Federal Practitioner

End-of-life discussions happen too late in the treatment of high-risk acute myelogenous leukemia, according to a review of 200 patients at Massachusetts General Hospital and the Dana Farber Cancer Institute, Boston.

The prognosis isn’t good for high-risk AML, defined in the study as either relapsing/recurrent disease or a diagnosis made past the age of 59 years. Almost 60% of the patients (114) died during the 7 years of the study, which started in 2014.

Therefore, it’s important to bring up end-of-life decisions when patients are still able to discuss them, so families aren’t left struggling to guess how aggressive their loved ones might have wanted their final care to be, said lead investigator Hannah Abrams, MD, an internal medicine resident at Massachusetts General. She presented these findings at the annual meeting of the American Society of Hematology.

Much of the time, however, end-of-life discussions come too late. The study team found that nearly 40% (45/114) of the patients who died during the study were not involved in their final code decisions, which most often were to administer comfort care only. Many patients were too ill to participate; the median time between the last code change and death was just 2 days.

Dr. Abrams said she’s seen how families agonize when patients haven’t addressed the issue beforehand. “Witnessing that made me think this is really important to look at. Having these conversations upfront is really important,” she said in an interview.

When asked for comment, hematologist-oncologist Toby Campbell, MD, chief of palliative care at the University of Wisconsin, Madison, agreed.

He called this issue a “missed opportunity for patient autonomy and self-determination. Patients with high-risk AML commonly experience rapid changes in their clinical condition, which catch everyone by surprise. Healthcare providers should do more to prepare patients and families, rather than allow them to be surprised,” Dr. Campbell said.

Part of the problem, Dr. Abrams said, is that end-of-life discussions can fall through the cracks amid urgent discussions about chemotherapy options and other matters.

“One of the biggest things to make this more feasible is to schedule and reimburse time in clinic for this to happen,” she said, noting a need to carve out and protect “15 minutes for patients and clinicians to talk about this.”

Another aspect is that patients are often overly optimistic about their prognoses, so end-of-life discussions don’t seem as pressing. Educational materials about the meaning of various code options and when they are appropriate could help, Dr. Abrams said.

As for the psychological impact of bringing up end-of-life decisions early on, Mikkael Sekeres, MD, chief of the division of hematology at the University of Miami, stressed the importance of telling patients, “We are having this conversation because you are doing well, not because you are doing poorly, and this is the time to have it.”

“Sometimes it does take a sentinel event like an ICU stay before some people want to engage in that conversation, and unfortunately, that is often too late,” said Dr. Sekeres, who moderated Dr. Abrams’ presentation at the meeting.

Among other findings, Dr. Abrams and her team reported that at diagnosis, 86.0% of patients were full-code, and 8.5% had restrictions on life-sustaining therapies. Overall, 57% (114/200) of patients experienced a code status transition, with a median of two transitions during their illness.

Among patients who died, older age and receipt of non-intensive chemotherapy were associated with earlier discussions about code status.

The next step in the project is to determine if palliative care consults yield earlier discussions and greater patient involvement.

There was no commercial funding for the study, and Dr. Abrams and Dr. Campbell didn’t have any relevant disclosures. Dr. Sekeres is an advisor to Novartis, Takeda, and BMS.

[email protected]

End-of-life discussions happen too late in the treatment of high-risk acute myelogenous leukemia, according to a review of 200 patients at Massachusetts General Hospital and the Dana Farber Cancer Institute, Boston.

The prognosis isn’t good for high-risk AML, defined in the study as either relapsing/recurrent disease or a diagnosis made past the age of 59 years. Almost 60% of the patients (114) died during the 7 years of the study, which started in 2014.

Therefore, it’s important to bring up end-of-life decisions when patients are still able to discuss them, so families aren’t left struggling to guess how aggressive their loved ones might have wanted their final care to be, said lead investigator Hannah Abrams, MD, an internal medicine resident at Massachusetts General. She presented these findings at the annual meeting of the American Society of Hematology.

Much of the time, however, end-of-life discussions come too late. The study team found that nearly 40% (45/114) of the patients who died during the study were not involved in their final code decisions, which most often were to administer comfort care only. Many patients were too ill to participate; the median time between the last code change and death was just 2 days.

Dr. Abrams said she’s seen how families agonize when patients haven’t addressed the issue beforehand. “Witnessing that made me think this is really important to look at. Having these conversations upfront is really important,” she said in an interview.

When asked for comment, hematologist-oncologist Toby Campbell, MD, chief of palliative care at the University of Wisconsin, Madison, agreed.

He called this issue a “missed opportunity for patient autonomy and self-determination. Patients with high-risk AML commonly experience rapid changes in their clinical condition, which catch everyone by surprise. Healthcare providers should do more to prepare patients and families, rather than allow them to be surprised,” Dr. Campbell said.

Part of the problem, Dr. Abrams said, is that end-of-life discussions can fall through the cracks amid urgent discussions about chemotherapy options and other matters.

“One of the biggest things to make this more feasible is to schedule and reimburse time in clinic for this to happen,” she said, noting a need to carve out and protect “15 minutes for patients and clinicians to talk about this.”

Another aspect is that patients are often overly optimistic about their prognoses, so end-of-life discussions don’t seem as pressing. Educational materials about the meaning of various code options and when they are appropriate could help, Dr. Abrams said.

As for the psychological impact of bringing up end-of-life decisions early on, Mikkael Sekeres, MD, chief of the division of hematology at the University of Miami, stressed the importance of telling patients, “We are having this conversation because you are doing well, not because you are doing poorly, and this is the time to have it.”

“Sometimes it does take a sentinel event like an ICU stay before some people want to engage in that conversation, and unfortunately, that is often too late,” said Dr. Sekeres, who moderated Dr. Abrams’ presentation at the meeting.

Among other findings, Dr. Abrams and her team reported that at diagnosis, 86.0% of patients were full-code, and 8.5% had restrictions on life-sustaining therapies. Overall, 57% (114/200) of patients experienced a code status transition, with a median of two transitions during their illness.

Among patients who died, older age and receipt of non-intensive chemotherapy were associated with earlier discussions about code status.

The next step in the project is to determine if palliative care consults yield earlier discussions and greater patient involvement.

There was no commercial funding for the study, and Dr. Abrams and Dr. Campbell didn’t have any relevant disclosures. Dr. Sekeres is an advisor to Novartis, Takeda, and BMS.

[email protected]

End-of-life discussions happen too late in the treatment of high-risk acute myelogenous leukemia, according to a review of 200 patients at Massachusetts General Hospital and the Dana Farber Cancer Institute, Boston.

The prognosis isn’t good for high-risk AML, defined in the study as either relapsing/recurrent disease or a diagnosis made past the age of 59 years. Almost 60% of the patients (114) died during the 7 years of the study, which started in 2014.

Therefore, it’s important to bring up end-of-life decisions when patients are still able to discuss them, so families aren’t left struggling to guess how aggressive their loved ones might have wanted their final care to be, said lead investigator Hannah Abrams, MD, an internal medicine resident at Massachusetts General. She presented these findings at the annual meeting of the American Society of Hematology.

Much of the time, however, end-of-life discussions come too late. The study team found that nearly 40% (45/114) of the patients who died during the study were not involved in their final code decisions, which most often were to administer comfort care only. Many patients were too ill to participate; the median time between the last code change and death was just 2 days.

Dr. Abrams said she’s seen how families agonize when patients haven’t addressed the issue beforehand. “Witnessing that made me think this is really important to look at. Having these conversations upfront is really important,” she said in an interview.

When asked for comment, hematologist-oncologist Toby Campbell, MD, chief of palliative care at the University of Wisconsin, Madison, agreed.

He called this issue a “missed opportunity for patient autonomy and self-determination. Patients with high-risk AML commonly experience rapid changes in their clinical condition, which catch everyone by surprise. Healthcare providers should do more to prepare patients and families, rather than allow them to be surprised,” Dr. Campbell said.

Part of the problem, Dr. Abrams said, is that end-of-life discussions can fall through the cracks amid urgent discussions about chemotherapy options and other matters.

“One of the biggest things to make this more feasible is to schedule and reimburse time in clinic for this to happen,” she said, noting a need to carve out and protect “15 minutes for patients and clinicians to talk about this.”

Another aspect is that patients are often overly optimistic about their prognoses, so end-of-life discussions don’t seem as pressing. Educational materials about the meaning of various code options and when they are appropriate could help, Dr. Abrams said.

As for the psychological impact of bringing up end-of-life decisions early on, Mikkael Sekeres, MD, chief of the division of hematology at the University of Miami, stressed the importance of telling patients, “We are having this conversation because you are doing well, not because you are doing poorly, and this is the time to have it.”

“Sometimes it does take a sentinel event like an ICU stay before some people want to engage in that conversation, and unfortunately, that is often too late,” said Dr. Sekeres, who moderated Dr. Abrams’ presentation at the meeting.

Among other findings, Dr. Abrams and her team reported that at diagnosis, 86.0% of patients were full-code, and 8.5% had restrictions on life-sustaining therapies. Overall, 57% (114/200) of patients experienced a code status transition, with a median of two transitions during their illness.

Among patients who died, older age and receipt of non-intensive chemotherapy were associated with earlier discussions about code status.

The next step in the project is to determine if palliative care consults yield earlier discussions and greater patient involvement.

There was no commercial funding for the study, and Dr. Abrams and Dr. Campbell didn’t have any relevant disclosures. Dr. Sekeres is an advisor to Novartis, Takeda, and BMS.

[email protected]

Nearly every patient with a myeloid malignancy seroconverted against COVID-19 after their second dose of the Moderna vaccine in a review of 46 patients at the Moffitt Cancer Center in Tampa, Fla.

Factors including age, gender, race, disease status, lower-intensity active treatment, baseline neutrophil and lymphocyte counts, and past history of stem cell transplant had no effects on seroconversion in the study, which, despite its small numbers, is one of the largest series to date among patients with myeloid cancers. The findings were reported at the annual meeting of the American Society of Hematology.

COVID vaccination “appears to induce a strong antibody response” in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), unlike with B-cell malignancies. “It indicates we should be aggressive about vaccinating such patients,” said senior investigator Jeffrey Lancet, MD, a blood cancer specialist at Moffitt, when he presented the findings at the meeting.

Presentation moderator Laura Michaelis, MD, a hematologist-oncologist at the Medical College of Wisconsin, Milwaukee, agreed.

The “strong antibody response in this group,” coupled with its high risk for severe COVID, “confirm the importance of these patients getting vaccinated,” she said.

Thirty patients with AML and 16 with MDS were included in the review. Most patients were in remission at the time of vaccination, but a third were in active treatment, including six on hypomethylating agents, six on targeted therapies, two on luspatercept, and one on lenalidomide. Thirty-two patients (69.6%) were a median of 17 months past allogeneic stem cell transplant.

Overall, 69.6% of patients developed IgG against spike proteins after the first shot and 95.7% of patients after the second dose, with a large increase in titer levels from the first to the second dose, from a mean of 315 AU/mL to 3,806.5 AU/mL following the second dose.

“Lab and clinical variables did not affect the antibody positivity rate after the second dose,” but patients on steroids and other immunosuppressants seemed less likely to respond to the first shot, Dr. Lancet said.

The study, conducted in early 2021, did not include acutely ill patients or those undergoing cheomotherapy induction and other aggressive treatments, because such patients were not being vaccinated at Moffitt during the study period.

The investigators measured anti-spike IgG by ELISA at baseline, then again about a month after the first shot and a month after the second shot.

Side effects were common and typically mild, including injection site pain, fatigue, headache, and arm swelling. Two patients with AML relapsed after vaccination.

Patients were a median of 68 years old when they were vaccinated; 58.7% were men; and almost all of the subjects were White. The median time from diagnosis to the first shot was 2 years.

The next step in the project is to study the timing of vaccination and response to it among patients on aggressive treatment and to perform neutralizing antibody assays to correlate IgG response with protection from COVID.

No funding was reported for the study. Investigators had numerous industry ties, including Dr. Lancet, a consultant for Celgene/BMS, Millenium Pharma/Takeda, AbbVie, and other firms. Dr. Michaelis didn’t have any disclosures.

[email protected]

Nearly every patient with a myeloid malignancy seroconverted against COVID-19 after their second dose of the Moderna vaccine in a review of 46 patients at the Moffitt Cancer Center in Tampa, Fla.

Factors including age, gender, race, disease status, lower-intensity active treatment, baseline neutrophil and lymphocyte counts, and past history of stem cell transplant had no effects on seroconversion in the study, which, despite its small numbers, is one of the largest series to date among patients with myeloid cancers. The findings were reported at the annual meeting of the American Society of Hematology.

COVID vaccination “appears to induce a strong antibody response” in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), unlike with B-cell malignancies. “It indicates we should be aggressive about vaccinating such patients,” said senior investigator Jeffrey Lancet, MD, a blood cancer specialist at Moffitt, when he presented the findings at the meeting.

Presentation moderator Laura Michaelis, MD, a hematologist-oncologist at the Medical College of Wisconsin, Milwaukee, agreed.

The “strong antibody response in this group,” coupled with its high risk for severe COVID, “confirm the importance of these patients getting vaccinated,” she said.

Thirty patients with AML and 16 with MDS were included in the review. Most patients were in remission at the time of vaccination, but a third were in active treatment, including six on hypomethylating agents, six on targeted therapies, two on luspatercept, and one on lenalidomide. Thirty-two patients (69.6%) were a median of 17 months past allogeneic stem cell transplant.

Overall, 69.6% of patients developed IgG against spike proteins after the first shot and 95.7% of patients after the second dose, with a large increase in titer levels from the first to the second dose, from a mean of 315 AU/mL to 3,806.5 AU/mL following the second dose.

“Lab and clinical variables did not affect the antibody positivity rate after the second dose,” but patients on steroids and other immunosuppressants seemed less likely to respond to the first shot, Dr. Lancet said.

The study, conducted in early 2021, did not include acutely ill patients or those undergoing cheomotherapy induction and other aggressive treatments, because such patients were not being vaccinated at Moffitt during the study period.

The investigators measured anti-spike IgG by ELISA at baseline, then again about a month after the first shot and a month after the second shot.

Side effects were common and typically mild, including injection site pain, fatigue, headache, and arm swelling. Two patients with AML relapsed after vaccination.

Patients were a median of 68 years old when they were vaccinated; 58.7% were men; and almost all of the subjects were White. The median time from diagnosis to the first shot was 2 years.

The next step in the project is to study the timing of vaccination and response to it among patients on aggressive treatment and to perform neutralizing antibody assays to correlate IgG response with protection from COVID.

No funding was reported for the study. Investigators had numerous industry ties, including Dr. Lancet, a consultant for Celgene/BMS, Millenium Pharma/Takeda, AbbVie, and other firms. Dr. Michaelis didn’t have any disclosures.

[email protected]

Nearly every patient with a myeloid malignancy seroconverted against COVID-19 after their second dose of the Moderna vaccine in a review of 46 patients at the Moffitt Cancer Center in Tampa, Fla.

Factors including age, gender, race, disease status, lower-intensity active treatment, baseline neutrophil and lymphocyte counts, and past history of stem cell transplant had no effects on seroconversion in the study, which, despite its small numbers, is one of the largest series to date among patients with myeloid cancers. The findings were reported at the annual meeting of the American Society of Hematology.

COVID vaccination “appears to induce a strong antibody response” in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), unlike with B-cell malignancies. “It indicates we should be aggressive about vaccinating such patients,” said senior investigator Jeffrey Lancet, MD, a blood cancer specialist at Moffitt, when he presented the findings at the meeting.

Presentation moderator Laura Michaelis, MD, a hematologist-oncologist at the Medical College of Wisconsin, Milwaukee, agreed.

The “strong antibody response in this group,” coupled with its high risk for severe COVID, “confirm the importance of these patients getting vaccinated,” she said.

Thirty patients with AML and 16 with MDS were included in the review. Most patients were in remission at the time of vaccination, but a third were in active treatment, including six on hypomethylating agents, six on targeted therapies, two on luspatercept, and one on lenalidomide. Thirty-two patients (69.6%) were a median of 17 months past allogeneic stem cell transplant.

Overall, 69.6% of patients developed IgG against spike proteins after the first shot and 95.7% of patients after the second dose, with a large increase in titer levels from the first to the second dose, from a mean of 315 AU/mL to 3,806.5 AU/mL following the second dose.

“Lab and clinical variables did not affect the antibody positivity rate after the second dose,” but patients on steroids and other immunosuppressants seemed less likely to respond to the first shot, Dr. Lancet said.

The study, conducted in early 2021, did not include acutely ill patients or those undergoing cheomotherapy induction and other aggressive treatments, because such patients were not being vaccinated at Moffitt during the study period.

The investigators measured anti-spike IgG by ELISA at baseline, then again about a month after the first shot and a month after the second shot.

Side effects were common and typically mild, including injection site pain, fatigue, headache, and arm swelling. Two patients with AML relapsed after vaccination.

Patients were a median of 68 years old when they were vaccinated; 58.7% were men; and almost all of the subjects were White. The median time from diagnosis to the first shot was 2 years.

The next step in the project is to study the timing of vaccination and response to it among patients on aggressive treatment and to perform neutralizing antibody assays to correlate IgG response with protection from COVID.

No funding was reported for the study. Investigators had numerous industry ties, including Dr. Lancet, a consultant for Celgene/BMS, Millenium Pharma/Takeda, AbbVie, and other firms. Dr. Michaelis didn’t have any disclosures.

[email protected]

An experimental bi-specific monoclonal antibody known as mosunetuzumab has induced high response rates and long-duration responses as monotherapy for patients with heavily pretreated, relapsed or refractory follicular lymphoma in a phase 2 expansion study.

At a median follow-up of 18.3 months, 54 of 90 patients (60%) had a complete response, and 18 (20%) had a partial response after treatment with mosunetuzumab, reported L. Elizabeth Budde, MD, PhD, from City of Hope Comprehensive Cancer Center in Duarte, Calif.

In contrast, the complete response rate for historical controls was just 14% (P < .0001), Dr. Budde noted.

“We have seen deep and durable responses in heavily pretreated, high-risk relapsed/refractory follicular lymphoma patients with fixed-duration treatment. We also observed a very favorable tolerability profile, with most cytokine release syndrome confined to cycle 1 and low grade, and treatment administration is without mandatory hospitalization,” she commented.

Budde was speaking at a press briefing prior to her presentation of the data at the annual meeting of the American Society of Hematology (ASH), held in a hybrid live/virtual format.

The manufacturer, Genentech, said in a statement that based on these “highly positive results,” it plans to submit the new data to the U.S. Food and Drug Administration (FDA) in the near future for approval consideration.

If approved, mosunetuzumab has the potential to be a first-in-class CD20xCD3 T-cell engaging bispecific antibody in non-Hodgkin lymphoma, the company added.

“Outstanding” data

A lymphoma specialist who was not involved in the study told this news organization that he was favorably impressed by the findings.

“To me, the single-agent data looks really outstanding, with a response rate of 80%, a complete response rate of 60%, and a median duration of response of 23 months, and really very acceptable rates of cytokine release syndrome,” commented Brad S. Kahl, MD, from the Siteman Cancer Center and Washington University School of Medicine in St. Louis.

“I think as a single agent — if it does get approval — it will be a really valuable addition to the armamentarium in follicular lymphoma,” he said.

Dr. Kahl pointed to a separate phase 1b study, also presented at the meeting, suggesting that the combination of mosunetuzumab and lenalidomide (Revlimid) was safe and showed promising antitumor activity in patients with follicular lymphoma that has relapsed after at least 1 line of therapy.

“I’m very interested to see how mosunetuzumab plus lenalidomide pans out in the long run,” he said.

Study details

Mosunetuzumab engages T cells and redirects them to eliminate malignant B cells. It has the potential to be used as an off-the-shelf product, Dr. Budde said.

In the single-arm phase 2 expansion trial, Dr. Budde and colleagues enrolled 90 patients with grades 1 to 3a follicular lymphoma whose disease relapsed or was refractory to at least two prior lines of therapy, including at least one anti-CD20 monoclonal antibody, and at least one alkylating agent.

Patients were treated with step-up dosing for the first 21-day cycle to mitigate the cytokine release syndrome. They then received eight cycles if they had a complete response, and 17 cycles if they had a partial response or stable disease after eight cycles.

The primary endpoint was complete response rate by independent review, which was 60%, and the overall response rate (ORR), a secondary efficacy endpoint, was 80%.

There were no significant differences in CR or ORR rates among subgroups according to patient age, number of prior lines of therapy, relapsed or refractory disease to last prior line of therapy, double-refractory disease, or disease progression within 24 months of primary therapy.

The median duration of response among all responders was 22.8 months, with a median time to first response of 1.4 months. The 12- and 18-months event-free rates were 62% and 57%, respectively.

The safety profile was manageable, Dr. Budde said, with grade 3 or 4 drug-related adverse events occurring in about half of patients, and serious adverse events occurring in a third.

There were two deaths during the study, but neither was judged to be related to mosunetuzumab, and there were only two events leading to drug discontinuation.

Cytokine release syndrome (CRS) of any grade occurred in 40 patients (44.4%), but only 1 patient each had a grade 3 or 4 CR. The median time to CRS onset was 5.2 hours in cycle 1, and 26.6 hours in subsequent cycles. The median duration of CRS was 3 days. Ten patients had CRS managed with corticosteroids, and seven had it managed with tocilizumab.

Immune effector cell-associated neurotoxicity syndrome (ICANS) events were infrequent, and all were grade 1 or 2 in severity.

The study was supported by Genentech. Dr. Budde disclosed consulting for the company and others. Dr. Kahl has previously disclosed financial considerations with AbbVie.



A version of this article first appeared on Medscape.com.

This article was updated 12/12/21.

An experimental bi-specific monoclonal antibody known as mosunetuzumab has induced high response rates and long-duration responses as monotherapy for patients with heavily pretreated, relapsed or refractory follicular lymphoma in a phase 2 expansion study.

At a median follow-up of 18.3 months, 54 of 90 patients (60%) had a complete response, and 18 (20%) had a partial response after treatment with mosunetuzumab, reported L. Elizabeth Budde, MD, PhD, from City of Hope Comprehensive Cancer Center in Duarte, Calif.

In contrast, the complete response rate for historical controls was just 14% (P < .0001), Dr. Budde noted.

“We have seen deep and durable responses in heavily pretreated, high-risk relapsed/refractory follicular lymphoma patients with fixed-duration treatment. We also observed a very favorable tolerability profile, with most cytokine release syndrome confined to cycle 1 and low grade, and treatment administration is without mandatory hospitalization,” she commented.

Budde was speaking at a press briefing prior to her presentation of the data at the annual meeting of the American Society of Hematology (ASH), held in a hybrid live/virtual format.

The manufacturer, Genentech, said in a statement that based on these “highly positive results,” it plans to submit the new data to the U.S. Food and Drug Administration (FDA) in the near future for approval consideration.

If approved, mosunetuzumab has the potential to be a first-in-class CD20xCD3 T-cell engaging bispecific antibody in non-Hodgkin lymphoma, the company added.

“Outstanding” data

A lymphoma specialist who was not involved in the study told this news organization that he was favorably impressed by the findings.

“To me, the single-agent data looks really outstanding, with a response rate of 80%, a complete response rate of 60%, and a median duration of response of 23 months, and really very acceptable rates of cytokine release syndrome,” commented Brad S. Kahl, MD, from the Siteman Cancer Center and Washington University School of Medicine in St. Louis.

“I think as a single agent — if it does get approval — it will be a really valuable addition to the armamentarium in follicular lymphoma,” he said.

Dr. Kahl pointed to a separate phase 1b study, also presented at the meeting, suggesting that the combination of mosunetuzumab and lenalidomide (Revlimid) was safe and showed promising antitumor activity in patients with follicular lymphoma that has relapsed after at least 1 line of therapy.

“I’m very interested to see how mosunetuzumab plus lenalidomide pans out in the long run,” he said.

Study details

Mosunetuzumab engages T cells and redirects them to eliminate malignant B cells. It has the potential to be used as an off-the-shelf product, Dr. Budde said.

In the single-arm phase 2 expansion trial, Dr. Budde and colleagues enrolled 90 patients with grades 1 to 3a follicular lymphoma whose disease relapsed or was refractory to at least two prior lines of therapy, including at least one anti-CD20 monoclonal antibody, and at least one alkylating agent.

Patients were treated with step-up dosing for the first 21-day cycle to mitigate the cytokine release syndrome. They then received eight cycles if they had a complete response, and 17 cycles if they had a partial response or stable disease after eight cycles.

The primary endpoint was complete response rate by independent review, which was 60%, and the overall response rate (ORR), a secondary efficacy endpoint, was 80%.

There were no significant differences in CR or ORR rates among subgroups according to patient age, number of prior lines of therapy, relapsed or refractory disease to last prior line of therapy, double-refractory disease, or disease progression within 24 months of primary therapy.

The median duration of response among all responders was 22.8 months, with a median time to first response of 1.4 months. The 12- and 18-months event-free rates were 62% and 57%, respectively.

The safety profile was manageable, Dr. Budde said, with grade 3 or 4 drug-related adverse events occurring in about half of patients, and serious adverse events occurring in a third.

There were two deaths during the study, but neither was judged to be related to mosunetuzumab, and there were only two events leading to drug discontinuation.

Cytokine release syndrome (CRS) of any grade occurred in 40 patients (44.4%), but only 1 patient each had a grade 3 or 4 CR. The median time to CRS onset was 5.2 hours in cycle 1, and 26.6 hours in subsequent cycles. The median duration of CRS was 3 days. Ten patients had CRS managed with corticosteroids, and seven had it managed with tocilizumab.

Immune effector cell-associated neurotoxicity syndrome (ICANS) events were infrequent, and all were grade 1 or 2 in severity.

The study was supported by Genentech. Dr. Budde disclosed consulting for the company and others. Dr. Kahl has previously disclosed financial considerations with AbbVie.



A version of this article first appeared on Medscape.com.

This article was updated 12/12/21.

An experimental bi-specific monoclonal antibody known as mosunetuzumab has induced high response rates and long-duration responses as monotherapy for patients with heavily pretreated, relapsed or refractory follicular lymphoma in a phase 2 expansion study.

At a median follow-up of 18.3 months, 54 of 90 patients (60%) had a complete response, and 18 (20%) had a partial response after treatment with mosunetuzumab, reported L. Elizabeth Budde, MD, PhD, from City of Hope Comprehensive Cancer Center in Duarte, Calif.

In contrast, the complete response rate for historical controls was just 14% (P < .0001), Dr. Budde noted.

“We have seen deep and durable responses in heavily pretreated, high-risk relapsed/refractory follicular lymphoma patients with fixed-duration treatment. We also observed a very favorable tolerability profile, with most cytokine release syndrome confined to cycle 1 and low grade, and treatment administration is without mandatory hospitalization,” she commented.

Budde was speaking at a press briefing prior to her presentation of the data at the annual meeting of the American Society of Hematology (ASH), held in a hybrid live/virtual format.

The manufacturer, Genentech, said in a statement that based on these “highly positive results,” it plans to submit the new data to the U.S. Food and Drug Administration (FDA) in the near future for approval consideration.

If approved, mosunetuzumab has the potential to be a first-in-class CD20xCD3 T-cell engaging bispecific antibody in non-Hodgkin lymphoma, the company added.

“Outstanding” data

A lymphoma specialist who was not involved in the study told this news organization that he was favorably impressed by the findings.

“To me, the single-agent data looks really outstanding, with a response rate of 80%, a complete response rate of 60%, and a median duration of response of 23 months, and really very acceptable rates of cytokine release syndrome,” commented Brad S. Kahl, MD, from the Siteman Cancer Center and Washington University School of Medicine in St. Louis.

“I think as a single agent — if it does get approval — it will be a really valuable addition to the armamentarium in follicular lymphoma,” he said.

Dr. Kahl pointed to a separate phase 1b study, also presented at the meeting, suggesting that the combination of mosunetuzumab and lenalidomide (Revlimid) was safe and showed promising antitumor activity in patients with follicular lymphoma that has relapsed after at least 1 line of therapy.

“I’m very interested to see how mosunetuzumab plus lenalidomide pans out in the long run,” he said.

Study details

Mosunetuzumab engages T cells and redirects them to eliminate malignant B cells. It has the potential to be used as an off-the-shelf product, Dr. Budde said.

In the single-arm phase 2 expansion trial, Dr. Budde and colleagues enrolled 90 patients with grades 1 to 3a follicular lymphoma whose disease relapsed or was refractory to at least two prior lines of therapy, including at least one anti-CD20 monoclonal antibody, and at least one alkylating agent.

Patients were treated with step-up dosing for the first 21-day cycle to mitigate the cytokine release syndrome. They then received eight cycles if they had a complete response, and 17 cycles if they had a partial response or stable disease after eight cycles.

The primary endpoint was complete response rate by independent review, which was 60%, and the overall response rate (ORR), a secondary efficacy endpoint, was 80%.

There were no significant differences in CR or ORR rates among subgroups according to patient age, number of prior lines of therapy, relapsed or refractory disease to last prior line of therapy, double-refractory disease, or disease progression within 24 months of primary therapy.

The median duration of response among all responders was 22.8 months, with a median time to first response of 1.4 months. The 12- and 18-months event-free rates were 62% and 57%, respectively.

The safety profile was manageable, Dr. Budde said, with grade 3 or 4 drug-related adverse events occurring in about half of patients, and serious adverse events occurring in a third.

There were two deaths during the study, but neither was judged to be related to mosunetuzumab, and there were only two events leading to drug discontinuation.

Cytokine release syndrome (CRS) of any grade occurred in 40 patients (44.4%), but only 1 patient each had a grade 3 or 4 CR. The median time to CRS onset was 5.2 hours in cycle 1, and 26.6 hours in subsequent cycles. The median duration of CRS was 3 days. Ten patients had CRS managed with corticosteroids, and seven had it managed with tocilizumab.

Immune effector cell-associated neurotoxicity syndrome (ICANS) events were infrequent, and all were grade 1 or 2 in severity.

The study was supported by Genentech. Dr. Budde disclosed consulting for the company and others. Dr. Kahl has previously disclosed financial considerations with AbbVie.



A version of this article first appeared on Medscape.com.

This article was updated 12/12/21.

Factors associated with the worst COVID-19-related outcomes for patients with acute leukemias and myelodysplastic syndromes include neutropenia, pre-COVID-19 prognosis, and deferral of ICU care, results of an American Society of Hematology (ASH) COVID-19 registry study suggest.

Rates of severe COVID-19 were significantly higher among patients who had active disease or neutropenia at the time of their COVID-19 diagnosis. Mortality related to COVID-19 was linked to neutropenia, primary disease prognosis of less than 6 months, and deferral of recommended ICU care, study results show.

By contrast, mortality was not associated with active primary disease or its treatment, according to researcher Pinkal Desai, MD, MPH.

Taken together, these findings provide preliminary evidence to support the use of aggressive supportive treatment of COVID-19 in patients with acute leukemias and myelodysplastic syndromes, said Dr. Desai, a hematologist-oncologist with Weill Cornell Medicine and NewYork-Presbyterian in New York.

“If desired by patients, aggressive support for hospitalized patients with COVID-19 is appropriate, regardless of remission status, given the results of our study,” Dr. Desai said in a press conference during the annual meeting of the American Society of Hematology.

In non-cancer patient populations, advanced age and cytopenias have been associated with mortality related to COVID-19, Dr. Desai said. Likewise, patients with acute leukemias and myelodysplastic syndrome are generally older and have disease- or treatment-related cytopenias, which might affect the severity of and mortality from COVID-19, she added.

With that concern in mind, Dr. Desai and co-investigators looked at predictors of severe COVID-19 disease and death among patients in the ASH Research Collaborative (ASH RC) COVID-19 Registry for Hematology.

This registry was started in the early days of the pandemic to provide real-time observational COVID-19 data to clinicians, according to an ASH news release.

The analysis by Dr. Desai and co-authors included 257 patients with COVID-19 as determined by their physician, including 135 with a primary diagnosis of acute myeloid leukemia, 82 with acute lymphocytic leukemia, and 40 with myelodysplastic syndromes. Sixty percent of the patients were hospitalized due to COVID-19.

At the time of COVID-19 diagnosis, 46% of patients were in remission, and 44% had active disease, according to the report.

Both neutropenia and active disease status at COVID-19 diagnosis were linked to severe COVID-19, defined as ICU admission due to a COVID-19-related reason, according to results of multivariable analysis. Among patients with severe COVID-19, 67% had active disease, meaning just 33% were in remission, Dr. Desai noted.

In multivariable analysis, two factors were significantly associated with mortality, she added: having an estimated pre-COVID-19 prognosis from the primary disease of less than 6 months, and deferral of ICU care when it was recommended to the patient.

Mortality was 21% overall, higher than would be expected in a non-cancer population, Dr. Desai said. For patients with COVID-19 requiring hospitalization, the mortality rate was 34% and for those patients who did go to the ICU, the mortality rate was 68%.

By contrast, there was no significant association between mortality and active disease as compared to disease in remission, Dr. Desai noted in her presentation. Likewise, mortality was not associated with active treatment at the time of COVID-19 diagnosis as compared to no treatment.

The Leukemia &amp; Lymphoma Society

Gwen Nichols, MD, executive vice president and chief medical officer of the Leukemia & Lymphoma Society, New York, said those are reassuring data for patients with acute leukemias and myelodysplastic syndromes and their healthcare providers.

“From our point of view, it helps us say, ‘do not stop your treatment because of worries about COVID-19—it’s more important that you treat your cancer,” Dr. Nichols said in an interview. “We now know we can help people through COVID-19, and I think this is just really important data to back that up,” she added.

Dr. Desai provided disclosures related to Agios, Kura Oncology, and Bristol Myers Squibb (consultancy), and to Janssen R&D and Astex (research funding).

Factors associated with the worst COVID-19-related outcomes for patients with acute leukemias and myelodysplastic syndromes include neutropenia, pre-COVID-19 prognosis, and deferral of ICU care, results of an American Society of Hematology (ASH) COVID-19 registry study suggest.

Rates of severe COVID-19 were significantly higher among patients who had active disease or neutropenia at the time of their COVID-19 diagnosis. Mortality related to COVID-19 was linked to neutropenia, primary disease prognosis of less than 6 months, and deferral of recommended ICU care, study results show.

By contrast, mortality was not associated with active primary disease or its treatment, according to researcher Pinkal Desai, MD, MPH.

Taken together, these findings provide preliminary evidence to support the use of aggressive supportive treatment of COVID-19 in patients with acute leukemias and myelodysplastic syndromes, said Dr. Desai, a hematologist-oncologist with Weill Cornell Medicine and NewYork-Presbyterian in New York.

“If desired by patients, aggressive support for hospitalized patients with COVID-19 is appropriate, regardless of remission status, given the results of our study,” Dr. Desai said in a press conference during the annual meeting of the American Society of Hematology.

In non-cancer patient populations, advanced age and cytopenias have been associated with mortality related to COVID-19, Dr. Desai said. Likewise, patients with acute leukemias and myelodysplastic syndrome are generally older and have disease- or treatment-related cytopenias, which might affect the severity of and mortality from COVID-19, she added.

With that concern in mind, Dr. Desai and co-investigators looked at predictors of severe COVID-19 disease and death among patients in the ASH Research Collaborative (ASH RC) COVID-19 Registry for Hematology.

This registry was started in the early days of the pandemic to provide real-time observational COVID-19 data to clinicians, according to an ASH news release.

The analysis by Dr. Desai and co-authors included 257 patients with COVID-19 as determined by their physician, including 135 with a primary diagnosis of acute myeloid leukemia, 82 with acute lymphocytic leukemia, and 40 with myelodysplastic syndromes. Sixty percent of the patients were hospitalized due to COVID-19.

At the time of COVID-19 diagnosis, 46% of patients were in remission, and 44% had active disease, according to the report.

Both neutropenia and active disease status at COVID-19 diagnosis were linked to severe COVID-19, defined as ICU admission due to a COVID-19-related reason, according to results of multivariable analysis. Among patients with severe COVID-19, 67% had active disease, meaning just 33% were in remission, Dr. Desai noted.

In multivariable analysis, two factors were significantly associated with mortality, she added: having an estimated pre-COVID-19 prognosis from the primary disease of less than 6 months, and deferral of ICU care when it was recommended to the patient.

Mortality was 21% overall, higher than would be expected in a non-cancer population, Dr. Desai said. For patients with COVID-19 requiring hospitalization, the mortality rate was 34% and for those patients who did go to the ICU, the mortality rate was 68%.

By contrast, there was no significant association between mortality and active disease as compared to disease in remission, Dr. Desai noted in her presentation. Likewise, mortality was not associated with active treatment at the time of COVID-19 diagnosis as compared to no treatment.

The Leukemia &amp; Lymphoma Society

Gwen Nichols, MD, executive vice president and chief medical officer of the Leukemia & Lymphoma Society, New York, said those are reassuring data for patients with acute leukemias and myelodysplastic syndromes and their healthcare providers.

“From our point of view, it helps us say, ‘do not stop your treatment because of worries about COVID-19—it’s more important that you treat your cancer,” Dr. Nichols said in an interview. “We now know we can help people through COVID-19, and I think this is just really important data to back that up,” she added.

Dr. Desai provided disclosures related to Agios, Kura Oncology, and Bristol Myers Squibb (consultancy), and to Janssen R&D and Astex (research funding).

Factors associated with the worst COVID-19-related outcomes for patients with acute leukemias and myelodysplastic syndromes include neutropenia, pre-COVID-19 prognosis, and deferral of ICU care, results of an American Society of Hematology (ASH) COVID-19 registry study suggest.

Rates of severe COVID-19 were significantly higher among patients who had active disease or neutropenia at the time of their COVID-19 diagnosis. Mortality related to COVID-19 was linked to neutropenia, primary disease prognosis of less than 6 months, and deferral of recommended ICU care, study results show.

By contrast, mortality was not associated with active primary disease or its treatment, according to researcher Pinkal Desai, MD, MPH.

Taken together, these findings provide preliminary evidence to support the use of aggressive supportive treatment of COVID-19 in patients with acute leukemias and myelodysplastic syndromes, said Dr. Desai, a hematologist-oncologist with Weill Cornell Medicine and NewYork-Presbyterian in New York.

“If desired by patients, aggressive support for hospitalized patients with COVID-19 is appropriate, regardless of remission status, given the results of our study,” Dr. Desai said in a press conference during the annual meeting of the American Society of Hematology.

In non-cancer patient populations, advanced age and cytopenias have been associated with mortality related to COVID-19, Dr. Desai said. Likewise, patients with acute leukemias and myelodysplastic syndrome are generally older and have disease- or treatment-related cytopenias, which might affect the severity of and mortality from COVID-19, she added.

With that concern in mind, Dr. Desai and co-investigators looked at predictors of severe COVID-19 disease and death among patients in the ASH Research Collaborative (ASH RC) COVID-19 Registry for Hematology.

This registry was started in the early days of the pandemic to provide real-time observational COVID-19 data to clinicians, according to an ASH news release.

The analysis by Dr. Desai and co-authors included 257 patients with COVID-19 as determined by their physician, including 135 with a primary diagnosis of acute myeloid leukemia, 82 with acute lymphocytic leukemia, and 40 with myelodysplastic syndromes. Sixty percent of the patients were hospitalized due to COVID-19.

At the time of COVID-19 diagnosis, 46% of patients were in remission, and 44% had active disease, according to the report.

Both neutropenia and active disease status at COVID-19 diagnosis were linked to severe COVID-19, defined as ICU admission due to a COVID-19-related reason, according to results of multivariable analysis. Among patients with severe COVID-19, 67% had active disease, meaning just 33% were in remission, Dr. Desai noted.

In multivariable analysis, two factors were significantly associated with mortality, she added: having an estimated pre-COVID-19 prognosis from the primary disease of less than 6 months, and deferral of ICU care when it was recommended to the patient.

Mortality was 21% overall, higher than would be expected in a non-cancer population, Dr. Desai said. For patients with COVID-19 requiring hospitalization, the mortality rate was 34% and for those patients who did go to the ICU, the mortality rate was 68%.

By contrast, there was no significant association between mortality and active disease as compared to disease in remission, Dr. Desai noted in her presentation. Likewise, mortality was not associated with active treatment at the time of COVID-19 diagnosis as compared to no treatment.

The Leukemia &amp; Lymphoma Society

Gwen Nichols, MD, executive vice president and chief medical officer of the Leukemia & Lymphoma Society, New York, said those are reassuring data for patients with acute leukemias and myelodysplastic syndromes and their healthcare providers.

“From our point of view, it helps us say, ‘do not stop your treatment because of worries about COVID-19—it’s more important that you treat your cancer,” Dr. Nichols said in an interview. “We now know we can help people through COVID-19, and I think this is just really important data to back that up,” she added.

Dr. Desai provided disclosures related to Agios, Kura Oncology, and Bristol Myers Squibb (consultancy), and to Janssen R&D and Astex (research funding).

In patients with transfusion-dependent beta-thalassemia, a single gene therapy infusion is capable of yielding durable transfusion independence and substantial improvements in iron overload, an investigator reported at the annual meeting of the American Society of Hematology.

Among patients who received betibeglogene autotemcel (beti-cel) in a phase 3 trial and enrolled in a long-term follow-up study, nearly 90% achieved durable transfusion independence, according to Alexis A. Thompson, MD, MPH, of the hematology section at the Ann & Robert H. Lurie Children’s Hospital of Chicago.

The median duration of ongoing transfusion independence was nearly 3 years as of this report, which Dr. Thompson described in a press conference at the meeting.

In a subanalysis of this international study, Dr. Thompson and co-investigators reported that in patients who achieve transfusion independence, chelation reduced iron, and iron markers stabilized even after chelation was stopped.

Beyond 2 years post-infusion, no adverse events related to the drug product were seen. This suggested that the therapy has a favorable long-term safety profile, according to Dr. Thompson.

“At this point, we believe that beti-cel is potentially curative for patients with TDT [transfusion-dependent beta-thalassemia],” Dr. Thompson said in the press conference.

This study answers one of the major outstanding questions about beti-cel and iron metabolism, according to Arielle L. Langer, MD, MPH, an instructor in medicine at Harvard Medical School and attending physician for adult thalassemia patients at Brigham and Women’s and Dana Farber Cancer Institute, both in Boston.

“Seeing the restoration of iron metabolism, it really takes us a step closer to really thinking the term ‘cure’ might truly apply,” Dr. Langer said in an interview.

Dr. Langer said she looks forward to “very long-term outcomes” of beti-cel-treated patients to see whether endocrinopathies and other long-term sequelae of TDT are also abated.

“This [study] is a great intermediate point, but really, when we think about how thalassemia harms and kills our patients, we really sometimes measure that in decades,” she said.

Beta-thalassemia is caused by mutations in the beta-globin gene, resulting in reduced levels of hemoglobin. Patients with TDT, the most serious form of the disease, have severe anemia and are often dependent on red blood cell transfusions from infancy onward, Dr. Thompson said.

With chronic transfusions needed to maintain hemoglobin levels, TDT patients inevitably experience iron overload, which can lead to organ damage and can be fatal. Consequently, patients will require lifelong iron chelation therapy, she added.

Beti-cel, an investigational ex vivo gene addition therapy currently under review by the U.S. Food and Drug Administration, involves adding functional copies of a modified form of the beta-globin gene into a patient’s own hematopoietic stem cells. Once those cells are reinfused, patients may produce adult hemoglobin at levels that eliminate the need for transfusions, according to Dr. Thompson.

At the meeting, Dr. Thompson reported on patients from two phase 1/2 and two phase 3 beti-cel clinical trials who subsequently enrolled in LTF-303, a 13-year follow-up study of the gene therapy’s safety and efficacy.

A total of 57 patients were included in this report, making it the largest gene therapy program to date in any blood disorder, according to Dr. Thompson. Before receiving beti-cel, the patients, who had a broad range of thalassemia genotypes, were receiving between 10 and almost 40 red blood cell transfusions per year, she reported.

Patients ranged in age from 5 to 35 years. The median age in the phase 1/2 studies was 20 years, while in the phase 3 studies it was 15 years.

“The early experience in the phase 1/2 trials allowed us to be more comfortable with enrolling more children, and that has actually helped us to understand safety and efficacy and children in the phase 3 setting,” Dr. Thompson said.

Fertility preservation measures had been undertaken by about 59% of patients from the phase 1/2 studies and 71% of patients from the phase 3 studies, the data show.

Among patients from the phase 3 beti-cel studies who could be evaluated, 31 out of 35 (or 89%) achieved durable transfusion independence, according to the investigator.

The median duration of ongoing transfusion independence was 32 months, with a range of about 18 to 49 months, she added.

Dr. Thompson also reported a subanalysis intended to assess iron status in 16 patients who restarted and then stopped chelation. That subanalysis demonstrated iron reduction in response to chelation, and then stabilization of iron markers after chelation was stopped. Post-gene therapy chelation led to reductions in liver iron concentration and serum ferritin that remained relatively stable after chelation was stopped, she said.

Serious adverse events occurred in eight patients in the long-term follow-up study. However, adverse events related to beti-cel have been absent beyond 2 years post-infusion, according to Dr. Thompson, who added that there have been no reported cases of replication-competent lentivirus, no clonal expansion, no insertional oncogenesis, and no malignancies observed.

“Very reassuringly, there have been 2 male patients, one of whom underwent fertility preservation, who report having healthy children with their partners,” she added.

Dr. Thompson provided disclosures related to Baxalta, Biomarin, bluebird bio, Inc., Celgene/BMS, CRISPR Therapeutics, Vertex, Editas, Graphite Bio, Novartis, Agios, Beam, and Global Blood Therapeutics.
 

In patients with transfusion-dependent beta-thalassemia, a single gene therapy infusion is capable of yielding durable transfusion independence and substantial improvements in iron overload, an investigator reported at the annual meeting of the American Society of Hematology.

Among patients who received betibeglogene autotemcel (beti-cel) in a phase 3 trial and enrolled in a long-term follow-up study, nearly 90% achieved durable transfusion independence, according to Alexis A. Thompson, MD, MPH, of the hematology section at the Ann & Robert H. Lurie Children’s Hospital of Chicago.

The median duration of ongoing transfusion independence was nearly 3 years as of this report, which Dr. Thompson described in a press conference at the meeting.

In a subanalysis of this international study, Dr. Thompson and co-investigators reported that in patients who achieve transfusion independence, chelation reduced iron, and iron markers stabilized even after chelation was stopped.

Beyond 2 years post-infusion, no adverse events related to the drug product were seen. This suggested that the therapy has a favorable long-term safety profile, according to Dr. Thompson.

“At this point, we believe that beti-cel is potentially curative for patients with TDT [transfusion-dependent beta-thalassemia],” Dr. Thompson said in the press conference.

This study answers one of the major outstanding questions about beti-cel and iron metabolism, according to Arielle L. Langer, MD, MPH, an instructor in medicine at Harvard Medical School and attending physician for adult thalassemia patients at Brigham and Women’s and Dana Farber Cancer Institute, both in Boston.

“Seeing the restoration of iron metabolism, it really takes us a step closer to really thinking the term ‘cure’ might truly apply,” Dr. Langer said in an interview.

Dr. Langer said she looks forward to “very long-term outcomes” of beti-cel-treated patients to see whether endocrinopathies and other long-term sequelae of TDT are also abated.

“This [study] is a great intermediate point, but really, when we think about how thalassemia harms and kills our patients, we really sometimes measure that in decades,” she said.

Beta-thalassemia is caused by mutations in the beta-globin gene, resulting in reduced levels of hemoglobin. Patients with TDT, the most serious form of the disease, have severe anemia and are often dependent on red blood cell transfusions from infancy onward, Dr. Thompson said.

With chronic transfusions needed to maintain hemoglobin levels, TDT patients inevitably experience iron overload, which can lead to organ damage and can be fatal. Consequently, patients will require lifelong iron chelation therapy, she added.

Beti-cel, an investigational ex vivo gene addition therapy currently under review by the U.S. Food and Drug Administration, involves adding functional copies of a modified form of the beta-globin gene into a patient’s own hematopoietic stem cells. Once those cells are reinfused, patients may produce adult hemoglobin at levels that eliminate the need for transfusions, according to Dr. Thompson.

At the meeting, Dr. Thompson reported on patients from two phase 1/2 and two phase 3 beti-cel clinical trials who subsequently enrolled in LTF-303, a 13-year follow-up study of the gene therapy’s safety and efficacy.

A total of 57 patients were included in this report, making it the largest gene therapy program to date in any blood disorder, according to Dr. Thompson. Before receiving beti-cel, the patients, who had a broad range of thalassemia genotypes, were receiving between 10 and almost 40 red blood cell transfusions per year, she reported.

Patients ranged in age from 5 to 35 years. The median age in the phase 1/2 studies was 20 years, while in the phase 3 studies it was 15 years.

“The early experience in the phase 1/2 trials allowed us to be more comfortable with enrolling more children, and that has actually helped us to understand safety and efficacy and children in the phase 3 setting,” Dr. Thompson said.

Fertility preservation measures had been undertaken by about 59% of patients from the phase 1/2 studies and 71% of patients from the phase 3 studies, the data show.

Among patients from the phase 3 beti-cel studies who could be evaluated, 31 out of 35 (or 89%) achieved durable transfusion independence, according to the investigator.

The median duration of ongoing transfusion independence was 32 months, with a range of about 18 to 49 months, she added.

Dr. Thompson also reported a subanalysis intended to assess iron status in 16 patients who restarted and then stopped chelation. That subanalysis demonstrated iron reduction in response to chelation, and then stabilization of iron markers after chelation was stopped. Post-gene therapy chelation led to reductions in liver iron concentration and serum ferritin that remained relatively stable after chelation was stopped, she said.

Serious adverse events occurred in eight patients in the long-term follow-up study. However, adverse events related to beti-cel have been absent beyond 2 years post-infusion, according to Dr. Thompson, who added that there have been no reported cases of replication-competent lentivirus, no clonal expansion, no insertional oncogenesis, and no malignancies observed.

“Very reassuringly, there have been 2 male patients, one of whom underwent fertility preservation, who report having healthy children with their partners,” she added.

Dr. Thompson provided disclosures related to Baxalta, Biomarin, bluebird bio, Inc., Celgene/BMS, CRISPR Therapeutics, Vertex, Editas, Graphite Bio, Novartis, Agios, Beam, and Global Blood Therapeutics.
 

In patients with transfusion-dependent beta-thalassemia, a single gene therapy infusion is capable of yielding durable transfusion independence and substantial improvements in iron overload, an investigator reported at the annual meeting of the American Society of Hematology.

Among patients who received betibeglogene autotemcel (beti-cel) in a phase 3 trial and enrolled in a long-term follow-up study, nearly 90% achieved durable transfusion independence, according to Alexis A. Thompson, MD, MPH, of the hematology section at the Ann & Robert H. Lurie Children’s Hospital of Chicago.

The median duration of ongoing transfusion independence was nearly 3 years as of this report, which Dr. Thompson described in a press conference at the meeting.

In a subanalysis of this international study, Dr. Thompson and co-investigators reported that in patients who achieve transfusion independence, chelation reduced iron, and iron markers stabilized even after chelation was stopped.

Beyond 2 years post-infusion, no adverse events related to the drug product were seen. This suggested that the therapy has a favorable long-term safety profile, according to Dr. Thompson.

“At this point, we believe that beti-cel is potentially curative for patients with TDT [transfusion-dependent beta-thalassemia],” Dr. Thompson said in the press conference.

This study answers one of the major outstanding questions about beti-cel and iron metabolism, according to Arielle L. Langer, MD, MPH, an instructor in medicine at Harvard Medical School and attending physician for adult thalassemia patients at Brigham and Women’s and Dana Farber Cancer Institute, both in Boston.

“Seeing the restoration of iron metabolism, it really takes us a step closer to really thinking the term ‘cure’ might truly apply,” Dr. Langer said in an interview.

Dr. Langer said she looks forward to “very long-term outcomes” of beti-cel-treated patients to see whether endocrinopathies and other long-term sequelae of TDT are also abated.

“This [study] is a great intermediate point, but really, when we think about how thalassemia harms and kills our patients, we really sometimes measure that in decades,” she said.

Beta-thalassemia is caused by mutations in the beta-globin gene, resulting in reduced levels of hemoglobin. Patients with TDT, the most serious form of the disease, have severe anemia and are often dependent on red blood cell transfusions from infancy onward, Dr. Thompson said.

With chronic transfusions needed to maintain hemoglobin levels, TDT patients inevitably experience iron overload, which can lead to organ damage and can be fatal. Consequently, patients will require lifelong iron chelation therapy, she added.

Beti-cel, an investigational ex vivo gene addition therapy currently under review by the U.S. Food and Drug Administration, involves adding functional copies of a modified form of the beta-globin gene into a patient’s own hematopoietic stem cells. Once those cells are reinfused, patients may produce adult hemoglobin at levels that eliminate the need for transfusions, according to Dr. Thompson.

At the meeting, Dr. Thompson reported on patients from two phase 1/2 and two phase 3 beti-cel clinical trials who subsequently enrolled in LTF-303, a 13-year follow-up study of the gene therapy’s safety and efficacy.

A total of 57 patients were included in this report, making it the largest gene therapy program to date in any blood disorder, according to Dr. Thompson. Before receiving beti-cel, the patients, who had a broad range of thalassemia genotypes, were receiving between 10 and almost 40 red blood cell transfusions per year, she reported.

Patients ranged in age from 5 to 35 years. The median age in the phase 1/2 studies was 20 years, while in the phase 3 studies it was 15 years.

“The early experience in the phase 1/2 trials allowed us to be more comfortable with enrolling more children, and that has actually helped us to understand safety and efficacy and children in the phase 3 setting,” Dr. Thompson said.

Fertility preservation measures had been undertaken by about 59% of patients from the phase 1/2 studies and 71% of patients from the phase 3 studies, the data show.

Among patients from the phase 3 beti-cel studies who could be evaluated, 31 out of 35 (or 89%) achieved durable transfusion independence, according to the investigator.

The median duration of ongoing transfusion independence was 32 months, with a range of about 18 to 49 months, she added.

Dr. Thompson also reported a subanalysis intended to assess iron status in 16 patients who restarted and then stopped chelation. That subanalysis demonstrated iron reduction in response to chelation, and then stabilization of iron markers after chelation was stopped. Post-gene therapy chelation led to reductions in liver iron concentration and serum ferritin that remained relatively stable after chelation was stopped, she said.

Serious adverse events occurred in eight patients in the long-term follow-up study. However, adverse events related to beti-cel have been absent beyond 2 years post-infusion, according to Dr. Thompson, who added that there have been no reported cases of replication-competent lentivirus, no clonal expansion, no insertional oncogenesis, and no malignancies observed.

“Very reassuringly, there have been 2 male patients, one of whom underwent fertility preservation, who report having healthy children with their partners,” she added.

Dr. Thompson provided disclosures related to Baxalta, Biomarin, bluebird bio, Inc., Celgene/BMS, CRISPR Therapeutics, Vertex, Editas, Graphite Bio, Novartis, Agios, Beam, and Global Blood Therapeutics.
 

ATLANTA — Chimeric antigen receptor (CAR) T-cell therapy has the potential to replace chemoimmunotherapy for second-line treatment of patients with large B-cell lymphoma (LBCL) that have relapsed or are refractory to first-line therapy, results of the phase 3 ZUMA-7 and TRANSFORM trials suggest.

Meletios Verras/Shutterstock

In the ZUMA-7 trial, at a median follow-up of 24.9 months, patients randomly assigned to receive CAR T-cell therapy with axicabtagene ciloleucel, or axi-cell (Yescarta) had a median event-free survival (EFS) of 8.3 months, compared with 2 months for patients randomly assigned to standard-of-care chemoimmunotherapy, reported Frederick L. Locke, MD, from the Moffitt Cancer Center in Tampa, Fla.

In TRANSFORM, comparing the CAR T construct lisocabtagene maraleucel, or liso-cel (Breyanzi) with standard-of-care second-line chemotherapy, median EFS was 10.1 months with liso-cel, compared with 2.3 months with standard of care, reported Manali Kamdar, MD, from the University of Colorado Cancer Center in Aurora.

The trials differed slightly in eligibility criteria and other details, but their overall results show great promise for improving second-line therapy for patients with relapsed or refractory LBCL, commented Laurie Sehn, MD, MPH, from the BC Cancer Centre for Lymphoid Cancer in Vancouver, Canada.

“It’s really remarkable that the results are so far in favor of the CAR T-cell therapy that I think it’s inevitable that this will become the standard of care,” Dr. Sehn commented. She was not an investigator in either of the two trials.

Dr. Sehn was speaking at a press briefing here during the annual meeting of the American Society of Hematology. The new data from the two studies were presented at oral sessions, and the results from ZUMA-7 were also simultaneously published in the New England Journal of Medicine.

“For somebody who treats patients with large B-cell lymphoma like I do, it’s incredibly frustrating when patients fail frontline therapy,” Dr. Sehn said. “We come into the second line with more chemotherapy and at higher doses to try and slam things down hard. Particularly for the patients who were enrolled in these studies, which were the worst of the worst — the patients who are either refractory to chemotherapy or relapsed relatively early, within 1 year — it’s not surprising that coming in with a novel approach and a cellular therapy that has a proven curative capacity may have outperformed coming in with more chemotherapy.”

In an interview with this news organization, Dr. Locke said that, based on the findings of the ZUMA-7 trial that he presented, it’s likely that chemotherapy in the second-line setting for relapsed/refractory LBCL will largely fall by the wayside.

The first question is to identify the patients who can tolerate CAR T-cell therapy. “We need to refer these patients to a CAR T-cell center to make that decision. That decision really can’t be made in the local oncologist’s office,” he said. “That being said, there are patients who need urgent therapy, and they may need to get second-line chemotherapy right away.”

“What we know with CAR T cells is that older patients and patients with comorbidities can get these therapies safely, so to me there is no obvious patient who can’t get CAR T-cell therapy,” he added.

Also at the briefing, Dr. Kamdar, who presented the TRANSFORM trial results, remarked that “in my opinion, this is a breakthrough therapy, which has shown superiority over standard of care, in terms of not just efficacy but also an extremely favorable safety profile,” she said at a briefing.   

For patients with LBCL for whom first-line therapy has failed, chemoimmunotherapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT) has been the standard of care, but only about 25% of patients who are candidates for ASCT achieve durable remissions, Dr. Kamdar noted.

Both ZUMA-7 and TRANSFORM were designed to test whether moving CAR T-cell therapy forward into the second line could improve outcomes.

ZUMA-7 results

THE ZUMA-7 trial randomly assigned 180 patients to receive CAR T-cell therapy with axi-cell and 179 patients to standard of care. This consisted of two or three cycles of investigator-selected, protocol-defined chemoimmunotherapy, with patients who had a complete or partial response going onto ASCT.

As noted, the primary endpoint of EFS according to blinded central review favored axi-cel, with 24-month event-free survival rates of 41% vs. 16% for standard of care. The difference translated into a hazard ratio (HR) for progression or death of 0.40 (P < .001).

In all, 65% of patients had a complete response (CR) to axi-cel, compared with 32% with standard of care. The respective overall response rates were 83% and 50% (P < .001).

Dr. Locke pointed out that 94% of the patients assigned to axi-cel received definitive therapy, compared with the 36% of patients in the standard-of-care arm who went on to ASCT.

In an interim analysis, 2-year estimated overall survival was 61% with axi-cel vs. 52% with standard of care, although this difference was not statistically significant.

Median overall survival was not reached with axi-cel, compared with 35.1 months with standard-of-care.

Grade 3 or higher adverse events occurred in 91% of patients with CAR T, and 83% with the standard of care. In the axi-cel arm, 6% of patients had grade 3 or higher cytokine release syndrome (CRS), and 21% had grade 3 or higher neurologic events, although there were no deaths related to CRS or neurologic events.

TRANSFORM results

The TRANSFORM trial had broader eligibility criteria than ZUMA-7, including patients who had diffuse LBCL not otherwise specified (de novo or transformed from indolent NHL), high-grade BCL (double- or triple-hit) with DLBCL histology, follicular lymphoma grade 3B, primary mediastinal LBCL, or T-cell/histocyte-rich LBCL.

A total of 184 patients were randomly assigned, 92 in each group, to receive either liso-cel or standard-of-care. Patients assigned to liso-cel were allowed to have bridging therapy, and crossover to liso-cel was allowed for patients assigned to standard of care who either did not have a response by week 9 after randomization, had disease progression at any time, or started a new antineoplastic therapy after ASCT.

As noted before, the primary endpoint of EFS significantly favored CAR T-cell therapy, with a hazard ratio of 0.349 (P < .0001).

The EFS rates at 6 months were 63.3% with liso-cel vs 33.4% with standard of care, and the EFS rates at 12 months were 44.5% vs. 23.7%, respectively.

“Overall survival data were still immature at the time of this analysis, but show a trend favoring liso-cel, despite crossover,” Dr. Kamdar said.

Grade 3 or higher adverse events (AEs) occurred in 92% of patients on liso-cell and 87% of patients on standard of care. There was one treatment-related death in the liso-cel arm, and two in the standard of care arm, both from grade 3 or higher AEs. Neutropenia, anemia, and thrombocytopenia were the most common treatment-emergent AEs in each group.

ZUMA-7 is supported by Kite. Dr. Locke disclosed serving as a scientific advisor to Kite and relationships with other companies. TRANSFORM is supported by Celgene (BMS). Dr. Kamdar disclosed consultancy fees from BMS and others.


A version of this article first appeared on Medscape.com.

ATLANTA — Chimeric antigen receptor (CAR) T-cell therapy has the potential to replace chemoimmunotherapy for second-line treatment of patients with large B-cell lymphoma (LBCL) that have relapsed or are refractory to first-line therapy, results of the phase 3 ZUMA-7 and TRANSFORM trials suggest.

Meletios Verras/Shutterstock

In the ZUMA-7 trial, at a median follow-up of 24.9 months, patients randomly assigned to receive CAR T-cell therapy with axicabtagene ciloleucel, or axi-cell (Yescarta) had a median event-free survival (EFS) of 8.3 months, compared with 2 months for patients randomly assigned to standard-of-care chemoimmunotherapy, reported Frederick L. Locke, MD, from the Moffitt Cancer Center in Tampa, Fla.

In TRANSFORM, comparing the CAR T construct lisocabtagene maraleucel, or liso-cel (Breyanzi) with standard-of-care second-line chemotherapy, median EFS was 10.1 months with liso-cel, compared with 2.3 months with standard of care, reported Manali Kamdar, MD, from the University of Colorado Cancer Center in Aurora.

The trials differed slightly in eligibility criteria and other details, but their overall results show great promise for improving second-line therapy for patients with relapsed or refractory LBCL, commented Laurie Sehn, MD, MPH, from the BC Cancer Centre for Lymphoid Cancer in Vancouver, Canada.

“It’s really remarkable that the results are so far in favor of the CAR T-cell therapy that I think it’s inevitable that this will become the standard of care,” Dr. Sehn commented. She was not an investigator in either of the two trials.

Dr. Sehn was speaking at a press briefing here during the annual meeting of the American Society of Hematology. The new data from the two studies were presented at oral sessions, and the results from ZUMA-7 were also simultaneously published in the New England Journal of Medicine.

“For somebody who treats patients with large B-cell lymphoma like I do, it’s incredibly frustrating when patients fail frontline therapy,” Dr. Sehn said. “We come into the second line with more chemotherapy and at higher doses to try and slam things down hard. Particularly for the patients who were enrolled in these studies, which were the worst of the worst — the patients who are either refractory to chemotherapy or relapsed relatively early, within 1 year — it’s not surprising that coming in with a novel approach and a cellular therapy that has a proven curative capacity may have outperformed coming in with more chemotherapy.”

In an interview with this news organization, Dr. Locke said that, based on the findings of the ZUMA-7 trial that he presented, it’s likely that chemotherapy in the second-line setting for relapsed/refractory LBCL will largely fall by the wayside.

The first question is to identify the patients who can tolerate CAR T-cell therapy. “We need to refer these patients to a CAR T-cell center to make that decision. That decision really can’t be made in the local oncologist’s office,” he said. “That being said, there are patients who need urgent therapy, and they may need to get second-line chemotherapy right away.”

“What we know with CAR T cells is that older patients and patients with comorbidities can get these therapies safely, so to me there is no obvious patient who can’t get CAR T-cell therapy,” he added.

Also at the briefing, Dr. Kamdar, who presented the TRANSFORM trial results, remarked that “in my opinion, this is a breakthrough therapy, which has shown superiority over standard of care, in terms of not just efficacy but also an extremely favorable safety profile,” she said at a briefing.   

For patients with LBCL for whom first-line therapy has failed, chemoimmunotherapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT) has been the standard of care, but only about 25% of patients who are candidates for ASCT achieve durable remissions, Dr. Kamdar noted.

Both ZUMA-7 and TRANSFORM were designed to test whether moving CAR T-cell therapy forward into the second line could improve outcomes.

ZUMA-7 results

THE ZUMA-7 trial randomly assigned 180 patients to receive CAR T-cell therapy with axi-cell and 179 patients to standard of care. This consisted of two or three cycles of investigator-selected, protocol-defined chemoimmunotherapy, with patients who had a complete or partial response going onto ASCT.

As noted, the primary endpoint of EFS according to blinded central review favored axi-cel, with 24-month event-free survival rates of 41% vs. 16% for standard of care. The difference translated into a hazard ratio (HR) for progression or death of 0.40 (P < .001).

In all, 65% of patients had a complete response (CR) to axi-cel, compared with 32% with standard of care. The respective overall response rates were 83% and 50% (P < .001).

Dr. Locke pointed out that 94% of the patients assigned to axi-cel received definitive therapy, compared with the 36% of patients in the standard-of-care arm who went on to ASCT.

In an interim analysis, 2-year estimated overall survival was 61% with axi-cel vs. 52% with standard of care, although this difference was not statistically significant.

Median overall survival was not reached with axi-cel, compared with 35.1 months with standard-of-care.

Grade 3 or higher adverse events occurred in 91% of patients with CAR T, and 83% with the standard of care. In the axi-cel arm, 6% of patients had grade 3 or higher cytokine release syndrome (CRS), and 21% had grade 3 or higher neurologic events, although there were no deaths related to CRS or neurologic events.

TRANSFORM results

The TRANSFORM trial had broader eligibility criteria than ZUMA-7, including patients who had diffuse LBCL not otherwise specified (de novo or transformed from indolent NHL), high-grade BCL (double- or triple-hit) with DLBCL histology, follicular lymphoma grade 3B, primary mediastinal LBCL, or T-cell/histocyte-rich LBCL.

A total of 184 patients were randomly assigned, 92 in each group, to receive either liso-cel or standard-of-care. Patients assigned to liso-cel were allowed to have bridging therapy, and crossover to liso-cel was allowed for patients assigned to standard of care who either did not have a response by week 9 after randomization, had disease progression at any time, or started a new antineoplastic therapy after ASCT.

As noted before, the primary endpoint of EFS significantly favored CAR T-cell therapy, with a hazard ratio of 0.349 (P < .0001).

The EFS rates at 6 months were 63.3% with liso-cel vs 33.4% with standard of care, and the EFS rates at 12 months were 44.5% vs. 23.7%, respectively.

“Overall survival data were still immature at the time of this analysis, but show a trend favoring liso-cel, despite crossover,” Dr. Kamdar said.

Grade 3 or higher adverse events (AEs) occurred in 92% of patients on liso-cell and 87% of patients on standard of care. There was one treatment-related death in the liso-cel arm, and two in the standard of care arm, both from grade 3 or higher AEs. Neutropenia, anemia, and thrombocytopenia were the most common treatment-emergent AEs in each group.

ZUMA-7 is supported by Kite. Dr. Locke disclosed serving as a scientific advisor to Kite and relationships with other companies. TRANSFORM is supported by Celgene (BMS). Dr. Kamdar disclosed consultancy fees from BMS and others.


A version of this article first appeared on Medscape.com.

ATLANTA — Chimeric antigen receptor (CAR) T-cell therapy has the potential to replace chemoimmunotherapy for second-line treatment of patients with large B-cell lymphoma (LBCL) that have relapsed or are refractory to first-line therapy, results of the phase 3 ZUMA-7 and TRANSFORM trials suggest.

Meletios Verras/Shutterstock

In the ZUMA-7 trial, at a median follow-up of 24.9 months, patients randomly assigned to receive CAR T-cell therapy with axicabtagene ciloleucel, or axi-cell (Yescarta) had a median event-free survival (EFS) of 8.3 months, compared with 2 months for patients randomly assigned to standard-of-care chemoimmunotherapy, reported Frederick L. Locke, MD, from the Moffitt Cancer Center in Tampa, Fla.

In TRANSFORM, comparing the CAR T construct lisocabtagene maraleucel, or liso-cel (Breyanzi) with standard-of-care second-line chemotherapy, median EFS was 10.1 months with liso-cel, compared with 2.3 months with standard of care, reported Manali Kamdar, MD, from the University of Colorado Cancer Center in Aurora.

The trials differed slightly in eligibility criteria and other details, but their overall results show great promise for improving second-line therapy for patients with relapsed or refractory LBCL, commented Laurie Sehn, MD, MPH, from the BC Cancer Centre for Lymphoid Cancer in Vancouver, Canada.

“It’s really remarkable that the results are so far in favor of the CAR T-cell therapy that I think it’s inevitable that this will become the standard of care,” Dr. Sehn commented. She was not an investigator in either of the two trials.

Dr. Sehn was speaking at a press briefing here during the annual meeting of the American Society of Hematology. The new data from the two studies were presented at oral sessions, and the results from ZUMA-7 were also simultaneously published in the New England Journal of Medicine.

“For somebody who treats patients with large B-cell lymphoma like I do, it’s incredibly frustrating when patients fail frontline therapy,” Dr. Sehn said. “We come into the second line with more chemotherapy and at higher doses to try and slam things down hard. Particularly for the patients who were enrolled in these studies, which were the worst of the worst — the patients who are either refractory to chemotherapy or relapsed relatively early, within 1 year — it’s not surprising that coming in with a novel approach and a cellular therapy that has a proven curative capacity may have outperformed coming in with more chemotherapy.”

In an interview with this news organization, Dr. Locke said that, based on the findings of the ZUMA-7 trial that he presented, it’s likely that chemotherapy in the second-line setting for relapsed/refractory LBCL will largely fall by the wayside.

The first question is to identify the patients who can tolerate CAR T-cell therapy. “We need to refer these patients to a CAR T-cell center to make that decision. That decision really can’t be made in the local oncologist’s office,” he said. “That being said, there are patients who need urgent therapy, and they may need to get second-line chemotherapy right away.”

“What we know with CAR T cells is that older patients and patients with comorbidities can get these therapies safely, so to me there is no obvious patient who can’t get CAR T-cell therapy,” he added.

Also at the briefing, Dr. Kamdar, who presented the TRANSFORM trial results, remarked that “in my opinion, this is a breakthrough therapy, which has shown superiority over standard of care, in terms of not just efficacy but also an extremely favorable safety profile,” she said at a briefing.   

For patients with LBCL for whom first-line therapy has failed, chemoimmunotherapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT) has been the standard of care, but only about 25% of patients who are candidates for ASCT achieve durable remissions, Dr. Kamdar noted.

Both ZUMA-7 and TRANSFORM were designed to test whether moving CAR T-cell therapy forward into the second line could improve outcomes.

ZUMA-7 results

THE ZUMA-7 trial randomly assigned 180 patients to receive CAR T-cell therapy with axi-cell and 179 patients to standard of care. This consisted of two or three cycles of investigator-selected, protocol-defined chemoimmunotherapy, with patients who had a complete or partial response going onto ASCT.

As noted, the primary endpoint of EFS according to blinded central review favored axi-cel, with 24-month event-free survival rates of 41% vs. 16% for standard of care. The difference translated into a hazard ratio (HR) for progression or death of 0.40 (P < .001).

In all, 65% of patients had a complete response (CR) to axi-cel, compared with 32% with standard of care. The respective overall response rates were 83% and 50% (P < .001).

Dr. Locke pointed out that 94% of the patients assigned to axi-cel received definitive therapy, compared with the 36% of patients in the standard-of-care arm who went on to ASCT.

In an interim analysis, 2-year estimated overall survival was 61% with axi-cel vs. 52% with standard of care, although this difference was not statistically significant.

Median overall survival was not reached with axi-cel, compared with 35.1 months with standard-of-care.

Grade 3 or higher adverse events occurred in 91% of patients with CAR T, and 83% with the standard of care. In the axi-cel arm, 6% of patients had grade 3 or higher cytokine release syndrome (CRS), and 21% had grade 3 or higher neurologic events, although there were no deaths related to CRS or neurologic events.

TRANSFORM results

The TRANSFORM trial had broader eligibility criteria than ZUMA-7, including patients who had diffuse LBCL not otherwise specified (de novo or transformed from indolent NHL), high-grade BCL (double- or triple-hit) with DLBCL histology, follicular lymphoma grade 3B, primary mediastinal LBCL, or T-cell/histocyte-rich LBCL.

A total of 184 patients were randomly assigned, 92 in each group, to receive either liso-cel or standard-of-care. Patients assigned to liso-cel were allowed to have bridging therapy, and crossover to liso-cel was allowed for patients assigned to standard of care who either did not have a response by week 9 after randomization, had disease progression at any time, or started a new antineoplastic therapy after ASCT.

As noted before, the primary endpoint of EFS significantly favored CAR T-cell therapy, with a hazard ratio of 0.349 (P < .0001).

The EFS rates at 6 months were 63.3% with liso-cel vs 33.4% with standard of care, and the EFS rates at 12 months were 44.5% vs. 23.7%, respectively.

“Overall survival data were still immature at the time of this analysis, but show a trend favoring liso-cel, despite crossover,” Dr. Kamdar said.

Grade 3 or higher adverse events (AEs) occurred in 92% of patients on liso-cell and 87% of patients on standard of care. There was one treatment-related death in the liso-cel arm, and two in the standard of care arm, both from grade 3 or higher AEs. Neutropenia, anemia, and thrombocytopenia were the most common treatment-emergent AEs in each group.

ZUMA-7 is supported by Kite. Dr. Locke disclosed serving as a scientific advisor to Kite and relationships with other companies. TRANSFORM is supported by Celgene (BMS). Dr. Kamdar disclosed consultancy fees from BMS and others.


A version of this article first appeared on Medscape.com.

Lower urinary tract symptoms (LUTS)are common and tend to increase in frequency with age. Managing LUTS can be complicated, requires an informed discussion between the primary care practitioner (PCP) and patient, and is best achieved by a thorough understanding of the many medical and surgical options available. Over the past 3 decades, medications have become the most common therapy; but recently, newer minimally invasive surgeries have challenged this paradigm. This article provides a comprehensive review for PCPs regarding the evaluation and management of LUTS in men and when to consider a urology referral.

Benign prostatic hyperplasia (BPH) and LUTS are common clinical encounters for most PCPs. About 50% of men will develop LUTS associated with BPH, and symptoms associated with these conditions increase as men age.^1,2 Studies have estimated that 90% of men aged 45 to 80 years demonstrate some symptoms of LUTS.³ Strong genetic influence seems to suggest heritability, but BPH also occurs in sporadic forms and is heavily influenced by androgens.⁴

BPH is a histologic diagnosis, whereas LUTS consists of complex symptomatology related to both static or dynamic components.¹ The enlarged prostate gland obstructs the urethra, simultaneously causing an increase in muscle tone and resistance at the bladder neck and prostatic urethra, leading to increased resistance to urine flow. As a result, there is a thickening of the detrusor muscles in the bladder wall and an overall decreased compliance. Urine becomes stored under increased pressure. These changes result in a weak or intermittent urine stream, incomplete emptying of the bladder, postvoid dribble, hesitancy, and irritative symptoms, such as urgency, frequency, and nocturia.

For many patients, BPH associated with LUTS is a quality of life (QOL) issue. The stigma associated with these symptoms often leads to delays in patients seeking care. Many patients do not seek treatment until symptoms have become so severe that changes in bladder health are often irreversible. Early intervention can dramatically improve a patient’s QOL. Also, early intervention has the potential to reduce overall health care expenditures. BPH-related spending exceeds $1 billion each year in the Medicare program alone.⁵

PCPs are in a unique position to help many patients who present with early-stage LUTS. Given the substantial impact this disease has on QOL, early recognition of symptoms and prompt treatment play a major role. Paramount to this effort is awareness and understanding of various treatments, their advantages, and adverse effects (AEs). This article highlights evidence-based evaluation and treatment of BPH/LUTS for PCPs who treat veterans and recommendations as to when to refer a patient to a urologist.

Evaluation of LUTS and BPH

Evaluation begins with a thorough medical history and physical examination. Particular attention should focus on ruling out other causes of LUTS, such as a urinary tract infection (UTI), acute prostatitis, malignancy, bladder dysfunction, neurogenic bladder, and other obstructive pathology, such as urethral stricture disease. The differential diagnosis of LUTS includes BPH, UTI, bladder neck obstruction, urethral stricture, bladder stones, polydipsia, overactive bladder (OAB), nocturnal polyuria, neurologic disease, genitourinary malignancy, renal failure, and acute/chronic urinary retention.⁶

Relevant medical history influencing urinary symptoms includes diabetes mellitus, underlying neurologic diseases, previous trauma, sexually transmitted infections, and certain medications. Symptom severity may be obtained using a validated questionnaire, such as the International Prostate Symptom Score (IPSS), which also aids clinicians in assessing the impact of LUTS on QOL. Additionally, urinary frequency or volume records (voiding diary) may help establish the severity of the patient’s symptoms and provide insight into other potential causes for LUTS. Patients with BPH often have concurrent erectile dysfunction (ED) or other sexual dysfunction symptoms. Patients should be evaluated for baseline sexual dysfunction before the initiation of treatment as many therapies worsen symptoms of ED or ejaculatory dysfunction.

A comprehensive physical examination with a focus on the genitourinary system should, at minimum, assess for abnormalities of the urethral meatus, prepuce, penis, groin nodes, and prior surgical scars. A digital rectal examination also should be performed. Although controversial, a digital rectal examination for prostate cancer screening may provide a rough estimate of prostate size, help rule out prostatitis, and detect incident prostate nodules. Prostate size does not necessarily correlate well with the degree of urinary obstruction or LUTS but is an important consideration when deciding among different therapies.¹

Laboratory and Adjunctive Tests

A urinalysis with microscopy helps identify other potential causes for urinary symptoms, including infection, proteinuria, or glucosuria. In patients who present with gross or microscopic hematuria, additional consideration should be given to bladder calculi and genitourinary cancer.² When a reversible source for the hematuria is not identified, these patients require referral to a urologist for a hematuria evaluation.

There is some controversy regarding prostate specific antigen (PSA) testing. Most professional organizations advocate for a shared decision-making approach before testing. The American Cancer Society recommends this informed discussion occur between the patient and the PCP for men aged > 50 years at average risk, men aged > 45 years at high risk of developing prostate cancer (African Americans or first-degree relative with early prostate cancer diagnosis), and aged 40 years for men with more than one first-degree relative with an early prostate cancer diagnosis.⁷

Adjunctive tests include postvoid residual (PVR), cystoscopy, uroflowmetry, urodynamics, and transrectal ultrasound. However, these are mostly performed by urologists. In some patients with bladder decompensation after prolonged partial bladder outlet obstruction, urodynamics may be used by urologists to determine whether a patient may benefit from an outlet obstruction procedure. Ordering additional imaging or serum studies for the assessment of LUTS is rarely helpful.

Treatment

Treatment includes management with or without lifestyle modification, medication administration, and surgical therapy. New to this paradigm are in-office minimally invasive surgical options. The goal of treatment is not only to reduce patient symptoms and improve QOL, but also to prevent the secondary sequala of urinary retention, bladder failure, and eventual renal impairment.⁷A basic understanding of these treatments can aid PCPs with appropriate patient counseling and urologic referral.⁸

Lifestyle and Behavior Modification

Behavior modification is the starting point for all patients with LUTS. Lifestyle modifications for LUTS include avoiding substances that exacerbate symptoms, such as α-agonists (decongestants), caffeine, alcohol, spicy/acidic foods, chocolate, and soda. These substances are known to be bladder irritants. Common medications contributing to LUTS include antidepressants, decongestants, antihistamines, bronchodilators, anticholinergics, and sympathomimetics. To decrease nocturia, behavioral modifications include limiting evening fluid intake, timed diuretic administration for patients already on a diuretic, and elevating legs 1 hour before bedtime. Counseling obese patients to lose weight and increasing physical activity have been linked to reduced LUTS.⁹ Other behavioral techniques include double voiding: a technique where patients void normally then change positions and return to void to empty the bladder. Another technique is timed voiding: Many patients have impaired sensation when the bladder is full. These patients are encouraged to void at regular intervals.

Complementary and Alternative Medicine

Multiple nutraceutical compounds claim improved urinary health and symptom reduction. These compounds are marketed to patients with little regulation and oversight since supplements are not regulated or held to the same standard as prescription medications. The most popular nutraceutical for prostate health and LUTS is saw palmetto. Despite its common usage for the treatment of LUTS, little data support saw palmetto health claims. In 2012, a systematic review of 32 randomized trials including 5666 patients compared saw palmetto with a placebo. The study found no difference in urinary symptom scores, urinary flow, or prostate size.^10,11 Other phytotherapy compounds often considered for urinary symptoms include stinging nettle extract and β-sitosterol compounds. The mechanism of action of these agents is unknown and efficacy data are lacking.

Historically, acupuncture and pelvic floor physical therapy have been used successfully for OAB symptoms. A meta-analysis found positive beneficial effects of acupuncture compared with a sham control for short- and medium-term follow-up in both IPSS and urine flow rates in some studies; however, when combining the studies for more statistical power, the benefits were less clear.¹² Physical therapists with specialized training and certification in pelvic health can incorporate certain bladder training techniques. These include voiding positional changes (double voiding and postvoid urethral milking) and timed voiding.^13,14 These interventions often address etiologies of LUTS for which medical therapies are not effective as the sole treatment option.

Medication Management

Medical management includes α-blockers, 5-α-reductase inhibitors (5-α-RIs), antimuscarinic or anticholinergic medicines, β-3 agonists, and phosphodiesterase inhibitors (Table). These medications work independently as well as synergistically. The use of medications to improve symptoms must be balanced against potential AEs and the consequences of a lifetime of drug usage, which can be additive.^15,16

First-line pharmacological therapy for BPH is α-blockers, which work by blocking α1A receptors in the prostate and bladder neck, leading to smooth muscle relaxation, increased diameter of the channel, and improved urinary flow. α-receptors in the bladder neck and prostate are expressed with increased frequency with age and are a potential cause for worsening symptoms as men age. Studies demonstrate that these medications reduce symptoms by 30 to 40% and increase flow rates by 16 to 25%.¹⁷ Commonly prescribed α-blockers include tamsulosin, alfuzosin, silodosin, doxazosin, and terazosin. Doxazosin and terazosin require dose titrations because they may cause significant hypotension. Orthostatic hypotension typically improves with time and is avoided if the patient takes the medication at bedtime. Both doxazosin and terazosin are on the American Geriatric Society’s Beers Criteria list and should be avoided in older patients.¹⁸ Tamsulosin, alfuzosin, and silodosin have a standardized dosing regimen and lower rates of hypotension. Significant AEs include ejaculation dysfunction, nasal congestion, and orthostatic hypotension. Duan and colleagues have linked tamsulosin with dementia. However, this association is not causal and further studies are necessary.^19,20 Patients who have taken these agents also are at risk for intraoperative floppy iris syndrome (IFIS). Permanent visual problems can arise if the intraoperative management is not managed to account for IFIS. These medications have a rapid onset of action and work immediately. However, to reach maximum benefit, patients must take the medication for several weeks. Unfortunately, up to one-third of patients will have no improvement with α-blocker therapy, and many patients will discontinue these medications because of significant AEs.^6,21

5-α-RIs (finasteride and dutasteride) inhibit the conversion of testosterone to more potent dihydrotestosterone. They effectively reduce prostate volume by 25 to 30%.²² The results occur slowly and can take 6 to 12 months to reach the desired outcome. These medications are effective in men with larger prostates and not as effective in men with smaller prostates.²³ These medications can improve urinary flow rates by about 10%, reduce IPSS scores by 20 to 30%, reduce the risk of urinary retention by 50%, and reduce the progression of BPH to the point where surgery is required by 50%.²⁴ Furthermore, 5-α-RIs lower PSA by > 50% after 12 months of treatment.²⁵

A baseline PSA should be established before administration and after 6 months of treatment. Any increase in the PSA even if the level is within normal limits should be evaluated for prostate cancer. Sarkar and colleagues recently published a study evaluating prostate cancer diagnosis in patients treated with 5-α-RI and found there was a delay in diagnosing prostate cancer in this population. Controversy also exists as to the potential of these medications increasing the risk for high-grade prostate cancer, which has led to a US Food and Drug Administration (FDA) warning. AEs include decreased libido (1.5%), ejaculatory dysfunction (3.4%), gynecomastia (1.3%), and/or ED (1.6%).^26-28 A recent study evaluating 5-α-RIs demonstrated about a 2-fold increased risk of depression.²⁹

There are well-established studies that note increased effectiveness when using combined α-blocker therapy with 5-α-RI medications. The Medical Therapy of Prostate Symptoms (MTOPS) and Combination Avodart and Tamsulosin (CombAT) trials showed that the combination of both medications was more effective in improving voiding symptoms and flow rates than either agent alone.^15,16 Combination therapy resulted in a 66% reduction in disease progression, 81% reduction in urinary retention, and a 67% reduction in the need for surgery compared with placebo.

Anticholinergic medication use in BPH with LUTS is well established, and their use is often combined with other therapies. Anticholinergics work by inhibiting muscarinic M3 receptors to reduce detrusor muscle contraction. This effectively decreases bladder contractions and delays the desire to void. Kaplan and colleagues showed that tolterodine significantly improved a patient’s QOL when added to α-blocker therapy.³⁰ Patients reported a positive outcome at 12 weeks, which resulted in a reduction in urgency incontinence, urgency, nocturia, and the overall number of voiding episodes within 24 hours.

β-3 agonists are a class of medications for OAB; mirabegron and vibegron have proven effective in reducing similar symptoms. In phase 3 clinical trials, mirabegron improved urinary incontinence episodes by 50% and reduced the number of voids in 24 hours.³¹ Mirabegron is well tolerated and avoids many common anticholinergic effects.³² Vibegron is the newest medication in the class and could soon become the preferred agent given it does not have cytochrome P450 interactions and does not cause hypertension like mirabegron.³³

Anticholinergics should be used with caution in patients with a history of urinary retention, elevated after-void residual, or other medications with known anticholinergic effects. AEs include sedation, confusion, dry mouth, constipation, and potential falls in older patients.¹⁸ Recent studies have noted an association with dementia in the prolonged use of these medications in older patients and should be used cautiously.²⁰

Phosphodiesterase-5 enzyme inhibitors (PDE-5) are adjunctive medications shown to improve LUTS. This class of medication is prescribed mostly for ED. However, tadalafil 5 mg taken daily also is FDA approved for the treatment of LUTS secondary to BPH given its prolonged half-life. The exact mechanism for improved BPH symptoms is unknown. Possibly the effects are due to an increase mediated by PDE-5 in cyclic guanosine monophosphate (cGMP), which increases smooth muscle relaxation and tissue perfusion of the prostate and bladder.³⁴ There have been limited studies on objective improvement in uroflowmetry parameters compared with other treatments. The daily dosing of tadalafil should not be prescribed in men with a creatinine clearance < 30 mL/min.²⁹ Tadalafil is not considered a first-line agent and is usually reserved for patients who experience ED in addition to BPH. When initiating BPH pharmacologic therapy, the PCP should be aware of adherence and high discontinuation rates.³⁵

Surgical Treatments

Surgical treatments are often delayed out of fear of potential AEs or considered a last resort when symptoms are too severe.³⁶ Early intervention is required to prevent irreversible deleterious changes to detrusor muscle structure and function (Figure). Patients fear urinary incontinence, ED or ejaculatory dysfunction, and anesthesia complications associated with surgical interventions.^6,37 Multiple studies show that patients fare better with early surgical intervention, experiencing improved IPSS scores, urinary flow, and QOL. The following is an overview of the most popular procedures.

Prostatic urethral lift (PUL) using the UroLift System is an FDA-approved, minimally-invasive treatment of LUTS secondary to BPH. This procedure treats prostates < 80 g with an absent median lobe.^6,21,38 Permanent implants are placed per the prostatic urethra to displace obstructing prostate tissue laterally. This opens the urethra directly without cutting, heating, or removing any prostate tissue. This procedure is minimally invasive, often done in the office as an outpatient procedure, and offers better symptom relief than medication with a lower risk profile than transurethral resection of the prostate (TURP).^39,40 The LIFT study was a multicenter, randomized, blinded trial; patients were randomized 2:1 to undergo UroLift or a sham operation. At 3 years, average improvements were statistically significant for total IPSS reduction (41%), QOL improvement (49%), and improved maximum flow rates by (51%).⁴¹ Risk for urinary incontinence is low, and the procedure has been shown to preserve erectile and ejaculatory function. Furthermore, patients report significant improvement in their QOL without the need for medications. Surgical retreatment rates at 5 years are 13.6%, with an additional 10.7% of subjects back on medication therapy with α-blockers or 5-α-RIs.⁴²

Water vapor thermal therapy or Rez¯um uses steam as thermal energy to destroy obstructing prostate tissue and relieve the obstruction.⁴³ The procedure differs from older conductive heat thermotherapies because the steam penetrates prostate zonal anatomy without affecting areas outside the targeted treatment zone. The procedure is done in the office with local anesthesia and provides long-lasting relief of LUTS with minimal risks. Following the procedure, patients require an indwelling urethral catheter for 3 to 7 days, and most patients begin to experience symptom improvement 2 to 4 weeks following the procedure.⁴⁴ The procedure received FDA approval in 2015. Four-year data show significant improvement in maximal flow rate (50%), IPSS (47%), and QOL (43%).⁴⁵ Surgical retreatment rates were 4.4%. Criticisms of this treatment include patient discomfort with the office procedure, the requirement for an indwelling catheter for a short period, and lack of long-term outcomes data. Guidelines support use in prostate volumes > 80 g with or without median lobe anatomy.

TURP is the gold standard to which other treatments are compared.⁴⁶ The surgery is performed in the operating room where urologists use a rigid cystoscope and resection element to effectively carve out and cauterize obstructing prostate tissue. Patients typically recover for a short period with an indwelling urethral catheter that is often removed 12 to 24 hours after surgery. New research points out that despite increasing mean age (55% of patients are aged > 70 years with associated comorbidities), the morbidity of TURP was < 1% and mortality rate of 0 to 0.3%.⁴⁷ Postoperative complications include bleeding that requires a transfusion (3%), retrograde ejaculation (65%), and rare urinary incontinence (2%).⁴⁷ Surgical retreatment rates for patients following a TURP are approximately 13 to 15% at 8 years.³⁴

Laser surgery for BPH includes multiple techniques: photovaporization of the prostate using a Greenlight XPS laser, holmium laser ablation, and holmium laser enucleation (HoLEP). Proponents of these treatments cite lower bleeding risks compared with TURP, but the operation is largely surgeon dependent on the technology chosen. Most studies comparing these technologies with TURP show similar outcomes of IPSS reports, quality of life improvements, and complications.

Patients with extremely large prostates, > 100 g or 4 times the normal size, pose a unique challenge to surgical treatment. Historically, patients were treated with an open simple prostatectomy operation or staged TURP procedures. Today, urologists use newer, safer ways to treat these patients. Both HoLEP and robot-assisted simple prostatectomy work well in relieving urinary symptoms with lower complications compared with older open surgery. Other minimally invasive procedures, such as prostatic artery embolism, have been described for the treatment of BPH specifically in men who may be unfit for surgery.⁴⁸Future treatments are constantly evolving. Many unanswered questions remain about BPH and the role of inflammation, metabolic dysfunction, obesity, and other genetic factors driving BPH and prostate growth. Pharmaceutical opportunities exist in mechanisms aimed to reduce prostate growth, induce cellular apoptosis, as well as other drugs to reduce bladder symptoms. Newer, minimally invasive therapies also will become more readily available, such as Aquablation, which is the first FDA-granted surgical robot for the autonomous removal of prostatic tissue due to BPH.⁴⁹ However, the goal of all future therapies should include the balance of alleviating disruptive symptoms while demonstrating a favorable risk profile. Many men discontinue taking medications, yet few present for surgery. Most concerning is the significant population of men who will develop irreversible bladder dysfunction while waiting for the perfect treatment. There are many opportunities for an effective treatment that is less invasive than surgery, provides durable relief, has minimal AEs, and is affordable.

Conclusions

There is no perfect treatment for patients with LUTS. All interventions have potential AEs and associated complications. Medications are often started as first-line therapy but are often discontinued at the onset of significant AEs. This process is often repeated. Many patients will try different medications without any significant improvement in their symptoms or short-term relief, which results in the gradual progression of the disease.

The PCP plays a significant role in the initial evaluation and management of BPH. These frontline clinicians can recognize patients who may already be experiencing sequela of prolonged bladder outlet obstruction and refer these men to urologists promptly. Counseling patients about their treatment options is an important duty for all PCPs.

A clear understanding of the available treatment options will help PCPs counsel patients appropriately about lifestyle modification, medications, and surgical treatment options for their symptoms. The treatment of this disorder is a rapidly evolving topic with the constant introduction of new technologies and medications, which are certain to continue to play an important role for PCPs and urologists.

Lower urinary tract symptoms (LUTS)are common and tend to increase in frequency with age. Managing LUTS can be complicated, requires an informed discussion between the primary care practitioner (PCP) and patient, and is best achieved by a thorough understanding of the many medical and surgical options available. Over the past 3 decades, medications have become the most common therapy; but recently, newer minimally invasive surgeries have challenged this paradigm. This article provides a comprehensive review for PCPs regarding the evaluation and management of LUTS in men and when to consider a urology referral.

Benign prostatic hyperplasia (BPH) and LUTS are common clinical encounters for most PCPs. About 50% of men will develop LUTS associated with BPH, and symptoms associated with these conditions increase as men age.^1,2 Studies have estimated that 90% of men aged 45 to 80 years demonstrate some symptoms of LUTS.³ Strong genetic influence seems to suggest heritability, but BPH also occurs in sporadic forms and is heavily influenced by androgens.⁴

BPH is a histologic diagnosis, whereas LUTS consists of complex symptomatology related to both static or dynamic components.¹ The enlarged prostate gland obstructs the urethra, simultaneously causing an increase in muscle tone and resistance at the bladder neck and prostatic urethra, leading to increased resistance to urine flow. As a result, there is a thickening of the detrusor muscles in the bladder wall and an overall decreased compliance. Urine becomes stored under increased pressure. These changes result in a weak or intermittent urine stream, incomplete emptying of the bladder, postvoid dribble, hesitancy, and irritative symptoms, such as urgency, frequency, and nocturia.

For many patients, BPH associated with LUTS is a quality of life (QOL) issue. The stigma associated with these symptoms often leads to delays in patients seeking care. Many patients do not seek treatment until symptoms have become so severe that changes in bladder health are often irreversible. Early intervention can dramatically improve a patient’s QOL. Also, early intervention has the potential to reduce overall health care expenditures. BPH-related spending exceeds $1 billion each year in the Medicare program alone.⁵

PCPs are in a unique position to help many patients who present with early-stage LUTS. Given the substantial impact this disease has on QOL, early recognition of symptoms and prompt treatment play a major role. Paramount to this effort is awareness and understanding of various treatments, their advantages, and adverse effects (AEs). This article highlights evidence-based evaluation and treatment of BPH/LUTS for PCPs who treat veterans and recommendations as to when to refer a patient to a urologist.

Evaluation of LUTS and BPH

Evaluation begins with a thorough medical history and physical examination. Particular attention should focus on ruling out other causes of LUTS, such as a urinary tract infection (UTI), acute prostatitis, malignancy, bladder dysfunction, neurogenic bladder, and other obstructive pathology, such as urethral stricture disease. The differential diagnosis of LUTS includes BPH, UTI, bladder neck obstruction, urethral stricture, bladder stones, polydipsia, overactive bladder (OAB), nocturnal polyuria, neurologic disease, genitourinary malignancy, renal failure, and acute/chronic urinary retention.⁶

Relevant medical history influencing urinary symptoms includes diabetes mellitus, underlying neurologic diseases, previous trauma, sexually transmitted infections, and certain medications. Symptom severity may be obtained using a validated questionnaire, such as the International Prostate Symptom Score (IPSS), which also aids clinicians in assessing the impact of LUTS on QOL. Additionally, urinary frequency or volume records (voiding diary) may help establish the severity of the patient’s symptoms and provide insight into other potential causes for LUTS. Patients with BPH often have concurrent erectile dysfunction (ED) or other sexual dysfunction symptoms. Patients should be evaluated for baseline sexual dysfunction before the initiation of treatment as many therapies worsen symptoms of ED or ejaculatory dysfunction.

A comprehensive physical examination with a focus on the genitourinary system should, at minimum, assess for abnormalities of the urethral meatus, prepuce, penis, groin nodes, and prior surgical scars. A digital rectal examination also should be performed. Although controversial, a digital rectal examination for prostate cancer screening may provide a rough estimate of prostate size, help rule out prostatitis, and detect incident prostate nodules. Prostate size does not necessarily correlate well with the degree of urinary obstruction or LUTS but is an important consideration when deciding among different therapies.¹

Laboratory and Adjunctive Tests

A urinalysis with microscopy helps identify other potential causes for urinary symptoms, including infection, proteinuria, or glucosuria. In patients who present with gross or microscopic hematuria, additional consideration should be given to bladder calculi and genitourinary cancer.² When a reversible source for the hematuria is not identified, these patients require referral to a urologist for a hematuria evaluation.

There is some controversy regarding prostate specific antigen (PSA) testing. Most professional organizations advocate for a shared decision-making approach before testing. The American Cancer Society recommends this informed discussion occur between the patient and the PCP for men aged > 50 years at average risk, men aged > 45 years at high risk of developing prostate cancer (African Americans or first-degree relative with early prostate cancer diagnosis), and aged 40 years for men with more than one first-degree relative with an early prostate cancer diagnosis.⁷

Adjunctive tests include postvoid residual (PVR), cystoscopy, uroflowmetry, urodynamics, and transrectal ultrasound. However, these are mostly performed by urologists. In some patients with bladder decompensation after prolonged partial bladder outlet obstruction, urodynamics may be used by urologists to determine whether a patient may benefit from an outlet obstruction procedure. Ordering additional imaging or serum studies for the assessment of LUTS is rarely helpful.

Treatment

Treatment includes management with or without lifestyle modification, medication administration, and surgical therapy. New to this paradigm are in-office minimally invasive surgical options. The goal of treatment is not only to reduce patient symptoms and improve QOL, but also to prevent the secondary sequala of urinary retention, bladder failure, and eventual renal impairment.⁷A basic understanding of these treatments can aid PCPs with appropriate patient counseling and urologic referral.⁸

Lifestyle and Behavior Modification

Behavior modification is the starting point for all patients with LUTS. Lifestyle modifications for LUTS include avoiding substances that exacerbate symptoms, such as α-agonists (decongestants), caffeine, alcohol, spicy/acidic foods, chocolate, and soda. These substances are known to be bladder irritants. Common medications contributing to LUTS include antidepressants, decongestants, antihistamines, bronchodilators, anticholinergics, and sympathomimetics. To decrease nocturia, behavioral modifications include limiting evening fluid intake, timed diuretic administration for patients already on a diuretic, and elevating legs 1 hour before bedtime. Counseling obese patients to lose weight and increasing physical activity have been linked to reduced LUTS.⁹ Other behavioral techniques include double voiding: a technique where patients void normally then change positions and return to void to empty the bladder. Another technique is timed voiding: Many patients have impaired sensation when the bladder is full. These patients are encouraged to void at regular intervals.

Complementary and Alternative Medicine

Multiple nutraceutical compounds claim improved urinary health and symptom reduction. These compounds are marketed to patients with little regulation and oversight since supplements are not regulated or held to the same standard as prescription medications. The most popular nutraceutical for prostate health and LUTS is saw palmetto. Despite its common usage for the treatment of LUTS, little data support saw palmetto health claims. In 2012, a systematic review of 32 randomized trials including 5666 patients compared saw palmetto with a placebo. The study found no difference in urinary symptom scores, urinary flow, or prostate size.^10,11 Other phytotherapy compounds often considered for urinary symptoms include stinging nettle extract and β-sitosterol compounds. The mechanism of action of these agents is unknown and efficacy data are lacking.

Historically, acupuncture and pelvic floor physical therapy have been used successfully for OAB symptoms. A meta-analysis found positive beneficial effects of acupuncture compared with a sham control for short- and medium-term follow-up in both IPSS and urine flow rates in some studies; however, when combining the studies for more statistical power, the benefits were less clear.¹² Physical therapists with specialized training and certification in pelvic health can incorporate certain bladder training techniques. These include voiding positional changes (double voiding and postvoid urethral milking) and timed voiding.^13,14 These interventions often address etiologies of LUTS for which medical therapies are not effective as the sole treatment option.

Medication Management

Medical management includes α-blockers, 5-α-reductase inhibitors (5-α-RIs), antimuscarinic or anticholinergic medicines, β-3 agonists, and phosphodiesterase inhibitors (Table). These medications work independently as well as synergistically. The use of medications to improve symptoms must be balanced against potential AEs and the consequences of a lifetime of drug usage, which can be additive.^15,16

First-line pharmacological therapy for BPH is α-blockers, which work by blocking α1A receptors in the prostate and bladder neck, leading to smooth muscle relaxation, increased diameter of the channel, and improved urinary flow. α-receptors in the bladder neck and prostate are expressed with increased frequency with age and are a potential cause for worsening symptoms as men age. Studies demonstrate that these medications reduce symptoms by 30 to 40% and increase flow rates by 16 to 25%.¹⁷ Commonly prescribed α-blockers include tamsulosin, alfuzosin, silodosin, doxazosin, and terazosin. Doxazosin and terazosin require dose titrations because they may cause significant hypotension. Orthostatic hypotension typically improves with time and is avoided if the patient takes the medication at bedtime. Both doxazosin and terazosin are on the American Geriatric Society’s Beers Criteria list and should be avoided in older patients.¹⁸ Tamsulosin, alfuzosin, and silodosin have a standardized dosing regimen and lower rates of hypotension. Significant AEs include ejaculation dysfunction, nasal congestion, and orthostatic hypotension. Duan and colleagues have linked tamsulosin with dementia. However, this association is not causal and further studies are necessary.^19,20 Patients who have taken these agents also are at risk for intraoperative floppy iris syndrome (IFIS). Permanent visual problems can arise if the intraoperative management is not managed to account for IFIS. These medications have a rapid onset of action and work immediately. However, to reach maximum benefit, patients must take the medication for several weeks. Unfortunately, up to one-third of patients will have no improvement with α-blocker therapy, and many patients will discontinue these medications because of significant AEs.^6,21

5-α-RIs (finasteride and dutasteride) inhibit the conversion of testosterone to more potent dihydrotestosterone. They effectively reduce prostate volume by 25 to 30%.²² The results occur slowly and can take 6 to 12 months to reach the desired outcome. These medications are effective in men with larger prostates and not as effective in men with smaller prostates.²³ These medications can improve urinary flow rates by about 10%, reduce IPSS scores by 20 to 30%, reduce the risk of urinary retention by 50%, and reduce the progression of BPH to the point where surgery is required by 50%.²⁴ Furthermore, 5-α-RIs lower PSA by > 50% after 12 months of treatment.²⁵

A baseline PSA should be established before administration and after 6 months of treatment. Any increase in the PSA even if the level is within normal limits should be evaluated for prostate cancer. Sarkar and colleagues recently published a study evaluating prostate cancer diagnosis in patients treated with 5-α-RI and found there was a delay in diagnosing prostate cancer in this population. Controversy also exists as to the potential of these medications increasing the risk for high-grade prostate cancer, which has led to a US Food and Drug Administration (FDA) warning. AEs include decreased libido (1.5%), ejaculatory dysfunction (3.4%), gynecomastia (1.3%), and/or ED (1.6%).^26-28 A recent study evaluating 5-α-RIs demonstrated about a 2-fold increased risk of depression.²⁹

There are well-established studies that note increased effectiveness when using combined α-blocker therapy with 5-α-RI medications. The Medical Therapy of Prostate Symptoms (MTOPS) and Combination Avodart and Tamsulosin (CombAT) trials showed that the combination of both medications was more effective in improving voiding symptoms and flow rates than either agent alone.^15,16 Combination therapy resulted in a 66% reduction in disease progression, 81% reduction in urinary retention, and a 67% reduction in the need for surgery compared with placebo.

Anticholinergic medication use in BPH with LUTS is well established, and their use is often combined with other therapies. Anticholinergics work by inhibiting muscarinic M3 receptors to reduce detrusor muscle contraction. This effectively decreases bladder contractions and delays the desire to void. Kaplan and colleagues showed that tolterodine significantly improved a patient’s QOL when added to α-blocker therapy.³⁰ Patients reported a positive outcome at 12 weeks, which resulted in a reduction in urgency incontinence, urgency, nocturia, and the overall number of voiding episodes within 24 hours.

β-3 agonists are a class of medications for OAB; mirabegron and vibegron have proven effective in reducing similar symptoms. In phase 3 clinical trials, mirabegron improved urinary incontinence episodes by 50% and reduced the number of voids in 24 hours.³¹ Mirabegron is well tolerated and avoids many common anticholinergic effects.³² Vibegron is the newest medication in the class and could soon become the preferred agent given it does not have cytochrome P450 interactions and does not cause hypertension like mirabegron.³³

Anticholinergics should be used with caution in patients with a history of urinary retention, elevated after-void residual, or other medications with known anticholinergic effects. AEs include sedation, confusion, dry mouth, constipation, and potential falls in older patients.¹⁸ Recent studies have noted an association with dementia in the prolonged use of these medications in older patients and should be used cautiously.²⁰

Phosphodiesterase-5 enzyme inhibitors (PDE-5) are adjunctive medications shown to improve LUTS. This class of medication is prescribed mostly for ED. However, tadalafil 5 mg taken daily also is FDA approved for the treatment of LUTS secondary to BPH given its prolonged half-life. The exact mechanism for improved BPH symptoms is unknown. Possibly the effects are due to an increase mediated by PDE-5 in cyclic guanosine monophosphate (cGMP), which increases smooth muscle relaxation and tissue perfusion of the prostate and bladder.³⁴ There have been limited studies on objective improvement in uroflowmetry parameters compared with other treatments. The daily dosing of tadalafil should not be prescribed in men with a creatinine clearance < 30 mL/min.²⁹ Tadalafil is not considered a first-line agent and is usually reserved for patients who experience ED in addition to BPH. When initiating BPH pharmacologic therapy, the PCP should be aware of adherence and high discontinuation rates.³⁵

Surgical Treatments

Surgical treatments are often delayed out of fear of potential AEs or considered a last resort when symptoms are too severe.³⁶ Early intervention is required to prevent irreversible deleterious changes to detrusor muscle structure and function (Figure). Patients fear urinary incontinence, ED or ejaculatory dysfunction, and anesthesia complications associated with surgical interventions.^6,37 Multiple studies show that patients fare better with early surgical intervention, experiencing improved IPSS scores, urinary flow, and QOL. The following is an overview of the most popular procedures.

Prostatic urethral lift (PUL) using the UroLift System is an FDA-approved, minimally-invasive treatment of LUTS secondary to BPH. This procedure treats prostates < 80 g with an absent median lobe.^6,21,38 Permanent implants are placed per the prostatic urethra to displace obstructing prostate tissue laterally. This opens the urethra directly without cutting, heating, or removing any prostate tissue. This procedure is minimally invasive, often done in the office as an outpatient procedure, and offers better symptom relief than medication with a lower risk profile than transurethral resection of the prostate (TURP).^39,40 The LIFT study was a multicenter, randomized, blinded trial; patients were randomized 2:1 to undergo UroLift or a sham operation. At 3 years, average improvements were statistically significant for total IPSS reduction (41%), QOL improvement (49%), and improved maximum flow rates by (51%).⁴¹ Risk for urinary incontinence is low, and the procedure has been shown to preserve erectile and ejaculatory function. Furthermore, patients report significant improvement in their QOL without the need for medications. Surgical retreatment rates at 5 years are 13.6%, with an additional 10.7% of subjects back on medication therapy with α-blockers or 5-α-RIs.⁴²

Water vapor thermal therapy or Rez¯um uses steam as thermal energy to destroy obstructing prostate tissue and relieve the obstruction.⁴³ The procedure differs from older conductive heat thermotherapies because the steam penetrates prostate zonal anatomy without affecting areas outside the targeted treatment zone. The procedure is done in the office with local anesthesia and provides long-lasting relief of LUTS with minimal risks. Following the procedure, patients require an indwelling urethral catheter for 3 to 7 days, and most patients begin to experience symptom improvement 2 to 4 weeks following the procedure.⁴⁴ The procedure received FDA approval in 2015. Four-year data show significant improvement in maximal flow rate (50%), IPSS (47%), and QOL (43%).⁴⁵ Surgical retreatment rates were 4.4%. Criticisms of this treatment include patient discomfort with the office procedure, the requirement for an indwelling catheter for a short period, and lack of long-term outcomes data. Guidelines support use in prostate volumes > 80 g with or without median lobe anatomy.

TURP is the gold standard to which other treatments are compared.⁴⁶ The surgery is performed in the operating room where urologists use a rigid cystoscope and resection element to effectively carve out and cauterize obstructing prostate tissue. Patients typically recover for a short period with an indwelling urethral catheter that is often removed 12 to 24 hours after surgery. New research points out that despite increasing mean age (55% of patients are aged > 70 years with associated comorbidities), the morbidity of TURP was < 1% and mortality rate of 0 to 0.3%.⁴⁷ Postoperative complications include bleeding that requires a transfusion (3%), retrograde ejaculation (65%), and rare urinary incontinence (2%).⁴⁷ Surgical retreatment rates for patients following a TURP are approximately 13 to 15% at 8 years.³⁴

Laser surgery for BPH includes multiple techniques: photovaporization of the prostate using a Greenlight XPS laser, holmium laser ablation, and holmium laser enucleation (HoLEP). Proponents of these treatments cite lower bleeding risks compared with TURP, but the operation is largely surgeon dependent on the technology chosen. Most studies comparing these technologies with TURP show similar outcomes of IPSS reports, quality of life improvements, and complications.

Patients with extremely large prostates, > 100 g or 4 times the normal size, pose a unique challenge to surgical treatment. Historically, patients were treated with an open simple prostatectomy operation or staged TURP procedures. Today, urologists use newer, safer ways to treat these patients. Both HoLEP and robot-assisted simple prostatectomy work well in relieving urinary symptoms with lower complications compared with older open surgery. Other minimally invasive procedures, such as prostatic artery embolism, have been described for the treatment of BPH specifically in men who may be unfit for surgery.⁴⁸Future treatments are constantly evolving. Many unanswered questions remain about BPH and the role of inflammation, metabolic dysfunction, obesity, and other genetic factors driving BPH and prostate growth. Pharmaceutical opportunities exist in mechanisms aimed to reduce prostate growth, induce cellular apoptosis, as well as other drugs to reduce bladder symptoms. Newer, minimally invasive therapies also will become more readily available, such as Aquablation, which is the first FDA-granted surgical robot for the autonomous removal of prostatic tissue due to BPH.⁴⁹ However, the goal of all future therapies should include the balance of alleviating disruptive symptoms while demonstrating a favorable risk profile. Many men discontinue taking medications, yet few present for surgery. Most concerning is the significant population of men who will develop irreversible bladder dysfunction while waiting for the perfect treatment. There are many opportunities for an effective treatment that is less invasive than surgery, provides durable relief, has minimal AEs, and is affordable.

Conclusions

There is no perfect treatment for patients with LUTS. All interventions have potential AEs and associated complications. Medications are often started as first-line therapy but are often discontinued at the onset of significant AEs. This process is often repeated. Many patients will try different medications without any significant improvement in their symptoms or short-term relief, which results in the gradual progression of the disease.

The PCP plays a significant role in the initial evaluation and management of BPH. These frontline clinicians can recognize patients who may already be experiencing sequela of prolonged bladder outlet obstruction and refer these men to urologists promptly. Counseling patients about their treatment options is an important duty for all PCPs.

A clear understanding of the available treatment options will help PCPs counsel patients appropriately about lifestyle modification, medications, and surgical treatment options for their symptoms. The treatment of this disorder is a rapidly evolving topic with the constant introduction of new technologies and medications, which are certain to continue to play an important role for PCPs and urologists.

Lower urinary tract symptoms (LUTS)are common and tend to increase in frequency with age. Managing LUTS can be complicated, requires an informed discussion between the primary care practitioner (PCP) and patient, and is best achieved by a thorough understanding of the many medical and surgical options available. Over the past 3 decades, medications have become the most common therapy; but recently, newer minimally invasive surgeries have challenged this paradigm. This article provides a comprehensive review for PCPs regarding the evaluation and management of LUTS in men and when to consider a urology referral.

Benign prostatic hyperplasia (BPH) and LUTS are common clinical encounters for most PCPs. About 50% of men will develop LUTS associated with BPH, and symptoms associated with these conditions increase as men age.^1,2 Studies have estimated that 90% of men aged 45 to 80 years demonstrate some symptoms of LUTS.³ Strong genetic influence seems to suggest heritability, but BPH also occurs in sporadic forms and is heavily influenced by androgens.⁴

BPH is a histologic diagnosis, whereas LUTS consists of complex symptomatology related to both static or dynamic components.¹ The enlarged prostate gland obstructs the urethra, simultaneously causing an increase in muscle tone and resistance at the bladder neck and prostatic urethra, leading to increased resistance to urine flow. As a result, there is a thickening of the detrusor muscles in the bladder wall and an overall decreased compliance. Urine becomes stored under increased pressure. These changes result in a weak or intermittent urine stream, incomplete emptying of the bladder, postvoid dribble, hesitancy, and irritative symptoms, such as urgency, frequency, and nocturia.

For many patients, BPH associated with LUTS is a quality of life (QOL) issue. The stigma associated with these symptoms often leads to delays in patients seeking care. Many patients do not seek treatment until symptoms have become so severe that changes in bladder health are often irreversible. Early intervention can dramatically improve a patient’s QOL. Also, early intervention has the potential to reduce overall health care expenditures. BPH-related spending exceeds $1 billion each year in the Medicare program alone.⁵

PCPs are in a unique position to help many patients who present with early-stage LUTS. Given the substantial impact this disease has on QOL, early recognition of symptoms and prompt treatment play a major role. Paramount to this effort is awareness and understanding of various treatments, their advantages, and adverse effects (AEs). This article highlights evidence-based evaluation and treatment of BPH/LUTS for PCPs who treat veterans and recommendations as to when to refer a patient to a urologist.

Evaluation of LUTS and BPH

Evaluation begins with a thorough medical history and physical examination. Particular attention should focus on ruling out other causes of LUTS, such as a urinary tract infection (UTI), acute prostatitis, malignancy, bladder dysfunction, neurogenic bladder, and other obstructive pathology, such as urethral stricture disease. The differential diagnosis of LUTS includes BPH, UTI, bladder neck obstruction, urethral stricture, bladder stones, polydipsia, overactive bladder (OAB), nocturnal polyuria, neurologic disease, genitourinary malignancy, renal failure, and acute/chronic urinary retention.⁶

Relevant medical history influencing urinary symptoms includes diabetes mellitus, underlying neurologic diseases, previous trauma, sexually transmitted infections, and certain medications. Symptom severity may be obtained using a validated questionnaire, such as the International Prostate Symptom Score (IPSS), which also aids clinicians in assessing the impact of LUTS on QOL. Additionally, urinary frequency or volume records (voiding diary) may help establish the severity of the patient’s symptoms and provide insight into other potential causes for LUTS. Patients with BPH often have concurrent erectile dysfunction (ED) or other sexual dysfunction symptoms. Patients should be evaluated for baseline sexual dysfunction before the initiation of treatment as many therapies worsen symptoms of ED or ejaculatory dysfunction.

A comprehensive physical examination with a focus on the genitourinary system should, at minimum, assess for abnormalities of the urethral meatus, prepuce, penis, groin nodes, and prior surgical scars. A digital rectal examination also should be performed. Although controversial, a digital rectal examination for prostate cancer screening may provide a rough estimate of prostate size, help rule out prostatitis, and detect incident prostate nodules. Prostate size does not necessarily correlate well with the degree of urinary obstruction or LUTS but is an important consideration when deciding among different therapies.¹

Laboratory and Adjunctive Tests

A urinalysis with microscopy helps identify other potential causes for urinary symptoms, including infection, proteinuria, or glucosuria. In patients who present with gross or microscopic hematuria, additional consideration should be given to bladder calculi and genitourinary cancer.² When a reversible source for the hematuria is not identified, these patients require referral to a urologist for a hematuria evaluation.

There is some controversy regarding prostate specific antigen (PSA) testing. Most professional organizations advocate for a shared decision-making approach before testing. The American Cancer Society recommends this informed discussion occur between the patient and the PCP for men aged > 50 years at average risk, men aged > 45 years at high risk of developing prostate cancer (African Americans or first-degree relative with early prostate cancer diagnosis), and aged 40 years for men with more than one first-degree relative with an early prostate cancer diagnosis.⁷

Adjunctive tests include postvoid residual (PVR), cystoscopy, uroflowmetry, urodynamics, and transrectal ultrasound. However, these are mostly performed by urologists. In some patients with bladder decompensation after prolonged partial bladder outlet obstruction, urodynamics may be used by urologists to determine whether a patient may benefit from an outlet obstruction procedure. Ordering additional imaging or serum studies for the assessment of LUTS is rarely helpful.

Treatment

Treatment includes management with or without lifestyle modification, medication administration, and surgical therapy. New to this paradigm are in-office minimally invasive surgical options. The goal of treatment is not only to reduce patient symptoms and improve QOL, but also to prevent the secondary sequala of urinary retention, bladder failure, and eventual renal impairment.⁷A basic understanding of these treatments can aid PCPs with appropriate patient counseling and urologic referral.⁸

Lifestyle and Behavior Modification

Behavior modification is the starting point for all patients with LUTS. Lifestyle modifications for LUTS include avoiding substances that exacerbate symptoms, such as α-agonists (decongestants), caffeine, alcohol, spicy/acidic foods, chocolate, and soda. These substances are known to be bladder irritants. Common medications contributing to LUTS include antidepressants, decongestants, antihistamines, bronchodilators, anticholinergics, and sympathomimetics. To decrease nocturia, behavioral modifications include limiting evening fluid intake, timed diuretic administration for patients already on a diuretic, and elevating legs 1 hour before bedtime. Counseling obese patients to lose weight and increasing physical activity have been linked to reduced LUTS.⁹ Other behavioral techniques include double voiding: a technique where patients void normally then change positions and return to void to empty the bladder. Another technique is timed voiding: Many patients have impaired sensation when the bladder is full. These patients are encouraged to void at regular intervals.

Complementary and Alternative Medicine

Multiple nutraceutical compounds claim improved urinary health and symptom reduction. These compounds are marketed to patients with little regulation and oversight since supplements are not regulated or held to the same standard as prescription medications. The most popular nutraceutical for prostate health and LUTS is saw palmetto. Despite its common usage for the treatment of LUTS, little data support saw palmetto health claims. In 2012, a systematic review of 32 randomized trials including 5666 patients compared saw palmetto with a placebo. The study found no difference in urinary symptom scores, urinary flow, or prostate size.^10,11 Other phytotherapy compounds often considered for urinary symptoms include stinging nettle extract and β-sitosterol compounds. The mechanism of action of these agents is unknown and efficacy data are lacking.

Historically, acupuncture and pelvic floor physical therapy have been used successfully for OAB symptoms. A meta-analysis found positive beneficial effects of acupuncture compared with a sham control for short- and medium-term follow-up in both IPSS and urine flow rates in some studies; however, when combining the studies for more statistical power, the benefits were less clear.¹² Physical therapists with specialized training and certification in pelvic health can incorporate certain bladder training techniques. These include voiding positional changes (double voiding and postvoid urethral milking) and timed voiding.^13,14 These interventions often address etiologies of LUTS for which medical therapies are not effective as the sole treatment option.

Medication Management

Medical management includes α-blockers, 5-α-reductase inhibitors (5-α-RIs), antimuscarinic or anticholinergic medicines, β-3 agonists, and phosphodiesterase inhibitors (Table). These medications work independently as well as synergistically. The use of medications to improve symptoms must be balanced against potential AEs and the consequences of a lifetime of drug usage, which can be additive.^15,16

First-line pharmacological therapy for BPH is α-blockers, which work by blocking α1A receptors in the prostate and bladder neck, leading to smooth muscle relaxation, increased diameter of the channel, and improved urinary flow. α-receptors in the bladder neck and prostate are expressed with increased frequency with age and are a potential cause for worsening symptoms as men age. Studies demonstrate that these medications reduce symptoms by 30 to 40% and increase flow rates by 16 to 25%.¹⁷ Commonly prescribed α-blockers include tamsulosin, alfuzosin, silodosin, doxazosin, and terazosin. Doxazosin and terazosin require dose titrations because they may cause significant hypotension. Orthostatic hypotension typically improves with time and is avoided if the patient takes the medication at bedtime. Both doxazosin and terazosin are on the American Geriatric Society’s Beers Criteria list and should be avoided in older patients.¹⁸ Tamsulosin, alfuzosin, and silodosin have a standardized dosing regimen and lower rates of hypotension. Significant AEs include ejaculation dysfunction, nasal congestion, and orthostatic hypotension. Duan and colleagues have linked tamsulosin with dementia. However, this association is not causal and further studies are necessary.^19,20 Patients who have taken these agents also are at risk for intraoperative floppy iris syndrome (IFIS). Permanent visual problems can arise if the intraoperative management is not managed to account for IFIS. These medications have a rapid onset of action and work immediately. However, to reach maximum benefit, patients must take the medication for several weeks. Unfortunately, up to one-third of patients will have no improvement with α-blocker therapy, and many patients will discontinue these medications because of significant AEs.^6,21

5-α-RIs (finasteride and dutasteride) inhibit the conversion of testosterone to more potent dihydrotestosterone. They effectively reduce prostate volume by 25 to 30%.²² The results occur slowly and can take 6 to 12 months to reach the desired outcome. These medications are effective in men with larger prostates and not as effective in men with smaller prostates.²³ These medications can improve urinary flow rates by about 10%, reduce IPSS scores by 20 to 30%, reduce the risk of urinary retention by 50%, and reduce the progression of BPH to the point where surgery is required by 50%.²⁴ Furthermore, 5-α-RIs lower PSA by > 50% after 12 months of treatment.²⁵

A baseline PSA should be established before administration and after 6 months of treatment. Any increase in the PSA even if the level is within normal limits should be evaluated for prostate cancer. Sarkar and colleagues recently published a study evaluating prostate cancer diagnosis in patients treated with 5-α-RI and found there was a delay in diagnosing prostate cancer in this population. Controversy also exists as to the potential of these medications increasing the risk for high-grade prostate cancer, which has led to a US Food and Drug Administration (FDA) warning. AEs include decreased libido (1.5%), ejaculatory dysfunction (3.4%), gynecomastia (1.3%), and/or ED (1.6%).^26-28 A recent study evaluating 5-α-RIs demonstrated about a 2-fold increased risk of depression.²⁹

There are well-established studies that note increased effectiveness when using combined α-blocker therapy with 5-α-RI medications. The Medical Therapy of Prostate Symptoms (MTOPS) and Combination Avodart and Tamsulosin (CombAT) trials showed that the combination of both medications was more effective in improving voiding symptoms and flow rates than either agent alone.^15,16 Combination therapy resulted in a 66% reduction in disease progression, 81% reduction in urinary retention, and a 67% reduction in the need for surgery compared with placebo.

Anticholinergic medication use in BPH with LUTS is well established, and their use is often combined with other therapies. Anticholinergics work by inhibiting muscarinic M3 receptors to reduce detrusor muscle contraction. This effectively decreases bladder contractions and delays the desire to void. Kaplan and colleagues showed that tolterodine significantly improved a patient’s QOL when added to α-blocker therapy.³⁰ Patients reported a positive outcome at 12 weeks, which resulted in a reduction in urgency incontinence, urgency, nocturia, and the overall number of voiding episodes within 24 hours.

β-3 agonists are a class of medications for OAB; mirabegron and vibegron have proven effective in reducing similar symptoms. In phase 3 clinical trials, mirabegron improved urinary incontinence episodes by 50% and reduced the number of voids in 24 hours.³¹ Mirabegron is well tolerated and avoids many common anticholinergic effects.³² Vibegron is the newest medication in the class and could soon become the preferred agent given it does not have cytochrome P450 interactions and does not cause hypertension like mirabegron.³³

Anticholinergics should be used with caution in patients with a history of urinary retention, elevated after-void residual, or other medications with known anticholinergic effects. AEs include sedation, confusion, dry mouth, constipation, and potential falls in older patients.¹⁸ Recent studies have noted an association with dementia in the prolonged use of these medications in older patients and should be used cautiously.²⁰

Phosphodiesterase-5 enzyme inhibitors (PDE-5) are adjunctive medications shown to improve LUTS. This class of medication is prescribed mostly for ED. However, tadalafil 5 mg taken daily also is FDA approved for the treatment of LUTS secondary to BPH given its prolonged half-life. The exact mechanism for improved BPH symptoms is unknown. Possibly the effects are due to an increase mediated by PDE-5 in cyclic guanosine monophosphate (cGMP), which increases smooth muscle relaxation and tissue perfusion of the prostate and bladder.³⁴ There have been limited studies on objective improvement in uroflowmetry parameters compared with other treatments. The daily dosing of tadalafil should not be prescribed in men with a creatinine clearance < 30 mL/min.²⁹ Tadalafil is not considered a first-line agent and is usually reserved for patients who experience ED in addition to BPH. When initiating BPH pharmacologic therapy, the PCP should be aware of adherence and high discontinuation rates.³⁵

Surgical Treatments

Surgical treatments are often delayed out of fear of potential AEs or considered a last resort when symptoms are too severe.³⁶ Early intervention is required to prevent irreversible deleterious changes to detrusor muscle structure and function (Figure). Patients fear urinary incontinence, ED or ejaculatory dysfunction, and anesthesia complications associated with surgical interventions.^6,37 Multiple studies show that patients fare better with early surgical intervention, experiencing improved IPSS scores, urinary flow, and QOL. The following is an overview of the most popular procedures.

Prostatic urethral lift (PUL) using the UroLift System is an FDA-approved, minimally-invasive treatment of LUTS secondary to BPH. This procedure treats prostates < 80 g with an absent median lobe.^6,21,38 Permanent implants are placed per the prostatic urethra to displace obstructing prostate tissue laterally. This opens the urethra directly without cutting, heating, or removing any prostate tissue. This procedure is minimally invasive, often done in the office as an outpatient procedure, and offers better symptom relief than medication with a lower risk profile than transurethral resection of the prostate (TURP).^39,40 The LIFT study was a multicenter, randomized, blinded trial; patients were randomized 2:1 to undergo UroLift or a sham operation. At 3 years, average improvements were statistically significant for total IPSS reduction (41%), QOL improvement (49%), and improved maximum flow rates by (51%).⁴¹ Risk for urinary incontinence is low, and the procedure has been shown to preserve erectile and ejaculatory function. Furthermore, patients report significant improvement in their QOL without the need for medications. Surgical retreatment rates at 5 years are 13.6%, with an additional 10.7% of subjects back on medication therapy with α-blockers or 5-α-RIs.⁴²

Water vapor thermal therapy or Rez¯um uses steam as thermal energy to destroy obstructing prostate tissue and relieve the obstruction.⁴³ The procedure differs from older conductive heat thermotherapies because the steam penetrates prostate zonal anatomy without affecting areas outside the targeted treatment zone. The procedure is done in the office with local anesthesia and provides long-lasting relief of LUTS with minimal risks. Following the procedure, patients require an indwelling urethral catheter for 3 to 7 days, and most patients begin to experience symptom improvement 2 to 4 weeks following the procedure.⁴⁴ The procedure received FDA approval in 2015. Four-year data show significant improvement in maximal flow rate (50%), IPSS (47%), and QOL (43%).⁴⁵ Surgical retreatment rates were 4.4%. Criticisms of this treatment include patient discomfort with the office procedure, the requirement for an indwelling catheter for a short period, and lack of long-term outcomes data. Guidelines support use in prostate volumes > 80 g with or without median lobe anatomy.

TURP is the gold standard to which other treatments are compared.⁴⁶ The surgery is performed in the operating room where urologists use a rigid cystoscope and resection element to effectively carve out and cauterize obstructing prostate tissue. Patients typically recover for a short period with an indwelling urethral catheter that is often removed 12 to 24 hours after surgery. New research points out that despite increasing mean age (55% of patients are aged > 70 years with associated comorbidities), the morbidity of TURP was < 1% and mortality rate of 0 to 0.3%.⁴⁷ Postoperative complications include bleeding that requires a transfusion (3%), retrograde ejaculation (65%), and rare urinary incontinence (2%).⁴⁷ Surgical retreatment rates for patients following a TURP are approximately 13 to 15% at 8 years.³⁴

Laser surgery for BPH includes multiple techniques: photovaporization of the prostate using a Greenlight XPS laser, holmium laser ablation, and holmium laser enucleation (HoLEP). Proponents of these treatments cite lower bleeding risks compared with TURP, but the operation is largely surgeon dependent on the technology chosen. Most studies comparing these technologies with TURP show similar outcomes of IPSS reports, quality of life improvements, and complications.

Patients with extremely large prostates, > 100 g or 4 times the normal size, pose a unique challenge to surgical treatment. Historically, patients were treated with an open simple prostatectomy operation or staged TURP procedures. Today, urologists use newer, safer ways to treat these patients. Both HoLEP and robot-assisted simple prostatectomy work well in relieving urinary symptoms with lower complications compared with older open surgery. Other minimally invasive procedures, such as prostatic artery embolism, have been described for the treatment of BPH specifically in men who may be unfit for surgery.⁴⁸Future treatments are constantly evolving. Many unanswered questions remain about BPH and the role of inflammation, metabolic dysfunction, obesity, and other genetic factors driving BPH and prostate growth. Pharmaceutical opportunities exist in mechanisms aimed to reduce prostate growth, induce cellular apoptosis, as well as other drugs to reduce bladder symptoms. Newer, minimally invasive therapies also will become more readily available, such as Aquablation, which is the first FDA-granted surgical robot for the autonomous removal of prostatic tissue due to BPH.⁴⁹ However, the goal of all future therapies should include the balance of alleviating disruptive symptoms while demonstrating a favorable risk profile. Many men discontinue taking medications, yet few present for surgery. Most concerning is the significant population of men who will develop irreversible bladder dysfunction while waiting for the perfect treatment. There are many opportunities for an effective treatment that is less invasive than surgery, provides durable relief, has minimal AEs, and is affordable.

Conclusions

There is no perfect treatment for patients with LUTS. All interventions have potential AEs and associated complications. Medications are often started as first-line therapy but are often discontinued at the onset of significant AEs. This process is often repeated. Many patients will try different medications without any significant improvement in their symptoms or short-term relief, which results in the gradual progression of the disease.

The PCP plays a significant role in the initial evaluation and management of BPH. These frontline clinicians can recognize patients who may already be experiencing sequela of prolonged bladder outlet obstruction and refer these men to urologists promptly. Counseling patients about their treatment options is an important duty for all PCPs.

A clear understanding of the available treatment options will help PCPs counsel patients appropriately about lifestyle modification, medications, and surgical treatment options for their symptoms. The treatment of this disorder is a rapidly evolving topic with the constant introduction of new technologies and medications, which are certain to continue to play an important role for PCPs and urologists.

Narrative competence is the ability to acquire, interpret, and act on the stories of others.¹ Developing this skill through guided medical storytelling can improve health care practitioners’ (HCPs) sense of empathy and satisfaction with their work.² Narrative medicine experiences for medical students can foster a deeper understanding of their patients beyond illness-associated identities.³