a retrospective comparative cohort study in two hospitals in the HOVON network. The shorted antibiotic group received a median of 9 days of antibiotics, compared to 19 days. The primary endpoint was the rate of serious medical complications; there was no statistical difference between the two groups (12.5% for shortened antibiotics vs 8.9% for prolonged antibiotics, P = 0.17).  There was no difference in serious medical complications when adjusting for age, AML risk, non-pulmonary HCT-CI score, and year of admission. There was also no significant difference in infection-related 30-day mortality among the two groups. This study suggests that for patients who develop febrile neutropenia while receiving induction chemotherapy, it may be safe to consider stopping antibiotics after 3 days in absence of infection. A prospective trial should be considered to further evaluate the safety of shortened antibiotic course.

First is an article from Elshaarawy O et al. who looked at preoperative and postoperative models to evaluate postresection survival. Between December 2010 and January 2017, 120 patients who underwent resection with curative intent, were analyzed for survival, liver decompensation, and posthepatectomy liver failure (PHLF). It will come as no surprise that HCC recurrence following resection adversely affected survival (hazard ratio (HR) = 11.67, 95%CI: 4.19-32.52, P < 0.001). Also affecting survival were the preoperative MELD score [HR = 1.37, 95%CI: 1.16-1.62, P < 0.001] and grades A through C of the PHLF score. Significant independent predictors of postoperative liver decompensation were the preoperative MELD score >10 [odds ratio (OR) = 2.7, 95%CI: 1.2-5.7, P = 0.013], tumor diameter >5 cm (OR = 5.4, 95%CI: 2-14.8, P = 0.001) and duration of hospital stay (6. 8 days vs 11.26 days; OR = 2.5, 95%CI: 1.5-4.2, P = 0.001).

Next, Lei GY et al. undertook a retrospective study of 244 patients with HCC who underwent hepatic resection with curative intent between January 200 and December 2017. They found that the overall postoperative 90-day mortality rate for HCC patients after hepatic resection was 5.3%. Significant predictors of mortality Child-Pugh score (p < 0.001), intraoperative blood loss (P = 0.013), the 50-50 criteria for PHLF (P < 0.001) on postoperative day 5, and peak serum bilirubin >119 µmol/L (P = 0.007) on postoperative day 3. In these patients, the overall postoperative 90-day mortality rate for HCC patients after hepatic resection was 5.3%.

Taken together, these studies confirm that underlying liver function both before and after surgery is a key predictor of how well a patient is likely to do after curative-intent surgery. Excellent multidisciplinary care remains important for patient well-being.

Finally, for patients who are not candidates for liver resection, Han X et al. evaluated the efficacy of radiofrequency ablation (RFA) and microwave ablation (MWA) in a retrospective study of 201 consecutive patients whose tumors were within Milan criteria, but were in challenging locations for resection. RFA was performed in 150 patients, while 51 patients underwent MWA between January 2012 and December 2016.  Median follow-up was 36.7 months. Cumulative overall survival rates at 1, 3, and 5 years were 97.9%, 92.3%, and 80.6%, respectively, for MWA patients and 96.4%, 87.4%, and 78.2%, respectively, for RFA patients (P = 0.450).  Major complication rates also were similar between the two groups (3.3% vs. 3.9%). The authors concluded that both procedures are equally safe and effective in patients with HCC.

First is an article from Elshaarawy O et al. who looked at preoperative and postoperative models to evaluate postresection survival. Between December 2010 and January 2017, 120 patients who underwent resection with curative intent, were analyzed for survival, liver decompensation, and posthepatectomy liver failure (PHLF). It will come as no surprise that HCC recurrence following resection adversely affected survival (hazard ratio (HR) = 11.67, 95%CI: 4.19-32.52, P < 0.001). Also affecting survival were the preoperative MELD score [HR = 1.37, 95%CI: 1.16-1.62, P < 0.001] and grades A through C of the PHLF score. Significant independent predictors of postoperative liver decompensation were the preoperative MELD score >10 [odds ratio (OR) = 2.7, 95%CI: 1.2-5.7, P = 0.013], tumor diameter >5 cm (OR = 5.4, 95%CI: 2-14.8, P = 0.001) and duration of hospital stay (6. 8 days vs 11.26 days; OR = 2.5, 95%CI: 1.5-4.2, P = 0.001).

Next, Lei GY et al. undertook a retrospective study of 244 patients with HCC who underwent hepatic resection with curative intent between January 200 and December 2017. They found that the overall postoperative 90-day mortality rate for HCC patients after hepatic resection was 5.3%. Significant predictors of mortality Child-Pugh score (p < 0.001), intraoperative blood loss (P = 0.013), the 50-50 criteria for PHLF (P < 0.001) on postoperative day 5, and peak serum bilirubin >119 µmol/L (P = 0.007) on postoperative day 3. In these patients, the overall postoperative 90-day mortality rate for HCC patients after hepatic resection was 5.3%.

Taken together, these studies confirm that underlying liver function both before and after surgery is a key predictor of how well a patient is likely to do after curative-intent surgery. Excellent multidisciplinary care remains important for patient well-being.

Finally, for patients who are not candidates for liver resection, Han X et al. evaluated the efficacy of radiofrequency ablation (RFA) and microwave ablation (MWA) in a retrospective study of 201 consecutive patients whose tumors were within Milan criteria, but were in challenging locations for resection. RFA was performed in 150 patients, while 51 patients underwent MWA between January 2012 and December 2016.  Median follow-up was 36.7 months. Cumulative overall survival rates at 1, 3, and 5 years were 97.9%, 92.3%, and 80.6%, respectively, for MWA patients and 96.4%, 87.4%, and 78.2%, respectively, for RFA patients (P = 0.450).  Major complication rates also were similar between the two groups (3.3% vs. 3.9%). The authors concluded that both procedures are equally safe and effective in patients with HCC.

First is an article from Elshaarawy O et al. who looked at preoperative and postoperative models to evaluate postresection survival. Between December 2010 and January 2017, 120 patients who underwent resection with curative intent, were analyzed for survival, liver decompensation, and posthepatectomy liver failure (PHLF). It will come as no surprise that HCC recurrence following resection adversely affected survival (hazard ratio (HR) = 11.67, 95%CI: 4.19-32.52, P < 0.001). Also affecting survival were the preoperative MELD score [HR = 1.37, 95%CI: 1.16-1.62, P < 0.001] and grades A through C of the PHLF score. Significant independent predictors of postoperative liver decompensation were the preoperative MELD score >10 [odds ratio (OR) = 2.7, 95%CI: 1.2-5.7, P = 0.013], tumor diameter >5 cm (OR = 5.4, 95%CI: 2-14.8, P = 0.001) and duration of hospital stay (6. 8 days vs 11.26 days; OR = 2.5, 95%CI: 1.5-4.2, P = 0.001).

Next, Lei GY et al. undertook a retrospective study of 244 patients with HCC who underwent hepatic resection with curative intent between January 200 and December 2017. They found that the overall postoperative 90-day mortality rate for HCC patients after hepatic resection was 5.3%. Significant predictors of mortality Child-Pugh score (p < 0.001), intraoperative blood loss (P = 0.013), the 50-50 criteria for PHLF (P < 0.001) on postoperative day 5, and peak serum bilirubin >119 µmol/L (P = 0.007) on postoperative day 3. In these patients, the overall postoperative 90-day mortality rate for HCC patients after hepatic resection was 5.3%.

Taken together, these studies confirm that underlying liver function both before and after surgery is a key predictor of how well a patient is likely to do after curative-intent surgery. Excellent multidisciplinary care remains important for patient well-being.

Finally, for patients who are not candidates for liver resection, Han X et al. evaluated the efficacy of radiofrequency ablation (RFA) and microwave ablation (MWA) in a retrospective study of 201 consecutive patients whose tumors were within Milan criteria, but were in challenging locations for resection. RFA was performed in 150 patients, while 51 patients underwent MWA between January 2012 and December 2016.  Median follow-up was 36.7 months. Cumulative overall survival rates at 1, 3, and 5 years were 97.9%, 92.3%, and 80.6%, respectively, for MWA patients and 96.4%, 87.4%, and 78.2%, respectively, for RFA patients (P = 0.450).  Major complication rates also were similar between the two groups (3.3% vs. 3.9%). The authors concluded that both procedures are equally safe and effective in patients with HCC.

Adjuvant T-DM1 is recommended for patients with HER2-positive early breast cancer with residual disease after neoadjuvant therapy based on phase 3 results. The KATHERINE study found a significant reduction for the risk of recurrence and death with adjuvant T-DM1 vs trastuzumab. Subgroup analyses from KATHERINE showed similar benefits with T-DM1 irrespective of type of neoadjuvant regimen. Furthermore, T-DM1 appeared to benefit small node-negative tumors and particularly those tumors considered high-risk (Mamounas). In the phase 3 TRAIN-2 study, similar pCR rates (68% vs 67%), as well as 3 year event-free (94% vs 93%) and overall (98% vs 98%) survival, were observed for non-anthracycline and anthracycline-containing regimens. These findings highlight the broad applicability of T-DM1 in the adjuvant setting, the rationale to support de-escalation and omission of anthracyclines for HER2-positive tumors, and the importance of tailoring therapy based on response.

Brain metastases occur in up to 50% of patients with HER2-positive metastatic breast cancer (MBC). Effective therapies for this population represent an unmet clinical need. The phase 2 PATRICIA study demonstrated activity of pertuzumab plus high-dose trastuzumab (6mg/kg weekly) for patients with HER2-positive MBC and central nervous system (CNS) progression after radiotherapy. In 37 patients evaluable for efficacy, the CNS objective response rate was 11%, clinical benefit rate at 4 and 6 months was 68% and 51%, respectively, and 2 patients had stable disease for over 2 years (Lin). Data supports the role of other HER2-targeted therapies for CNS disease including T-DM1, neratinib, and tucatinib. Among 291 patients with brain metastases in HER2CLIMB, the combination of tucatinib, capecitabine, and trastuzumab improved median overall survival (18 vs 12 months) and CNS progression-free survival (9.9 vs 4.2 months), compared with capecitabine plus trastuzumab. Further investigation exploring other novel therapy combinations and biomarkers will help further improve outcomes for these patients.

Adjuvant endocrine therapy decreases the risk for recurrence and improves survival for women diagnosed with HR-positive breast cancer. For young women, endocrine therapy options include tamoxifen, as well as ovarian suppression plus tamoxifen, or an aromatase inhibitor. Recommended duration of therapy is at least 5 years and can extend to 10 years. These treatments and duration may present challenges related to childbearing attempts and raise fertility concerns among young women.  In the Young Women’s Breast Cancer Study, among 643 women aged 40 years or younger and diagnosed with early stage HR-positive breast cancer, one-third reported fertility concerns impacting endocrine therapy decisions. Those who reported fertility concerns were more likely to exhibit non-initiation or non-persistence to endocrine therapy (40% vs 20%). Among women with fertility concerns, 7% did not initiate endocrine therapy, and 33% were non-persistent over 5 years (Sella). It is essential to integrate early oncofertility dialogue to help achieve optimal endocrine therapy and address family planning goals.

Studies have shown sugar-sweetened beverages (SSB) increase the risk for insulin resistance, diabetes, and heart disease. In a subsample of Women’s Health Initiative participants, higher levels of insulin resistance were shown to be linked to an increased incidence of breast cancer and all-cause mortality after breast cancer. Researchers found that among 8,863 women diagnosed with early breast cancer, those who consumed SSB after diagnosis had higher breast cancer-specific mortality and all-cause mortality. Additionally, replacing SSB with coffee, tea or water was linked to a decrease in mortality (Farvid). These findings support discussion of lifestyle and dietary behaviors in the survivorship setting, as these modifiable risk factors can potentially have significant health implications.

References:

van der Voort A, van Ramshorst MS, van Werkhoven ED, et al. Three-year follow-up of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2-blockade for HER2-positive breast cancer (TRAIN-2): A randomized phase III trial. J Clin Oncol. 2020;38S:ASCO #501.

Lin NU, Borges V, Anders C, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. J Clin Oncol. 2020;38(23):2610-2619.

Pan K, Chlebowski RT, Mortimer JE, et al. Insulin resistance and breast cancer incidence and mortality in postmenopausal women in the Women's Health Initiative. Cancer. 2020;126(16):3638-3647.

Adjuvant T-DM1 is recommended for patients with HER2-positive early breast cancer with residual disease after neoadjuvant therapy based on phase 3 results. The KATHERINE study found a significant reduction for the risk of recurrence and death with adjuvant T-DM1 vs trastuzumab. Subgroup analyses from KATHERINE showed similar benefits with T-DM1 irrespective of type of neoadjuvant regimen. Furthermore, T-DM1 appeared to benefit small node-negative tumors and particularly those tumors considered high-risk (Mamounas). In the phase 3 TRAIN-2 study, similar pCR rates (68% vs 67%), as well as 3 year event-free (94% vs 93%) and overall (98% vs 98%) survival, were observed for non-anthracycline and anthracycline-containing regimens. These findings highlight the broad applicability of T-DM1 in the adjuvant setting, the rationale to support de-escalation and omission of anthracyclines for HER2-positive tumors, and the importance of tailoring therapy based on response.

Brain metastases occur in up to 50% of patients with HER2-positive metastatic breast cancer (MBC). Effective therapies for this population represent an unmet clinical need. The phase 2 PATRICIA study demonstrated activity of pertuzumab plus high-dose trastuzumab (6mg/kg weekly) for patients with HER2-positive MBC and central nervous system (CNS) progression after radiotherapy. In 37 patients evaluable for efficacy, the CNS objective response rate was 11%, clinical benefit rate at 4 and 6 months was 68% and 51%, respectively, and 2 patients had stable disease for over 2 years (Lin). Data supports the role of other HER2-targeted therapies for CNS disease including T-DM1, neratinib, and tucatinib. Among 291 patients with brain metastases in HER2CLIMB, the combination of tucatinib, capecitabine, and trastuzumab improved median overall survival (18 vs 12 months) and CNS progression-free survival (9.9 vs 4.2 months), compared with capecitabine plus trastuzumab. Further investigation exploring other novel therapy combinations and biomarkers will help further improve outcomes for these patients.

Adjuvant endocrine therapy decreases the risk for recurrence and improves survival for women diagnosed with HR-positive breast cancer. For young women, endocrine therapy options include tamoxifen, as well as ovarian suppression plus tamoxifen, or an aromatase inhibitor. Recommended duration of therapy is at least 5 years and can extend to 10 years. These treatments and duration may present challenges related to childbearing attempts and raise fertility concerns among young women.  In the Young Women’s Breast Cancer Study, among 643 women aged 40 years or younger and diagnosed with early stage HR-positive breast cancer, one-third reported fertility concerns impacting endocrine therapy decisions. Those who reported fertility concerns were more likely to exhibit non-initiation or non-persistence to endocrine therapy (40% vs 20%). Among women with fertility concerns, 7% did not initiate endocrine therapy, and 33% were non-persistent over 5 years (Sella). It is essential to integrate early oncofertility dialogue to help achieve optimal endocrine therapy and address family planning goals.

Studies have shown sugar-sweetened beverages (SSB) increase the risk for insulin resistance, diabetes, and heart disease. In a subsample of Women’s Health Initiative participants, higher levels of insulin resistance were shown to be linked to an increased incidence of breast cancer and all-cause mortality after breast cancer. Researchers found that among 8,863 women diagnosed with early breast cancer, those who consumed SSB after diagnosis had higher breast cancer-specific mortality and all-cause mortality. Additionally, replacing SSB with coffee, tea or water was linked to a decrease in mortality (Farvid). These findings support discussion of lifestyle and dietary behaviors in the survivorship setting, as these modifiable risk factors can potentially have significant health implications.

References:

van der Voort A, van Ramshorst MS, van Werkhoven ED, et al. Three-year follow-up of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2-blockade for HER2-positive breast cancer (TRAIN-2): A randomized phase III trial. J Clin Oncol. 2020;38S:ASCO #501.

Lin NU, Borges V, Anders C, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. J Clin Oncol. 2020;38(23):2610-2619.

Pan K, Chlebowski RT, Mortimer JE, et al. Insulin resistance and breast cancer incidence and mortality in postmenopausal women in the Women's Health Initiative. Cancer. 2020;126(16):3638-3647.

Adjuvant T-DM1 is recommended for patients with HER2-positive early breast cancer with residual disease after neoadjuvant therapy based on phase 3 results. The KATHERINE study found a significant reduction for the risk of recurrence and death with adjuvant T-DM1 vs trastuzumab. Subgroup analyses from KATHERINE showed similar benefits with T-DM1 irrespective of type of neoadjuvant regimen. Furthermore, T-DM1 appeared to benefit small node-negative tumors and particularly those tumors considered high-risk (Mamounas). In the phase 3 TRAIN-2 study, similar pCR rates (68% vs 67%), as well as 3 year event-free (94% vs 93%) and overall (98% vs 98%) survival, were observed for non-anthracycline and anthracycline-containing regimens. These findings highlight the broad applicability of T-DM1 in the adjuvant setting, the rationale to support de-escalation and omission of anthracyclines for HER2-positive tumors, and the importance of tailoring therapy based on response.

Brain metastases occur in up to 50% of patients with HER2-positive metastatic breast cancer (MBC). Effective therapies for this population represent an unmet clinical need. The phase 2 PATRICIA study demonstrated activity of pertuzumab plus high-dose trastuzumab (6mg/kg weekly) for patients with HER2-positive MBC and central nervous system (CNS) progression after radiotherapy. In 37 patients evaluable for efficacy, the CNS objective response rate was 11%, clinical benefit rate at 4 and 6 months was 68% and 51%, respectively, and 2 patients had stable disease for over 2 years (Lin). Data supports the role of other HER2-targeted therapies for CNS disease including T-DM1, neratinib, and tucatinib. Among 291 patients with brain metastases in HER2CLIMB, the combination of tucatinib, capecitabine, and trastuzumab improved median overall survival (18 vs 12 months) and CNS progression-free survival (9.9 vs 4.2 months), compared with capecitabine plus trastuzumab. Further investigation exploring other novel therapy combinations and biomarkers will help further improve outcomes for these patients.

Adjuvant endocrine therapy decreases the risk for recurrence and improves survival for women diagnosed with HR-positive breast cancer. For young women, endocrine therapy options include tamoxifen, as well as ovarian suppression plus tamoxifen, or an aromatase inhibitor. Recommended duration of therapy is at least 5 years and can extend to 10 years. These treatments and duration may present challenges related to childbearing attempts and raise fertility concerns among young women.  In the Young Women’s Breast Cancer Study, among 643 women aged 40 years or younger and diagnosed with early stage HR-positive breast cancer, one-third reported fertility concerns impacting endocrine therapy decisions. Those who reported fertility concerns were more likely to exhibit non-initiation or non-persistence to endocrine therapy (40% vs 20%). Among women with fertility concerns, 7% did not initiate endocrine therapy, and 33% were non-persistent over 5 years (Sella). It is essential to integrate early oncofertility dialogue to help achieve optimal endocrine therapy and address family planning goals.

Studies have shown sugar-sweetened beverages (SSB) increase the risk for insulin resistance, diabetes, and heart disease. In a subsample of Women’s Health Initiative participants, higher levels of insulin resistance were shown to be linked to an increased incidence of breast cancer and all-cause mortality after breast cancer. Researchers found that among 8,863 women diagnosed with early breast cancer, those who consumed SSB after diagnosis had higher breast cancer-specific mortality and all-cause mortality. Additionally, replacing SSB with coffee, tea or water was linked to a decrease in mortality (Farvid). These findings support discussion of lifestyle and dietary behaviors in the survivorship setting, as these modifiable risk factors can potentially have significant health implications.

References:

van der Voort A, van Ramshorst MS, van Werkhoven ED, et al. Three-year follow-up of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2-blockade for HER2-positive breast cancer (TRAIN-2): A randomized phase III trial. J Clin Oncol. 2020;38S:ASCO #501.

Lin NU, Borges V, Anders C, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. J Clin Oncol. 2020;38(23):2610-2619.

Pan K, Chlebowski RT, Mortimer JE, et al. Insulin resistance and breast cancer incidence and mortality in postmenopausal women in the Women's Health Initiative. Cancer. 2020;126(16):3638-3647.