Article

Background 

Of the approximately 80,000 individuals diagnosed annually in the United States with a non-Hodgkin lymphoma (NHL), MCL accounts for an estimated 5%.^1,2 At the time of diagnosis, most of these patients have advanced disease. The diagnosis of MCL is made based on characteristic immunophenotype and the presence of (11;14)(q13;q32) translocation resulting in overexpression of cyclin D1.^3,4 Long-term survival has been observed in a small proportion of patients with MCL, but this disease is generally considered incurable.⁵

Except for the approximately 10% of patients with MCL who present with asymptomatic indolent disease, for whom a watch-and-wait approach is generally used,⁶ there are 2 types of treatment strategies. One is applied to people who are fit and relatively young. In these cases, intensive chemotherapy with or without ASCT has been the dominant approach. In patients who are poor candidates for the toxicities associated with aggressive treatment, less intensive approaches are applied. These strategies include not only better-tolerated combinations of cytotoxic chemotherapies, but also various combinations that involve immunomodulators or small molecule enzyme inhibitors. Although less toxic, these regimens are active, often achieving a complete response (CR) and an extended progression-free survival (PFS).³

These 2 pathways of MCL treatment are reflected in guidelines from the National Comprehensive Cancer Network (NCCN), which describe separate first-line algorithms for stage I and stage II non-bulky disease and stage II bulky and advanced stage disease.⁷ For stage II bulky or advanced stage disease, separate pathways are described for indolent, TP53-mutated, and TP53 wild-type MCL and are further divided into pathways for those who are candidates for ASCT and those who are not.

Currently, “chemotherapy-free” therapies, a term that is sometimes used to identify drug combinations with modest or no cytotoxic effects, though inaccurate, are not preferred for first-line therapy in any group in the NCCN guidelines. However, immunomodulators, such as lenalidomide and targeted therapies, such as Bruton tyrosine kinase inhibitors (BTKis) are being actively tested in the front-line setting with promising results. Practical approaches to the application of these agents are described in trials presented or published in the last year, including TRIANGLE and SHINE.^10,11

Rethinking Front-Line MCL Therapy in the Young and Fit

Case Study

A 52-year-old man with a history of smoking presented with shortness of breath and general fatigue. The medical history included no major chronic diseases. The patient, who was referred after a routine examination, reported a recent decrease in body weight of unknown cause. Enlargement of inguinal, axillary, and submaxillary lymph nodes on examination along with laboratory abnormalities, such as anemia, and elevated lymphoid cells in the peripheral blood, raised suspicion of a lymphoproliferative disorder. A diagnosis of MCL was reached based on characteristic lymphoid cell morphology and immunotyping positive for CCND1 on lymph node biopsy. Ki-67 was 50% with wild-type TP53 on next-generation sequencing. The disease was characterized as stage III with intermediate risk MIPI (Mantle Cell Lymphoma International Prognostic Index).

For this presentation, one NCCN-guideline recommendation is a cytarabine-containing intensive chemotherapy regimen with rituximab followed by ASCT with maintenance rituximab in patients who are fit for transplant,⁷ but the recent data from the multicenter open-label TRIANGLE study has challenged this paradigm.¹⁰

In TRIANGLE, 870 treatment-naïve patients younger than age 65 (median age 57 years) were randomized to 1 of 3 study arms.¹⁰ In the control arm, patients received the standard-of-care induction with intensive chemoimmunotherapy (CIT) with ASCT consolidation (CIT + ASCT). In 1 of 2 experimental arms, patients received CIT + ibrutinib followed by ASCT consolidation and 2 years of ibrutinib maintenance (CIT + I + ASCT). In the other experimental arm, patients received CIT + ibrutinib followed by 2 years of ibrutinib maintenance with ASCT omitted (CIT + I). Rituximab maintenance as a single dose administered every 2 months for up to 3 years was permitted in all arms.

Most (87%) of the patients in TRIANGLE had stage IV disease and most (85%) had low- or intermediate-risk MIPI. The primary endpoint was failure-free survival (FFS). Rates of FFS at 3 years were 72% for the CIT+ ASCT arm, 88% for the CIT + I + ASCT arm, and 86% for the CIT + I arm. Overall survival (OS) at 3 years, during which time the trial was amended to permit rituximab maintenance in all 3 study arms, numerically favored ibrutinib arms (92% for CIT + I and 91% for CIT + I + ASCT), over chemotherapy alone (86% for CIT + ASCT).

The TRIANGLE trial does not yet establish a new standard for the types of patients enrolled, but it does show clearly that the use of ibrutinib with CIT was not inferior to the standard intensive approach integrating ASCT, and most types of adverse events occurred with less frequency in the ibrutinib-only arm.

There are numerous questions to pose and a broader understanding of applicability to be gained as more follow-up of this study and other studies utilizing targeted therapies, including other BTK inhibitors, provide mor data. Of particular interest is whether the presence of minimal residual disease (MRD) and the prognostic implications of MRD are affected by the use of a BTKi and/or ASCT. The E4151 and E4181 clinical trials may collectively provide greater insight here.^12,13

Rethinking Front-Line MCL Therapy in Older Patients

Case Study

A 74-year-old man with a history of cardiovascular disease, including a prior ST-elevated myocardial infarction, presents with nonspecific symptoms, including night sweats, intermittent fevers, and fatigue. Despite his symptoms, he continues to work 3 days per week and participates in a weekly game of doubles tennis. Axillary swelling leads him to seek medical attention. Imaging demonstrates diffuse lymphadenopathy. An axillary lymph node biopsy confirms a diagnosis of MC with FISH (fluorescence in situ hybridization) positive for t(11;14). He is of intermediate risk on MIPI scoring.

Due to his age and concurrent heart disease, he is not a candidate for aggressive chemotherapy and ASCT. Less aggressive therapies including bendamustine plus rituximab (BR),^14,15 lenalidomide plus rituximab (RR),⁸ and rituximab, bendamustine, and cytarabine (R-BAC) are discussed with this patient.¹⁶

Based on STiL data and BRIGHT studies, BR has become a widely used regimen.^14,15 However, attempts are being made to improve upon the BR backbone with the addition of BTK inhibitors.¹¹ In SHINE, BR plus ibrutinib further improved PFS relative to BR alone. SHINE was a 2-arm study, which was restricted to patients 65 years of age or older (median age 71 years); 523 previously untreated patients with good performance status and acceptable organ function were randomized to BR or BR plus ibrutinib. Most patients had intermediate- (~48%) or high- (~34%) risk MIPI. More than 90% had advanced-stage disease. Of patients in whom the TP53 mutation status was established, only about 10% were positive.

In the arm receiving BR alone, the median PFS was 52.9 months. With the addition of 560 mg once-daily ibrutinib to 6 cycles of BR followed by maintenance rituximab and continued ibrutinib, the median PFS, which was the primary endpoint, climbed to a median of 80.6 months. BR plus ibrutini was associated with a 41% reduction in the hazard ratio (HR) for progression or death (HR 0.75; P=.01). When stratified by risk factors, the advantage of BR plus ibrutinib was particularly pronounced in patients with intermediate-risk, (although not high-risk) nonmutated TP53, and less bulky disease.¹¹

There was no significant effect of the addition of ibrutinib on OS at the last analysis, but the longer PFS was achieved with only a modest increase in adverse events (AEs). For AEs of grade 3 or higher, the AE rates for BR plus ibrutinib and BR alone were 81.5% and 77.3%, respectively. Rates of cytopenias, including grade 3 or higher, were similar in the 2 arms. Rash and gastrointestinal AEs, such as diarrhea, nausea, and abdominal pain, occurred more frequently among patients who received ibrutinib.¹¹

Without an OS advantage, the SHINE trial does not establish a new standard of care, particularly given that it was voluntarily revoked from the market for the treatment of MCL. However, results are likely to accelerate interest in evaluating other targeted therapies, in combination with other relatively well-tolerated treatments. In patients with MCL unfit for ASCT, there is interest in pursuing other BTK inhibitors, particularly with ibrutinib being revoked as an indication for MCL. including the newer noncovalent pirtobrutinib, which was recently approved for MCL in the relapsed/refractory setting,¹⁷ and bispecific T-cell engagers (BiTEs) such as glofitamab.¹⁸

Rethinking Front-Line in TP53-Mutated MCL

Case Study

A previously healthy 62-year-old woman who presents with rapidly progressing lymphadenopathy and constitutional symptoms is diagnosed with MCL that has multiple adverse features. She has a Ki-67 level higher than 30%, a TP53 mutation, and blastoid morphology.¹⁹

The NCCN guidelines strongly recommend a clinical trial for patients with a TP53 mutation.⁷ Despite various high-intensity combinations to control disease in these patients, the 2017 pooled analysis demonstrated that most patients with TP53 mutations have a poor or no response to chemotherapy with a high side effect burden.¹⁹ In particular, such patients derive little benefit from high-intensity chemotherapy using ASCT.¹⁹

Nonetheless, for TP53-mutated MCL, several regimens have demonstrated activity. Most of these have used highly targeted therapies that offer the potential for low relative rates of toxicity. Two “chemotherapy-free” combinations involving venetoclax, the CD20-targeted obinutuzumab, and BTK inhibitors have completed phase 2 trials with promising results.^20,21 In a study evaluating the BOVen regimen (the second-generation BTK inhibitor zanubrutinib, obinutuzumab, and venetoclax) as time-limited therapy in TP53-mutated patients, 89% of patients achieved MRD at 26 months of follow-up.²⁰

Several novel therapies being tested in the relapsed/refractory setting have generated interest for evaluation in front-line clinical studies. These strategies include the BiTE glofitamab,¹⁸ the antibody-drug conjugate zilovertamab vedotin,²² and the chimeric antigen receptor (CAR) T-cell therapy brexucabtagene autoleucel (brexu-cel).²³ Brexu-cel is already approved in relapsed/refractory MCL.²³ Given the poor response to available treatments seen in patients with TP53 mutations, these novel therapies have the potential to improve outcomes in this population of high unmet need.

Summary

Durable remissions of MCL can be achieved with aggressive combinations of chemotherapy, but recent studies suggest a momentum away from cytotoxic drugs toward therapies with more targeted effects. In at least some patient populations, these therapies can rival the degree and duration of disease control achieved with less well-tolerated treatment. If ongoing trials corroborate the long-term efficacy and safety of these approaches, these therapies may represent an important evolution in MCL management.

Click to read more from 2023 Rare Diseases Report: Cancers

Background 

Of the approximately 80,000 individuals diagnosed annually in the United States with a non-Hodgkin lymphoma (NHL), MCL accounts for an estimated 5%.^1,2 At the time of diagnosis, most of these patients have advanced disease. The diagnosis of MCL is made based on characteristic immunophenotype and the presence of (11;14)(q13;q32) translocation resulting in overexpression of cyclin D1.^3,4 Long-term survival has been observed in a small proportion of patients with MCL, but this disease is generally considered incurable.⁵

Except for the approximately 10% of patients with MCL who present with asymptomatic indolent disease, for whom a watch-and-wait approach is generally used,⁶ there are 2 types of treatment strategies. One is applied to people who are fit and relatively young. In these cases, intensive chemotherapy with or without ASCT has been the dominant approach. In patients who are poor candidates for the toxicities associated with aggressive treatment, less intensive approaches are applied. These strategies include not only better-tolerated combinations of cytotoxic chemotherapies, but also various combinations that involve immunomodulators or small molecule enzyme inhibitors. Although less toxic, these regimens are active, often achieving a complete response (CR) and an extended progression-free survival (PFS).³

These 2 pathways of MCL treatment are reflected in guidelines from the National Comprehensive Cancer Network (NCCN), which describe separate first-line algorithms for stage I and stage II non-bulky disease and stage II bulky and advanced stage disease.⁷ For stage II bulky or advanced stage disease, separate pathways are described for indolent, TP53-mutated, and TP53 wild-type MCL and are further divided into pathways for those who are candidates for ASCT and those who are not.

Currently, “chemotherapy-free” therapies, a term that is sometimes used to identify drug combinations with modest or no cytotoxic effects, though inaccurate, are not preferred for first-line therapy in any group in the NCCN guidelines. However, immunomodulators, such as lenalidomide and targeted therapies, such as Bruton tyrosine kinase inhibitors (BTKis) are being actively tested in the front-line setting with promising results. Practical approaches to the application of these agents are described in trials presented or published in the last year, including TRIANGLE and SHINE.^10,11

Rethinking Front-Line MCL Therapy in the Young and Fit

Case Study

A 52-year-old man with a history of smoking presented with shortness of breath and general fatigue. The medical history included no major chronic diseases. The patient, who was referred after a routine examination, reported a recent decrease in body weight of unknown cause. Enlargement of inguinal, axillary, and submaxillary lymph nodes on examination along with laboratory abnormalities, such as anemia, and elevated lymphoid cells in the peripheral blood, raised suspicion of a lymphoproliferative disorder. A diagnosis of MCL was reached based on characteristic lymphoid cell morphology and immunotyping positive for CCND1 on lymph node biopsy. Ki-67 was 50% with wild-type TP53 on next-generation sequencing. The disease was characterized as stage III with intermediate risk MIPI (Mantle Cell Lymphoma International Prognostic Index).

For this presentation, one NCCN-guideline recommendation is a cytarabine-containing intensive chemotherapy regimen with rituximab followed by ASCT with maintenance rituximab in patients who are fit for transplant,⁷ but the recent data from the multicenter open-label TRIANGLE study has challenged this paradigm.¹⁰

In TRIANGLE, 870 treatment-naïve patients younger than age 65 (median age 57 years) were randomized to 1 of 3 study arms.¹⁰ In the control arm, patients received the standard-of-care induction with intensive chemoimmunotherapy (CIT) with ASCT consolidation (CIT + ASCT). In 1 of 2 experimental arms, patients received CIT + ibrutinib followed by ASCT consolidation and 2 years of ibrutinib maintenance (CIT + I + ASCT). In the other experimental arm, patients received CIT + ibrutinib followed by 2 years of ibrutinib maintenance with ASCT omitted (CIT + I). Rituximab maintenance as a single dose administered every 2 months for up to 3 years was permitted in all arms.

Most (87%) of the patients in TRIANGLE had stage IV disease and most (85%) had low- or intermediate-risk MIPI. The primary endpoint was failure-free survival (FFS). Rates of FFS at 3 years were 72% for the CIT+ ASCT arm, 88% for the CIT + I + ASCT arm, and 86% for the CIT + I arm. Overall survival (OS) at 3 years, during which time the trial was amended to permit rituximab maintenance in all 3 study arms, numerically favored ibrutinib arms (92% for CIT + I and 91% for CIT + I + ASCT), over chemotherapy alone (86% for CIT + ASCT).

The TRIANGLE trial does not yet establish a new standard for the types of patients enrolled, but it does show clearly that the use of ibrutinib with CIT was not inferior to the standard intensive approach integrating ASCT, and most types of adverse events occurred with less frequency in the ibrutinib-only arm.

There are numerous questions to pose and a broader understanding of applicability to be gained as more follow-up of this study and other studies utilizing targeted therapies, including other BTK inhibitors, provide mor data. Of particular interest is whether the presence of minimal residual disease (MRD) and the prognostic implications of MRD are affected by the use of a BTKi and/or ASCT. The E4151 and E4181 clinical trials may collectively provide greater insight here.^12,13

Rethinking Front-Line MCL Therapy in Older Patients

Case Study

A 74-year-old man with a history of cardiovascular disease, including a prior ST-elevated myocardial infarction, presents with nonspecific symptoms, including night sweats, intermittent fevers, and fatigue. Despite his symptoms, he continues to work 3 days per week and participates in a weekly game of doubles tennis. Axillary swelling leads him to seek medical attention. Imaging demonstrates diffuse lymphadenopathy. An axillary lymph node biopsy confirms a diagnosis of MC with FISH (fluorescence in situ hybridization) positive for t(11;14). He is of intermediate risk on MIPI scoring.

Due to his age and concurrent heart disease, he is not a candidate for aggressive chemotherapy and ASCT. Less aggressive therapies including bendamustine plus rituximab (BR),^14,15 lenalidomide plus rituximab (RR),⁸ and rituximab, bendamustine, and cytarabine (R-BAC) are discussed with this patient.¹⁶

Based on STiL data and BRIGHT studies, BR has become a widely used regimen.^14,15 However, attempts are being made to improve upon the BR backbone with the addition of BTK inhibitors.¹¹ In SHINE, BR plus ibrutinib further improved PFS relative to BR alone. SHINE was a 2-arm study, which was restricted to patients 65 years of age or older (median age 71 years); 523 previously untreated patients with good performance status and acceptable organ function were randomized to BR or BR plus ibrutinib. Most patients had intermediate- (~48%) or high- (~34%) risk MIPI. More than 90% had advanced-stage disease. Of patients in whom the TP53 mutation status was established, only about 10% were positive.

In the arm receiving BR alone, the median PFS was 52.9 months. With the addition of 560 mg once-daily ibrutinib to 6 cycles of BR followed by maintenance rituximab and continued ibrutinib, the median PFS, which was the primary endpoint, climbed to a median of 80.6 months. BR plus ibrutini was associated with a 41% reduction in the hazard ratio (HR) for progression or death (HR 0.75; P=.01). When stratified by risk factors, the advantage of BR plus ibrutinib was particularly pronounced in patients with intermediate-risk, (although not high-risk) nonmutated TP53, and less bulky disease.¹¹

There was no significant effect of the addition of ibrutinib on OS at the last analysis, but the longer PFS was achieved with only a modest increase in adverse events (AEs). For AEs of grade 3 or higher, the AE rates for BR plus ibrutinib and BR alone were 81.5% and 77.3%, respectively. Rates of cytopenias, including grade 3 or higher, were similar in the 2 arms. Rash and gastrointestinal AEs, such as diarrhea, nausea, and abdominal pain, occurred more frequently among patients who received ibrutinib.¹¹

Without an OS advantage, the SHINE trial does not establish a new standard of care, particularly given that it was voluntarily revoked from the market for the treatment of MCL. However, results are likely to accelerate interest in evaluating other targeted therapies, in combination with other relatively well-tolerated treatments. In patients with MCL unfit for ASCT, there is interest in pursuing other BTK inhibitors, particularly with ibrutinib being revoked as an indication for MCL. including the newer noncovalent pirtobrutinib, which was recently approved for MCL in the relapsed/refractory setting,¹⁷ and bispecific T-cell engagers (BiTEs) such as glofitamab.¹⁸

Rethinking Front-Line in TP53-Mutated MCL

Case Study

A previously healthy 62-year-old woman who presents with rapidly progressing lymphadenopathy and constitutional symptoms is diagnosed with MCL that has multiple adverse features. She has a Ki-67 level higher than 30%, a TP53 mutation, and blastoid morphology.¹⁹

The NCCN guidelines strongly recommend a clinical trial for patients with a TP53 mutation.⁷ Despite various high-intensity combinations to control disease in these patients, the 2017 pooled analysis demonstrated that most patients with TP53 mutations have a poor or no response to chemotherapy with a high side effect burden.¹⁹ In particular, such patients derive little benefit from high-intensity chemotherapy using ASCT.¹⁹

Nonetheless, for TP53-mutated MCL, several regimens have demonstrated activity. Most of these have used highly targeted therapies that offer the potential for low relative rates of toxicity. Two “chemotherapy-free” combinations involving venetoclax, the CD20-targeted obinutuzumab, and BTK inhibitors have completed phase 2 trials with promising results.^20,21 In a study evaluating the BOVen regimen (the second-generation BTK inhibitor zanubrutinib, obinutuzumab, and venetoclax) as time-limited therapy in TP53-mutated patients, 89% of patients achieved MRD at 26 months of follow-up.²⁰

Several novel therapies being tested in the relapsed/refractory setting have generated interest for evaluation in front-line clinical studies. These strategies include the BiTE glofitamab,¹⁸ the antibody-drug conjugate zilovertamab vedotin,²² and the chimeric antigen receptor (CAR) T-cell therapy brexucabtagene autoleucel (brexu-cel).²³ Brexu-cel is already approved in relapsed/refractory MCL.²³ Given the poor response to available treatments seen in patients with TP53 mutations, these novel therapies have the potential to improve outcomes in this population of high unmet need.

Summary

Durable remissions of MCL can be achieved with aggressive combinations of chemotherapy, but recent studies suggest a momentum away from cytotoxic drugs toward therapies with more targeted effects. In at least some patient populations, these therapies can rival the degree and duration of disease control achieved with less well-tolerated treatment. If ongoing trials corroborate the long-term efficacy and safety of these approaches, these therapies may represent an important evolution in MCL management.

Click to read more from 2023 Rare Diseases Report: Cancers

Background 

Of the approximately 80,000 individuals diagnosed annually in the United States with a non-Hodgkin lymphoma (NHL), MCL accounts for an estimated 5%.^1,2 At the time of diagnosis, most of these patients have advanced disease. The diagnosis of MCL is made based on characteristic immunophenotype and the presence of (11;14)(q13;q32) translocation resulting in overexpression of cyclin D1.^3,4 Long-term survival has been observed in a small proportion of patients with MCL, but this disease is generally considered incurable.⁵

Except for the approximately 10% of patients with MCL who present with asymptomatic indolent disease, for whom a watch-and-wait approach is generally used,⁶ there are 2 types of treatment strategies. One is applied to people who are fit and relatively young. In these cases, intensive chemotherapy with or without ASCT has been the dominant approach. In patients who are poor candidates for the toxicities associated with aggressive treatment, less intensive approaches are applied. These strategies include not only better-tolerated combinations of cytotoxic chemotherapies, but also various combinations that involve immunomodulators or small molecule enzyme inhibitors. Although less toxic, these regimens are active, often achieving a complete response (CR) and an extended progression-free survival (PFS).³

These 2 pathways of MCL treatment are reflected in guidelines from the National Comprehensive Cancer Network (NCCN), which describe separate first-line algorithms for stage I and stage II non-bulky disease and stage II bulky and advanced stage disease.⁷ For stage II bulky or advanced stage disease, separate pathways are described for indolent, TP53-mutated, and TP53 wild-type MCL and are further divided into pathways for those who are candidates for ASCT and those who are not.

Currently, “chemotherapy-free” therapies, a term that is sometimes used to identify drug combinations with modest or no cytotoxic effects, though inaccurate, are not preferred for first-line therapy in any group in the NCCN guidelines. However, immunomodulators, such as lenalidomide and targeted therapies, such as Bruton tyrosine kinase inhibitors (BTKis) are being actively tested in the front-line setting with promising results. Practical approaches to the application of these agents are described in trials presented or published in the last year, including TRIANGLE and SHINE.^10,11

Rethinking Front-Line MCL Therapy in the Young and Fit

Case Study

A 52-year-old man with a history of smoking presented with shortness of breath and general fatigue. The medical history included no major chronic diseases. The patient, who was referred after a routine examination, reported a recent decrease in body weight of unknown cause. Enlargement of inguinal, axillary, and submaxillary lymph nodes on examination along with laboratory abnormalities, such as anemia, and elevated lymphoid cells in the peripheral blood, raised suspicion of a lymphoproliferative disorder. A diagnosis of MCL was reached based on characteristic lymphoid cell morphology and immunotyping positive for CCND1 on lymph node biopsy. Ki-67 was 50% with wild-type TP53 on next-generation sequencing. The disease was characterized as stage III with intermediate risk MIPI (Mantle Cell Lymphoma International Prognostic Index).

For this presentation, one NCCN-guideline recommendation is a cytarabine-containing intensive chemotherapy regimen with rituximab followed by ASCT with maintenance rituximab in patients who are fit for transplant,⁷ but the recent data from the multicenter open-label TRIANGLE study has challenged this paradigm.¹⁰

In TRIANGLE, 870 treatment-naïve patients younger than age 65 (median age 57 years) were randomized to 1 of 3 study arms.¹⁰ In the control arm, patients received the standard-of-care induction with intensive chemoimmunotherapy (CIT) with ASCT consolidation (CIT + ASCT). In 1 of 2 experimental arms, patients received CIT + ibrutinib followed by ASCT consolidation and 2 years of ibrutinib maintenance (CIT + I + ASCT). In the other experimental arm, patients received CIT + ibrutinib followed by 2 years of ibrutinib maintenance with ASCT omitted (CIT + I). Rituximab maintenance as a single dose administered every 2 months for up to 3 years was permitted in all arms.

Most (87%) of the patients in TRIANGLE had stage IV disease and most (85%) had low- or intermediate-risk MIPI. The primary endpoint was failure-free survival (FFS). Rates of FFS at 3 years were 72% for the CIT+ ASCT arm, 88% for the CIT + I + ASCT arm, and 86% for the CIT + I arm. Overall survival (OS) at 3 years, during which time the trial was amended to permit rituximab maintenance in all 3 study arms, numerically favored ibrutinib arms (92% for CIT + I and 91% for CIT + I + ASCT), over chemotherapy alone (86% for CIT + ASCT).

The TRIANGLE trial does not yet establish a new standard for the types of patients enrolled, but it does show clearly that the use of ibrutinib with CIT was not inferior to the standard intensive approach integrating ASCT, and most types of adverse events occurred with less frequency in the ibrutinib-only arm.

There are numerous questions to pose and a broader understanding of applicability to be gained as more follow-up of this study and other studies utilizing targeted therapies, including other BTK inhibitors, provide mor data. Of particular interest is whether the presence of minimal residual disease (MRD) and the prognostic implications of MRD are affected by the use of a BTKi and/or ASCT. The E4151 and E4181 clinical trials may collectively provide greater insight here.^12,13

Rethinking Front-Line MCL Therapy in Older Patients

Case Study

A 74-year-old man with a history of cardiovascular disease, including a prior ST-elevated myocardial infarction, presents with nonspecific symptoms, including night sweats, intermittent fevers, and fatigue. Despite his symptoms, he continues to work 3 days per week and participates in a weekly game of doubles tennis. Axillary swelling leads him to seek medical attention. Imaging demonstrates diffuse lymphadenopathy. An axillary lymph node biopsy confirms a diagnosis of MC with FISH (fluorescence in situ hybridization) positive for t(11;14). He is of intermediate risk on MIPI scoring.

Due to his age and concurrent heart disease, he is not a candidate for aggressive chemotherapy and ASCT. Less aggressive therapies including bendamustine plus rituximab (BR),^14,15 lenalidomide plus rituximab (RR),⁸ and rituximab, bendamustine, and cytarabine (R-BAC) are discussed with this patient.¹⁶

Based on STiL data and BRIGHT studies, BR has become a widely used regimen.^14,15 However, attempts are being made to improve upon the BR backbone with the addition of BTK inhibitors.¹¹ In SHINE, BR plus ibrutinib further improved PFS relative to BR alone. SHINE was a 2-arm study, which was restricted to patients 65 years of age or older (median age 71 years); 523 previously untreated patients with good performance status and acceptable organ function were randomized to BR or BR plus ibrutinib. Most patients had intermediate- (~48%) or high- (~34%) risk MIPI. More than 90% had advanced-stage disease. Of patients in whom the TP53 mutation status was established, only about 10% were positive.

In the arm receiving BR alone, the median PFS was 52.9 months. With the addition of 560 mg once-daily ibrutinib to 6 cycles of BR followed by maintenance rituximab and continued ibrutinib, the median PFS, which was the primary endpoint, climbed to a median of 80.6 months. BR plus ibrutini was associated with a 41% reduction in the hazard ratio (HR) for progression or death (HR 0.75; P=.01). When stratified by risk factors, the advantage of BR plus ibrutinib was particularly pronounced in patients with intermediate-risk, (although not high-risk) nonmutated TP53, and less bulky disease.¹¹

There was no significant effect of the addition of ibrutinib on OS at the last analysis, but the longer PFS was achieved with only a modest increase in adverse events (AEs). For AEs of grade 3 or higher, the AE rates for BR plus ibrutinib and BR alone were 81.5% and 77.3%, respectively. Rates of cytopenias, including grade 3 or higher, were similar in the 2 arms. Rash and gastrointestinal AEs, such as diarrhea, nausea, and abdominal pain, occurred more frequently among patients who received ibrutinib.¹¹

Without an OS advantage, the SHINE trial does not establish a new standard of care, particularly given that it was voluntarily revoked from the market for the treatment of MCL. However, results are likely to accelerate interest in evaluating other targeted therapies, in combination with other relatively well-tolerated treatments. In patients with MCL unfit for ASCT, there is interest in pursuing other BTK inhibitors, particularly with ibrutinib being revoked as an indication for MCL. including the newer noncovalent pirtobrutinib, which was recently approved for MCL in the relapsed/refractory setting,¹⁷ and bispecific T-cell engagers (BiTEs) such as glofitamab.¹⁸

Rethinking Front-Line in TP53-Mutated MCL

Case Study

A previously healthy 62-year-old woman who presents with rapidly progressing lymphadenopathy and constitutional symptoms is diagnosed with MCL that has multiple adverse features. She has a Ki-67 level higher than 30%, a TP53 mutation, and blastoid morphology.¹⁹

The NCCN guidelines strongly recommend a clinical trial for patients with a TP53 mutation.⁷ Despite various high-intensity combinations to control disease in these patients, the 2017 pooled analysis demonstrated that most patients with TP53 mutations have a poor or no response to chemotherapy with a high side effect burden.¹⁹ In particular, such patients derive little benefit from high-intensity chemotherapy using ASCT.¹⁹

Nonetheless, for TP53-mutated MCL, several regimens have demonstrated activity. Most of these have used highly targeted therapies that offer the potential for low relative rates of toxicity. Two “chemotherapy-free” combinations involving venetoclax, the CD20-targeted obinutuzumab, and BTK inhibitors have completed phase 2 trials with promising results.^20,21 In a study evaluating the BOVen regimen (the second-generation BTK inhibitor zanubrutinib, obinutuzumab, and venetoclax) as time-limited therapy in TP53-mutated patients, 89% of patients achieved MRD at 26 months of follow-up.²⁰

Several novel therapies being tested in the relapsed/refractory setting have generated interest for evaluation in front-line clinical studies. These strategies include the BiTE glofitamab,¹⁸ the antibody-drug conjugate zilovertamab vedotin,²² and the chimeric antigen receptor (CAR) T-cell therapy brexucabtagene autoleucel (brexu-cel).²³ Brexu-cel is already approved in relapsed/refractory MCL.²³ Given the poor response to available treatments seen in patients with TP53 mutations, these novel therapies have the potential to improve outcomes in this population of high unmet need.

Summary

Durable remissions of MCL can be achieved with aggressive combinations of chemotherapy, but recent studies suggest a momentum away from cytotoxic drugs toward therapies with more targeted effects. In at least some patient populations, these therapies can rival the degree and duration of disease control achieved with less well-tolerated treatment. If ongoing trials corroborate the long-term efficacy and safety of these approaches, these therapies may represent an important evolution in MCL management.

Click to read more from 2023 Rare Diseases Report: Cancers

While people living with rare cancers continue to face daunting obstacles, progress is being made, and there are reasons to hope for a better future. Advances in genomic testing and precision medicine provide increasing evidence that rare cancers can be more efficiently and effectively diagnosed and treated. Genomic tests examine tumor DNA to identify mutations that are unique to an individual’s cancer. This genetic information enables a more precise diagnosis and targeted treatment approach. Jim Palma, Co-Lead of the NORD Rare Cancer Coalition, said “There is promise for rare cancer patients due to increased legislative efforts to cover the costs of genomic testing coupled by an increase in FDA approvals for targeted and tissue agnostic therapies.”

In 2019, the National Cancer Institute established MyPART, a vast pediatric and adult rare tumor network that aims to bolster patient involvement in research and develop effective therapies through tumor sample collection, shared data, shared samples, new methods to test treatments, and new trial designs. In 2022, MyPART welcomed NORD’s Rare Cancer Coalition as an advocacy partner.

Meanwhile, advocacy organizations are giving rare cancer a rising voice. NORD’s Rare Cancer Coalition unites rare cancer patient advocacy organizations and helps them drive progress together. The coalition promotes research and awareness through its annual Rare Cancer Day (September 30) campaign. Additionally, NORD has produced over 22 continuing medical education modules on rare cancers in collaboration with PlatformQ Health, providing updates on new therapies and treatment approaches. NORD also offers rare disease reports and educational videos on rare cancers, sessions inclusive of rare cancer topics at the annual NORD Summit, and a quarterly e-newsletter, “Caring for Rare” for healthcare professionals. Please visit us at rarediseases.org to access these resources.

Much work on rare cancers remains to be done, but the progress over recent years points to better outcomes moving forward. We are grateful for the work you do and your dedication to your patients, including those with rare cancers and other rare conditions. We hope you will find the information in this special issue useful for your clinical practice.

– Katie Kowalski, MPH
Associate Director of Education
National Organization for Rare Disorders

Click to read more from 2023 Rare Diseases Report: Cancers

While people living with rare cancers continue to face daunting obstacles, progress is being made, and there are reasons to hope for a better future. Advances in genomic testing and precision medicine provide increasing evidence that rare cancers can be more efficiently and effectively diagnosed and treated. Genomic tests examine tumor DNA to identify mutations that are unique to an individual’s cancer. This genetic information enables a more precise diagnosis and targeted treatment approach. Jim Palma, Co-Lead of the NORD Rare Cancer Coalition, said “There is promise for rare cancer patients due to increased legislative efforts to cover the costs of genomic testing coupled by an increase in FDA approvals for targeted and tissue agnostic therapies.”

In 2019, the National Cancer Institute established MyPART, a vast pediatric and adult rare tumor network that aims to bolster patient involvement in research and develop effective therapies through tumor sample collection, shared data, shared samples, new methods to test treatments, and new trial designs. In 2022, MyPART welcomed NORD’s Rare Cancer Coalition as an advocacy partner.

Meanwhile, advocacy organizations are giving rare cancer a rising voice. NORD’s Rare Cancer Coalition unites rare cancer patient advocacy organizations and helps them drive progress together. The coalition promotes research and awareness through its annual Rare Cancer Day (September 30) campaign. Additionally, NORD has produced over 22 continuing medical education modules on rare cancers in collaboration with PlatformQ Health, providing updates on new therapies and treatment approaches. NORD also offers rare disease reports and educational videos on rare cancers, sessions inclusive of rare cancer topics at the annual NORD Summit, and a quarterly e-newsletter, “Caring for Rare” for healthcare professionals. Please visit us at rarediseases.org to access these resources.

Much work on rare cancers remains to be done, but the progress over recent years points to better outcomes moving forward. We are grateful for the work you do and your dedication to your patients, including those with rare cancers and other rare conditions. We hope you will find the information in this special issue useful for your clinical practice.

– Katie Kowalski, MPH
Associate Director of Education
National Organization for Rare Disorders

Click to read more from 2023 Rare Diseases Report: Cancers

While people living with rare cancers continue to face daunting obstacles, progress is being made, and there are reasons to hope for a better future. Advances in genomic testing and precision medicine provide increasing evidence that rare cancers can be more efficiently and effectively diagnosed and treated. Genomic tests examine tumor DNA to identify mutations that are unique to an individual’s cancer. This genetic information enables a more precise diagnosis and targeted treatment approach. Jim Palma, Co-Lead of the NORD Rare Cancer Coalition, said “There is promise for rare cancer patients due to increased legislative efforts to cover the costs of genomic testing coupled by an increase in FDA approvals for targeted and tissue agnostic therapies.”

In 2019, the National Cancer Institute established MyPART, a vast pediatric and adult rare tumor network that aims to bolster patient involvement in research and develop effective therapies through tumor sample collection, shared data, shared samples, new methods to test treatments, and new trial designs. In 2022, MyPART welcomed NORD’s Rare Cancer Coalition as an advocacy partner.

Meanwhile, advocacy organizations are giving rare cancer a rising voice. NORD’s Rare Cancer Coalition unites rare cancer patient advocacy organizations and helps them drive progress together. The coalition promotes research and awareness through its annual Rare Cancer Day (September 30) campaign. Additionally, NORD has produced over 22 continuing medical education modules on rare cancers in collaboration with PlatformQ Health, providing updates on new therapies and treatment approaches. NORD also offers rare disease reports and educational videos on rare cancers, sessions inclusive of rare cancer topics at the annual NORD Summit, and a quarterly e-newsletter, “Caring for Rare” for healthcare professionals. Please visit us at rarediseases.org to access these resources.

Much work on rare cancers remains to be done, but the progress over recent years points to better outcomes moving forward. We are grateful for the work you do and your dedication to your patients, including those with rare cancers and other rare conditions. We hope you will find the information in this special issue useful for your clinical practice.

– Katie Kowalski, MPH
Associate Director of Education
National Organization for Rare Disorders

Click to read more from 2023 Rare Diseases Report: Cancers

This edition of Rare Diseases Report: Cancers highlights the latest breakthroughs and remaining unmet needs in the management of rare cancers. In addition to celebrating the great progress that has been made in recent years, we also discuss new challenges, such as how the healthcare system can prepare to manage the growing number of rare cancer survivors who are living longer due to improvements in disease management. 

INTRODUCTION

NORD: Making Progress Through Collaboration
By Katie Kowalski, MPH

IN THIS ISSUE

The Complex Challenge of Survival After HPV-Associated Oropharyngeal Cancer
By Vlad C. Sandulache, MD, PhD

Progress in Ovarian Cancer: Discovery of Fallopian Tube Involvement
By Ronny Drapkin, MD, PhD

An Evolving Understanding of Adenosquamous Carcinoma of the Lung
By Rajwanth Veluswamy, MD, MSCR

Gastrointestinal Stromal Tumor: Reflecting on 2 Decades of Clinical Advancements
By Jason K. Sicklick, MD, FACS

Progress in Treating Testicular Cancer
By Liang Cheng, MD

Strategies to Improve Long-Term Outcomes in Younger Patients with Hodgkin Lymphoma
By Ann LaCasce, MD, MMSc

Targeted Therapies in Younger and Older Patients with Mantle Cell Lymphoma
By Reem Karmali, MD, MS

Advances in Management of Relapsed/Refractory Hairy Cell Leukemia
By Robert J. Kreitman, MD

Treatment Needs of Older Adults With Newly Diagnosed Acute Myeloid Leukemia
By Harry Erba, MD, PhD

Progress in Management of Advanced Acute Lymphocytic Leukemia in Children
By Susan Colace, MD, MSCI

This edition of Rare Diseases Report: Cancers highlights the latest breakthroughs and remaining unmet needs in the management of rare cancers. In addition to celebrating the great progress that has been made in recent years, we also discuss new challenges, such as how the healthcare system can prepare to manage the growing number of rare cancer survivors who are living longer due to improvements in disease management. 

INTRODUCTION

NORD: Making Progress Through Collaboration
By Katie Kowalski, MPH

IN THIS ISSUE

The Complex Challenge of Survival After HPV-Associated Oropharyngeal Cancer
By Vlad C. Sandulache, MD, PhD

Progress in Ovarian Cancer: Discovery of Fallopian Tube Involvement
By Ronny Drapkin, MD, PhD

An Evolving Understanding of Adenosquamous Carcinoma of the Lung
By Rajwanth Veluswamy, MD, MSCR

Gastrointestinal Stromal Tumor: Reflecting on 2 Decades of Clinical Advancements
By Jason K. Sicklick, MD, FACS

Progress in Treating Testicular Cancer
By Liang Cheng, MD

Strategies to Improve Long-Term Outcomes in Younger Patients with Hodgkin Lymphoma
By Ann LaCasce, MD, MMSc

Targeted Therapies in Younger and Older Patients with Mantle Cell Lymphoma
By Reem Karmali, MD, MS

Advances in Management of Relapsed/Refractory Hairy Cell Leukemia
By Robert J. Kreitman, MD

Treatment Needs of Older Adults With Newly Diagnosed Acute Myeloid Leukemia
By Harry Erba, MD, PhD

Progress in Management of Advanced Acute Lymphocytic Leukemia in Children
By Susan Colace, MD, MSCI

This edition of Rare Diseases Report: Cancers highlights the latest breakthroughs and remaining unmet needs in the management of rare cancers. In addition to celebrating the great progress that has been made in recent years, we also discuss new challenges, such as how the healthcare system can prepare to manage the growing number of rare cancer survivors who are living longer due to improvements in disease management. 

INTRODUCTION

NORD: Making Progress Through Collaboration
By Katie Kowalski, MPH

IN THIS ISSUE

The Complex Challenge of Survival After HPV-Associated Oropharyngeal Cancer
By Vlad C. Sandulache, MD, PhD

Progress in Ovarian Cancer: Discovery of Fallopian Tube Involvement
By Ronny Drapkin, MD, PhD

An Evolving Understanding of Adenosquamous Carcinoma of the Lung
By Rajwanth Veluswamy, MD, MSCR

Gastrointestinal Stromal Tumor: Reflecting on 2 Decades of Clinical Advancements
By Jason K. Sicklick, MD, FACS

Progress in Treating Testicular Cancer
By Liang Cheng, MD

Strategies to Improve Long-Term Outcomes in Younger Patients with Hodgkin Lymphoma
By Ann LaCasce, MD, MMSc

Targeted Therapies in Younger and Older Patients with Mantle Cell Lymphoma
By Reem Karmali, MD, MS

Advances in Management of Relapsed/Refractory Hairy Cell Leukemia
By Robert J. Kreitman, MD

Treatment Needs of Older Adults With Newly Diagnosed Acute Myeloid Leukemia
By Harry Erba, MD, PhD

Progress in Management of Advanced Acute Lymphocytic Leukemia in Children
By Susan Colace, MD, MSCI

Background

Hodgkin lymphoma occurs in fewer than 9,000 individuals in the United States each year,¹ but it is one of the most common types of cancer in AYAs.² For the purposes of cHL, AYA is typically defined as an age range of 18 to 39 years, which covers the first of 2 bimodal peaks in incidence but stops short of the second.^3,4 The first of these peaks occurs between the ages of 15 and 34 years, while the second begins at about age 55.⁵ Children younger than 15 years of age can also develop Hodgkin lymphoma, but it is less common.⁶

In AYAs and in adults, more than 90% of patients with Hodgkin lymphoma have cHL.⁷ Most AYAs present with the nodular sclerosis subtype, but cHL is managed differently in pediatric patients versus in adult centers.^8,9 Evidence suggests that the specific risks of common treatment protocols, although similar, are not the same in AYAs as in adults.^10,11 Even though the literature evaluating the presentation and management of AYA cHL has been growing since 2005, when the AYA Oncology Progress Review Group called for AYAs to be recognized
as a distinct group, clinical trials specific to AYA cHL remain limited.⁹

Major Hodgkin lymphoma guidelines only partially address AYAs as a distinct group. In guidelines issued by the National Cancer Institute, the differences in clinical presentation of AYAs are described for young children, AYAs, and older adults, but there are no treatment recommendations specific to AYAs.¹² Guidelines from the EuroNet Paediatric Hodgkin Lymphoma Group offer recommendations for relapsed and refractory Hodgkin lymphoma, but do not differentiate between children and adolescents.¹³ The National Comprehensive Cancer Network (NCCN) provides separate treatment recommendations for patients 18 years or younger and those who are older than 18.^14,15 For Hodgkin lymphoma, AYA is not addressed as a separate category even though the NCCN has provided general guidelines for treatment of malignancies in AYA.¹⁶

First-line therapies are effective in children, AYAs, and adults. Survival rates at 5 years have increased steadily, approaching or exceeding 90% across age groups even for patients with unfavorable risk characteristics.¹⁷ This success has permitted greater focus on developing strategies that preserve efficacy with lower acute and long-term risks.

Risk-Adapted Therapies

While the potential for new and novel therapies to reduce the risk of long-term toxicities continues to be explored, adjusting existing regimens to reduce these risks has proven to be a viable strategy. This adjustment is a standard of care in the pediatric setting based on results from such studies as German GPOH-HD 95, which suggested that doses of radiotherapy, a major contributor to late toxicities,¹⁸ can be omitted in patients with a complete response after chemotherapy.¹¹ This pediatric trial contained both younger children and adolescents, but subsequent secondary analyses looking specifically at AYAs in this and other trials have suggested that efficacy is similarly preserved with risk-adapted strategies.⁹

However, due to AYA patients with cHL being treated using both pediatric and adult approaches, the persistent debate about optimal therapies in this age group complicates the effort to define a well-accepted strategy for risk adjustment. While risk-adapted strategies that rely on interim positron emission tomography (PET) to calibrate treatment intensity are now being used routinely across age stratifications, other initiatives are creating additional opportunities to gauge the impact on late effects in AYAs. These include strategies to improve collaboration across groups of trialists and data generated by observational cohorts, which can evaluate late effects not captured in time-limited clinical trials.

Among recent data supporting risk-adjusted therapy, the toxicity outcomes from a multicenter trial of PET-guided intensive treatment in patients with newly diagnosed advanced cHL were presented at the 2022 annual meeting of the American Society of Hematology.¹⁹ This phase 3 trial enrolled patients younger than 60 years, 79% of whom were younger than 45 years. Building on previous evidence that PET guidance improves the safety of eBEACOPP (escalated doses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), nearly 1,500 patients were randomized to this strategy or to PET-guided BrECADD, a modified eBEACOPP in which the antibody conjugate brentuximab vedotin (BV) was substituted for bleomycin. For an adjudicated endpoint of treatment-related morbidity, the experimental BrECAAD regimen reduced the risk by nearly 30% (hazard ratio [HR] 0.72). It is unclear whether this strategy will be used in the United States, where trials have been built on ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) rather than BEACOPP.

Efficacy data from this trial are not yet available, and these data will be important. There is concern that PET-directed therapy might result in lower toxicity at a cost of reduced rates of disease control. It is possible that the serious consequences of late toxicities—including infertility, compromised cardiovascular function, secondary cancers, and other organ damage—might need to be balanced against some loss of efficacy.

Novel Targeted Therapies

The goal of reducing late toxicities of cHL therapy in AYAs is also likely to be advanced by novel therapies. Research endeavors include a multicenter collaboration between US and Canadian investigators that is exploring the combination of nivolumab (a checkpoint inhibitor) plus BV.²⁰ The trial recently completed accrual and includes both adult and pediatric patients. If novel agents prove effective for improving efficacy while reducing the risk of late complications in AYAs, they are expected to have a profound effect on clinical practice.

Arguably, the era of targeted and novel therapies in cHL was initiated more than 10 years ago with the introduction of BV for the treatment of advanced disease in older adults.²¹ BV was moved into the front line for patients 18 years of age or older with advanced cHL in a trial that compared the standard of ABVD to the same drugs with BV substituted for bleomycin.²² In this study, the BV-containing regimen was associated with a significantly improved progression-free survival (PFS) (P = .04) and a lower rate of adverse events, including pulmonary toxicity (1% vs 3%) after 2 years of follow-up.

A similar study recently associated a BV-containing regimen with even greater efficacy in pediatric high-risk cHL.²³ In this multicenter study with 600 treatment-naïve patients ranging in age from 2 to 21 years, the standard pediatric regimen of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide was compared to the same regimen with BV substituted for bleomycin. With event-free survival as the primary endpoint, the experimental regimen was associated with a nearly 60% reduction in the risk of an adverse event or death (HR 0.41). However, no substantial differences were noted in toxicity after a follow-up of 42 months. It not yet clear whether the elimination of bleomycin will translate into less late toxicity, such as pulmonary or cardiovascular morbidity.

In the era of targeted therapies, the experience with BV has been a step toward more effective treatments using novel mechanisms of action to improve outcomes when used in the first-line treatment of patients with high-risk disease. Historically, many regimens and treatments that have demonstrated efficacy in relapsed and refractory cHL have found their way into the first-line setting. This trend might also be true of the checkpoint inhibitors, which have been tested extensively in relapsed/refractory cHL. In AYA patients with cHL, the rationale for these treatments might not only include a poor predicted response to current regimens, but a reduced risk of late toxicities if long-term follow-up demonstrates these treatments reduce late complications, such as secondary malignancies, which are associated with standard strategies, particularly those that include radiotherapy.

If targeted therapies do preserve efficacy and reduce risk of late complications, strategies to individualize therapy will remain relevant. Many of the emerging targeted therapies involve challenging and costly treatment protocols that demand selective application. Efforts to develop simpler and more precise biomarkers might streamline this task. Of promising developments in this area, cell-free DNA (cfDNA) appears to be near routine clinical application. A small study of cfDNA conducted in 121 patients found that minimal residual disease assessment by repeat cfDNA sequencing predicted response and PFS when performed as early as a week after treatment initiation.²⁴ If larger studies confirm accuracy, this biomarker strategy might prove simpler and more convenient than PET imaging.

Summary

In the treatment of hematologic malignancies, cHL is widely regarded as a success story with high rates of extended survival among children, AYAs, and older adults. This level of success does not obviate the need for even more effective treatments, and also permits more attention to be directed to reducing the risk of late toxicities. For the AYA population, which represents a large group with cHL, the current directions of clinical research offer the promise of imminent changes in how the disease is controlled and a reduction in treatment-related late morbidity and mortality.

Click to read more from 2023 Rare Diseases Report: Cancers

Background

Hodgkin lymphoma occurs in fewer than 9,000 individuals in the United States each year,¹ but it is one of the most common types of cancer in AYAs.² For the purposes of cHL, AYA is typically defined as an age range of 18 to 39 years, which covers the first of 2 bimodal peaks in incidence but stops short of the second.^3,4 The first of these peaks occurs between the ages of 15 and 34 years, while the second begins at about age 55.⁵ Children younger than 15 years of age can also develop Hodgkin lymphoma, but it is less common.⁶

In AYAs and in adults, more than 90% of patients with Hodgkin lymphoma have cHL.⁷ Most AYAs present with the nodular sclerosis subtype, but cHL is managed differently in pediatric patients versus in adult centers.^8,9 Evidence suggests that the specific risks of common treatment protocols, although similar, are not the same in AYAs as in adults.^10,11 Even though the literature evaluating the presentation and management of AYA cHL has been growing since 2005, when the AYA Oncology Progress Review Group called for AYAs to be recognized
as a distinct group, clinical trials specific to AYA cHL remain limited.⁹

Major Hodgkin lymphoma guidelines only partially address AYAs as a distinct group. In guidelines issued by the National Cancer Institute, the differences in clinical presentation of AYAs are described for young children, AYAs, and older adults, but there are no treatment recommendations specific to AYAs.¹² Guidelines from the EuroNet Paediatric Hodgkin Lymphoma Group offer recommendations for relapsed and refractory Hodgkin lymphoma, but do not differentiate between children and adolescents.¹³ The National Comprehensive Cancer Network (NCCN) provides separate treatment recommendations for patients 18 years or younger and those who are older than 18.^14,15 For Hodgkin lymphoma, AYA is not addressed as a separate category even though the NCCN has provided general guidelines for treatment of malignancies in AYA.¹⁶

First-line therapies are effective in children, AYAs, and adults. Survival rates at 5 years have increased steadily, approaching or exceeding 90% across age groups even for patients with unfavorable risk characteristics.¹⁷ This success has permitted greater focus on developing strategies that preserve efficacy with lower acute and long-term risks.

Risk-Adapted Therapies

While the potential for new and novel therapies to reduce the risk of long-term toxicities continues to be explored, adjusting existing regimens to reduce these risks has proven to be a viable strategy. This adjustment is a standard of care in the pediatric setting based on results from such studies as German GPOH-HD 95, which suggested that doses of radiotherapy, a major contributor to late toxicities,¹⁸ can be omitted in patients with a complete response after chemotherapy.¹¹ This pediatric trial contained both younger children and adolescents, but subsequent secondary analyses looking specifically at AYAs in this and other trials have suggested that efficacy is similarly preserved with risk-adapted strategies.⁹

However, due to AYA patients with cHL being treated using both pediatric and adult approaches, the persistent debate about optimal therapies in this age group complicates the effort to define a well-accepted strategy for risk adjustment. While risk-adapted strategies that rely on interim positron emission tomography (PET) to calibrate treatment intensity are now being used routinely across age stratifications, other initiatives are creating additional opportunities to gauge the impact on late effects in AYAs. These include strategies to improve collaboration across groups of trialists and data generated by observational cohorts, which can evaluate late effects not captured in time-limited clinical trials.

Among recent data supporting risk-adjusted therapy, the toxicity outcomes from a multicenter trial of PET-guided intensive treatment in patients with newly diagnosed advanced cHL were presented at the 2022 annual meeting of the American Society of Hematology.¹⁹ This phase 3 trial enrolled patients younger than 60 years, 79% of whom were younger than 45 years. Building on previous evidence that PET guidance improves the safety of eBEACOPP (escalated doses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), nearly 1,500 patients were randomized to this strategy or to PET-guided BrECADD, a modified eBEACOPP in which the antibody conjugate brentuximab vedotin (BV) was substituted for bleomycin. For an adjudicated endpoint of treatment-related morbidity, the experimental BrECAAD regimen reduced the risk by nearly 30% (hazard ratio [HR] 0.72). It is unclear whether this strategy will be used in the United States, where trials have been built on ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) rather than BEACOPP.

Efficacy data from this trial are not yet available, and these data will be important. There is concern that PET-directed therapy might result in lower toxicity at a cost of reduced rates of disease control. It is possible that the serious consequences of late toxicities—including infertility, compromised cardiovascular function, secondary cancers, and other organ damage—might need to be balanced against some loss of efficacy.

Novel Targeted Therapies

The goal of reducing late toxicities of cHL therapy in AYAs is also likely to be advanced by novel therapies. Research endeavors include a multicenter collaboration between US and Canadian investigators that is exploring the combination of nivolumab (a checkpoint inhibitor) plus BV.²⁰ The trial recently completed accrual and includes both adult and pediatric patients. If novel agents prove effective for improving efficacy while reducing the risk of late complications in AYAs, they are expected to have a profound effect on clinical practice.

Arguably, the era of targeted and novel therapies in cHL was initiated more than 10 years ago with the introduction of BV for the treatment of advanced disease in older adults.²¹ BV was moved into the front line for patients 18 years of age or older with advanced cHL in a trial that compared the standard of ABVD to the same drugs with BV substituted for bleomycin.²² In this study, the BV-containing regimen was associated with a significantly improved progression-free survival (PFS) (P = .04) and a lower rate of adverse events, including pulmonary toxicity (1% vs 3%) after 2 years of follow-up.

A similar study recently associated a BV-containing regimen with even greater efficacy in pediatric high-risk cHL.²³ In this multicenter study with 600 treatment-naïve patients ranging in age from 2 to 21 years, the standard pediatric regimen of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide was compared to the same regimen with BV substituted for bleomycin. With event-free survival as the primary endpoint, the experimental regimen was associated with a nearly 60% reduction in the risk of an adverse event or death (HR 0.41). However, no substantial differences were noted in toxicity after a follow-up of 42 months. It not yet clear whether the elimination of bleomycin will translate into less late toxicity, such as pulmonary or cardiovascular morbidity.

In the era of targeted therapies, the experience with BV has been a step toward more effective treatments using novel mechanisms of action to improve outcomes when used in the first-line treatment of patients with high-risk disease. Historically, many regimens and treatments that have demonstrated efficacy in relapsed and refractory cHL have found their way into the first-line setting. This trend might also be true of the checkpoint inhibitors, which have been tested extensively in relapsed/refractory cHL. In AYA patients with cHL, the rationale for these treatments might not only include a poor predicted response to current regimens, but a reduced risk of late toxicities if long-term follow-up demonstrates these treatments reduce late complications, such as secondary malignancies, which are associated with standard strategies, particularly those that include radiotherapy.

If targeted therapies do preserve efficacy and reduce risk of late complications, strategies to individualize therapy will remain relevant. Many of the emerging targeted therapies involve challenging and costly treatment protocols that demand selective application. Efforts to develop simpler and more precise biomarkers might streamline this task. Of promising developments in this area, cell-free DNA (cfDNA) appears to be near routine clinical application. A small study of cfDNA conducted in 121 patients found that minimal residual disease assessment by repeat cfDNA sequencing predicted response and PFS when performed as early as a week after treatment initiation.²⁴ If larger studies confirm accuracy, this biomarker strategy might prove simpler and more convenient than PET imaging.

Summary

In the treatment of hematologic malignancies, cHL is widely regarded as a success story with high rates of extended survival among children, AYAs, and older adults. This level of success does not obviate the need for even more effective treatments, and also permits more attention to be directed to reducing the risk of late toxicities. For the AYA population, which represents a large group with cHL, the current directions of clinical research offer the promise of imminent changes in how the disease is controlled and a reduction in treatment-related late morbidity and mortality.

Click to read more from 2023 Rare Diseases Report: Cancers

Background

Hodgkin lymphoma occurs in fewer than 9,000 individuals in the United States each year,¹ but it is one of the most common types of cancer in AYAs.² For the purposes of cHL, AYA is typically defined as an age range of 18 to 39 years, which covers the first of 2 bimodal peaks in incidence but stops short of the second.^3,4 The first of these peaks occurs between the ages of 15 and 34 years, while the second begins at about age 55.⁵ Children younger than 15 years of age can also develop Hodgkin lymphoma, but it is less common.⁶

In AYAs and in adults, more than 90% of patients with Hodgkin lymphoma have cHL.⁷ Most AYAs present with the nodular sclerosis subtype, but cHL is managed differently in pediatric patients versus in adult centers.^8,9 Evidence suggests that the specific risks of common treatment protocols, although similar, are not the same in AYAs as in adults.^10,11 Even though the literature evaluating the presentation and management of AYA cHL has been growing since 2005, when the AYA Oncology Progress Review Group called for AYAs to be recognized
as a distinct group, clinical trials specific to AYA cHL remain limited.⁹

Major Hodgkin lymphoma guidelines only partially address AYAs as a distinct group. In guidelines issued by the National Cancer Institute, the differences in clinical presentation of AYAs are described for young children, AYAs, and older adults, but there are no treatment recommendations specific to AYAs.¹² Guidelines from the EuroNet Paediatric Hodgkin Lymphoma Group offer recommendations for relapsed and refractory Hodgkin lymphoma, but do not differentiate between children and adolescents.¹³ The National Comprehensive Cancer Network (NCCN) provides separate treatment recommendations for patients 18 years or younger and those who are older than 18.^14,15 For Hodgkin lymphoma, AYA is not addressed as a separate category even though the NCCN has provided general guidelines for treatment of malignancies in AYA.¹⁶

First-line therapies are effective in children, AYAs, and adults. Survival rates at 5 years have increased steadily, approaching or exceeding 90% across age groups even for patients with unfavorable risk characteristics.¹⁷ This success has permitted greater focus on developing strategies that preserve efficacy with lower acute and long-term risks.

Risk-Adapted Therapies

While the potential for new and novel therapies to reduce the risk of long-term toxicities continues to be explored, adjusting existing regimens to reduce these risks has proven to be a viable strategy. This adjustment is a standard of care in the pediatric setting based on results from such studies as German GPOH-HD 95, which suggested that doses of radiotherapy, a major contributor to late toxicities,¹⁸ can be omitted in patients with a complete response after chemotherapy.¹¹ This pediatric trial contained both younger children and adolescents, but subsequent secondary analyses looking specifically at AYAs in this and other trials have suggested that efficacy is similarly preserved with risk-adapted strategies.⁹

However, due to AYA patients with cHL being treated using both pediatric and adult approaches, the persistent debate about optimal therapies in this age group complicates the effort to define a well-accepted strategy for risk adjustment. While risk-adapted strategies that rely on interim positron emission tomography (PET) to calibrate treatment intensity are now being used routinely across age stratifications, other initiatives are creating additional opportunities to gauge the impact on late effects in AYAs. These include strategies to improve collaboration across groups of trialists and data generated by observational cohorts, which can evaluate late effects not captured in time-limited clinical trials.

Among recent data supporting risk-adjusted therapy, the toxicity outcomes from a multicenter trial of PET-guided intensive treatment in patients with newly diagnosed advanced cHL were presented at the 2022 annual meeting of the American Society of Hematology.¹⁹ This phase 3 trial enrolled patients younger than 60 years, 79% of whom were younger than 45 years. Building on previous evidence that PET guidance improves the safety of eBEACOPP (escalated doses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), nearly 1,500 patients were randomized to this strategy or to PET-guided BrECADD, a modified eBEACOPP in which the antibody conjugate brentuximab vedotin (BV) was substituted for bleomycin. For an adjudicated endpoint of treatment-related morbidity, the experimental BrECAAD regimen reduced the risk by nearly 30% (hazard ratio [HR] 0.72). It is unclear whether this strategy will be used in the United States, where trials have been built on ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) rather than BEACOPP.

Efficacy data from this trial are not yet available, and these data will be important. There is concern that PET-directed therapy might result in lower toxicity at a cost of reduced rates of disease control. It is possible that the serious consequences of late toxicities—including infertility, compromised cardiovascular function, secondary cancers, and other organ damage—might need to be balanced against some loss of efficacy.

Novel Targeted Therapies

The goal of reducing late toxicities of cHL therapy in AYAs is also likely to be advanced by novel therapies. Research endeavors include a multicenter collaboration between US and Canadian investigators that is exploring the combination of nivolumab (a checkpoint inhibitor) plus BV.²⁰ The trial recently completed accrual and includes both adult and pediatric patients. If novel agents prove effective for improving efficacy while reducing the risk of late complications in AYAs, they are expected to have a profound effect on clinical practice.

Arguably, the era of targeted and novel therapies in cHL was initiated more than 10 years ago with the introduction of BV for the treatment of advanced disease in older adults.²¹ BV was moved into the front line for patients 18 years of age or older with advanced cHL in a trial that compared the standard of ABVD to the same drugs with BV substituted for bleomycin.²² In this study, the BV-containing regimen was associated with a significantly improved progression-free survival (PFS) (P = .04) and a lower rate of adverse events, including pulmonary toxicity (1% vs 3%) after 2 years of follow-up.

A similar study recently associated a BV-containing regimen with even greater efficacy in pediatric high-risk cHL.²³ In this multicenter study with 600 treatment-naïve patients ranging in age from 2 to 21 years, the standard pediatric regimen of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide was compared to the same regimen with BV substituted for bleomycin. With event-free survival as the primary endpoint, the experimental regimen was associated with a nearly 60% reduction in the risk of an adverse event or death (HR 0.41). However, no substantial differences were noted in toxicity after a follow-up of 42 months. It not yet clear whether the elimination of bleomycin will translate into less late toxicity, such as pulmonary or cardiovascular morbidity.

In the era of targeted therapies, the experience with BV has been a step toward more effective treatments using novel mechanisms of action to improve outcomes when used in the first-line treatment of patients with high-risk disease. Historically, many regimens and treatments that have demonstrated efficacy in relapsed and refractory cHL have found their way into the first-line setting. This trend might also be true of the checkpoint inhibitors, which have been tested extensively in relapsed/refractory cHL. In AYA patients with cHL, the rationale for these treatments might not only include a poor predicted response to current regimens, but a reduced risk of late toxicities if long-term follow-up demonstrates these treatments reduce late complications, such as secondary malignancies, which are associated with standard strategies, particularly those that include radiotherapy.

If targeted therapies do preserve efficacy and reduce risk of late complications, strategies to individualize therapy will remain relevant. Many of the emerging targeted therapies involve challenging and costly treatment protocols that demand selective application. Efforts to develop simpler and more precise biomarkers might streamline this task. Of promising developments in this area, cell-free DNA (cfDNA) appears to be near routine clinical application. A small study of cfDNA conducted in 121 patients found that minimal residual disease assessment by repeat cfDNA sequencing predicted response and PFS when performed as early as a week after treatment initiation.²⁴ If larger studies confirm accuracy, this biomarker strategy might prove simpler and more convenient than PET imaging.

Summary

In the treatment of hematologic malignancies, cHL is widely regarded as a success story with high rates of extended survival among children, AYAs, and older adults. This level of success does not obviate the need for even more effective treatments, and also permits more attention to be directed to reducing the risk of late toxicities. For the AYA population, which represents a large group with cHL, the current directions of clinical research offer the promise of imminent changes in how the disease is controlled and a reduction in treatment-related late morbidity and mortality.

Click to read more from 2023 Rare Diseases Report: Cancers

REVIEW
 

Butterfly iQ+: Offering day-to-day portable ultrasound tech

The Butterfly iQ+ app with an ultrasound probe and cable is available from Butterfly Network, Inc, in Guilford, Connecticut.

Background. It could be reasonably argued that ultrasonography has surpassed the speculum as the single most important tool in ObGyn. From its origins in 1949 with the pioneering work of George Ludwig using A-mode (amplitude-mode) ultrasound and the first publication of its use in pregnancy using B-mode (brightness-mode) ultrasound in Lancet in 1958 by Donald and colleagues, this technology has become so ingrained into ObGyn that it is often frustrating to practice comfortably without it. Thus, today, the biggest question facing most practitioners is not whether or not to have an ultrasound in their practice but which one to have.

Given the wide range of quality, functionality, and price within the ultrasound device space, choosing the right technology can feel as daunting as choosing the perfect restaurant in New York City. That said, when looking for entry-level ultrasound technology to address the day-to-day basic needs of your average ObGyn, the Butterfly iQ+ may be an easy choice.

Design/Functionality. The Butterfly iQ+ app does not come with a screen. Rather, the device is compatible with both iOS and Android systems and readily connects to a vast array of easily purchased devices, with either lightening or USB-C ports. In our office, we use an iPad mini. The probe is lightweight (309 g) and contains a rechargeable 2600 mAh lithium ion battery, so that its power source is independent of the device to which it is attached. The probe is a 2D array with 9000 micro-machined sensors. It allows for imaging using M-mode, B-mode, Color Doppler, Power Doppler, and Pulsed Wave Doppler. (I don’t know what the last two are or what they are used for, but they sound important.) It has a scan depth range of 1 cm to 30 cm. The downloadable Butterfly iQ+ app that has the software that makes the probe functional has more tools, controls, and presets than anyone could ever need. But that’s not all. The App has data encrypted HIPAA/HITECH-compliant Cloud-based connectivity that offers unlimited image storage, access to reports, and embedded CPT codes should billing capabilities be needed.

The true beauty of the Butterfly iQ+ is that the image quality is awesome and it is really easy to use. The software is mostly intuitive and takes only a minimal effort to learn. The device holds its charge more than adequately for a day in the office and the recharging process is fast and easy. When it comes to the device’s design and functionality–as a Capricorn–I am still looking for its flaws.

Innovation. The real innovations of the Butterfly iQ+ are its “ultrasound-on-a-chip”™ technology and its incorporation of a rechargeable battery into the probe. This combination allows for crystal clear imaging in a cordless, portable device. While most other similar technologies waste their time, technology, space, and cost on the screen, the Butterfly iQ+ punted on that challenge and put all their efforts into the probe and the software. It was a great choice.

Summary. In our office, the Butterfly iQ+ has changed the way we practice. Our trusty fetal dopplers are mostly gone, having been replaced by the Butterfly iQ+. At almost every prenatal visit, patients can now see their baby rather than just hear the heartbeat (and they can hear it too if they want by using the M-mode functionality on the device). Patients love it, and so do the doctors. Instead of just hearing heart beats, fetal position and quick fluid checks are now routine, so we think our care is actually a little better than it was. The Butterfly iQ+ is also great for confirming IUD locations after placement or when the strings are not visible. All-in-all, I love this product. Who doesn’t love butterflies?!

For more information, visit https://www.butterflynetwork.com

The views of the author are personal opinions and do not necessarily represent the views of OBG Management. Dr. Greenberg personally trials all the products he reviews. Dr. Greenberg has no conflicts of interest with this product or the company that produces it.

References

1. Kaproth-Joslin KA, Nicola R, Dogra VS. The History of US: from bats and boats to the bedside and beyond: RSNA centennial article. Radiographics. 2015;35:960-970.
2. Donald I, MacVicar J, Brown TG. Investigation of abdominal masses by pulsed ultrasound. Lancet. 1958;1:1188-1195.

REVIEW
 

Butterfly iQ+: Offering day-to-day portable ultrasound tech

The Butterfly iQ+ app with an ultrasound probe and cable is available from Butterfly Network, Inc, in Guilford, Connecticut.

Background. It could be reasonably argued that ultrasonography has surpassed the speculum as the single most important tool in ObGyn. From its origins in 1949 with the pioneering work of George Ludwig using A-mode (amplitude-mode) ultrasound and the first publication of its use in pregnancy using B-mode (brightness-mode) ultrasound in Lancet in 1958 by Donald and colleagues, this technology has become so ingrained into ObGyn that it is often frustrating to practice comfortably without it. Thus, today, the biggest question facing most practitioners is not whether or not to have an ultrasound in their practice but which one to have.

Given the wide range of quality, functionality, and price within the ultrasound device space, choosing the right technology can feel as daunting as choosing the perfect restaurant in New York City. That said, when looking for entry-level ultrasound technology to address the day-to-day basic needs of your average ObGyn, the Butterfly iQ+ may be an easy choice.

Design/Functionality. The Butterfly iQ+ app does not come with a screen. Rather, the device is compatible with both iOS and Android systems and readily connects to a vast array of easily purchased devices, with either lightening or USB-C ports. In our office, we use an iPad mini. The probe is lightweight (309 g) and contains a rechargeable 2600 mAh lithium ion battery, so that its power source is independent of the device to which it is attached. The probe is a 2D array with 9000 micro-machined sensors. It allows for imaging using M-mode, B-mode, Color Doppler, Power Doppler, and Pulsed Wave Doppler. (I don’t know what the last two are or what they are used for, but they sound important.) It has a scan depth range of 1 cm to 30 cm. The downloadable Butterfly iQ+ app that has the software that makes the probe functional has more tools, controls, and presets than anyone could ever need. But that’s not all. The App has data encrypted HIPAA/HITECH-compliant Cloud-based connectivity that offers unlimited image storage, access to reports, and embedded CPT codes should billing capabilities be needed.

The true beauty of the Butterfly iQ+ is that the image quality is awesome and it is really easy to use. The software is mostly intuitive and takes only a minimal effort to learn. The device holds its charge more than adequately for a day in the office and the recharging process is fast and easy. When it comes to the device’s design and functionality–as a Capricorn–I am still looking for its flaws.

Innovation. The real innovations of the Butterfly iQ+ are its “ultrasound-on-a-chip”™ technology and its incorporation of a rechargeable battery into the probe. This combination allows for crystal clear imaging in a cordless, portable device. While most other similar technologies waste their time, technology, space, and cost on the screen, the Butterfly iQ+ punted on that challenge and put all their efforts into the probe and the software. It was a great choice.

Summary. In our office, the Butterfly iQ+ has changed the way we practice. Our trusty fetal dopplers are mostly gone, having been replaced by the Butterfly iQ+. At almost every prenatal visit, patients can now see their baby rather than just hear the heartbeat (and they can hear it too if they want by using the M-mode functionality on the device). Patients love it, and so do the doctors. Instead of just hearing heart beats, fetal position and quick fluid checks are now routine, so we think our care is actually a little better than it was. The Butterfly iQ+ is also great for confirming IUD locations after placement or when the strings are not visible. All-in-all, I love this product. Who doesn’t love butterflies?!

For more information, visit https://www.butterflynetwork.com

The views of the author are personal opinions and do not necessarily represent the views of OBG Management. Dr. Greenberg personally trials all the products he reviews. Dr. Greenberg has no conflicts of interest with this product or the company that produces it.

References

1. Kaproth-Joslin KA, Nicola R, Dogra VS. The History of US: from bats and boats to the bedside and beyond: RSNA centennial article. Radiographics. 2015;35:960-970.
2. Donald I, MacVicar J, Brown TG. Investigation of abdominal masses by pulsed ultrasound. Lancet. 1958;1:1188-1195.

REVIEW
 

Butterfly iQ+: Offering day-to-day portable ultrasound tech

The Butterfly iQ+ app with an ultrasound probe and cable is available from Butterfly Network, Inc, in Guilford, Connecticut.

Background. It could be reasonably argued that ultrasonography has surpassed the speculum as the single most important tool in ObGyn. From its origins in 1949 with the pioneering work of George Ludwig using A-mode (amplitude-mode) ultrasound and the first publication of its use in pregnancy using B-mode (brightness-mode) ultrasound in Lancet in 1958 by Donald and colleagues, this technology has become so ingrained into ObGyn that it is often frustrating to practice comfortably without it. Thus, today, the biggest question facing most practitioners is not whether or not to have an ultrasound in their practice but which one to have.

Given the wide range of quality, functionality, and price within the ultrasound device space, choosing the right technology can feel as daunting as choosing the perfect restaurant in New York City. That said, when looking for entry-level ultrasound technology to address the day-to-day basic needs of your average ObGyn, the Butterfly iQ+ may be an easy choice.

Design/Functionality. The Butterfly iQ+ app does not come with a screen. Rather, the device is compatible with both iOS and Android systems and readily connects to a vast array of easily purchased devices, with either lightening or USB-C ports. In our office, we use an iPad mini. The probe is lightweight (309 g) and contains a rechargeable 2600 mAh lithium ion battery, so that its power source is independent of the device to which it is attached. The probe is a 2D array with 9000 micro-machined sensors. It allows for imaging using M-mode, B-mode, Color Doppler, Power Doppler, and Pulsed Wave Doppler. (I don’t know what the last two are or what they are used for, but they sound important.) It has a scan depth range of 1 cm to 30 cm. The downloadable Butterfly iQ+ app that has the software that makes the probe functional has more tools, controls, and presets than anyone could ever need. But that’s not all. The App has data encrypted HIPAA/HITECH-compliant Cloud-based connectivity that offers unlimited image storage, access to reports, and embedded CPT codes should billing capabilities be needed.

The true beauty of the Butterfly iQ+ is that the image quality is awesome and it is really easy to use. The software is mostly intuitive and takes only a minimal effort to learn. The device holds its charge more than adequately for a day in the office and the recharging process is fast and easy. When it comes to the device’s design and functionality–as a Capricorn–I am still looking for its flaws.

Innovation. The real innovations of the Butterfly iQ+ are its “ultrasound-on-a-chip”™ technology and its incorporation of a rechargeable battery into the probe. This combination allows for crystal clear imaging in a cordless, portable device. While most other similar technologies waste their time, technology, space, and cost on the screen, the Butterfly iQ+ punted on that challenge and put all their efforts into the probe and the software. It was a great choice.

Summary. In our office, the Butterfly iQ+ has changed the way we practice. Our trusty fetal dopplers are mostly gone, having been replaced by the Butterfly iQ+. At almost every prenatal visit, patients can now see their baby rather than just hear the heartbeat (and they can hear it too if they want by using the M-mode functionality on the device). Patients love it, and so do the doctors. Instead of just hearing heart beats, fetal position and quick fluid checks are now routine, so we think our care is actually a little better than it was. The Butterfly iQ+ is also great for confirming IUD locations after placement or when the strings are not visible. All-in-all, I love this product. Who doesn’t love butterflies?!

For more information, visit https://www.butterflynetwork.com

The views of the author are personal opinions and do not necessarily represent the views of OBG Management. Dr. Greenberg personally trials all the products he reviews. Dr. Greenberg has no conflicts of interest with this product or the company that produces it.

References

1. Kaproth-Joslin KA, Nicola R, Dogra VS. The History of US: from bats and boats to the bedside and beyond: RSNA centennial article. Radiographics. 2015;35:960-970.
2. Donald I, MacVicar J, Brown TG. Investigation of abdominal masses by pulsed ultrasound. Lancet. 1958;1:1188-1195.

Silverberg and colleagues described a very well-designed, vehicle-controlled, randomized 8-week study of a topical formulation of a purified strain of Nitrosomonas eutropha, an ammonia-oxidizing bacterium. In theory, this bacterium may reduce Staphylococcus aureus. The study compared two concentrations of the bacterium vs vehicle delivered as a spray twice per day. Study participants were adults with AD affecting 10%-40% of body surface area.

The study found "meaningful" improvements in itch and objective signs of disease, with clear separation between both doses of the bacterial spray compared with vehicle. At week 4, about 23% of participants treated with the bacterium were clear or almost clear (with a 2-point improvement) compared with 12% in the vehicle group (for comparison, in a phase 2 study comparing topical ruxolitinib with 0.1% triamcinolone cream, there was a 25% clear or almost clear rate [with 2-point improvement] in the triamcinolone-treated individuals).

Though an "all-natural" bacterial approach to managing AD may be appealing to some, it sounded like magic to me. But this well-done study makes it seem like the bacterial approach could be more promising than I had thought. This study also reported about twice as many adverse events (including gastrointestinal issues) with the bacterium-treated participants compared with those who received vehicle, adding to my belief that the bacterial product has efficacy. Whether any other topical will be more effective and safer than is topical triamcinolone remains to be seen. I'm still pessimistic about topicals because of patients' poor adherence to topical treatment, but perhaps an easy-to-use spray that isn't associated with patients' fear of "steroids" will be helpful.

Chen and colleagues. They analyzed data on hundreds of thousands of patients with and without AD. Adults with AD had a "significantly increased risk" of developing venous thromboembolism compared with adults without AD. The huge sample size of their study seems compelling. That huge sample size allows detection of effects so small that they may be clinically insignificant.

They report that patients with AD had a venous thromboembolism at a rate of 1.05/1000 patients-years; the rate was 0.82 for patients without AD. From that, we can calculate that there would be an additional 23 patients with venous thromboembolism for every 100,000 patient-years or about one more venous thromboembolism in the AD group in every 4000 patient-years. Though the finding was statistically significant, I don't think it is clinically meaningful.

The authors correctly conclude that "vascular examination and consultation with the emergency department, cardiologists, or pulmonologists are indicated for patients with AD who present with relevant symptoms (eg, unexplained dyspnea, chest tightness, and limb swelling)." But it is probably also true that vascular examination and consultation with the emergency department, cardiologists, or pulmonologists are indicated for patients without AD who present with those symptoms. I think the authors might have been on solid ground if they had concluded that there was a statistically significant but clinically insignificant increased risk for venous thromboembolism in patients with AD.

Eichenfeld and colleagues examined the use of topical crisaborole once per day as a maintenance treatment for patients with mild to moderate AD. The study compared patients given topical crisaborole with those randomly assigned to vehicle. The active treatment was effective because topical crisaborole treated patients had longer times to the first flare following treatment and fewer flares over the 1 year of treatment. The differences were not huge, but I think they were clinically meaningful. I'm guessing that the topical crisaborole maintenance treatment would have been even more effective had it been used regularly. The study did not, as far as I could tell, assess how well the treatment was used.

An interesting aspect of this study is that it began with nearly 500 participants who started on twice daily topical crisaborole. The 270 patients who responded to the treatment (achieving clear or almost clear with at least a 2-point improvement) were enrolled in the 1-year maintenance phase. Thus, the participants in the maintenance phase were preselected for patients who respond to topical crisaborole. We don't know why they were responders (I, of course, expect it is because they selected for patients who are better than others are at using a topical treatment), but it may be best not to try to generalize these results and assume this form of maintenance treatment would work equally well in a population who achieve initial success with an oral therapy regimen (for example, a quick course of oral prednisone).

Dupilumab was a revolutionary treatment for AD. I didn't think that I'd ever see a more effective treatment. It's so safe too! It has been a first-line treatment for AD since its introduction. Now, we also have oral Janus kinase inhibitor options. Blauvelt and colleagues examined what happens when patients who have been on dupilumab are switched to a high dose (30 mg/d) of upadacitinib (the standard starting dose of upadacitinib is 15 mg/d). Though dupilumab is very effective, upadacitinib is more so. After 4 weeks of switching to upadacitinib, nearly half the patients were completely clear of AD compared with only 16.0% after 24 weeks of dupilumab! The authors point out, optimistically, that "No new safety risks were observed." Though there were no cancers, gastrointestinal perforations, major adverse cardiovascular events, or venous thromboembolic events, there were cases of eczema herpeticum and zoster in patients treated with upadacitinib. Having upadacitinib available for patients who fail dupilumab is a clear benefit; the role of upadacitinib before dupilumab seems less clear.

Patients doing great on dupilumab for AD may be wondering: Do I still need to take it every 2 weeks? Spekhorst and colleagues may have the answer. They describe the response to tapering dupilumab in patients who had been on the drug for at least 1 year with well-controlled disease for at least 6 months. Patients in the study then continued dupilumab with the longest possible dosing interval while maintaining control of their AD.

Generally, patients maintained good control of their AD, with only a small increase in mean disease severity and in concomitant use of topical steroids. For the patients who attempted prolongation, 83% successfully continued dupilumab treatment with a prolonged interval. Not at all surprisingly, the authors calculated that prolonging the interval between dosing led to large savings in cost.

One of the nice features of dupilumab treatment is that loss of response over time seems unusual. Perhaps there is a low propensity for forming antidrug antibodies when dupilumab is used in the standard every 2-week dosing regimen. I don't know whether antidrug antibodies would be more likely with the intermittent dosing regimen. But now that we have other good systemic treatment options for AD, losing dupilumab efficacy would not be as critical a problem as it used to be. I also want to point out that patients' adherence to injection treatment, though better than adherence to topicals, is far from perfect. It's likely that many patients have already been prolonging the interval between taking their treatments. If you want to know, just ask them. The way I like to phrase the question is: "Are you keeping the extra injectors you've accumulated refrigerated like you are supposed to?"

Silverberg and colleagues described a very well-designed, vehicle-controlled, randomized 8-week study of a topical formulation of a purified strain of Nitrosomonas eutropha, an ammonia-oxidizing bacterium. In theory, this bacterium may reduce Staphylococcus aureus. The study compared two concentrations of the bacterium vs vehicle delivered as a spray twice per day. Study participants were adults with AD affecting 10%-40% of body surface area.

The study found "meaningful" improvements in itch and objective signs of disease, with clear separation between both doses of the bacterial spray compared with vehicle. At week 4, about 23% of participants treated with the bacterium were clear or almost clear (with a 2-point improvement) compared with 12% in the vehicle group (for comparison, in a phase 2 study comparing topical ruxolitinib with 0.1% triamcinolone cream, there was a 25% clear or almost clear rate [with 2-point improvement] in the triamcinolone-treated individuals).

Though an "all-natural" bacterial approach to managing AD may be appealing to some, it sounded like magic to me. But this well-done study makes it seem like the bacterial approach could be more promising than I had thought. This study also reported about twice as many adverse events (including gastrointestinal issues) with the bacterium-treated participants compared with those who received vehicle, adding to my belief that the bacterial product has efficacy. Whether any other topical will be more effective and safer than is topical triamcinolone remains to be seen. I'm still pessimistic about topicals because of patients' poor adherence to topical treatment, but perhaps an easy-to-use spray that isn't associated with patients' fear of "steroids" will be helpful.

Chen and colleagues. They analyzed data on hundreds of thousands of patients with and without AD. Adults with AD had a "significantly increased risk" of developing venous thromboembolism compared with adults without AD. The huge sample size of their study seems compelling. That huge sample size allows detection of effects so small that they may be clinically insignificant.

They report that patients with AD had a venous thromboembolism at a rate of 1.05/1000 patients-years; the rate was 0.82 for patients without AD. From that, we can calculate that there would be an additional 23 patients with venous thromboembolism for every 100,000 patient-years or about one more venous thromboembolism in the AD group in every 4000 patient-years. Though the finding was statistically significant, I don't think it is clinically meaningful.

The authors correctly conclude that "vascular examination and consultation with the emergency department, cardiologists, or pulmonologists are indicated for patients with AD who present with relevant symptoms (eg, unexplained dyspnea, chest tightness, and limb swelling)." But it is probably also true that vascular examination and consultation with the emergency department, cardiologists, or pulmonologists are indicated for patients without AD who present with those symptoms. I think the authors might have been on solid ground if they had concluded that there was a statistically significant but clinically insignificant increased risk for venous thromboembolism in patients with AD.

Eichenfeld and colleagues examined the use of topical crisaborole once per day as a maintenance treatment for patients with mild to moderate AD. The study compared patients given topical crisaborole with those randomly assigned to vehicle. The active treatment was effective because topical crisaborole treated patients had longer times to the first flare following treatment and fewer flares over the 1 year of treatment. The differences were not huge, but I think they were clinically meaningful. I'm guessing that the topical crisaborole maintenance treatment would have been even more effective had it been used regularly. The study did not, as far as I could tell, assess how well the treatment was used.

An interesting aspect of this study is that it began with nearly 500 participants who started on twice daily topical crisaborole. The 270 patients who responded to the treatment (achieving clear or almost clear with at least a 2-point improvement) were enrolled in the 1-year maintenance phase. Thus, the participants in the maintenance phase were preselected for patients who respond to topical crisaborole. We don't know why they were responders (I, of course, expect it is because they selected for patients who are better than others are at using a topical treatment), but it may be best not to try to generalize these results and assume this form of maintenance treatment would work equally well in a population who achieve initial success with an oral therapy regimen (for example, a quick course of oral prednisone).

Dupilumab was a revolutionary treatment for AD. I didn't think that I'd ever see a more effective treatment. It's so safe too! It has been a first-line treatment for AD since its introduction. Now, we also have oral Janus kinase inhibitor options. Blauvelt and colleagues examined what happens when patients who have been on dupilumab are switched to a high dose (30 mg/d) of upadacitinib (the standard starting dose of upadacitinib is 15 mg/d). Though dupilumab is very effective, upadacitinib is more so. After 4 weeks of switching to upadacitinib, nearly half the patients were completely clear of AD compared with only 16.0% after 24 weeks of dupilumab! The authors point out, optimistically, that "No new safety risks were observed." Though there were no cancers, gastrointestinal perforations, major adverse cardiovascular events, or venous thromboembolic events, there were cases of eczema herpeticum and zoster in patients treated with upadacitinib. Having upadacitinib available for patients who fail dupilumab is a clear benefit; the role of upadacitinib before dupilumab seems less clear.

Patients doing great on dupilumab for AD may be wondering: Do I still need to take it every 2 weeks? Spekhorst and colleagues may have the answer. They describe the response to tapering dupilumab in patients who had been on the drug for at least 1 year with well-controlled disease for at least 6 months. Patients in the study then continued dupilumab with the longest possible dosing interval while maintaining control of their AD.

Generally, patients maintained good control of their AD, with only a small increase in mean disease severity and in concomitant use of topical steroids. For the patients who attempted prolongation, 83% successfully continued dupilumab treatment with a prolonged interval. Not at all surprisingly, the authors calculated that prolonging the interval between dosing led to large savings in cost.

One of the nice features of dupilumab treatment is that loss of response over time seems unusual. Perhaps there is a low propensity for forming antidrug antibodies when dupilumab is used in the standard every 2-week dosing regimen. I don't know whether antidrug antibodies would be more likely with the intermittent dosing regimen. But now that we have other good systemic treatment options for AD, losing dupilumab efficacy would not be as critical a problem as it used to be. I also want to point out that patients' adherence to injection treatment, though better than adherence to topicals, is far from perfect. It's likely that many patients have already been prolonging the interval between taking their treatments. If you want to know, just ask them. The way I like to phrase the question is: "Are you keeping the extra injectors you've accumulated refrigerated like you are supposed to?"

Silverberg and colleagues described a very well-designed, vehicle-controlled, randomized 8-week study of a topical formulation of a purified strain of Nitrosomonas eutropha, an ammonia-oxidizing bacterium. In theory, this bacterium may reduce Staphylococcus aureus. The study compared two concentrations of the bacterium vs vehicle delivered as a spray twice per day. Study participants were adults with AD affecting 10%-40% of body surface area.

The study found "meaningful" improvements in itch and objective signs of disease, with clear separation between both doses of the bacterial spray compared with vehicle. At week 4, about 23% of participants treated with the bacterium were clear or almost clear (with a 2-point improvement) compared with 12% in the vehicle group (for comparison, in a phase 2 study comparing topical ruxolitinib with 0.1% triamcinolone cream, there was a 25% clear or almost clear rate [with 2-point improvement] in the triamcinolone-treated individuals).

Though an "all-natural" bacterial approach to managing AD may be appealing to some, it sounded like magic to me. But this well-done study makes it seem like the bacterial approach could be more promising than I had thought. This study also reported about twice as many adverse events (including gastrointestinal issues) with the bacterium-treated participants compared with those who received vehicle, adding to my belief that the bacterial product has efficacy. Whether any other topical will be more effective and safer than is topical triamcinolone remains to be seen. I'm still pessimistic about topicals because of patients' poor adherence to topical treatment, but perhaps an easy-to-use spray that isn't associated with patients' fear of "steroids" will be helpful.

Chen and colleagues. They analyzed data on hundreds of thousands of patients with and without AD. Adults with AD had a "significantly increased risk" of developing venous thromboembolism compared with adults without AD. The huge sample size of their study seems compelling. That huge sample size allows detection of effects so small that they may be clinically insignificant.

They report that patients with AD had a venous thromboembolism at a rate of 1.05/1000 patients-years; the rate was 0.82 for patients without AD. From that, we can calculate that there would be an additional 23 patients with venous thromboembolism for every 100,000 patient-years or about one more venous thromboembolism in the AD group in every 4000 patient-years. Though the finding was statistically significant, I don't think it is clinically meaningful.

The authors correctly conclude that "vascular examination and consultation with the emergency department, cardiologists, or pulmonologists are indicated for patients with AD who present with relevant symptoms (eg, unexplained dyspnea, chest tightness, and limb swelling)." But it is probably also true that vascular examination and consultation with the emergency department, cardiologists, or pulmonologists are indicated for patients without AD who present with those symptoms. I think the authors might have been on solid ground if they had concluded that there was a statistically significant but clinically insignificant increased risk for venous thromboembolism in patients with AD.

Eichenfeld and colleagues examined the use of topical crisaborole once per day as a maintenance treatment for patients with mild to moderate AD. The study compared patients given topical crisaborole with those randomly assigned to vehicle. The active treatment was effective because topical crisaborole treated patients had longer times to the first flare following treatment and fewer flares over the 1 year of treatment. The differences were not huge, but I think they were clinically meaningful. I'm guessing that the topical crisaborole maintenance treatment would have been even more effective had it been used regularly. The study did not, as far as I could tell, assess how well the treatment was used.

An interesting aspect of this study is that it began with nearly 500 participants who started on twice daily topical crisaborole. The 270 patients who responded to the treatment (achieving clear or almost clear with at least a 2-point improvement) were enrolled in the 1-year maintenance phase. Thus, the participants in the maintenance phase were preselected for patients who respond to topical crisaborole. We don't know why they were responders (I, of course, expect it is because they selected for patients who are better than others are at using a topical treatment), but it may be best not to try to generalize these results and assume this form of maintenance treatment would work equally well in a population who achieve initial success with an oral therapy regimen (for example, a quick course of oral prednisone).

Dupilumab was a revolutionary treatment for AD. I didn't think that I'd ever see a more effective treatment. It's so safe too! It has been a first-line treatment for AD since its introduction. Now, we also have oral Janus kinase inhibitor options. Blauvelt and colleagues examined what happens when patients who have been on dupilumab are switched to a high dose (30 mg/d) of upadacitinib (the standard starting dose of upadacitinib is 15 mg/d). Though dupilumab is very effective, upadacitinib is more so. After 4 weeks of switching to upadacitinib, nearly half the patients were completely clear of AD compared with only 16.0% after 24 weeks of dupilumab! The authors point out, optimistically, that "No new safety risks were observed." Though there were no cancers, gastrointestinal perforations, major adverse cardiovascular events, or venous thromboembolic events, there were cases of eczema herpeticum and zoster in patients treated with upadacitinib. Having upadacitinib available for patients who fail dupilumab is a clear benefit; the role of upadacitinib before dupilumab seems less clear.

Patients doing great on dupilumab for AD may be wondering: Do I still need to take it every 2 weeks? Spekhorst and colleagues may have the answer. They describe the response to tapering dupilumab in patients who had been on the drug for at least 1 year with well-controlled disease for at least 6 months. Patients in the study then continued dupilumab with the longest possible dosing interval while maintaining control of their AD.

Generally, patients maintained good control of their AD, with only a small increase in mean disease severity and in concomitant use of topical steroids. For the patients who attempted prolongation, 83% successfully continued dupilumab treatment with a prolonged interval. Not at all surprisingly, the authors calculated that prolonging the interval between dosing led to large savings in cost.

One of the nice features of dupilumab treatment is that loss of response over time seems unusual. Perhaps there is a low propensity for forming antidrug antibodies when dupilumab is used in the standard every 2-week dosing regimen. I don't know whether antidrug antibodies would be more likely with the intermittent dosing regimen. But now that we have other good systemic treatment options for AD, losing dupilumab efficacy would not be as critical a problem as it used to be. I also want to point out that patients' adherence to injection treatment, though better than adherence to topicals, is far from perfect. It's likely that many patients have already been prolonging the interval between taking their treatments. If you want to know, just ask them. The way I like to phrase the question is: "Are you keeping the extra injectors you've accumulated refrigerated like you are supposed to?"

There is a tremendous amount of atopic dermatitis (AD) research underway. This month, we have several interesting articles to present.

Silverberg and colleagues described a very well-designed, vehicle-controlled, randomized 8-week study of a topical formulation of a purified strain of Nitrosomonas eutropha, an ammonia-oxidizing bacterium. In theory, this bacterium may reduce Staphylococcus aureus. The study compared two concentrations of the bacterium vs vehicle delivered as a spray twice per day. Study participants were adults with AD affecting 10%-40% of body surface area.

The study found "meaningful" improvements in itch and objective signs of disease, with clear separation between both doses of the bacterial spray compared with vehicle. At week 4, about 23% of participants treated with the bacterium were clear or almost clear (with a 2-point improvement) compared with 12% in the vehicle group (for comparison, in a phase 2 study comparing topical ruxolitinib with 0.1% triamcinolone cream, there was a 25% clear or almost clear rate [with 2-point improvement] in the triamcinolone-treated individuals).

Though an "all-natural" bacterial approach to managing AD may be appealing to some, it sounded like magic to me. But this well-done study makes it seem like the bacterial approach could be more promising than I had thought. This study also reported about twice as many adverse events (including gastrointestinal issues) with the bacterium-treated participants compared with those who received vehicle, adding to my belief that the bacterial product has efficacy. Whether any other topical will be more effective and safer than is topical triamcinolone remains to be seen. I'm still pessimistic about topicals because of patients' poor adherence to topical treatment, but perhaps an easy-to-use spray that isn't associated with patients' fear of "steroids" will be helpful.

I love articles like this one from Chen and colleagues. They analyzed data on hundreds of thousands of patients with and without AD. Adults with AD had a "significantly increased risk" of developing venous thromboembolism compared with adults without AD. The huge sample size of their study seems compelling. That huge sample size allows detection of effects so small that they may be clinically insignificant.

They report that patients with AD had a venous thromboembolism at a rate of 1.05/1000 patients-years; the rate was 0.82 for patients without AD. From that, we can calculate that there would be an additional 23 patients with venous thromboembolism for every 100,000 patient-years or about one more venous thromboembolism in the AD group in every 4000 patient-years. Though the finding was statistically significant, I don't think it is clinically meaningful.

The authors correctly conclude that "vascular examination and consultation with the emergency department, cardiologists, or pulmonologists are indicated for patients with AD who present with relevant symptoms (eg, unexplained dyspnea, chest tightness, and limb swelling)." But it is probably also true that vascular examination and consultation with the emergency department, cardiologists, or pulmonologists are indicated for patients without AD who present with those symptoms. I think the authors might have been on solid ground if they had concluded that there was a statistically significant but clinically insignificant increased risk for venous thromboembolism in patients with AD.

Eichenfeld and colleagues examined the use of topical crisaborole once per day as a maintenance treatment for patients with mild to moderate AD. The study compared patients given topical crisaborole with those randomly assigned to vehicle. The active treatment was effective because topical crisaborole treated patients had longer times to the first flare following treatment and fewer flares over the 1 year of treatment. The differences were not huge, but I think they were clinically meaningful. I'm guessing that the topical crisaborole maintenance treatment would have been even more effective had it been used regularly. The study did not, as far as I could tell, assess how well the treatment was used.

An interesting aspect of this study is that it began with nearly 500 participants who started on twice daily topical crisaborole. The 270 patients who responded to the treatment (achieving clear or almost clear with at least a 2-point improvement) were enrolled in the 1-year maintenance phase. Thus, the participants in the maintenance phase were preselected for patients who respond to topical crisaborole. We don't know why they were responders (I, of course, expect it is because they selected for patients who are better than others are at using a topical treatment), but it may be best not to try to generalize these results and assume this form of maintenance treatment would work equally well in a population who achieve initial success with an oral therapy regimen (for example, a quick course of oral prednisone).

Dupilumab was a revolutionary treatment for AD. I didn't think that I'd ever see a more effective treatment. It's so safe too! It has been a first-line treatment for AD since its introduction. Now, we also have oral Janus kinase inhibitor options. Blauvelt and colleagues examined what happens when patients who have been on dupilumab are switched to a high dose (30 mg/d) of upadacitinib (the standard starting dose of upadacitinib is 15 mg/d). Though dupilumab is very effective, upadacitinib is more so. After 4 weeks of switching to upadacitinib, nearly half the patients were completely clear of AD compared with only 16.0% after 24 weeks of dupilumab! The authors point out, optimistically, that "No new safety risks were observed." Though there were no cancers, gastrointestinal perforations, major adverse cardiovascular events, or venous thromboembolic events, there were cases of eczema herpeticum and zoster in patients treated with upadacitinib. Having upadacitinib available for patients who fail dupilumab is a clear benefit; the role of upadacitinib before dupilumab seems less clear.

Patients doing great on dupilumab for AD may be wondering: Do I still need to take it every 2 weeks? Spekhorst and colleagues may have the answer. They describe the response to tapering dupilumab in patients who had been on the drug for at least 1 year with well-controlled disease for at least 6 months. Patients in the study then continued dupilumab with the longest possible dosing interval while maintaining control of their AD.

Generally, patients maintained good control of their AD, with only a small increase in mean disease severity and in concomitant use of topical steroids. For the patients who attempted prolongation, 83% successfully continued dupilumab treatment with a prolonged interval. Not at all surprisingly, the authors calculated that prolonging the interval between dosing led to large savings in cost.

One of the nice features of dupilumab treatment is that loss of response over time seems unusual. Perhaps there is a low propensity for forming antidrug antibodies when dupilumab is used in the standard every 2-week dosing regimen. I don't know whether antidrug antibodies would be more likely with the intermittent dosing regimen. But now that we have other good systemic treatment options for AD, losing dupilumab efficacy would not be as critical a problem as it used to be. I also want to point out that patients' adherence to injection treatment, though better than adherence to topicals, is far from perfect. It's likely that many patients have already been prolonging the interval between taking their treatments. If you want to know, just ask them. The way I like to phrase the question is: "Are you keeping the extra injectors you've accumulated refrigerated like you are supposed to?"

There is a tremendous amount of atopic dermatitis (AD) research underway. This month, we have several interesting articles to present.

Silverberg and colleagues described a very well-designed, vehicle-controlled, randomized 8-week study of a topical formulation of a purified strain of Nitrosomonas eutropha, an ammonia-oxidizing bacterium. In theory, this bacterium may reduce Staphylococcus aureus. The study compared two concentrations of the bacterium vs vehicle delivered as a spray twice per day. Study participants were adults with AD affecting 10%-40% of body surface area.

The study found "meaningful" improvements in itch and objective signs of disease, with clear separation between both doses of the bacterial spray compared with vehicle. At week 4, about 23% of participants treated with the bacterium were clear or almost clear (with a 2-point improvement) compared with 12% in the vehicle group (for comparison, in a phase 2 study comparing topical ruxolitinib with 0.1% triamcinolone cream, there was a 25% clear or almost clear rate [with 2-point improvement] in the triamcinolone-treated individuals).

Though an "all-natural" bacterial approach to managing AD may be appealing to some, it sounded like magic to me. But this well-done study makes it seem like the bacterial approach could be more promising than I had thought. This study also reported about twice as many adverse events (including gastrointestinal issues) with the bacterium-treated participants compared with those who received vehicle, adding to my belief that the bacterial product has efficacy. Whether any other topical will be more effective and safer than is topical triamcinolone remains to be seen. I'm still pessimistic about topicals because of patients' poor adherence to topical treatment, but perhaps an easy-to-use spray that isn't associated with patients' fear of "steroids" will be helpful.

I love articles like this one from Chen and colleagues. They analyzed data on hundreds of thousands of patients with and without AD. Adults with AD had a "significantly increased risk" of developing venous thromboembolism compared with adults without AD. The huge sample size of their study seems compelling. That huge sample size allows detection of effects so small that they may be clinically insignificant.

They report that patients with AD had a venous thromboembolism at a rate of 1.05/1000 patients-years; the rate was 0.82 for patients without AD. From that, we can calculate that there would be an additional 23 patients with venous thromboembolism for every 100,000 patient-years or about one more venous thromboembolism in the AD group in every 4000 patient-years. Though the finding was statistically significant, I don't think it is clinically meaningful.

The authors correctly conclude that "vascular examination and consultation with the emergency department, cardiologists, or pulmonologists are indicated for patients with AD who present with relevant symptoms (eg, unexplained dyspnea, chest tightness, and limb swelling)." But it is probably also true that vascular examination and consultation with the emergency department, cardiologists, or pulmonologists are indicated for patients without AD who present with those symptoms. I think the authors might have been on solid ground if they had concluded that there was a statistically significant but clinically insignificant increased risk for venous thromboembolism in patients with AD.

Eichenfeld and colleagues examined the use of topical crisaborole once per day as a maintenance treatment for patients with mild to moderate AD. The study compared patients given topical crisaborole with those randomly assigned to vehicle. The active treatment was effective because topical crisaborole treated patients had longer times to the first flare following treatment and fewer flares over the 1 year of treatment. The differences were not huge, but I think they were clinically meaningful. I'm guessing that the topical crisaborole maintenance treatment would have been even more effective had it been used regularly. The study did not, as far as I could tell, assess how well the treatment was used.

An interesting aspect of this study is that it began with nearly 500 participants who started on twice daily topical crisaborole. The 270 patients who responded to the treatment (achieving clear or almost clear with at least a 2-point improvement) were enrolled in the 1-year maintenance phase. Thus, the participants in the maintenance phase were preselected for patients who respond to topical crisaborole. We don't know why they were responders (I, of course, expect it is because they selected for patients who are better than others are at using a topical treatment), but it may be best not to try to generalize these results and assume this form of maintenance treatment would work equally well in a population who achieve initial success with an oral therapy regimen (for example, a quick course of oral prednisone).

Dupilumab was a revolutionary treatment for AD. I didn't think that I'd ever see a more effective treatment. It's so safe too! It has been a first-line treatment for AD since its introduction. Now, we also have oral Janus kinase inhibitor options. Blauvelt and colleagues examined what happens when patients who have been on dupilumab are switched to a high dose (30 mg/d) of upadacitinib (the standard starting dose of upadacitinib is 15 mg/d). Though dupilumab is very effective, upadacitinib is more so. After 4 weeks of switching to upadacitinib, nearly half the patients were completely clear of AD compared with only 16.0% after 24 weeks of dupilumab! The authors point out, optimistically, that "No new safety risks were observed." Though there were no cancers, gastrointestinal perforations, major adverse cardiovascular events, or venous thromboembolic events, there were cases of eczema herpeticum and zoster in patients treated with upadacitinib. Having upadacitinib available for patients who fail dupilumab is a clear benefit; the role of upadacitinib before dupilumab seems less clear.

Patients doing great on dupilumab for AD may be wondering: Do I still need to take it every 2 weeks? Spekhorst and colleagues may have the answer. They describe the response to tapering dupilumab in patients who had been on the drug for at least 1 year with well-controlled disease for at least 6 months. Patients in the study then continued dupilumab with the longest possible dosing interval while maintaining control of their AD.

Generally, patients maintained good control of their AD, with only a small increase in mean disease severity and in concomitant use of topical steroids. For the patients who attempted prolongation, 83% successfully continued dupilumab treatment with a prolonged interval. Not at all surprisingly, the authors calculated that prolonging the interval between dosing led to large savings in cost.

One of the nice features of dupilumab treatment is that loss of response over time seems unusual. Perhaps there is a low propensity for forming antidrug antibodies when dupilumab is used in the standard every 2-week dosing regimen. I don't know whether antidrug antibodies would be more likely with the intermittent dosing regimen. But now that we have other good systemic treatment options for AD, losing dupilumab efficacy would not be as critical a problem as it used to be. I also want to point out that patients' adherence to injection treatment, though better than adherence to topicals, is far from perfect. It's likely that many patients have already been prolonging the interval between taking their treatments. If you want to know, just ask them. The way I like to phrase the question is: "Are you keeping the extra injectors you've accumulated refrigerated like you are supposed to?"

There is a tremendous amount of atopic dermatitis (AD) research underway. This month, we have several interesting articles to present.

Silverberg and colleagues described a very well-designed, vehicle-controlled, randomized 8-week study of a topical formulation of a purified strain of Nitrosomonas eutropha, an ammonia-oxidizing bacterium. In theory, this bacterium may reduce Staphylococcus aureus. The study compared two concentrations of the bacterium vs vehicle delivered as a spray twice per day. Study participants were adults with AD affecting 10%-40% of body surface area.

The study found "meaningful" improvements in itch and objective signs of disease, with clear separation between both doses of the bacterial spray compared with vehicle. At week 4, about 23% of participants treated with the bacterium were clear or almost clear (with a 2-point improvement) compared with 12% in the vehicle group (for comparison, in a phase 2 study comparing topical ruxolitinib with 0.1% triamcinolone cream, there was a 25% clear or almost clear rate [with 2-point improvement] in the triamcinolone-treated individuals).

Though an "all-natural" bacterial approach to managing AD may be appealing to some, it sounded like magic to me. But this well-done study makes it seem like the bacterial approach could be more promising than I had thought. This study also reported about twice as many adverse events (including gastrointestinal issues) with the bacterium-treated participants compared with those who received vehicle, adding to my belief that the bacterial product has efficacy. Whether any other topical will be more effective and safer than is topical triamcinolone remains to be seen. I'm still pessimistic about topicals because of patients' poor adherence to topical treatment, but perhaps an easy-to-use spray that isn't associated with patients' fear of "steroids" will be helpful.

I love articles like this one from Chen and colleagues. They analyzed data on hundreds of thousands of patients with and without AD. Adults with AD had a "significantly increased risk" of developing venous thromboembolism compared with adults without AD. The huge sample size of their study seems compelling. That huge sample size allows detection of effects so small that they may be clinically insignificant.

They report that patients with AD had a venous thromboembolism at a rate of 1.05/1000 patients-years; the rate was 0.82 for patients without AD. From that, we can calculate that there would be an additional 23 patients with venous thromboembolism for every 100,000 patient-years or about one more venous thromboembolism in the AD group in every 4000 patient-years. Though the finding was statistically significant, I don't think it is clinically meaningful.

The authors correctly conclude that "vascular examination and consultation with the emergency department, cardiologists, or pulmonologists are indicated for patients with AD who present with relevant symptoms (eg, unexplained dyspnea, chest tightness, and limb swelling)." But it is probably also true that vascular examination and consultation with the emergency department, cardiologists, or pulmonologists are indicated for patients without AD who present with those symptoms. I think the authors might have been on solid ground if they had concluded that there was a statistically significant but clinically insignificant increased risk for venous thromboembolism in patients with AD.

Eichenfeld and colleagues examined the use of topical crisaborole once per day as a maintenance treatment for patients with mild to moderate AD. The study compared patients given topical crisaborole with those randomly assigned to vehicle. The active treatment was effective because topical crisaborole treated patients had longer times to the first flare following treatment and fewer flares over the 1 year of treatment. The differences were not huge, but I think they were clinically meaningful. I'm guessing that the topical crisaborole maintenance treatment would have been even more effective had it been used regularly. The study did not, as far as I could tell, assess how well the treatment was used.

An interesting aspect of this study is that it began with nearly 500 participants who started on twice daily topical crisaborole. The 270 patients who responded to the treatment (achieving clear or almost clear with at least a 2-point improvement) were enrolled in the 1-year maintenance phase. Thus, the participants in the maintenance phase were preselected for patients who respond to topical crisaborole. We don't know why they were responders (I, of course, expect it is because they selected for patients who are better than others are at using a topical treatment), but it may be best not to try to generalize these results and assume this form of maintenance treatment would work equally well in a population who achieve initial success with an oral therapy regimen (for example, a quick course of oral prednisone).

Dupilumab was a revolutionary treatment for AD. I didn't think that I'd ever see a more effective treatment. It's so safe too! It has been a first-line treatment for AD since its introduction. Now, we also have oral Janus kinase inhibitor options. Blauvelt and colleagues examined what happens when patients who have been on dupilumab are switched to a high dose (30 mg/d) of upadacitinib (the standard starting dose of upadacitinib is 15 mg/d). Though dupilumab is very effective, upadacitinib is more so. After 4 weeks of switching to upadacitinib, nearly half the patients were completely clear of AD compared with only 16.0% after 24 weeks of dupilumab! The authors point out, optimistically, that "No new safety risks were observed." Though there were no cancers, gastrointestinal perforations, major adverse cardiovascular events, or venous thromboembolic events, there were cases of eczema herpeticum and zoster in patients treated with upadacitinib. Having upadacitinib available for patients who fail dupilumab is a clear benefit; the role of upadacitinib before dupilumab seems less clear.

Patients doing great on dupilumab for AD may be wondering: Do I still need to take it every 2 weeks? Spekhorst and colleagues may have the answer. They describe the response to tapering dupilumab in patients who had been on the drug for at least 1 year with well-controlled disease for at least 6 months. Patients in the study then continued dupilumab with the longest possible dosing interval while maintaining control of their AD.

Generally, patients maintained good control of their AD, with only a small increase in mean disease severity and in concomitant use of topical steroids. For the patients who attempted prolongation, 83% successfully continued dupilumab treatment with a prolonged interval. Not at all surprisingly, the authors calculated that prolonging the interval between dosing led to large savings in cost.

One of the nice features of dupilumab treatment is that loss of response over time seems unusual. Perhaps there is a low propensity for forming antidrug antibodies when dupilumab is used in the standard every 2-week dosing regimen. I don't know whether antidrug antibodies would be more likely with the intermittent dosing regimen. But now that we have other good systemic treatment options for AD, losing dupilumab efficacy would not be as critical a problem as it used to be. I also want to point out that patients' adherence to injection treatment, though better than adherence to topicals, is far from perfect. It's likely that many patients have already been prolonging the interval between taking their treatments. If you want to know, just ask them. The way I like to phrase the question is: "Are you keeping the extra injectors you've accumulated refrigerated like you are supposed to?"

AUSTIN, TEX. – Self-treatment of migraines using cannabis can be effective but comes at risk of significant side effects, according to results from a randomized, controlled trial of cannabis products in migraine. The study also suggests that typical recreational doses may be higher than needed, and that products with a mixture of THC and CBD might limit adverse effects, according to lead author Nathaniel Schuster, MD.

“Patients are using cannabis on their own, treating themselves without us having known whether this is effective in a placebo-controlled study. Knowing that there’s a lot of interest in THC and CBD, [it would be useful to know] whether one or both might be effective, as well as a mix,” said Dr. Schuster in an interview. He presented the results at the annual meeting of the American Headache Society.

Dr. Schuster and colleagues tested a cannabis product with 6% THC based on prior studies showing efficacy of that concentration for other pain conditions, according to Dr. Schuster, who is an associate professor and associate clinical director at the University of California, San Diego, center for pain medicine. He added that the study is the first randomized, controlled trial of cannabis in migraine patients that he is aware of. “It’s just hard to do this research. It’s very regulated. We had to go through a lot of government approvals to do this,” he said.

The study produced a key message. “I think one of the really important things for patients to take from this is that recreational doses are probably not necessary. The doses that we studied are lower than people use recreationally. Patients who are self-treating on their own right now are probably using higher doses than they need for the purpose of treating migraine,” said Dr. Schuster.

He also pointed out that the results offer potential insight into reducing side effects. “If [patients] are using THC only, they can hopefully have less of the side effects and tolerate it better by using a THC-CBD mix,” said Dr. Schuster.
 

Four therapies tested

Participants in the study could self-treat up to four migraine attacks. They were instructed to treat each migraine with one of four therapies, which were provided in a randomized, double-blind order: These included a 6% THC formulation; a mix of THC (6%) and CBD (11%); a CBD 11% formulation; and placebo cannabis with THC and CBD removed by alcohol extraction. Participants filled out a questionnaire 2 hours after treatment, and were then allowed to use rescue treatments if needed, but not additional cannabis. The age range was from 21 to 65, and inclusion criteria included 2-23 migraine days per month. Exclusion criteria included a positive urine test for THC, barbiturates, opioids, oxycodone, or methadone prior to enrollment.

The study included 73 patients who treated a migraine during the study period. There were 247 migraine attacks treated. Among participants, the median age was 41, 82.6% were female and 17.4% were male, and the median body mass index was 26.0 kg/m². Participants experienced a median of 15 headache days per month and 6 migraine days per month, and 27.2% had chronic migraine.

At 2 hours, pain relief occurred in 48.3% of placebo treatments, 54.4% of the CBD treatments, 70.5% of the THC treatments (P = .007 versus placebo), and 69.0% of the THC/CBD treatments (P = .014 versus placebo). At 2 hours, pain freedom occurred in 15.5% of the placebo treatments, 24.6% of the CBD treatments, 29.5% of the THC treatments, and 36.2% of the THC/CBD treatments (P = .010 versus placebo). At 2 hours, freedom from most bothersome symptoms (MBS) occurred in 36.2% of the placebo treatments, 43.9% of the CBD treatments, 49.2% of the THC treatments, and 62.1% of the THC/CBD treatments (P = .004 versus placebo).

To achieve at least a 20% improvement in pain relief, compared with placebo, the number needed to treat (NNT) with THC/CBD was five. For at least a 20% improvement in pain freedom, the NNT was five, and for a 20% improvement in freedom from most bothersome symptoms, the NNT was four.

Treatment with THC was associated with the highest frequency of any adverse event (31.0%), followed by CBD and THC/CBD (19.6% each), and placebo (5.0%). At 2 hours, 18.0% of the THC treatments had an adverse event, compared with 7.0% of the CBD treatments, 6.9% of the THC/CBD treatments, and 5.2% of placebo treatments.

The number needed to treat of five for pain relief was encouraging, according to Dr. Schuster. “It’s better than some other things, but at the expense of side effects. The side effects that we see are certainly higher with cannabis than it is with other migraine treatments that patients certainly should be using beforehand. There’s also a risk of addiction, which is a concern,” said Dr. Schuster.
 

Useful data but questions remain

Having a clinical trial will be useful for physicians, said Ali Ezzati, MD, who attended the session. “I think it was an impressive study. Obviously, there are some challenges with cannabis studies in the medical world because of the stigma that comes with it and also the possibility of inducing addiction [and] promoting that to patients. But at the end of the day, it’s very, very common for our patients to ask us about cannabinoid use, and we really don’t have data on it. I’m glad that there are people who are running these studies so we will be able at least to answer our patients,” said Dr. Ezzati, who is an associate professor of neurology at University of California, Irvine.

Dr. Ezzati also noted that clinical trials have investigated cannabinoid use for other types of pain, such as arthritic or generalized pain. Although he said that there are some clinical similarities between other types of pain and migraine, the pathophysiology appears to be unique, which means that more work needs to be done. “It will probably take 5 or 10 years to have sufficient data to give patients a direct path for using (cannabinoids),” said Dr. Ezzati.

The study was funded by the Migraine Research Foundation. Dr. Schuster has consulted with Schedule 1 Therapeutics and Vectura Fertin. Dr. Ezzati has no relevant financial disclosures.

AUSTIN, TEX. – Self-treatment of migraines using cannabis can be effective but comes at risk of significant side effects, according to results from a randomized, controlled trial of cannabis products in migraine. The study also suggests that typical recreational doses may be higher than needed, and that products with a mixture of THC and CBD might limit adverse effects, according to lead author Nathaniel Schuster, MD.

“Patients are using cannabis on their own, treating themselves without us having known whether this is effective in a placebo-controlled study. Knowing that there’s a lot of interest in THC and CBD, [it would be useful to know] whether one or both might be effective, as well as a mix,” said Dr. Schuster in an interview. He presented the results at the annual meeting of the American Headache Society.

Dr. Schuster and colleagues tested a cannabis product with 6% THC based on prior studies showing efficacy of that concentration for other pain conditions, according to Dr. Schuster, who is an associate professor and associate clinical director at the University of California, San Diego, center for pain medicine. He added that the study is the first randomized, controlled trial of cannabis in migraine patients that he is aware of. “It’s just hard to do this research. It’s very regulated. We had to go through a lot of government approvals to do this,” he said.

The study produced a key message. “I think one of the really important things for patients to take from this is that recreational doses are probably not necessary. The doses that we studied are lower than people use recreationally. Patients who are self-treating on their own right now are probably using higher doses than they need for the purpose of treating migraine,” said Dr. Schuster.

He also pointed out that the results offer potential insight into reducing side effects. “If [patients] are using THC only, they can hopefully have less of the side effects and tolerate it better by using a THC-CBD mix,” said Dr. Schuster.
 

Four therapies tested

Participants in the study could self-treat up to four migraine attacks. They were instructed to treat each migraine with one of four therapies, which were provided in a randomized, double-blind order: These included a 6% THC formulation; a mix of THC (6%) and CBD (11%); a CBD 11% formulation; and placebo cannabis with THC and CBD removed by alcohol extraction. Participants filled out a questionnaire 2 hours after treatment, and were then allowed to use rescue treatments if needed, but not additional cannabis. The age range was from 21 to 65, and inclusion criteria included 2-23 migraine days per month. Exclusion criteria included a positive urine test for THC, barbiturates, opioids, oxycodone, or methadone prior to enrollment.

The study included 73 patients who treated a migraine during the study period. There were 247 migraine attacks treated. Among participants, the median age was 41, 82.6% were female and 17.4% were male, and the median body mass index was 26.0 kg/m². Participants experienced a median of 15 headache days per month and 6 migraine days per month, and 27.2% had chronic migraine.

At 2 hours, pain relief occurred in 48.3% of placebo treatments, 54.4% of the CBD treatments, 70.5% of the THC treatments (P = .007 versus placebo), and 69.0% of the THC/CBD treatments (P = .014 versus placebo). At 2 hours, pain freedom occurred in 15.5% of the placebo treatments, 24.6% of the CBD treatments, 29.5% of the THC treatments, and 36.2% of the THC/CBD treatments (P = .010 versus placebo). At 2 hours, freedom from most bothersome symptoms (MBS) occurred in 36.2% of the placebo treatments, 43.9% of the CBD treatments, 49.2% of the THC treatments, and 62.1% of the THC/CBD treatments (P = .004 versus placebo).

To achieve at least a 20% improvement in pain relief, compared with placebo, the number needed to treat (NNT) with THC/CBD was five. For at least a 20% improvement in pain freedom, the NNT was five, and for a 20% improvement in freedom from most bothersome symptoms, the NNT was four.

Treatment with THC was associated with the highest frequency of any adverse event (31.0%), followed by CBD and THC/CBD (19.6% each), and placebo (5.0%). At 2 hours, 18.0% of the THC treatments had an adverse event, compared with 7.0% of the CBD treatments, 6.9% of the THC/CBD treatments, and 5.2% of placebo treatments.

The number needed to treat of five for pain relief was encouraging, according to Dr. Schuster. “It’s better than some other things, but at the expense of side effects. The side effects that we see are certainly higher with cannabis than it is with other migraine treatments that patients certainly should be using beforehand. There’s also a risk of addiction, which is a concern,” said Dr. Schuster.
 

Useful data but questions remain

Having a clinical trial will be useful for physicians, said Ali Ezzati, MD, who attended the session. “I think it was an impressive study. Obviously, there are some challenges with cannabis studies in the medical world because of the stigma that comes with it and also the possibility of inducing addiction [and] promoting that to patients. But at the end of the day, it’s very, very common for our patients to ask us about cannabinoid use, and we really don’t have data on it. I’m glad that there are people who are running these studies so we will be able at least to answer our patients,” said Dr. Ezzati, who is an associate professor of neurology at University of California, Irvine.

Dr. Ezzati also noted that clinical trials have investigated cannabinoid use for other types of pain, such as arthritic or generalized pain. Although he said that there are some clinical similarities between other types of pain and migraine, the pathophysiology appears to be unique, which means that more work needs to be done. “It will probably take 5 or 10 years to have sufficient data to give patients a direct path for using (cannabinoids),” said Dr. Ezzati.

The study was funded by the Migraine Research Foundation. Dr. Schuster has consulted with Schedule 1 Therapeutics and Vectura Fertin. Dr. Ezzati has no relevant financial disclosures.

AUSTIN, TEX. – Self-treatment of migraines using cannabis can be effective but comes at risk of significant side effects, according to results from a randomized, controlled trial of cannabis products in migraine. The study also suggests that typical recreational doses may be higher than needed, and that products with a mixture of THC and CBD might limit adverse effects, according to lead author Nathaniel Schuster, MD.

“Patients are using cannabis on their own, treating themselves without us having known whether this is effective in a placebo-controlled study. Knowing that there’s a lot of interest in THC and CBD, [it would be useful to know] whether one or both might be effective, as well as a mix,” said Dr. Schuster in an interview. He presented the results at the annual meeting of the American Headache Society.

Dr. Schuster and colleagues tested a cannabis product with 6% THC based on prior studies showing efficacy of that concentration for other pain conditions, according to Dr. Schuster, who is an associate professor and associate clinical director at the University of California, San Diego, center for pain medicine. He added that the study is the first randomized, controlled trial of cannabis in migraine patients that he is aware of. “It’s just hard to do this research. It’s very regulated. We had to go through a lot of government approvals to do this,” he said.

The study produced a key message. “I think one of the really important things for patients to take from this is that recreational doses are probably not necessary. The doses that we studied are lower than people use recreationally. Patients who are self-treating on their own right now are probably using higher doses than they need for the purpose of treating migraine,” said Dr. Schuster.

He also pointed out that the results offer potential insight into reducing side effects. “If [patients] are using THC only, they can hopefully have less of the side effects and tolerate it better by using a THC-CBD mix,” said Dr. Schuster.
 

Four therapies tested

Participants in the study could self-treat up to four migraine attacks. They were instructed to treat each migraine with one of four therapies, which were provided in a randomized, double-blind order: These included a 6% THC formulation; a mix of THC (6%) and CBD (11%); a CBD 11% formulation; and placebo cannabis with THC and CBD removed by alcohol extraction. Participants filled out a questionnaire 2 hours after treatment, and were then allowed to use rescue treatments if needed, but not additional cannabis. The age range was from 21 to 65, and inclusion criteria included 2-23 migraine days per month. Exclusion criteria included a positive urine test for THC, barbiturates, opioids, oxycodone, or methadone prior to enrollment.

The study included 73 patients who treated a migraine during the study period. There were 247 migraine attacks treated. Among participants, the median age was 41, 82.6% were female and 17.4% were male, and the median body mass index was 26.0 kg/m². Participants experienced a median of 15 headache days per month and 6 migraine days per month, and 27.2% had chronic migraine.

At 2 hours, pain relief occurred in 48.3% of placebo treatments, 54.4% of the CBD treatments, 70.5% of the THC treatments (P = .007 versus placebo), and 69.0% of the THC/CBD treatments (P = .014 versus placebo). At 2 hours, pain freedom occurred in 15.5% of the placebo treatments, 24.6% of the CBD treatments, 29.5% of the THC treatments, and 36.2% of the THC/CBD treatments (P = .010 versus placebo). At 2 hours, freedom from most bothersome symptoms (MBS) occurred in 36.2% of the placebo treatments, 43.9% of the CBD treatments, 49.2% of the THC treatments, and 62.1% of the THC/CBD treatments (P = .004 versus placebo).

To achieve at least a 20% improvement in pain relief, compared with placebo, the number needed to treat (NNT) with THC/CBD was five. For at least a 20% improvement in pain freedom, the NNT was five, and for a 20% improvement in freedom from most bothersome symptoms, the NNT was four.

Treatment with THC was associated with the highest frequency of any adverse event (31.0%), followed by CBD and THC/CBD (19.6% each), and placebo (5.0%). At 2 hours, 18.0% of the THC treatments had an adverse event, compared with 7.0% of the CBD treatments, 6.9% of the THC/CBD treatments, and 5.2% of placebo treatments.

The number needed to treat of five for pain relief was encouraging, according to Dr. Schuster. “It’s better than some other things, but at the expense of side effects. The side effects that we see are certainly higher with cannabis than it is with other migraine treatments that patients certainly should be using beforehand. There’s also a risk of addiction, which is a concern,” said Dr. Schuster.
 

Useful data but questions remain

Having a clinical trial will be useful for physicians, said Ali Ezzati, MD, who attended the session. “I think it was an impressive study. Obviously, there are some challenges with cannabis studies in the medical world because of the stigma that comes with it and also the possibility of inducing addiction [and] promoting that to patients. But at the end of the day, it’s very, very common for our patients to ask us about cannabinoid use, and we really don’t have data on it. I’m glad that there are people who are running these studies so we will be able at least to answer our patients,” said Dr. Ezzati, who is an associate professor of neurology at University of California, Irvine.

Dr. Ezzati also noted that clinical trials have investigated cannabinoid use for other types of pain, such as arthritic or generalized pain. Although he said that there are some clinical similarities between other types of pain and migraine, the pathophysiology appears to be unique, which means that more work needs to be done. “It will probably take 5 or 10 years to have sufficient data to give patients a direct path for using (cannabinoids),” said Dr. Ezzati.

The study was funded by the Migraine Research Foundation. Dr. Schuster has consulted with Schedule 1 Therapeutics and Vectura Fertin. Dr. Ezzati has no relevant financial disclosures.

Dr Harold J. Burstein, of the Dana-Farber Cancer Institute in Boston, Massachusetts, highlights key abstracts on early breast cancer from the 2023 American Society of Clinical Oncology (ASCO) annual meeting. 

Dr Burstein first reports on exciting results from the phase 3 NATALEE trial, which compared adjuvant use of CDK4/6 inhibitor ribociclib plus endocrine therapy (ET) vs ET alone in patients with HR+/HER2- early breast cancer and found that the combination lowered risk for recurrence.  

The results of NATALEE, together with the recent findings of the monarchE trial, provide strong evidence that the addition of a CDK4/6 inhibitor to ET is useful in the adjuvant setting. Dr Burstein suggests that these findings may point to an emerging treatment paradigm in HR+/HER2- patients, particularly those with higher-risk breast cancers. 

Dr Burstein next discusses important data from the Early Breast Cancer Trialists Collaborative Group (EBCTCG). Their meta-analysis of 25 randomized trials on ovarian ablation in premenopausal women showed that ovarian ablation provided a substantial reduction in 15-year risk for recurrence and death. 

Finally, Dr Burstein reports on data from an analysis of patients enrolled in the PENELOPE-B trial to assess the value of circulating tumor DNA (ctDNA) in predicting clinical relapse. Dr Burstein reports that the results indicated that ctDNA was a strong prognostic factor for disease recurrence. 

--

Harold J. Burstein, MD, PhD, Professor, Department of Medicine, Harvard Medical School; Institute Physician, Dana-Farber Cancer Institute, Boston, Massachusetts 

Harold J. Burstein, MD, PhD, has disclosed no relevant financial relationships. 

Dr Harold J. Burstein, of the Dana-Farber Cancer Institute in Boston, Massachusetts, highlights key abstracts on early breast cancer from the 2023 American Society of Clinical Oncology (ASCO) annual meeting. 

Dr Burstein first reports on exciting results from the phase 3 NATALEE trial, which compared adjuvant use of CDK4/6 inhibitor ribociclib plus endocrine therapy (ET) vs ET alone in patients with HR+/HER2- early breast cancer and found that the combination lowered risk for recurrence.  

The results of NATALEE, together with the recent findings of the monarchE trial, provide strong evidence that the addition of a CDK4/6 inhibitor to ET is useful in the adjuvant setting. Dr Burstein suggests that these findings may point to an emerging treatment paradigm in HR+/HER2- patients, particularly those with higher-risk breast cancers. 

Dr Burstein next discusses important data from the Early Breast Cancer Trialists Collaborative Group (EBCTCG). Their meta-analysis of 25 randomized trials on ovarian ablation in premenopausal women showed that ovarian ablation provided a substantial reduction in 15-year risk for recurrence and death. 

Finally, Dr Burstein reports on data from an analysis of patients enrolled in the PENELOPE-B trial to assess the value of circulating tumor DNA (ctDNA) in predicting clinical relapse. Dr Burstein reports that the results indicated that ctDNA was a strong prognostic factor for disease recurrence. 

--

Harold J. Burstein, MD, PhD, Professor, Department of Medicine, Harvard Medical School; Institute Physician, Dana-Farber Cancer Institute, Boston, Massachusetts 

Harold J. Burstein, MD, PhD, has disclosed no relevant financial relationships. 

Dr Harold J. Burstein, of the Dana-Farber Cancer Institute in Boston, Massachusetts, highlights key abstracts on early breast cancer from the 2023 American Society of Clinical Oncology (ASCO) annual meeting. 

Dr Burstein first reports on exciting results from the phase 3 NATALEE trial, which compared adjuvant use of CDK4/6 inhibitor ribociclib plus endocrine therapy (ET) vs ET alone in patients with HR+/HER2- early breast cancer and found that the combination lowered risk for recurrence.  

The results of NATALEE, together with the recent findings of the monarchE trial, provide strong evidence that the addition of a CDK4/6 inhibitor to ET is useful in the adjuvant setting. Dr Burstein suggests that these findings may point to an emerging treatment paradigm in HR+/HER2- patients, particularly those with higher-risk breast cancers. 

Dr Burstein next discusses important data from the Early Breast Cancer Trialists Collaborative Group (EBCTCG). Their meta-analysis of 25 randomized trials on ovarian ablation in premenopausal women showed that ovarian ablation provided a substantial reduction in 15-year risk for recurrence and death. 

Finally, Dr Burstein reports on data from an analysis of patients enrolled in the PENELOPE-B trial to assess the value of circulating tumor DNA (ctDNA) in predicting clinical relapse. Dr Burstein reports that the results indicated that ctDNA was a strong prognostic factor for disease recurrence. 

--

Harold J. Burstein, MD, PhD, Professor, Department of Medicine, Harvard Medical School; Institute Physician, Dana-Farber Cancer Institute, Boston, Massachusetts 

Harold J. Burstein, MD, PhD, has disclosed no relevant financial relationships. 

Dr Harold J. Burstein, of the Dana-Farber Cancer Institute in Boston, Massachusetts, presents key abstracts on metastatic breast cancer (mBC) from the 2023 American Society of Clinical Oncology (ASCO) annual meeting. 

Dr Burstein first highlights results from the SONIA study, which compared endocrine therapy followed by a CDK4/6 inhibitor in the second-line with the use of a CDK4/6 inhibitor in the first line. Although the CDK4/6 inhibitor in first-line improved progression-free survival, overall survival remained unchanged.  

Dr Burstein next discusses results from the CANKADO trial, which randomized patients with mBC to report symptoms via a smartphone app. The app users reported fewer adverse events and better quality of life. 

Dr Burstein reports on the potentially practice-changing results of the X-7/7 trial comparing a fixed dose of capecitabine (7/7) with the standard dose (14/7). Although both dosing schedules showed similar overall survival results, the fixed dose was better tolerated.  

Finally, Dr Burstein turns to advances in the use of antibody-drug conjugates (ADCs), starting with an update from the TROPiCS-02 study comparing sacituzumab govitecan (SG) with standard chemotherapy. The 12.75-month follow-up showed an overall survival benefit when using SG in third- or fourth-line treatment.  

He also highlights phase 2 trial results with another ADC, HER3-DXd (patritumab deruxtecan), which showed significant response rates across a broad range of HER3 expression levels. 

--

Harold J. Burstein, MD, PhD, Professor, Department of Medicine, Harvard Medical School; Institute Physician, Dana-Farber Cancer Institute, Boston, Massachusetts 

Harold J. Burstein, MD, PhD, has disclosed no relevant financial relationships. 

Dr Harold J. Burstein, of the Dana-Farber Cancer Institute in Boston, Massachusetts, presents key abstracts on metastatic breast cancer (mBC) from the 2023 American Society of Clinical Oncology (ASCO) annual meeting. 

Dr Burstein first highlights results from the SONIA study, which compared endocrine therapy followed by a CDK4/6 inhibitor in the second-line with the use of a CDK4/6 inhibitor in the first line. Although the CDK4/6 inhibitor in first-line improved progression-free survival, overall survival remained unchanged.  

Dr Burstein next discusses results from the CANKADO trial, which randomized patients with mBC to report symptoms via a smartphone app. The app users reported fewer adverse events and better quality of life. 

Dr Burstein reports on the potentially practice-changing results of the X-7/7 trial comparing a fixed dose of capecitabine (7/7) with the standard dose (14/7). Although both dosing schedules showed similar overall survival results, the fixed dose was better tolerated.  

Finally, Dr Burstein turns to advances in the use of antibody-drug conjugates (ADCs), starting with an update from the TROPiCS-02 study comparing sacituzumab govitecan (SG) with standard chemotherapy. The 12.75-month follow-up showed an overall survival benefit when using SG in third- or fourth-line treatment.  

He also highlights phase 2 trial results with another ADC, HER3-DXd (patritumab deruxtecan), which showed significant response rates across a broad range of HER3 expression levels. 

--

Harold J. Burstein, MD, PhD, Professor, Department of Medicine, Harvard Medical School; Institute Physician, Dana-Farber Cancer Institute, Boston, Massachusetts 

Harold J. Burstein, MD, PhD, has disclosed no relevant financial relationships. 

Dr Harold J. Burstein, of the Dana-Farber Cancer Institute in Boston, Massachusetts, presents key abstracts on metastatic breast cancer (mBC) from the 2023 American Society of Clinical Oncology (ASCO) annual meeting. 

Dr Burstein first highlights results from the SONIA study, which compared endocrine therapy followed by a CDK4/6 inhibitor in the second-line with the use of a CDK4/6 inhibitor in the first line. Although the CDK4/6 inhibitor in first-line improved progression-free survival, overall survival remained unchanged.  

Dr Burstein next discusses results from the CANKADO trial, which randomized patients with mBC to report symptoms via a smartphone app. The app users reported fewer adverse events and better quality of life. 

Dr Burstein reports on the potentially practice-changing results of the X-7/7 trial comparing a fixed dose of capecitabine (7/7) with the standard dose (14/7). Although both dosing schedules showed similar overall survival results, the fixed dose was better tolerated.  

Finally, Dr Burstein turns to advances in the use of antibody-drug conjugates (ADCs), starting with an update from the TROPiCS-02 study comparing sacituzumab govitecan (SG) with standard chemotherapy. The 12.75-month follow-up showed an overall survival benefit when using SG in third- or fourth-line treatment.  

He also highlights phase 2 trial results with another ADC, HER3-DXd (patritumab deruxtecan), which showed significant response rates across a broad range of HER3 expression levels. 

--

Harold J. Burstein, MD, PhD, Professor, Department of Medicine, Harvard Medical School; Institute Physician, Dana-Farber Cancer Institute, Boston, Massachusetts 

Harold J. Burstein, MD, PhD, has disclosed no relevant financial relationships.