SAN FRANCISCO – The immune checkpoint inhibitor pembrolizumab (Keytruda) may soon unseat chemotherapy as standard second-line therapy for certain advanced cancers of the esophagus or gastroesophageal junction, according to data from the global phase 3 KEYNOTE-181 trial.

Susan London/MDEdge News

“Patients with advanced esophageal cancer after first-line therapy have a poor prognosis and limited treatment options,” said lead investigator Takashi Kojima, MD, of the National Cancer Center Hospital East, Kashiwa, Japan. “Taxanes and irinotecan are commonly used after first-line chemotherapy; however, no overall survival benefit has been demonstrated for chemotherapy in a phase 3 study.”

The 628 patients in KEYNOTE-181 were randomly assigned to chemotherapy (paclitaxel, docetaxel, or irinotecan, left to investigator’s choice) or pembrolizumab, an antibody to programmed death 1 (PD-1). Currently, pembrolizumab is approved in the United States for use as third- or later-line therapy for gastric or gastroesophageal junction cancer that is positive for programmed death ligand 1 (PD-L1) as defined by a combined positive score (CPS) of 1 or greater, among many other indications.

Main trial results reported at the 2019 GI Cancers Symposium showed that among patients with high PD-L1 expression, defined by a CPS of 10 or higher, pembrolizumab reduced risk of death by about one-third, prolonging survival by 2.6 months. The difference met the predefined threshold for statistical significance.

There was a more modest, nonsignificant benefit among patients with tumors having squamous cell carcinoma histology and among the entire intention-to-treat population.

The rate of treatment-related adverse events of grade 3-5 was roughly half as high with pembrolizumab versus chemotherapy (18.2% vs. 40.9%).

“These data suggest that pembrolizumab should be considered a new standard of care for patients with PD-L1 CPS of 10 or greater metastatic esophageal cancer in the second-line setting,” Dr. Kojima concluded.
 

Implications for practice

“In the intention-to-treat population, the KEYNOTE-181 study failed to meet its primary endpoint of overall survival, so pembrolizumab is not indicated in unselected esophageal cancer patients,” said invited discussant Harry H. Yoon, MD, cochair of the Esophageal/Gastric Cancer Disease Group at the Mayo Clinic Cancer Center, Rochester, Minn.

Susan London/MDedge News

For the patients with squamous histology, the negative findings are unlikely to be due to underpowering and may instead be related to the trial’s use of multiple primary endpoints, in his opinion. “Some may advocate using pembrolizumab off protocol [in this population], particularly for patients who cannot tolerate chemotherapy, because it is after all better tolerated than chemo. This can be a discussion point for guideline committees,” he said.

The results for the group with PD-L1 CPS scores of 10 or higher are statistically significant and clinically meaningful, as well as internally valid – with the caveat that patients were not stratified by PD-L1 status and some favorable risk factors were more common in the pembrolizumab group, according to Dr. Yoon. The 43% survival rate at 12 months translates to a number needed to treat of just four patients for one patient to be alive at that time point.

“A multivariate analysis could help clarify whether the positive results in the PD-L1 CPS 10-or-higher subgroup are explained by a higher frequency of favorable patient characteristics in the pembrolizumab arm,” he noted. “The strength of those results could influence guideline recommendations and implementation in clinical practice.”

Subgroup analyses suggested benefit was mainly seen in Asian patients, who tend to have higher prevalence of squamous tumors, Dr. Yoon said. Potential molecular differences at play here may be elucidated by ongoing research.

Ultimately, the findings in the PD-L1 CPS 10-or-higher group have potential implications for biomarker testing. “For the patient in front of me, I currently order PD-L1 and HER2 at first metastatic diagnosis in gastroesophageal adenocarcinomas,” he elaborated. “It’s reasonable to consider a practice change. This means ordering PD-L1 at first metastatic diagnosis in patients with squamous carcinoma of the esophagus. This would also mean some pathology labs may need to report a more detailed PD-L1 CPS score, if they don’t already.”

These findings also have potential implications for treatment. “For the second-line setting, for squamous carcinoma of the esophagus, esophageal adenocarcinomas, and Siewert 1 adenocarcinomas with a PD-L1 CPS of 10 or more, it’s reasonable to consider pembrolizumab,” Dr. Yoon noted. “This should be discussed within guideline committees, and the results will be submitted to regulatory authorities, who will have access to more detailed data. It’s possible that these recommendations could be modified in the near future.”
 

Study details

As KEYNOTE-181 had three primary endpoints (overall survival in each of three populations), P values required for statistical significance were defined accordingly. “The study was positive if one of the primary endpoints was met,” Dr. Kojima explained at the symposium, which was sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Some 35% of trial patients had a PD-L1 CPS of 10 or greater. In this population, median overall survival was 9.3 months with pembrolizumab and 6.7 months with chemotherapy. The hazard ratio was 0.69, with the P value (.0074) meeting that predefined for statistical significance in this population (less than or equal to .0085). The 12-month rate of overall survival was 43% and 20%, respectively.

About 64% of trial patients had squamous cell carcinoma histology. In this population, median overall survival was 8.2 months with pembrolizumab and 7.1 months with chemotherapy. The hazard ratio was 0.78, but the P value (.0095) did not meet that predefined for statistical significance in this group (less than or equal to .0077).

Finally, in the entire intention-to-treat population, median overall survival was identical, at 7.1 months, with pembrolizumab and with chemotherapy. The hazard ratio was 0.89 in favor of the antibody, but the P value (.0560) did not meet that predefined for statistical significance in this population (less than or equal to .0077).

A similar pattern was seen for other outcomes, with patients having PD-L1 CPS greater than or equal to 10 deriving greatest benefit from pembrolizumab over chemotherapy in terms of progression-free survival (hazard ratio, 0.73), response rate (21.5% vs. 6.1%), and median duration of response (9.3 vs. 7.7 months).

“Toxicity profiles were in line with previous reports of each treatment. No new safety signals were observed,” Dr. Kojima reported. Pembrolizumab was associated with a higher rate of immune-mediated and infusion reactions (23.2% vs. 7.4%), but lower rates of most gastrointestinal and hematologic adverse events.

Dr. Kojima disclosed ties to Oncolys BioPharma, Astellas, Amgen, MSD, Ono Pharmaceutical, and Shionogi. Merck Sharp & Dohme sponsored the trial.

SOURCE: Kojima T et al. GI Cancers Symposium Abstract 2, https://meetinglibrary.asco.org/record/169377/abstract.

SAN FRANCISCO – The immune checkpoint inhibitor pembrolizumab (Keytruda) may soon unseat chemotherapy as standard second-line therapy for certain advanced cancers of the esophagus or gastroesophageal junction, according to data from the global phase 3 KEYNOTE-181 trial.

Susan London/MDEdge News

“Patients with advanced esophageal cancer after first-line therapy have a poor prognosis and limited treatment options,” said lead investigator Takashi Kojima, MD, of the National Cancer Center Hospital East, Kashiwa, Japan. “Taxanes and irinotecan are commonly used after first-line chemotherapy; however, no overall survival benefit has been demonstrated for chemotherapy in a phase 3 study.”

The 628 patients in KEYNOTE-181 were randomly assigned to chemotherapy (paclitaxel, docetaxel, or irinotecan, left to investigator’s choice) or pembrolizumab, an antibody to programmed death 1 (PD-1). Currently, pembrolizumab is approved in the United States for use as third- or later-line therapy for gastric or gastroesophageal junction cancer that is positive for programmed death ligand 1 (PD-L1) as defined by a combined positive score (CPS) of 1 or greater, among many other indications.

Main trial results reported at the 2019 GI Cancers Symposium showed that among patients with high PD-L1 expression, defined by a CPS of 10 or higher, pembrolizumab reduced risk of death by about one-third, prolonging survival by 2.6 months. The difference met the predefined threshold for statistical significance.

There was a more modest, nonsignificant benefit among patients with tumors having squamous cell carcinoma histology and among the entire intention-to-treat population.

The rate of treatment-related adverse events of grade 3-5 was roughly half as high with pembrolizumab versus chemotherapy (18.2% vs. 40.9%).

“These data suggest that pembrolizumab should be considered a new standard of care for patients with PD-L1 CPS of 10 or greater metastatic esophageal cancer in the second-line setting,” Dr. Kojima concluded.
 

Implications for practice

“In the intention-to-treat population, the KEYNOTE-181 study failed to meet its primary endpoint of overall survival, so pembrolizumab is not indicated in unselected esophageal cancer patients,” said invited discussant Harry H. Yoon, MD, cochair of the Esophageal/Gastric Cancer Disease Group at the Mayo Clinic Cancer Center, Rochester, Minn.

Susan London/MDedge News

For the patients with squamous histology, the negative findings are unlikely to be due to underpowering and may instead be related to the trial’s use of multiple primary endpoints, in his opinion. “Some may advocate using pembrolizumab off protocol [in this population], particularly for patients who cannot tolerate chemotherapy, because it is after all better tolerated than chemo. This can be a discussion point for guideline committees,” he said.

The results for the group with PD-L1 CPS scores of 10 or higher are statistically significant and clinically meaningful, as well as internally valid – with the caveat that patients were not stratified by PD-L1 status and some favorable risk factors were more common in the pembrolizumab group, according to Dr. Yoon. The 43% survival rate at 12 months translates to a number needed to treat of just four patients for one patient to be alive at that time point.

“A multivariate analysis could help clarify whether the positive results in the PD-L1 CPS 10-or-higher subgroup are explained by a higher frequency of favorable patient characteristics in the pembrolizumab arm,” he noted. “The strength of those results could influence guideline recommendations and implementation in clinical practice.”

Subgroup analyses suggested benefit was mainly seen in Asian patients, who tend to have higher prevalence of squamous tumors, Dr. Yoon said. Potential molecular differences at play here may be elucidated by ongoing research.

Ultimately, the findings in the PD-L1 CPS 10-or-higher group have potential implications for biomarker testing. “For the patient in front of me, I currently order PD-L1 and HER2 at first metastatic diagnosis in gastroesophageal adenocarcinomas,” he elaborated. “It’s reasonable to consider a practice change. This means ordering PD-L1 at first metastatic diagnosis in patients with squamous carcinoma of the esophagus. This would also mean some pathology labs may need to report a more detailed PD-L1 CPS score, if they don’t already.”

These findings also have potential implications for treatment. “For the second-line setting, for squamous carcinoma of the esophagus, esophageal adenocarcinomas, and Siewert 1 adenocarcinomas with a PD-L1 CPS of 10 or more, it’s reasonable to consider pembrolizumab,” Dr. Yoon noted. “This should be discussed within guideline committees, and the results will be submitted to regulatory authorities, who will have access to more detailed data. It’s possible that these recommendations could be modified in the near future.”
 

Study details

As KEYNOTE-181 had three primary endpoints (overall survival in each of three populations), P values required for statistical significance were defined accordingly. “The study was positive if one of the primary endpoints was met,” Dr. Kojima explained at the symposium, which was sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Some 35% of trial patients had a PD-L1 CPS of 10 or greater. In this population, median overall survival was 9.3 months with pembrolizumab and 6.7 months with chemotherapy. The hazard ratio was 0.69, with the P value (.0074) meeting that predefined for statistical significance in this population (less than or equal to .0085). The 12-month rate of overall survival was 43% and 20%, respectively.

About 64% of trial patients had squamous cell carcinoma histology. In this population, median overall survival was 8.2 months with pembrolizumab and 7.1 months with chemotherapy. The hazard ratio was 0.78, but the P value (.0095) did not meet that predefined for statistical significance in this group (less than or equal to .0077).

Finally, in the entire intention-to-treat population, median overall survival was identical, at 7.1 months, with pembrolizumab and with chemotherapy. The hazard ratio was 0.89 in favor of the antibody, but the P value (.0560) did not meet that predefined for statistical significance in this population (less than or equal to .0077).

A similar pattern was seen for other outcomes, with patients having PD-L1 CPS greater than or equal to 10 deriving greatest benefit from pembrolizumab over chemotherapy in terms of progression-free survival (hazard ratio, 0.73), response rate (21.5% vs. 6.1%), and median duration of response (9.3 vs. 7.7 months).

“Toxicity profiles were in line with previous reports of each treatment. No new safety signals were observed,” Dr. Kojima reported. Pembrolizumab was associated with a higher rate of immune-mediated and infusion reactions (23.2% vs. 7.4%), but lower rates of most gastrointestinal and hematologic adverse events.

Dr. Kojima disclosed ties to Oncolys BioPharma, Astellas, Amgen, MSD, Ono Pharmaceutical, and Shionogi. Merck Sharp & Dohme sponsored the trial.

SOURCE: Kojima T et al. GI Cancers Symposium Abstract 2, https://meetinglibrary.asco.org/record/169377/abstract.

SAN FRANCISCO – The immune checkpoint inhibitor pembrolizumab (Keytruda) may soon unseat chemotherapy as standard second-line therapy for certain advanced cancers of the esophagus or gastroesophageal junction, according to data from the global phase 3 KEYNOTE-181 trial.

Susan London/MDEdge News

“Patients with advanced esophageal cancer after first-line therapy have a poor prognosis and limited treatment options,” said lead investigator Takashi Kojima, MD, of the National Cancer Center Hospital East, Kashiwa, Japan. “Taxanes and irinotecan are commonly used after first-line chemotherapy; however, no overall survival benefit has been demonstrated for chemotherapy in a phase 3 study.”

The 628 patients in KEYNOTE-181 were randomly assigned to chemotherapy (paclitaxel, docetaxel, or irinotecan, left to investigator’s choice) or pembrolizumab, an antibody to programmed death 1 (PD-1). Currently, pembrolizumab is approved in the United States for use as third- or later-line therapy for gastric or gastroesophageal junction cancer that is positive for programmed death ligand 1 (PD-L1) as defined by a combined positive score (CPS) of 1 or greater, among many other indications.

Main trial results reported at the 2019 GI Cancers Symposium showed that among patients with high PD-L1 expression, defined by a CPS of 10 or higher, pembrolizumab reduced risk of death by about one-third, prolonging survival by 2.6 months. The difference met the predefined threshold for statistical significance.

There was a more modest, nonsignificant benefit among patients with tumors having squamous cell carcinoma histology and among the entire intention-to-treat population.

The rate of treatment-related adverse events of grade 3-5 was roughly half as high with pembrolizumab versus chemotherapy (18.2% vs. 40.9%).

“These data suggest that pembrolizumab should be considered a new standard of care for patients with PD-L1 CPS of 10 or greater metastatic esophageal cancer in the second-line setting,” Dr. Kojima concluded.
 

Implications for practice

“In the intention-to-treat population, the KEYNOTE-181 study failed to meet its primary endpoint of overall survival, so pembrolizumab is not indicated in unselected esophageal cancer patients,” said invited discussant Harry H. Yoon, MD, cochair of the Esophageal/Gastric Cancer Disease Group at the Mayo Clinic Cancer Center, Rochester, Minn.

Susan London/MDedge News

For the patients with squamous histology, the negative findings are unlikely to be due to underpowering and may instead be related to the trial’s use of multiple primary endpoints, in his opinion. “Some may advocate using pembrolizumab off protocol [in this population], particularly for patients who cannot tolerate chemotherapy, because it is after all better tolerated than chemo. This can be a discussion point for guideline committees,” he said.

The results for the group with PD-L1 CPS scores of 10 or higher are statistically significant and clinically meaningful, as well as internally valid – with the caveat that patients were not stratified by PD-L1 status and some favorable risk factors were more common in the pembrolizumab group, according to Dr. Yoon. The 43% survival rate at 12 months translates to a number needed to treat of just four patients for one patient to be alive at that time point.

“A multivariate analysis could help clarify whether the positive results in the PD-L1 CPS 10-or-higher subgroup are explained by a higher frequency of favorable patient characteristics in the pembrolizumab arm,” he noted. “The strength of those results could influence guideline recommendations and implementation in clinical practice.”

Subgroup analyses suggested benefit was mainly seen in Asian patients, who tend to have higher prevalence of squamous tumors, Dr. Yoon said. Potential molecular differences at play here may be elucidated by ongoing research.

Ultimately, the findings in the PD-L1 CPS 10-or-higher group have potential implications for biomarker testing. “For the patient in front of me, I currently order PD-L1 and HER2 at first metastatic diagnosis in gastroesophageal adenocarcinomas,” he elaborated. “It’s reasonable to consider a practice change. This means ordering PD-L1 at first metastatic diagnosis in patients with squamous carcinoma of the esophagus. This would also mean some pathology labs may need to report a more detailed PD-L1 CPS score, if they don’t already.”

These findings also have potential implications for treatment. “For the second-line setting, for squamous carcinoma of the esophagus, esophageal adenocarcinomas, and Siewert 1 adenocarcinomas with a PD-L1 CPS of 10 or more, it’s reasonable to consider pembrolizumab,” Dr. Yoon noted. “This should be discussed within guideline committees, and the results will be submitted to regulatory authorities, who will have access to more detailed data. It’s possible that these recommendations could be modified in the near future.”
 

Study details

As KEYNOTE-181 had three primary endpoints (overall survival in each of three populations), P values required for statistical significance were defined accordingly. “The study was positive if one of the primary endpoints was met,” Dr. Kojima explained at the symposium, which was sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Some 35% of trial patients had a PD-L1 CPS of 10 or greater. In this population, median overall survival was 9.3 months with pembrolizumab and 6.7 months with chemotherapy. The hazard ratio was 0.69, with the P value (.0074) meeting that predefined for statistical significance in this population (less than or equal to .0085). The 12-month rate of overall survival was 43% and 20%, respectively.

About 64% of trial patients had squamous cell carcinoma histology. In this population, median overall survival was 8.2 months with pembrolizumab and 7.1 months with chemotherapy. The hazard ratio was 0.78, but the P value (.0095) did not meet that predefined for statistical significance in this group (less than or equal to .0077).

Finally, in the entire intention-to-treat population, median overall survival was identical, at 7.1 months, with pembrolizumab and with chemotherapy. The hazard ratio was 0.89 in favor of the antibody, but the P value (.0560) did not meet that predefined for statistical significance in this population (less than or equal to .0077).

A similar pattern was seen for other outcomes, with patients having PD-L1 CPS greater than or equal to 10 deriving greatest benefit from pembrolizumab over chemotherapy in terms of progression-free survival (hazard ratio, 0.73), response rate (21.5% vs. 6.1%), and median duration of response (9.3 vs. 7.7 months).

“Toxicity profiles were in line with previous reports of each treatment. No new safety signals were observed,” Dr. Kojima reported. Pembrolizumab was associated with a higher rate of immune-mediated and infusion reactions (23.2% vs. 7.4%), but lower rates of most gastrointestinal and hematologic adverse events.

Dr. Kojima disclosed ties to Oncolys BioPharma, Astellas, Amgen, MSD, Ono Pharmaceutical, and Shionogi. Merck Sharp & Dohme sponsored the trial.

SOURCE: Kojima T et al. GI Cancers Symposium Abstract 2, https://meetinglibrary.asco.org/record/169377/abstract.

PREIMPLANTATION GENETIC TESTING

In a retrospective study published in Fertility and Sterility, Spectrum, a single-nucleotide polymorphism (SNP)-based PGT-A technology, was successful in screening all 24 chromosomes to provide comprehensive embryo aneuploidy results. Natera says that the study results showed that use of Spectrum PGT-A during IVF led to excellent implantation (70%), clinical pregnancy (71%), and live birth (65%) rates during single embryo transfer.

Spectrum evaluates the number of chromosomes in embryos to detect extra or missing chromosomes and screens for inherited genetic disorders to help provide the best chance of transferring a healthy embryo with the correct number of chromosomes.

FOR MORE INFORMATION, VISIT: https://www.natera.com/spectrum
 

PORTABLE BREAST ULTRASOUND

Viera is a wireless, handheld breast ultrasound scanner that Hologic says produces exceptional image quality. The scanner uses a 14-4 MHz linear transducer, contains 192 elements, and has 4 parallel software beamformers. It utilizes spatial compounding to reduce image noise and speckle. Presets are available for breast, dense breast, and interventional procedures with B, M, power Doppler, color Doppler, and needle enhancement modes. On-demand high-resolution images are transmitted wirelessly to smart devices and patient archive systems (PACS) in the office, exam room, or surgical suite, or to the Cloud for efficient documentation. Smart device platforms include iOS and Android devices using WiFi and Bluetooth connectivity. The system includes a 1.2-lb scanner, 2 rechargeable batteries, and a charger with global AC adapter.

FOR MORE INFORMATION, VISIT: https://www.vieraportableultrasound.com

HOME SPERM TEST

The customer downloads the smart-phone app and acquires the YO Kit. After collecting a semen sample, he uses a pipette from the kit to place semen on a slide, which is slipped into the Yo Clip. The clip slides onto the smartphone, which uses its camera to take a high-resolution video. Test results and the sperm video appear in about 2 minutes.

At $59.95, the YO Kit includes 2 tests, in case a second sample is desired.

FOR MORE INFORMATION, VISIT:

https://www.yospermtest.com
 

Continue to Improving the Mammography Experience…

IMPROVING THE MAMMOGRAPHY EXPERIENCE

SmartCurve is standard on Hologic’s new 3Dimensions™ mammography system and as an enhancement option to existing Hologic Selenia^®Dimensions^® systems.

FOR MORE INFORMATION, VISIT:https://www.smartcurvesystem.com

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

PREIMPLANTATION GENETIC TESTING

In a retrospective study published in Fertility and Sterility, Spectrum, a single-nucleotide polymorphism (SNP)-based PGT-A technology, was successful in screening all 24 chromosomes to provide comprehensive embryo aneuploidy results. Natera says that the study results showed that use of Spectrum PGT-A during IVF led to excellent implantation (70%), clinical pregnancy (71%), and live birth (65%) rates during single embryo transfer.

Spectrum evaluates the number of chromosomes in embryos to detect extra or missing chromosomes and screens for inherited genetic disorders to help provide the best chance of transferring a healthy embryo with the correct number of chromosomes.

FOR MORE INFORMATION, VISIT: https://www.natera.com/spectrum
 

PORTABLE BREAST ULTRASOUND

Viera is a wireless, handheld breast ultrasound scanner that Hologic says produces exceptional image quality. The scanner uses a 14-4 MHz linear transducer, contains 192 elements, and has 4 parallel software beamformers. It utilizes spatial compounding to reduce image noise and speckle. Presets are available for breast, dense breast, and interventional procedures with B, M, power Doppler, color Doppler, and needle enhancement modes. On-demand high-resolution images are transmitted wirelessly to smart devices and patient archive systems (PACS) in the office, exam room, or surgical suite, or to the Cloud for efficient documentation. Smart device platforms include iOS and Android devices using WiFi and Bluetooth connectivity. The system includes a 1.2-lb scanner, 2 rechargeable batteries, and a charger with global AC adapter.

FOR MORE INFORMATION, VISIT: https://www.vieraportableultrasound.com

HOME SPERM TEST

The customer downloads the smart-phone app and acquires the YO Kit. After collecting a semen sample, he uses a pipette from the kit to place semen on a slide, which is slipped into the Yo Clip. The clip slides onto the smartphone, which uses its camera to take a high-resolution video. Test results and the sperm video appear in about 2 minutes.

At $59.95, the YO Kit includes 2 tests, in case a second sample is desired.

FOR MORE INFORMATION, VISIT:

https://www.yospermtest.com
 

Continue to Improving the Mammography Experience…

IMPROVING THE MAMMOGRAPHY EXPERIENCE

SmartCurve is standard on Hologic’s new 3Dimensions™ mammography system and as an enhancement option to existing Hologic Selenia^®Dimensions^® systems.

FOR MORE INFORMATION, VISIT:https://www.smartcurvesystem.com

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

PREIMPLANTATION GENETIC TESTING

In a retrospective study published in Fertility and Sterility, Spectrum, a single-nucleotide polymorphism (SNP)-based PGT-A technology, was successful in screening all 24 chromosomes to provide comprehensive embryo aneuploidy results. Natera says that the study results showed that use of Spectrum PGT-A during IVF led to excellent implantation (70%), clinical pregnancy (71%), and live birth (65%) rates during single embryo transfer.

Spectrum evaluates the number of chromosomes in embryos to detect extra or missing chromosomes and screens for inherited genetic disorders to help provide the best chance of transferring a healthy embryo with the correct number of chromosomes.

FOR MORE INFORMATION, VISIT: https://www.natera.com/spectrum
 

PORTABLE BREAST ULTRASOUND

Viera is a wireless, handheld breast ultrasound scanner that Hologic says produces exceptional image quality. The scanner uses a 14-4 MHz linear transducer, contains 192 elements, and has 4 parallel software beamformers. It utilizes spatial compounding to reduce image noise and speckle. Presets are available for breast, dense breast, and interventional procedures with B, M, power Doppler, color Doppler, and needle enhancement modes. On-demand high-resolution images are transmitted wirelessly to smart devices and patient archive systems (PACS) in the office, exam room, or surgical suite, or to the Cloud for efficient documentation. Smart device platforms include iOS and Android devices using WiFi and Bluetooth connectivity. The system includes a 1.2-lb scanner, 2 rechargeable batteries, and a charger with global AC adapter.

FOR MORE INFORMATION, VISIT: https://www.vieraportableultrasound.com

HOME SPERM TEST

The customer downloads the smart-phone app and acquires the YO Kit. After collecting a semen sample, he uses a pipette from the kit to place semen on a slide, which is slipped into the Yo Clip. The clip slides onto the smartphone, which uses its camera to take a high-resolution video. Test results and the sperm video appear in about 2 minutes.

At $59.95, the YO Kit includes 2 tests, in case a second sample is desired.

FOR MORE INFORMATION, VISIT:

https://www.yospermtest.com
 

Continue to Improving the Mammography Experience…

IMPROVING THE MAMMOGRAPHY EXPERIENCE

SmartCurve is standard on Hologic’s new 3Dimensions™ mammography system and as an enhancement option to existing Hologic Selenia^®Dimensions^® systems.

FOR MORE INFORMATION, VISIT:https://www.smartcurvesystem.com

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

Clinical question: What is the effect of increasing attending physician supervision on a resident inpatient team for both patient safety and education?

Background: Residents need autonomy to help develop their clinical skills and to gain competence to practice independently; however, there is rising concern that increased supervision is needed for patient safety.

Study Design: Randomized, crossover clinical trial.

Setting: 1,100-bed academic medical center at Massachusetts General Hospital, Boston.

Bottom line: Attending physician presence on work rounds does not improve patient safety and may have deleterious effects on resident education.

Citation: Finn KM et al. Effect of increased inpatient attending physician supervision on medical errors, patient safety, and resident education. JAMA Intern Med. 2018;178(7):925-59

Dr. Ciarkowski is clinical instructor of medicine and an academic hospitalist, University of Utah, Salt Lake City.

Clinical question: What is the effect of increasing attending physician supervision on a resident inpatient team for both patient safety and education?

Background: Residents need autonomy to help develop their clinical skills and to gain competence to practice independently; however, there is rising concern that increased supervision is needed for patient safety.

Study Design: Randomized, crossover clinical trial.

Setting: 1,100-bed academic medical center at Massachusetts General Hospital, Boston.

Bottom line: Attending physician presence on work rounds does not improve patient safety and may have deleterious effects on resident education.

Citation: Finn KM et al. Effect of increased inpatient attending physician supervision on medical errors, patient safety, and resident education. JAMA Intern Med. 2018;178(7):925-59

Dr. Ciarkowski is clinical instructor of medicine and an academic hospitalist, University of Utah, Salt Lake City.

Clinical question: What is the effect of increasing attending physician supervision on a resident inpatient team for both patient safety and education?

Background: Residents need autonomy to help develop their clinical skills and to gain competence to practice independently; however, there is rising concern that increased supervision is needed for patient safety.

Study Design: Randomized, crossover clinical trial.

Setting: 1,100-bed academic medical center at Massachusetts General Hospital, Boston.

Bottom line: Attending physician presence on work rounds does not improve patient safety and may have deleterious effects on resident education.

Citation: Finn KM et al. Effect of increased inpatient attending physician supervision on medical errors, patient safety, and resident education. JAMA Intern Med. 2018;178(7):925-59

Dr. Ciarkowski is clinical instructor of medicine and an academic hospitalist, University of Utah, Salt Lake City.

Prescribed opioids were associated with an increase in community-acquired pneumonia in patients with and without HIV infection, according to results of a large database study.

People living with HIV (PLWH) appeared to have a greater community-acquired pneumonia (CAP) risk at lower opioid doses and particularly with immunosuppressive opioids compared with uninfected patients, although the difference was not significant, E. Jennifer Edelman, MD, of Yale University, New Haven, Conn., and her colleagues wrote in JAMA Internal Medicine.

The researchers performed a nested case-control study comprising 25,392 participants (98.9% men; mean age, 55 years) in the Veterans Aging Cohort Study from Jan. 1, 2000, through Dec. 31, 2012.

Dr. Edelman and her colleagues compared the characteristics of 4,246 CAP cases with those of 21,146 uninfected controls in the sample. They also compared cases and controls by HIV status. They ran bivariate and multivariate analysis to estimate odds ratios for CAP risk associated with opioid exposure. In addition, the researchers ran models stratified by HIV status and formally checked for an interaction between prescribed opioid characteristics and HIV status.

In unadjusted logistic regression, prescribed opioids were associated with increased odds of CAP, with the greatest risk observed with currently prescribed opioids, compared with past prescribed opioids or no opioids.

Prescribed opioids remained associated with CAP in the adjusted models for past unknown or nonimmunosuppressive (adjusted OR, 1.24; 95% confidence interval, 1.09-1.40) and past immunosuppressive opioid use (aOR, 1.42; 95% CI, 1.21-1.67).

For currently prescribed opioids, nonimmunosuppressive or unknown, the aOR was 1.23 (95% CI, 1.03-1.48). For currently prescribed immunosuppressive opioids, the aOR was 3.18 (95% CI, 2.44-4.14).

The researchers also found evidence of a dose-response effect such that currently prescribed high-dose opioids were associated with the greatest CAP risk, followed by medium- and then by low-dose opioids, whether immunosuppressive or not.

With regard to the effect of HIV status in stratified, adjusted analyses, CAP risk tended to be greater among PLWH with current prescribed opioids, especially immunosuppressive opioids, compared with uninfected patients. However, the overall interaction term for opioid × HIV status was not significant (P = .36).

Although the researchers stated that a limitation of their study was an inability to prove causality or rule out respiratory depression (vs. immunosuppression) as the cause of the increased CAP risk, “the observed effects of opioid immunosuppressive properties and CAP risk lend support to our hypothesis that opioids have clinically relevant immunosuppressive properties.”

Dr. Edelman and her colleagues cited several limitations. For example, they were not able to determine whether patients took their prescribed medications appropriately and assess whether the patients took nonmedically prescribed opioids. Also, because men made up such a large portion of the study population, it is unclear whether the results are generalizable to women.

Nevertheless, the study “adds to growing evidence of potential medical harms associated with prescribed opioids,” they wrote.

“Health care professionals should be aware of this additional CAP risk when they prescribe opioids, and future studies should investigate the effects of opioids prescribed for longer durations and on other immune-related outcomes,” wrote Dr. Edelman and her colleagues. “Understanding whether mitigating the risk of prescribed opioids for CAP is possible by using a lower dose and nonimmunosuppressive opioids awaits further study.”

However, without such data, when prescribed opioids are warranted, physicians should attempt to modify other factors known to affect CAP risk, including smoking and lack of vaccination, Dr. Edelman and her colleagues concluded.

Several U.S. government agencies and Yale University provided funding for the study. The authors reported that they had no conflicts.

mlesney@mdedge.com

SOURCE: Edelman EJ et al. JAMA Intern Med. 2019 Jan 7. doi: 10.1001/jamainternmed.2018.6101.

Prescribed opioids were associated with an increase in community-acquired pneumonia in patients with and without HIV infection, according to results of a large database study.

People living with HIV (PLWH) appeared to have a greater community-acquired pneumonia (CAP) risk at lower opioid doses and particularly with immunosuppressive opioids compared with uninfected patients, although the difference was not significant, E. Jennifer Edelman, MD, of Yale University, New Haven, Conn., and her colleagues wrote in JAMA Internal Medicine.

The researchers performed a nested case-control study comprising 25,392 participants (98.9% men; mean age, 55 years) in the Veterans Aging Cohort Study from Jan. 1, 2000, through Dec. 31, 2012.

Dr. Edelman and her colleagues compared the characteristics of 4,246 CAP cases with those of 21,146 uninfected controls in the sample. They also compared cases and controls by HIV status. They ran bivariate and multivariate analysis to estimate odds ratios for CAP risk associated with opioid exposure. In addition, the researchers ran models stratified by HIV status and formally checked for an interaction between prescribed opioid characteristics and HIV status.

In unadjusted logistic regression, prescribed opioids were associated with increased odds of CAP, with the greatest risk observed with currently prescribed opioids, compared with past prescribed opioids or no opioids.

Prescribed opioids remained associated with CAP in the adjusted models for past unknown or nonimmunosuppressive (adjusted OR, 1.24; 95% confidence interval, 1.09-1.40) and past immunosuppressive opioid use (aOR, 1.42; 95% CI, 1.21-1.67).

For currently prescribed opioids, nonimmunosuppressive or unknown, the aOR was 1.23 (95% CI, 1.03-1.48). For currently prescribed immunosuppressive opioids, the aOR was 3.18 (95% CI, 2.44-4.14).

The researchers also found evidence of a dose-response effect such that currently prescribed high-dose opioids were associated with the greatest CAP risk, followed by medium- and then by low-dose opioids, whether immunosuppressive or not.

With regard to the effect of HIV status in stratified, adjusted analyses, CAP risk tended to be greater among PLWH with current prescribed opioids, especially immunosuppressive opioids, compared with uninfected patients. However, the overall interaction term for opioid × HIV status was not significant (P = .36).

Although the researchers stated that a limitation of their study was an inability to prove causality or rule out respiratory depression (vs. immunosuppression) as the cause of the increased CAP risk, “the observed effects of opioid immunosuppressive properties and CAP risk lend support to our hypothesis that opioids have clinically relevant immunosuppressive properties.”

Dr. Edelman and her colleagues cited several limitations. For example, they were not able to determine whether patients took their prescribed medications appropriately and assess whether the patients took nonmedically prescribed opioids. Also, because men made up such a large portion of the study population, it is unclear whether the results are generalizable to women.

Nevertheless, the study “adds to growing evidence of potential medical harms associated with prescribed opioids,” they wrote.

“Health care professionals should be aware of this additional CAP risk when they prescribe opioids, and future studies should investigate the effects of opioids prescribed for longer durations and on other immune-related outcomes,” wrote Dr. Edelman and her colleagues. “Understanding whether mitigating the risk of prescribed opioids for CAP is possible by using a lower dose and nonimmunosuppressive opioids awaits further study.”

However, without such data, when prescribed opioids are warranted, physicians should attempt to modify other factors known to affect CAP risk, including smoking and lack of vaccination, Dr. Edelman and her colleagues concluded.

Several U.S. government agencies and Yale University provided funding for the study. The authors reported that they had no conflicts.

mlesney@mdedge.com

SOURCE: Edelman EJ et al. JAMA Intern Med. 2019 Jan 7. doi: 10.1001/jamainternmed.2018.6101.

Prescribed opioids were associated with an increase in community-acquired pneumonia in patients with and without HIV infection, according to results of a large database study.

People living with HIV (PLWH) appeared to have a greater community-acquired pneumonia (CAP) risk at lower opioid doses and particularly with immunosuppressive opioids compared with uninfected patients, although the difference was not significant, E. Jennifer Edelman, MD, of Yale University, New Haven, Conn., and her colleagues wrote in JAMA Internal Medicine.

The researchers performed a nested case-control study comprising 25,392 participants (98.9% men; mean age, 55 years) in the Veterans Aging Cohort Study from Jan. 1, 2000, through Dec. 31, 2012.

Dr. Edelman and her colleagues compared the characteristics of 4,246 CAP cases with those of 21,146 uninfected controls in the sample. They also compared cases and controls by HIV status. They ran bivariate and multivariate analysis to estimate odds ratios for CAP risk associated with opioid exposure. In addition, the researchers ran models stratified by HIV status and formally checked for an interaction between prescribed opioid characteristics and HIV status.

In unadjusted logistic regression, prescribed opioids were associated with increased odds of CAP, with the greatest risk observed with currently prescribed opioids, compared with past prescribed opioids or no opioids.

Prescribed opioids remained associated with CAP in the adjusted models for past unknown or nonimmunosuppressive (adjusted OR, 1.24; 95% confidence interval, 1.09-1.40) and past immunosuppressive opioid use (aOR, 1.42; 95% CI, 1.21-1.67).

For currently prescribed opioids, nonimmunosuppressive or unknown, the aOR was 1.23 (95% CI, 1.03-1.48). For currently prescribed immunosuppressive opioids, the aOR was 3.18 (95% CI, 2.44-4.14).

The researchers also found evidence of a dose-response effect such that currently prescribed high-dose opioids were associated with the greatest CAP risk, followed by medium- and then by low-dose opioids, whether immunosuppressive or not.

With regard to the effect of HIV status in stratified, adjusted analyses, CAP risk tended to be greater among PLWH with current prescribed opioids, especially immunosuppressive opioids, compared with uninfected patients. However, the overall interaction term for opioid × HIV status was not significant (P = .36).

Although the researchers stated that a limitation of their study was an inability to prove causality or rule out respiratory depression (vs. immunosuppression) as the cause of the increased CAP risk, “the observed effects of opioid immunosuppressive properties and CAP risk lend support to our hypothesis that opioids have clinically relevant immunosuppressive properties.”

Dr. Edelman and her colleagues cited several limitations. For example, they were not able to determine whether patients took their prescribed medications appropriately and assess whether the patients took nonmedically prescribed opioids. Also, because men made up such a large portion of the study population, it is unclear whether the results are generalizable to women.

Nevertheless, the study “adds to growing evidence of potential medical harms associated with prescribed opioids,” they wrote.

“Health care professionals should be aware of this additional CAP risk when they prescribe opioids, and future studies should investigate the effects of opioids prescribed for longer durations and on other immune-related outcomes,” wrote Dr. Edelman and her colleagues. “Understanding whether mitigating the risk of prescribed opioids for CAP is possible by using a lower dose and nonimmunosuppressive opioids awaits further study.”

However, without such data, when prescribed opioids are warranted, physicians should attempt to modify other factors known to affect CAP risk, including smoking and lack of vaccination, Dr. Edelman and her colleagues concluded.

Several U.S. government agencies and Yale University provided funding for the study. The authors reported that they had no conflicts.

mlesney@mdedge.com

SOURCE: Edelman EJ et al. JAMA Intern Med. 2019 Jan 7. doi: 10.1001/jamainternmed.2018.6101.

IgG4-related disease can be grouped into four distinct clusters based on the distribution of organs involved, according to researchers who analyzed a large, multicenter cohort of patients with this heterogeneous, autoimmune-mediated condition.

The four groups also varied by age, race, sex, time to diagnosis, and concentration of serum IgG4, according to the investigators, led by Zachary S. Wallace, MD, of the division of rheumatology, allergy, and immunology at Massachusetts General Hospital and Harvard Medical School, both in Boston.

“These phenotypes may be used by clinicians to improve recognition of IgG4-related disease,” Dr. Wallace and his coauthors wrote in a report on the study that appears in the Annals of the Rheumatic Diseases.

First described in a Japanese population, IgG4-related disease has been subsequently seen in all racial and ethnic groups, according to the researchers. It is associated with organ failure and can affect nearly any organ or anatomic site, most notably the lungs, kidneys, lymph nodes, salivary glands, pancreatobiliary structures, and retroperitoneum.


In the present study, Dr. Wallace and his coinvestigators used a novel cluster analysis method, called latent class analysis, to categorize 765 cases of IgG4-related disease submitted by 52 investigators from 17 countries. The investigators included 493 of those cases in a primary study population, and the remaining 272 in a smaller cohort used to replicate the results.

In the larger, primary study cohort, about 65% of cases were male, 58% were non-Asian and 40% were white, and the mean age at diagnosis was 59.5 years. The replication cohort had similar characteristics, according to the investigators.

The clustering analysis revealed four distinct subgroups, characterized by pancreato-hepatobiliary, accounting for 31% of cases; retroperitoneal fibrosis and/or aortitis in 24%; disease generally limited to head and neck structures in 24%, and head and neck disease consistent with Mikulicz syndrome plus systemic involvement in 22%.

The highest IgG4 concentrations were seen in the group of patients with Mikulicz syndrome and systemic involvement, according to Dr. Wallace and his coauthors. The serum concentration was 1,170 mg/dL in that group, compared with 445 mg/dL in the group of patients with head and neck-limited disease, 316 mg/dL in the pancreato-hepatobiliary group, and just 178 mg/dL in the retroperitoneal fibrosis/aorta group.

Female and Asian patients were overrepresented in the group characterized by head and neck involvement, investigators also found. Moreover, that group had a significantly lower mean age at diagnosis than did the other groups.

Those variations suggested differences in genetic or environmental risk factors between clusters, according to the investigators.

“Given the similar distribution of subspecialists among investigators in this study practicing in Asian and non-Asian countries, the observed differences are unlikely to be the result of detection or selection biases,” they said in their report.

The findings of this study help to inform subsequent investigations intended to evaluate those factors in more detail, they said.

Dr. Wallace and his coauthors reported no conflicts of interest related to their work, which was previously presented at the American College of Rheumatology annual meeting.

SOURCE: Wallace ZS et al. Ann Rheum Dis. 2019 Jan 5. doi: 10.1136/annrheumdis-2018-214603

IgG4-related disease can be grouped into four distinct clusters based on the distribution of organs involved, according to researchers who analyzed a large, multicenter cohort of patients with this heterogeneous, autoimmune-mediated condition.

The four groups also varied by age, race, sex, time to diagnosis, and concentration of serum IgG4, according to the investigators, led by Zachary S. Wallace, MD, of the division of rheumatology, allergy, and immunology at Massachusetts General Hospital and Harvard Medical School, both in Boston.

“These phenotypes may be used by clinicians to improve recognition of IgG4-related disease,” Dr. Wallace and his coauthors wrote in a report on the study that appears in the Annals of the Rheumatic Diseases.

First described in a Japanese population, IgG4-related disease has been subsequently seen in all racial and ethnic groups, according to the researchers. It is associated with organ failure and can affect nearly any organ or anatomic site, most notably the lungs, kidneys, lymph nodes, salivary glands, pancreatobiliary structures, and retroperitoneum.


In the present study, Dr. Wallace and his coinvestigators used a novel cluster analysis method, called latent class analysis, to categorize 765 cases of IgG4-related disease submitted by 52 investigators from 17 countries. The investigators included 493 of those cases in a primary study population, and the remaining 272 in a smaller cohort used to replicate the results.

In the larger, primary study cohort, about 65% of cases were male, 58% were non-Asian and 40% were white, and the mean age at diagnosis was 59.5 years. The replication cohort had similar characteristics, according to the investigators.

The clustering analysis revealed four distinct subgroups, characterized by pancreato-hepatobiliary, accounting for 31% of cases; retroperitoneal fibrosis and/or aortitis in 24%; disease generally limited to head and neck structures in 24%, and head and neck disease consistent with Mikulicz syndrome plus systemic involvement in 22%.

The highest IgG4 concentrations were seen in the group of patients with Mikulicz syndrome and systemic involvement, according to Dr. Wallace and his coauthors. The serum concentration was 1,170 mg/dL in that group, compared with 445 mg/dL in the group of patients with head and neck-limited disease, 316 mg/dL in the pancreato-hepatobiliary group, and just 178 mg/dL in the retroperitoneal fibrosis/aorta group.

Female and Asian patients were overrepresented in the group characterized by head and neck involvement, investigators also found. Moreover, that group had a significantly lower mean age at diagnosis than did the other groups.

Those variations suggested differences in genetic or environmental risk factors between clusters, according to the investigators.

“Given the similar distribution of subspecialists among investigators in this study practicing in Asian and non-Asian countries, the observed differences are unlikely to be the result of detection or selection biases,” they said in their report.

The findings of this study help to inform subsequent investigations intended to evaluate those factors in more detail, they said.

Dr. Wallace and his coauthors reported no conflicts of interest related to their work, which was previously presented at the American College of Rheumatology annual meeting.

SOURCE: Wallace ZS et al. Ann Rheum Dis. 2019 Jan 5. doi: 10.1136/annrheumdis-2018-214603

IgG4-related disease can be grouped into four distinct clusters based on the distribution of organs involved, according to researchers who analyzed a large, multicenter cohort of patients with this heterogeneous, autoimmune-mediated condition.

The four groups also varied by age, race, sex, time to diagnosis, and concentration of serum IgG4, according to the investigators, led by Zachary S. Wallace, MD, of the division of rheumatology, allergy, and immunology at Massachusetts General Hospital and Harvard Medical School, both in Boston.

“These phenotypes may be used by clinicians to improve recognition of IgG4-related disease,” Dr. Wallace and his coauthors wrote in a report on the study that appears in the Annals of the Rheumatic Diseases.

First described in a Japanese population, IgG4-related disease has been subsequently seen in all racial and ethnic groups, according to the researchers. It is associated with organ failure and can affect nearly any organ or anatomic site, most notably the lungs, kidneys, lymph nodes, salivary glands, pancreatobiliary structures, and retroperitoneum.


In the present study, Dr. Wallace and his coinvestigators used a novel cluster analysis method, called latent class analysis, to categorize 765 cases of IgG4-related disease submitted by 52 investigators from 17 countries. The investigators included 493 of those cases in a primary study population, and the remaining 272 in a smaller cohort used to replicate the results.

In the larger, primary study cohort, about 65% of cases were male, 58% were non-Asian and 40% were white, and the mean age at diagnosis was 59.5 years. The replication cohort had similar characteristics, according to the investigators.

The clustering analysis revealed four distinct subgroups, characterized by pancreato-hepatobiliary, accounting for 31% of cases; retroperitoneal fibrosis and/or aortitis in 24%; disease generally limited to head and neck structures in 24%, and head and neck disease consistent with Mikulicz syndrome plus systemic involvement in 22%.

The highest IgG4 concentrations were seen in the group of patients with Mikulicz syndrome and systemic involvement, according to Dr. Wallace and his coauthors. The serum concentration was 1,170 mg/dL in that group, compared with 445 mg/dL in the group of patients with head and neck-limited disease, 316 mg/dL in the pancreato-hepatobiliary group, and just 178 mg/dL in the retroperitoneal fibrosis/aorta group.

Female and Asian patients were overrepresented in the group characterized by head and neck involvement, investigators also found. Moreover, that group had a significantly lower mean age at diagnosis than did the other groups.

Those variations suggested differences in genetic or environmental risk factors between clusters, according to the investigators.

“Given the similar distribution of subspecialists among investigators in this study practicing in Asian and non-Asian countries, the observed differences are unlikely to be the result of detection or selection biases,” they said in their report.

The findings of this study help to inform subsequent investigations intended to evaluate those factors in more detail, they said.

Dr. Wallace and his coauthors reported no conflicts of interest related to their work, which was previously presented at the American College of Rheumatology annual meeting.

SOURCE: Wallace ZS et al. Ann Rheum Dis. 2019 Jan 5. doi: 10.1136/annrheumdis-2018-214603

Gail Erlick Robinson, MD, joins Lorenzo Norris, MD, at the 2018 meeting of the Group for the Advancement of Psychiatry in White Plains, N.Y., to talk about violence against women.Dr. Robinson is professor of psychiatry and obstetrics/gynecology and professor of equality, gender, and population at the University of Toronto. She’s also chair of GAP’s Committee on Gender & Mental Health. In this episode, Dr. Robinson delves into strategies for interacting with survivors of violence, the roots of the “Me Too” movement, as well as rising rates of maternal mortality in the United States.
​​​​​​​Amazon
Apple Podcasts
Google Podcasts
Spotify


 

Gail Erlick Robinson, MD, joins Lorenzo Norris, MD, at the 2018 meeting of the Group for the Advancement of Psychiatry in White Plains, N.Y., to talk about violence against women.Dr. Robinson is professor of psychiatry and obstetrics/gynecology and professor of equality, gender, and population at the University of Toronto. She’s also chair of GAP’s Committee on Gender & Mental Health. In this episode, Dr. Robinson delves into strategies for interacting with survivors of violence, the roots of the “Me Too” movement, as well as rising rates of maternal mortality in the United States.
​​​​​​​Amazon
Apple Podcasts
Google Podcasts
Spotify


 

Gail Erlick Robinson, MD, joins Lorenzo Norris, MD, at the 2018 meeting of the Group for the Advancement of Psychiatry in White Plains, N.Y., to talk about violence against women.Dr. Robinson is professor of psychiatry and obstetrics/gynecology and professor of equality, gender, and population at the University of Toronto. She’s also chair of GAP’s Committee on Gender & Mental Health. In this episode, Dr. Robinson delves into strategies for interacting with survivors of violence, the roots of the “Me Too” movement, as well as rising rates of maternal mortality in the United States.
​​​​​​​Amazon
Apple Podcasts
Google Podcasts
Spotify


 

Parents were much more confident about vaccinating their children against the human papillomavirus when they were told about the disease that the vaccine prevents rather than about vaccine safety. Also today, FDA labeling templates smooth the way for over-the-counter naloxone, a revised Affordable Care Act premium calculator could increase the rate of uninsured, and confidential parent-free discussion should occur by age 13.

Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
 

Parents were much more confident about vaccinating their children against the human papillomavirus when they were told about the disease that the vaccine prevents rather than about vaccine safety. Also today, FDA labeling templates smooth the way for over-the-counter naloxone, a revised Affordable Care Act premium calculator could increase the rate of uninsured, and confidential parent-free discussion should occur by age 13.

Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
 

Parents were much more confident about vaccinating their children against the human papillomavirus when they were told about the disease that the vaccine prevents rather than about vaccine safety. Also today, FDA labeling templates smooth the way for over-the-counter naloxone, a revised Affordable Care Act premium calculator could increase the rate of uninsured, and confidential parent-free discussion should occur by age 13.

Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
 

Cognitive changes related to multiple sclerosis (MS) were first mentioned by Jean-Martin Charcot in 1877; however, it is only within the past 25-30 years that cognitive impairment in MS has received significant clinical study. Despite a growing body of research, though, formal screening of cognitive function is not always part of routine MS clinical care.

Q)How common are cognitive symptoms in MS?

Cognitive changes affect up to 65% of patients in MS clinic samples and about one-third of pediatric MS patients.¹ Cognitive deficits occur in all the MS disease courses, including clinically isolated syndrome, although they are most prevalent in secondary progressive and primary progressive disease.¹ Cognitive changes have even been observed in radiographically isolated syndrome, in which MRI changes consistent with MS are observed without any neurologic symptoms or signs.²

Q)What cognitive domains are affected in MS?

Strong correlations have been demonstrated between cognitive impairment and MRI findings, including whole brain atrophy and, to some degree, overall white matter lesion burden. Cognitive changes also result from damage in specific areas, including deep gray matter and the corpus callosum, cerebral cortex, and mesial temporal lobe.^3-5

The type and severity of cognitive deficits vary widely among people with MS. However, difficulties with information processing speed and short-term memory are the symptoms most commonly seen in this population. Processing speed problems affect new learning and impact memory and executive function. Other domains that can be affected are complex attention, verbal fluency, and visuospatial perception.¹

Q)Are cognitive symptoms in MS progressive?

Not everyone with cognitive symptoms related to MS will show progressive changes. However, in a longitudinal study, increasing age and degree of physical disability were predictive of worsening cognitive symptoms. Also, people who demonstrate early cognitive symptoms may experience greater worsening.⁶

Q)What impact do cognitive symptoms have?

Changes in cognition are a common reason for someone to experience performance issues in the workplace and as such significantly affect a person’s ability to maintain employment. Impaired cognition is a primary cause of early departure from the workforceand has significant implications for self-image and self-esteem.⁷

Furthermore, cognitive symptoms can impact adherence to medications. They also can negatively affect daily life, through increased risk for motor vehicle accidents, difficulties with routine household tasks, and significant challenges to relationships (particularly but not exclusively those with caregivers).

Continue to: How are cognitive symptoms assessed?

Q)How are cognitive symptoms assessed?

There are several screening tools that take very little time to administer and can be used in the clinic setting. The Symbol Digit Modalities Test (SDMT; www.wpspublish.com/store/p/2955/sdmt-symbol-digit-modalities-test) is validated in MS and takes approximately 90 s to complete. This screening instrument is proprietary and has a small fee associated with its use.⁸

Other possible causes of cognitive dysfunction should be investigated as well. These include an examination of medications being used—such as anticholinergics, benzodiazepines, other sedatives, cannabis, topiramate, and opioids—and consideration of other diseases and conditions, including vascular conditions, metabolic deficiencies, infection, tumor, substance abuse, early dementia, or hypothyroidism, which may contribute to or cause cognitive impairment.

Should cognitive problems be identified—either through the history, during the clinic visit, or via screening tests—more formal testing, usually performed by a neuropsychologist, may be useful in identifying the domains of function that are impaired. This information can help to identify and implement appropriate compensatory strategies, plan cognitive rehabilitation interventions, and (in the United States) assist the individual to obtain Social Security disability benefits.

Q)How are cognitive symptoms managed?

Multiple clinical trials of cognitive rehabilitation strategies have demonstrated the efficacy of computer-based programs in improving new learning, short-term memory, processing speed, and attention.⁹ Cognitive rehabilitation programs should be administered and/or supervised by a health care professional who is knowledgeable about MS as well as cognitive rehabilitation. Professionals such as neuropsychologists, occupational therapists, and speech language pathologists often direct cognitive training programs.

Medications that stimulate the central nervous system have been used to improve mental alertness. However, clinical trials are few and have yielded mixed results.

Continue to: In clinical trials...

In clinical trials, physical exercise has been shown to improve processing speed. More research is needed to demonstrate the type of exercise that is most beneficial and the extent of improvement in cognitive function that results.

SUMMARY

Cognitive function can be negatively impacted by MS. Activities of daily living, including employment and relationships, can be negatively impacted by changes in cognition. Regular screening of cognition is recommended by the National MS Society, using validated screening tools such as the SDMT. Additional testing is warranted for individuals reporting cognitive difficulties at home or work, or those who score below controls on screening tests. Cognitive rehabilitation may help some individuals improve their cognitive function. More research is needed to identify additional cognitive training techniques, better understand the role of physical exercise, and identify medications that may be of benefit to maintain cognitive function.

Cognitive changes related to multiple sclerosis (MS) were first mentioned by Jean-Martin Charcot in 1877; however, it is only within the past 25-30 years that cognitive impairment in MS has received significant clinical study. Despite a growing body of research, though, formal screening of cognitive function is not always part of routine MS clinical care.

Q)How common are cognitive symptoms in MS?

Cognitive changes affect up to 65% of patients in MS clinic samples and about one-third of pediatric MS patients.¹ Cognitive deficits occur in all the MS disease courses, including clinically isolated syndrome, although they are most prevalent in secondary progressive and primary progressive disease.¹ Cognitive changes have even been observed in radiographically isolated syndrome, in which MRI changes consistent with MS are observed without any neurologic symptoms or signs.²

Q)What cognitive domains are affected in MS?

Strong correlations have been demonstrated between cognitive impairment and MRI findings, including whole brain atrophy and, to some degree, overall white matter lesion burden. Cognitive changes also result from damage in specific areas, including deep gray matter and the corpus callosum, cerebral cortex, and mesial temporal lobe.^3-5

The type and severity of cognitive deficits vary widely among people with MS. However, difficulties with information processing speed and short-term memory are the symptoms most commonly seen in this population. Processing speed problems affect new learning and impact memory and executive function. Other domains that can be affected are complex attention, verbal fluency, and visuospatial perception.¹

Q)Are cognitive symptoms in MS progressive?

Not everyone with cognitive symptoms related to MS will show progressive changes. However, in a longitudinal study, increasing age and degree of physical disability were predictive of worsening cognitive symptoms. Also, people who demonstrate early cognitive symptoms may experience greater worsening.⁶

Q)What impact do cognitive symptoms have?

Changes in cognition are a common reason for someone to experience performance issues in the workplace and as such significantly affect a person’s ability to maintain employment. Impaired cognition is a primary cause of early departure from the workforceand has significant implications for self-image and self-esteem.⁷

Furthermore, cognitive symptoms can impact adherence to medications. They also can negatively affect daily life, through increased risk for motor vehicle accidents, difficulties with routine household tasks, and significant challenges to relationships (particularly but not exclusively those with caregivers).

Continue to: How are cognitive symptoms assessed?

Q)How are cognitive symptoms assessed?

There are several screening tools that take very little time to administer and can be used in the clinic setting. The Symbol Digit Modalities Test (SDMT; www.wpspublish.com/store/p/2955/sdmt-symbol-digit-modalities-test) is validated in MS and takes approximately 90 s to complete. This screening instrument is proprietary and has a small fee associated with its use.⁸

Other possible causes of cognitive dysfunction should be investigated as well. These include an examination of medications being used—such as anticholinergics, benzodiazepines, other sedatives, cannabis, topiramate, and opioids—and consideration of other diseases and conditions, including vascular conditions, metabolic deficiencies, infection, tumor, substance abuse, early dementia, or hypothyroidism, which may contribute to or cause cognitive impairment.

Should cognitive problems be identified—either through the history, during the clinic visit, or via screening tests—more formal testing, usually performed by a neuropsychologist, may be useful in identifying the domains of function that are impaired. This information can help to identify and implement appropriate compensatory strategies, plan cognitive rehabilitation interventions, and (in the United States) assist the individual to obtain Social Security disability benefits.

Q)How are cognitive symptoms managed?

Multiple clinical trials of cognitive rehabilitation strategies have demonstrated the efficacy of computer-based programs in improving new learning, short-term memory, processing speed, and attention.⁹ Cognitive rehabilitation programs should be administered and/or supervised by a health care professional who is knowledgeable about MS as well as cognitive rehabilitation. Professionals such as neuropsychologists, occupational therapists, and speech language pathologists often direct cognitive training programs.

Medications that stimulate the central nervous system have been used to improve mental alertness. However, clinical trials are few and have yielded mixed results.

Continue to: In clinical trials...

In clinical trials, physical exercise has been shown to improve processing speed. More research is needed to demonstrate the type of exercise that is most beneficial and the extent of improvement in cognitive function that results.

SUMMARY

Cognitive function can be negatively impacted by MS. Activities of daily living, including employment and relationships, can be negatively impacted by changes in cognition. Regular screening of cognition is recommended by the National MS Society, using validated screening tools such as the SDMT. Additional testing is warranted for individuals reporting cognitive difficulties at home or work, or those who score below controls on screening tests. Cognitive rehabilitation may help some individuals improve their cognitive function. More research is needed to identify additional cognitive training techniques, better understand the role of physical exercise, and identify medications that may be of benefit to maintain cognitive function.

Cognitive changes related to multiple sclerosis (MS) were first mentioned by Jean-Martin Charcot in 1877; however, it is only within the past 25-30 years that cognitive impairment in MS has received significant clinical study. Despite a growing body of research, though, formal screening of cognitive function is not always part of routine MS clinical care.

Q)How common are cognitive symptoms in MS?

Cognitive changes affect up to 65% of patients in MS clinic samples and about one-third of pediatric MS patients.¹ Cognitive deficits occur in all the MS disease courses, including clinically isolated syndrome, although they are most prevalent in secondary progressive and primary progressive disease.¹ Cognitive changes have even been observed in radiographically isolated syndrome, in which MRI changes consistent with MS are observed without any neurologic symptoms or signs.²

Q)What cognitive domains are affected in MS?

Strong correlations have been demonstrated between cognitive impairment and MRI findings, including whole brain atrophy and, to some degree, overall white matter lesion burden. Cognitive changes also result from damage in specific areas, including deep gray matter and the corpus callosum, cerebral cortex, and mesial temporal lobe.^3-5

The type and severity of cognitive deficits vary widely among people with MS. However, difficulties with information processing speed and short-term memory are the symptoms most commonly seen in this population. Processing speed problems affect new learning and impact memory and executive function. Other domains that can be affected are complex attention, verbal fluency, and visuospatial perception.¹

Q)Are cognitive symptoms in MS progressive?

Not everyone with cognitive symptoms related to MS will show progressive changes. However, in a longitudinal study, increasing age and degree of physical disability were predictive of worsening cognitive symptoms. Also, people who demonstrate early cognitive symptoms may experience greater worsening.⁶

Q)What impact do cognitive symptoms have?

Changes in cognition are a common reason for someone to experience performance issues in the workplace and as such significantly affect a person’s ability to maintain employment. Impaired cognition is a primary cause of early departure from the workforceand has significant implications for self-image and self-esteem.⁷

Furthermore, cognitive symptoms can impact adherence to medications. They also can negatively affect daily life, through increased risk for motor vehicle accidents, difficulties with routine household tasks, and significant challenges to relationships (particularly but not exclusively those with caregivers).

Continue to: How are cognitive symptoms assessed?

Q)How are cognitive symptoms assessed?

There are several screening tools that take very little time to administer and can be used in the clinic setting. The Symbol Digit Modalities Test (SDMT; www.wpspublish.com/store/p/2955/sdmt-symbol-digit-modalities-test) is validated in MS and takes approximately 90 s to complete. This screening instrument is proprietary and has a small fee associated with its use.⁸

Other possible causes of cognitive dysfunction should be investigated as well. These include an examination of medications being used—such as anticholinergics, benzodiazepines, other sedatives, cannabis, topiramate, and opioids—and consideration of other diseases and conditions, including vascular conditions, metabolic deficiencies, infection, tumor, substance abuse, early dementia, or hypothyroidism, which may contribute to or cause cognitive impairment.

Should cognitive problems be identified—either through the history, during the clinic visit, or via screening tests—more formal testing, usually performed by a neuropsychologist, may be useful in identifying the domains of function that are impaired. This information can help to identify and implement appropriate compensatory strategies, plan cognitive rehabilitation interventions, and (in the United States) assist the individual to obtain Social Security disability benefits.

Q)How are cognitive symptoms managed?

Multiple clinical trials of cognitive rehabilitation strategies have demonstrated the efficacy of computer-based programs in improving new learning, short-term memory, processing speed, and attention.⁹ Cognitive rehabilitation programs should be administered and/or supervised by a health care professional who is knowledgeable about MS as well as cognitive rehabilitation. Professionals such as neuropsychologists, occupational therapists, and speech language pathologists often direct cognitive training programs.

Medications that stimulate the central nervous system have been used to improve mental alertness. However, clinical trials are few and have yielded mixed results.

Continue to: In clinical trials...

In clinical trials, physical exercise has been shown to improve processing speed. More research is needed to demonstrate the type of exercise that is most beneficial and the extent of improvement in cognitive function that results.

SUMMARY

Cognitive function can be negatively impacted by MS. Activities of daily living, including employment and relationships, can be negatively impacted by changes in cognition. Regular screening of cognition is recommended by the National MS Society, using validated screening tools such as the SDMT. Additional testing is warranted for individuals reporting cognitive difficulties at home or work, or those who score below controls on screening tests. Cognitive rehabilitation may help some individuals improve their cognitive function. More research is needed to identify additional cognitive training techniques, better understand the role of physical exercise, and identify medications that may be of benefit to maintain cognitive function.

Aplastic anemia is a rare hematologic disorder marked by pancytopenia and a hypocellular marrow. Aplastic anemia results from either inherited or acquired causes, and the treatment approach varies significantly between the 2 causes. This article reviews the treatment of inherited and acquired forms of aplastic anemia. The approach to evaluation and diagnosis of aplastic anemia is reviewed in a separate article.

Inherited Aplastic Anemia

First-line treatment options for patients with inherited marrow failure syndromes (IMFS) are androgen therapy and hematopoietic stem cell transplant (HSCT). When evaluating patients for HSCT, it is critical to identify the presence of an IMFS, as the risk and mortality associated with the conditioning regimen, stem cell source, graft-versus-host disease (GVHD), and secondary malignancies differ between patients with IMFS and those with acquired marrow failure syndromes or hematologic malignancies.

Potential sibling donors need to be screened for donor candidacy as well as for the inherited defect.¹ Among patients with Fanconi anemia or a telomere biology disorder, the stem cell source must be considered, with bone marrow demonstrating lower rates of acute GVHD than a peripheral blood stem cell source.^2-4 In IMFS patients, the donor cell type may affect the choice of conditioning regimen.^5,6 Reduced-intensity conditioning in lieu of myeloablative conditioning without total body irradiation has proved feasible in patients with Fanconi anemia, and is associated with a reduced risk of secondary malignancies.^5,6 Incorporation of fludarabine in the conditioning regimen of patients without a matched sibling donor is associated with superior engraftment and survival^2,5,7 compared to cyclophosphamide conditioning, which was historically used in matched related donors.^6,8 The addition of fludarabine appears to be especially beneficial in older patients, in whom its use is associated with lower rates of graft failure, likely due to increased immunosuppression at the time of engraftment.^7,9 Fludarabine has also been incorporated into conditioning regimens for patients with a telomere biology disorder, but outcomes data is limited.⁵

For patients presenting with acute myeloid leukemia (AML) or a high-risk myelodysplastic syndrome (MDS) who are subsequently diagnosed with an IMFS, treatment can be more complex, as these patients are at high risk for toxicity from standard chemotherapy. Limited data suggests that induction therapy and transplantation are feasible in this group of patients, and this approach is associated with increased overall survival (OS) despite lower OS rates than those of IMFS patients who present prior to the development of MDS or AML.^10,11 Further work is needed to determine the optimal induction regimen that balances the risks of treatment-related mortality and complications associated with conditioning regimens, risk of relapse, and risk of secondary malignancies, especially in the cohort of patients diagnosed at an older age.

Acquired Aplastic Anemia

Supportive Care

While the workup and treatment plan is being established, attention should be directed at supportive care for prevention of complications. The most common complications leading to death in patients with significant pancytopenia and neutropenia are opportunistic infections and hemorrhagic complications.¹²

Transfusion support is critical to avoid symptomatic anemia and hemorrhagic complications related to thrombocytopenia, which typically occur with platelet counts lower than 10,000 cells/µL. However, transfusion carries the risk of alloimmunization (which may persist for years following transfusion) and transfusion-related graft versus host disease (trGVHD), and thus use of transfusion should be minimized when possible.^13,14 Transfusion support is often required to prevent complications associated with thrombocytopenia and anemia; all blood products given to patients with aplastic anemia should be irradiated and leukoreduced to reduce the risk of both alloimmunization and trGVHD. Guidelines from the British Society for Haematology recommend routine screening for Rh and Kell antibodies to reduce the risk of alloimmunization.¹⁵ Infectious complications remain a common cause of morbidity and mortality in patients with aplastic anemia who have prolonged neutropenia (defined as an absolute neutrophil count [ANC] < 500 cells/µL).^16-19 Therefore, patients should receive broad-spectrum antibiotics with antipseudomonal coverage. In a study by Tichelli and colleagues evaluating the role of granulocyte-colony stimulating factor (G-CSF) in patients with SAA receiving immunosuppressive therapy, 55% of all patient deaths were secondary to infection.²⁰ There was no OS benefit seen in patients who received G-CSF, though a significantly lower rate of infection was observed in the G-CSF arm compared to those not receiving G-CSF (56% versus 81%, P = 0.006).This difference was largely driven by a decrease in infectious episodes in patients with very severe aplastic anemia (VSAA) treated with G-CSF as compared to those who did not receive this therapy (22% versus 48%, P = 0.014).²⁰

Angio-invasive pulmonary aspergillosis and Zygomycetes (eg, Rhizopus, Mucor species) remain major causes of mortality related to opportunistic mycotic infections in patients with aplastic anemia.¹⁸ The infectious risk is directly related to the duration and severity of neutropenia, with one study demonstrating a significant increase in risk in AML patients with neutropenia lasting longer than 3 weeks.²¹ Invasive fungal infections carry a high mortality in patients with severe neutropenia, though due to earlier recognition and empiric antifungal therapy with extended-spectrum azoles, overall mortality secondary to invasive fungal infections is declining.^19,22

While neutropenia related to cytotoxic chemotherapy is commonly associated with gram-negative bacteria due to disruption of mucosal barriers, patients with aplastic anemia have an increased incidence of gram-positive bacteremia with staphylococcal species compared to other neutropenic populations.^18,19 This appears to be changing with time. Valdez and colleagues demonstrated a decrease in prevalence of coagulase-negative staphylococcal infections, increased prevalence of gram-positive bacilli bacteremia, and no change in prevalence of gram-negative bacteremia in patients with aplastic anemia treated between 1989 and 2008.²² Gram-negative bacteremia caused by Stenotrophomonas maltophila, Escherichia coli, Klebsiella pneumoniae, Citrobacter, and Proteus has also been reported.¹⁹ Despite a lack of clinical trials investigating the role of antifungal and antibacterial prophylaxis for patients with aplastic anemia, most centers initiate antifungal prophylaxis in patients with severe aplastic anema (SAA) or VSAA with an anti-mold agent such as voriconazole or posaconazole (which has the additional benefit compared to voriconazole of covering Mucor species).^17,23 This is especially true for patients who have received ATG or undergone HSCT. For antimicrobial prophylaxis, a fluoroquinolone antibiotic with a spectrum of activity against Pseudomonas should be considered for patients with an ANC < 500 cells/µL.¹⁷ Acyclovir or valacyclovir prophylaxis is recommended for varicella-zoster virus and herpes simplex virus. Cytomegalovirus reactivation is minimal in patients with aplastic anemia, unless multiple courses of ATG are used.

Iron overload is another complication the provider must be aware of in the setting of increased transfusions in aplastic anemia patients. Lee and colleagues demonstrated that iron chelation therapy using deferasirox is effective at reducing serum ferritin levels in patients with aplastic anemia (median ferritin level: 3254 ng/mL prior to therapy, 1854 ng/mL following), and is associated with no serious adverse events (most common adverse events included nausea, diarrhea, vomiting, and rash).²⁴ Approximately 25% of patients in this trial demonstrated an increase in creatinine, with patients taking concomitant cyclosporine more affected than those on chelation therapy alone.²⁴ For patients following HSCT or with improved hematopoiesis following immunosuppressive therapy, phlebotomy can be used to treat iron overload in lieu of chelation therapy.¹⁵

Approach to Therapy

The main treatment options for SAA and VSAA include allogeneic bone marrow transplant and immunosuppression. The deciding factors as to which treatment is best initially depends on the availability of HLA-matched related donors and age (Figure 1 and Figure 2). Survival is decreased in patients with SAA or VSAA who delay initiation of therapy, and therefore prompt referral for HLA typing and evaluation for bone marrow transplant is a very important first step in managing aplastic anemia.

Matched Sibling Donor Transplant

Current standards of care recommend HLA-matched sibling donor transplant for patients with SAA or VSAA who are younger than 50 years of age, with the caveat that integration of fludarabine and reduced cyclophosphamide dosing along with ATG shows the best overall outcomes. Locasciulli and colleagues examined outcomes in patients given either immunosuppressive therapy or sibling HSCT between 1991-1996 and 1997-2002, respectively, and found that sibling HSCT was associated with a superior 10-year OS compared to immunosuppressive therapy (73% versus 68%).²⁵ Interestingly in this study, there was no OS improvement seen with immunosuppressive therapy alone (69% versus 73%) between the 2 time periods, despite increased OS in both sibling HSCT (74% and 80%) and matched unrelated donor HSCT (38% and 65%).²⁵ Though total body irradiation has been used in the past, it is typically not included in current conditioning regimens for matched related donor transplants.²⁶

Current conditioning regimens typically use a combination of cyclophosphamide and ATG^27,28 with or without fludarabine. Fludarabine-based conditioning regimens have shown promise in patients undergoing sibling HSCT. Maury and colleagues evaluated the role of fludarabine in addition to low-dose cyclophosphamide and ATG compared to cyclophosphamide alone or in combination with ATG in patients over age 30 undergoing sibling HSCT.⁹ There was a nonsignificant improvement in 5-year OS in the fludarabine arm compared to controls (77% ± 8% versus 60% ± 3%, P = 0.14) in the pooled analysis, but when adjusted for age the fludarabine arm had a significantly lower relative risk (RR) of death (RR, 0.44; P = 0.04) compared to the control arm. Shin et al reported outcomes with fludarabine/cyclophosphamide/ATG, with excellent overall outcomes and no difference in patients older or younger than 40 years.²⁹ In addition, Kim et al evaluated their experience with patients older than 40 years of age receiving matched related donors, finding comparable outcomes in those aged 41 to 50 years compared to younger patients. Outcomes did decline in those over the age of 50 years.³⁰ Long-term data for matched related donor transplant for aplastic anemia shows excellent long-term outcomes, with minimal chronic GVHD and good performance status.³¹ Hence, these factors support the role of matched related donor transplant as the initial treatment in SAA and VSAA.

Regarding the role of transplant for patients who lack a matched related donor, a growing body of literature demonstrating identical outcomes between matched related and matched unrelated donor (MUD) transplants for pediatric patients^32,33 supports recent recommendations for upfront unrelated donor transplantation for aplastic anemia.^34,35

Immunosuppressive Therapy

For patients without an HLA-matched sibling donor or those who are older than 50 years of age, immunosuppressive therapy is the first-line therapy. ATG and cyclosporine A are the treatments of choice.³⁶ The potential effectiveness of immunosuppressive therapy in treating aplastic anemia was initially observed in patients in whom autologous transplant failed but who still experienced hematopoietic reconstitution despite the failed graft; this observation led to the hypothesis that the conditioning regimen may have an effect on hematopoiesis.^16,36,37

Anti-thymocyte globulin. Immunosuppressive therapy with ATG has been used for the treatment of aplastic anemia since the 1980s.³⁸ Historically, rabbit ATG had been used, but a 2011 study of horse ATG demonstrated superior hematological response at 6 months compared to rabbit ATG (68% versus 37%).¹⁶ Superior survival was also seen with horse ATG compared to rabbit ATG (3-year OS: 96% versus 76%). Due to these results, horse ATG is preferred over rabbit ATG. ATG should be used in combination with cyclosporine A to optimize outcomes.

Cyclosporine A. Early studies also demonstrated the efficacy of cyclosporine A in the treatment of aplastic anemia, with response rates equivalent to that of ATG monotherapy.³⁹ Recent publications still note the efficacy of cyclosporine A in the treatment of aplastic anemia. Its role as an affordable option for single-agent therapy in developing countries is intriguing.³⁹

The combination of the ATG and cyclosporine A was proven superior to either agent alone in a study by Frickhofen et al.³⁷ In this study patients were randomly assigned to a control arm that received ATG plus methylprednisolone or to an arm that received ATG plus cyclosporine A and methylprednisolone. At 6 months, 70% of patients in the cyclosporine A arm had a complete remission (CR) or partial remission compared to 46% in the control arm.⁴⁰ Further work confirmed the long-term efficacy of this regimen, reporting a 7-year OS of 55%.⁴¹ Among a pediatric population, immunosuppressive therapy was associated with an 83% 10-year OS.⁴²

It is recommended that patients remain on cyclosporine therapy for a minimum of 6 months, after which a gradual taper may be considered, although there is variation among practitioners, with some continuing immunosuppressive therapy for a minimum of 12 months due to a proportion of patients being cyclosporine dependent.^42,43 A study found that within a population of patients who responded to immunosuppressive therapy, 18% became cyclosporine dependent.⁴² The median duration of cyclosporine A treatment at full dose was 12 months, with tapering completed over a median of 19 months after patients had been in a stable CR for a minimum of 3 months. Relapse occurred more often when patients were tapered quickly (decrease ≥ 0.8 mg/kg/month) compared to slowly (0.4-0.7 mg/kg/month) or very slowly (< 0.3 mg/kg/month).

Immunosuppressive therapy plus eltrombopag. Townsley and colleagues recently investigated incorporating the use of the thrombopoietin receptor agonist eltrombopag with immunosuppressive therapy as first-line therapy in aplastic anemia.⁴⁴ When given at a dose of 150 mg daily in patients aged 12 years and older or 75 mg daily in patients younger than 12 years, in conjunction with cyclosporine A and ATG, patients demonstrated markedly improved hematological response compared to historical treatment with standard immunosuppressive therapy alone.⁴⁴ In the patient cohort administered eltrombopag starting on day 1 and continuing for 6 months, the complete response rate was 58%. Eltrombopag led to improvement in all cell lines among all treatment subgroups, and OS (censored for patients who proceeded to transplant) was 99% at 2 years.⁴⁵ Overall, toxicities associated with this therapy were low, with liver enzyme elevations most commonly observed.⁴⁴ Recently, a phase 2 trial of immunosuppressive therapy with or without eltrombopag was reported. Of the 38 patients enrolled, overall response, complete response, and time to response were not statistically different.⁴⁶ With this recent finding, the role of eltrombopag in addition to immunosuppressive therapy is not clearly defined, and further studies are warranted.

OS for patients who do not respond to immunosuppressive therapy is approximately 57% at 5 years, largely due to improved supportive measures among this patient population.^4,22 Therefore, it is important to recognize those patients who have a low chance of response so that second-line therapy can be pursued to improve outcomes.

Matched Unrelated Donor Transplant

For patients with refractory disease following immunosuppressive therapy who lack a matched sibling donor, MUD HSCT is considered standard therapy given the marked improvement in overall outcomes with modulating conditioning regimens and high-resolution HLA typing. A European Society for Blood and Marrow Transplantation analysis comparing matched sibling HSCT to MUD HSCT noted significantly higher rates of acute grade II-IV and grade III-V GVHD (grade II-IV 13% versus 25%, grade III-IV 5% versus 10%) among patients undergoing MUD transplant.⁴⁷ Chronic GVHD rates were 14% in the sibling group, as compared to 26% in the MUD group. Additional benefits seen in this analysis included improved survival when transplanted under age 20 years (84% versus 72%), when transplanted within 6 months of diagnosis (85% versus 72%), the use of ATG in the conditioning regimen (81% versus 73%), and when the donor and recipient were cytomegalovirus-negative compared to other combinations (82% versus 76%).⁴⁷ Interestingly, this study demonstrated that OS was not significantly increased when using a sibling HSCT compared to a MUD HSCT, likely as a result of improved understanding of conditioning regimens, GVHD prophylaxis, and supportive care.

Additional studies of MUD HSCT have shown outcomes similar to those seen in sibling HSCT.^4,43 A French study found a significant increase in survival in patients undergoing MUD HSCT compared to historical cohorts (2000-2005: OS 52%; 2006-2012: OS 74%).³³ The majority of patients underwent conditioning with cyclophosphamide or a combination of busulfan and cyclophosphamide, with or without fludarabine; 81% of patients included underwent in vivo T-cell depletion, and a bone marrow donor source was utilized. OS was significantly lower in patients over age 30 years undergoing MUD HSCT (57%) compared to those under age 30 years (70%). Improved OS was also seen when patients underwent transplant within 1 year of diagnosis and when a 10/10 matched donor (compared to a 9/10 mismatched donor) was utilized.⁴ A 2015 study investigated the role of MUD HSCT as frontline therapy instead of immunosuppressive therapy in patients without a matched sibling donor.³³ The 2-year OS was 96% in the MUD HSCT cohort compared to 91%, 94%, and 74% in historical cohorts of sibling HSCT, frontline immunosuppressive therapy, and second-line MUD HSCT following failed immunosuppressive therapy, respectively. Additionally, event-free survival in the MUD HSCT cohort (defined by the authors as death, lack of response, relapse, occurrence of clonal evolution/clinical paroxysmal nocturnal hemoglobinuria, malignancies developing over follow‐up, and transplant for patients receiving immunosuppressive therapy frontline) was similar compared to sibling HSCT and superior to frontline immunosuppressive therapy and second-line MUD HSCT. Furthermore, Samarasinghe et al highlighted the importance of in vivo T-cell depletion with either ATG or alemtuzumab (anti-CD52 monoclonal antibody) in the prevention of acute and chronic GVHD in both sibling HSCT and MUD HSCT.⁴⁸

With continued improvement of less toxic and more immunomodulating conditioning regimens, utilization of bone marrow as a donor cell source, in vivo T-cell depletion, and use of GVHD and antimicrobial prophylaxis, more clinical evidence supports elevating MUD HSCT in the treatment plan for patients without a matched sibling donor.⁴⁹ However, there is still a large population of patients without matched sibling or unrelated donor options. In an effort to expand the transplant pool and thus avoid clonal hematopoiesis, clinically significant paroxysmal nocturnal hemoglobinuria, and relapsed aplastic anemia, more work continues to recognize the expanding role of alternative donor transplants (cord blood and haploidentical) as another viable treatment strategy for aplastic anemia after immunosuppressive therapy failure.⁵⁰

Summary

Aplastic anemia is a rare but potentially life-threatening disorder characterized by pancytopenia and a marked reduction in the hematopoietic stem cell compartment. Treatment should be instituted as soon as the dignosis of aplastic anemia is established. Treatment outcomes are excellent with modern supportive care and the current approach to allogeneic transplantation, and therefore referral to a bone marrow transplant program to evaluate for early transplantation is the new standard of care.

Aplastic anemia is a rare hematologic disorder marked by pancytopenia and a hypocellular marrow. Aplastic anemia results from either inherited or acquired causes, and the treatment approach varies significantly between the 2 causes. This article reviews the treatment of inherited and acquired forms of aplastic anemia. The approach to evaluation and diagnosis of aplastic anemia is reviewed in a separate article.

Inherited Aplastic Anemia

First-line treatment options for patients with inherited marrow failure syndromes (IMFS) are androgen therapy and hematopoietic stem cell transplant (HSCT). When evaluating patients for HSCT, it is critical to identify the presence of an IMFS, as the risk and mortality associated with the conditioning regimen, stem cell source, graft-versus-host disease (GVHD), and secondary malignancies differ between patients with IMFS and those with acquired marrow failure syndromes or hematologic malignancies.

Potential sibling donors need to be screened for donor candidacy as well as for the inherited defect.¹ Among patients with Fanconi anemia or a telomere biology disorder, the stem cell source must be considered, with bone marrow demonstrating lower rates of acute GVHD than a peripheral blood stem cell source.^2-4 In IMFS patients, the donor cell type may affect the choice of conditioning regimen.^5,6 Reduced-intensity conditioning in lieu of myeloablative conditioning without total body irradiation has proved feasible in patients with Fanconi anemia, and is associated with a reduced risk of secondary malignancies.^5,6 Incorporation of fludarabine in the conditioning regimen of patients without a matched sibling donor is associated with superior engraftment and survival^2,5,7 compared to cyclophosphamide conditioning, which was historically used in matched related donors.^6,8 The addition of fludarabine appears to be especially beneficial in older patients, in whom its use is associated with lower rates of graft failure, likely due to increased immunosuppression at the time of engraftment.^7,9 Fludarabine has also been incorporated into conditioning regimens for patients with a telomere biology disorder, but outcomes data is limited.⁵

For patients presenting with acute myeloid leukemia (AML) or a high-risk myelodysplastic syndrome (MDS) who are subsequently diagnosed with an IMFS, treatment can be more complex, as these patients are at high risk for toxicity from standard chemotherapy. Limited data suggests that induction therapy and transplantation are feasible in this group of patients, and this approach is associated with increased overall survival (OS) despite lower OS rates than those of IMFS patients who present prior to the development of MDS or AML.^10,11 Further work is needed to determine the optimal induction regimen that balances the risks of treatment-related mortality and complications associated with conditioning regimens, risk of relapse, and risk of secondary malignancies, especially in the cohort of patients diagnosed at an older age.

Acquired Aplastic Anemia

Supportive Care

While the workup and treatment plan is being established, attention should be directed at supportive care for prevention of complications. The most common complications leading to death in patients with significant pancytopenia and neutropenia are opportunistic infections and hemorrhagic complications.¹²

Transfusion support is critical to avoid symptomatic anemia and hemorrhagic complications related to thrombocytopenia, which typically occur with platelet counts lower than 10,000 cells/µL. However, transfusion carries the risk of alloimmunization (which may persist for years following transfusion) and transfusion-related graft versus host disease (trGVHD), and thus use of transfusion should be minimized when possible.^13,14 Transfusion support is often required to prevent complications associated with thrombocytopenia and anemia; all blood products given to patients with aplastic anemia should be irradiated and leukoreduced to reduce the risk of both alloimmunization and trGVHD. Guidelines from the British Society for Haematology recommend routine screening for Rh and Kell antibodies to reduce the risk of alloimmunization.¹⁵ Infectious complications remain a common cause of morbidity and mortality in patients with aplastic anemia who have prolonged neutropenia (defined as an absolute neutrophil count [ANC] < 500 cells/µL).^16-19 Therefore, patients should receive broad-spectrum antibiotics with antipseudomonal coverage. In a study by Tichelli and colleagues evaluating the role of granulocyte-colony stimulating factor (G-CSF) in patients with SAA receiving immunosuppressive therapy, 55% of all patient deaths were secondary to infection.²⁰ There was no OS benefit seen in patients who received G-CSF, though a significantly lower rate of infection was observed in the G-CSF arm compared to those not receiving G-CSF (56% versus 81%, P = 0.006).This difference was largely driven by a decrease in infectious episodes in patients with very severe aplastic anemia (VSAA) treated with G-CSF as compared to those who did not receive this therapy (22% versus 48%, P = 0.014).²⁰

Angio-invasive pulmonary aspergillosis and Zygomycetes (eg, Rhizopus, Mucor species) remain major causes of mortality related to opportunistic mycotic infections in patients with aplastic anemia.¹⁸ The infectious risk is directly related to the duration and severity of neutropenia, with one study demonstrating a significant increase in risk in AML patients with neutropenia lasting longer than 3 weeks.²¹ Invasive fungal infections carry a high mortality in patients with severe neutropenia, though due to earlier recognition and empiric antifungal therapy with extended-spectrum azoles, overall mortality secondary to invasive fungal infections is declining.^19,22

While neutropenia related to cytotoxic chemotherapy is commonly associated with gram-negative bacteria due to disruption of mucosal barriers, patients with aplastic anemia have an increased incidence of gram-positive bacteremia with staphylococcal species compared to other neutropenic populations.^18,19 This appears to be changing with time. Valdez and colleagues demonstrated a decrease in prevalence of coagulase-negative staphylococcal infections, increased prevalence of gram-positive bacilli bacteremia, and no change in prevalence of gram-negative bacteremia in patients with aplastic anemia treated between 1989 and 2008.²² Gram-negative bacteremia caused by Stenotrophomonas maltophila, Escherichia coli, Klebsiella pneumoniae, Citrobacter, and Proteus has also been reported.¹⁹ Despite a lack of clinical trials investigating the role of antifungal and antibacterial prophylaxis for patients with aplastic anemia, most centers initiate antifungal prophylaxis in patients with severe aplastic anema (SAA) or VSAA with an anti-mold agent such as voriconazole or posaconazole (which has the additional benefit compared to voriconazole of covering Mucor species).^17,23 This is especially true for patients who have received ATG or undergone HSCT. For antimicrobial prophylaxis, a fluoroquinolone antibiotic with a spectrum of activity against Pseudomonas should be considered for patients with an ANC < 500 cells/µL.¹⁷ Acyclovir or valacyclovir prophylaxis is recommended for varicella-zoster virus and herpes simplex virus. Cytomegalovirus reactivation is minimal in patients with aplastic anemia, unless multiple courses of ATG are used.

Iron overload is another complication the provider must be aware of in the setting of increased transfusions in aplastic anemia patients. Lee and colleagues demonstrated that iron chelation therapy using deferasirox is effective at reducing serum ferritin levels in patients with aplastic anemia (median ferritin level: 3254 ng/mL prior to therapy, 1854 ng/mL following), and is associated with no serious adverse events (most common adverse events included nausea, diarrhea, vomiting, and rash).²⁴ Approximately 25% of patients in this trial demonstrated an increase in creatinine, with patients taking concomitant cyclosporine more affected than those on chelation therapy alone.²⁴ For patients following HSCT or with improved hematopoiesis following immunosuppressive therapy, phlebotomy can be used to treat iron overload in lieu of chelation therapy.¹⁵

Approach to Therapy

The main treatment options for SAA and VSAA include allogeneic bone marrow transplant and immunosuppression. The deciding factors as to which treatment is best initially depends on the availability of HLA-matched related donors and age (Figure 1 and Figure 2). Survival is decreased in patients with SAA or VSAA who delay initiation of therapy, and therefore prompt referral for HLA typing and evaluation for bone marrow transplant is a very important first step in managing aplastic anemia.

Matched Sibling Donor Transplant

Current standards of care recommend HLA-matched sibling donor transplant for patients with SAA or VSAA who are younger than 50 years of age, with the caveat that integration of fludarabine and reduced cyclophosphamide dosing along with ATG shows the best overall outcomes. Locasciulli and colleagues examined outcomes in patients given either immunosuppressive therapy or sibling HSCT between 1991-1996 and 1997-2002, respectively, and found that sibling HSCT was associated with a superior 10-year OS compared to immunosuppressive therapy (73% versus 68%).²⁵ Interestingly in this study, there was no OS improvement seen with immunosuppressive therapy alone (69% versus 73%) between the 2 time periods, despite increased OS in both sibling HSCT (74% and 80%) and matched unrelated donor HSCT (38% and 65%).²⁵ Though total body irradiation has been used in the past, it is typically not included in current conditioning regimens for matched related donor transplants.²⁶

Current conditioning regimens typically use a combination of cyclophosphamide and ATG^27,28 with or without fludarabine. Fludarabine-based conditioning regimens have shown promise in patients undergoing sibling HSCT. Maury and colleagues evaluated the role of fludarabine in addition to low-dose cyclophosphamide and ATG compared to cyclophosphamide alone or in combination with ATG in patients over age 30 undergoing sibling HSCT.⁹ There was a nonsignificant improvement in 5-year OS in the fludarabine arm compared to controls (77% ± 8% versus 60% ± 3%, P = 0.14) in the pooled analysis, but when adjusted for age the fludarabine arm had a significantly lower relative risk (RR) of death (RR, 0.44; P = 0.04) compared to the control arm. Shin et al reported outcomes with fludarabine/cyclophosphamide/ATG, with excellent overall outcomes and no difference in patients older or younger than 40 years.²⁹ In addition, Kim et al evaluated their experience with patients older than 40 years of age receiving matched related donors, finding comparable outcomes in those aged 41 to 50 years compared to younger patients. Outcomes did decline in those over the age of 50 years.³⁰ Long-term data for matched related donor transplant for aplastic anemia shows excellent long-term outcomes, with minimal chronic GVHD and good performance status.³¹ Hence, these factors support the role of matched related donor transplant as the initial treatment in SAA and VSAA.

Regarding the role of transplant for patients who lack a matched related donor, a growing body of literature demonstrating identical outcomes between matched related and matched unrelated donor (MUD) transplants for pediatric patients^32,33 supports recent recommendations for upfront unrelated donor transplantation for aplastic anemia.^34,35

Immunosuppressive Therapy

For patients without an HLA-matched sibling donor or those who are older than 50 years of age, immunosuppressive therapy is the first-line therapy. ATG and cyclosporine A are the treatments of choice.³⁶ The potential effectiveness of immunosuppressive therapy in treating aplastic anemia was initially observed in patients in whom autologous transplant failed but who still experienced hematopoietic reconstitution despite the failed graft; this observation led to the hypothesis that the conditioning regimen may have an effect on hematopoiesis.^16,36,37

Anti-thymocyte globulin. Immunosuppressive therapy with ATG has been used for the treatment of aplastic anemia since the 1980s.³⁸ Historically, rabbit ATG had been used, but a 2011 study of horse ATG demonstrated superior hematological response at 6 months compared to rabbit ATG (68% versus 37%).¹⁶ Superior survival was also seen with horse ATG compared to rabbit ATG (3-year OS: 96% versus 76%). Due to these results, horse ATG is preferred over rabbit ATG. ATG should be used in combination with cyclosporine A to optimize outcomes.

Cyclosporine A. Early studies also demonstrated the efficacy of cyclosporine A in the treatment of aplastic anemia, with response rates equivalent to that of ATG monotherapy.³⁹ Recent publications still note the efficacy of cyclosporine A in the treatment of aplastic anemia. Its role as an affordable option for single-agent therapy in developing countries is intriguing.³⁹

The combination of the ATG and cyclosporine A was proven superior to either agent alone in a study by Frickhofen et al.³⁷ In this study patients were randomly assigned to a control arm that received ATG plus methylprednisolone or to an arm that received ATG plus cyclosporine A and methylprednisolone. At 6 months, 70% of patients in the cyclosporine A arm had a complete remission (CR) or partial remission compared to 46% in the control arm.⁴⁰ Further work confirmed the long-term efficacy of this regimen, reporting a 7-year OS of 55%.⁴¹ Among a pediatric population, immunosuppressive therapy was associated with an 83% 10-year OS.⁴²

It is recommended that patients remain on cyclosporine therapy for a minimum of 6 months, after which a gradual taper may be considered, although there is variation among practitioners, with some continuing immunosuppressive therapy for a minimum of 12 months due to a proportion of patients being cyclosporine dependent.^42,43 A study found that within a population of patients who responded to immunosuppressive therapy, 18% became cyclosporine dependent.⁴² The median duration of cyclosporine A treatment at full dose was 12 months, with tapering completed over a median of 19 months after patients had been in a stable CR for a minimum of 3 months. Relapse occurred more often when patients were tapered quickly (decrease ≥ 0.8 mg/kg/month) compared to slowly (0.4-0.7 mg/kg/month) or very slowly (< 0.3 mg/kg/month).

Immunosuppressive therapy plus eltrombopag. Townsley and colleagues recently investigated incorporating the use of the thrombopoietin receptor agonist eltrombopag with immunosuppressive therapy as first-line therapy in aplastic anemia.⁴⁴ When given at a dose of 150 mg daily in patients aged 12 years and older or 75 mg daily in patients younger than 12 years, in conjunction with cyclosporine A and ATG, patients demonstrated markedly improved hematological response compared to historical treatment with standard immunosuppressive therapy alone.⁴⁴ In the patient cohort administered eltrombopag starting on day 1 and continuing for 6 months, the complete response rate was 58%. Eltrombopag led to improvement in all cell lines among all treatment subgroups, and OS (censored for patients who proceeded to transplant) was 99% at 2 years.⁴⁵ Overall, toxicities associated with this therapy were low, with liver enzyme elevations most commonly observed.⁴⁴ Recently, a phase 2 trial of immunosuppressive therapy with or without eltrombopag was reported. Of the 38 patients enrolled, overall response, complete response, and time to response were not statistically different.⁴⁶ With this recent finding, the role of eltrombopag in addition to immunosuppressive therapy is not clearly defined, and further studies are warranted.

OS for patients who do not respond to immunosuppressive therapy is approximately 57% at 5 years, largely due to improved supportive measures among this patient population.^4,22 Therefore, it is important to recognize those patients who have a low chance of response so that second-line therapy can be pursued to improve outcomes.

Matched Unrelated Donor Transplant

For patients with refractory disease following immunosuppressive therapy who lack a matched sibling donor, MUD HSCT is considered standard therapy given the marked improvement in overall outcomes with modulating conditioning regimens and high-resolution HLA typing. A European Society for Blood and Marrow Transplantation analysis comparing matched sibling HSCT to MUD HSCT noted significantly higher rates of acute grade II-IV and grade III-V GVHD (grade II-IV 13% versus 25%, grade III-IV 5% versus 10%) among patients undergoing MUD transplant.⁴⁷ Chronic GVHD rates were 14% in the sibling group, as compared to 26% in the MUD group. Additional benefits seen in this analysis included improved survival when transplanted under age 20 years (84% versus 72%), when transplanted within 6 months of diagnosis (85% versus 72%), the use of ATG in the conditioning regimen (81% versus 73%), and when the donor and recipient were cytomegalovirus-negative compared to other combinations (82% versus 76%).⁴⁷ Interestingly, this study demonstrated that OS was not significantly increased when using a sibling HSCT compared to a MUD HSCT, likely as a result of improved understanding of conditioning regimens, GVHD prophylaxis, and supportive care.

Additional studies of MUD HSCT have shown outcomes similar to those seen in sibling HSCT.^4,43 A French study found a significant increase in survival in patients undergoing MUD HSCT compared to historical cohorts (2000-2005: OS 52%; 2006-2012: OS 74%).³³ The majority of patients underwent conditioning with cyclophosphamide or a combination of busulfan and cyclophosphamide, with or without fludarabine; 81% of patients included underwent in vivo T-cell depletion, and a bone marrow donor source was utilized. OS was significantly lower in patients over age 30 years undergoing MUD HSCT (57%) compared to those under age 30 years (70%). Improved OS was also seen when patients underwent transplant within 1 year of diagnosis and when a 10/10 matched donor (compared to a 9/10 mismatched donor) was utilized.⁴ A 2015 study investigated the role of MUD HSCT as frontline therapy instead of immunosuppressive therapy in patients without a matched sibling donor.³³ The 2-year OS was 96% in the MUD HSCT cohort compared to 91%, 94%, and 74% in historical cohorts of sibling HSCT, frontline immunosuppressive therapy, and second-line MUD HSCT following failed immunosuppressive therapy, respectively. Additionally, event-free survival in the MUD HSCT cohort (defined by the authors as death, lack of response, relapse, occurrence of clonal evolution/clinical paroxysmal nocturnal hemoglobinuria, malignancies developing over follow‐up, and transplant for patients receiving immunosuppressive therapy frontline) was similar compared to sibling HSCT and superior to frontline immunosuppressive therapy and second-line MUD HSCT. Furthermore, Samarasinghe et al highlighted the importance of in vivo T-cell depletion with either ATG or alemtuzumab (anti-CD52 monoclonal antibody) in the prevention of acute and chronic GVHD in both sibling HSCT and MUD HSCT.⁴⁸

With continued improvement of less toxic and more immunomodulating conditioning regimens, utilization of bone marrow as a donor cell source, in vivo T-cell depletion, and use of GVHD and antimicrobial prophylaxis, more clinical evidence supports elevating MUD HSCT in the treatment plan for patients without a matched sibling donor.⁴⁹ However, there is still a large population of patients without matched sibling or unrelated donor options. In an effort to expand the transplant pool and thus avoid clonal hematopoiesis, clinically significant paroxysmal nocturnal hemoglobinuria, and relapsed aplastic anemia, more work continues to recognize the expanding role of alternative donor transplants (cord blood and haploidentical) as another viable treatment strategy for aplastic anemia after immunosuppressive therapy failure.⁵⁰

Summary

Aplastic anemia is a rare but potentially life-threatening disorder characterized by pancytopenia and a marked reduction in the hematopoietic stem cell compartment. Treatment should be instituted as soon as the dignosis of aplastic anemia is established. Treatment outcomes are excellent with modern supportive care and the current approach to allogeneic transplantation, and therefore referral to a bone marrow transplant program to evaluate for early transplantation is the new standard of care.

Aplastic anemia is a rare hematologic disorder marked by pancytopenia and a hypocellular marrow. Aplastic anemia results from either inherited or acquired causes, and the treatment approach varies significantly between the 2 causes. This article reviews the treatment of inherited and acquired forms of aplastic anemia. The approach to evaluation and diagnosis of aplastic anemia is reviewed in a separate article.

Inherited Aplastic Anemia

First-line treatment options for patients with inherited marrow failure syndromes (IMFS) are androgen therapy and hematopoietic stem cell transplant (HSCT). When evaluating patients for HSCT, it is critical to identify the presence of an IMFS, as the risk and mortality associated with the conditioning regimen, stem cell source, graft-versus-host disease (GVHD), and secondary malignancies differ between patients with IMFS and those with acquired marrow failure syndromes or hematologic malignancies.

Potential sibling donors need to be screened for donor candidacy as well as for the inherited defect.¹ Among patients with Fanconi anemia or a telomere biology disorder, the stem cell source must be considered, with bone marrow demonstrating lower rates of acute GVHD than a peripheral blood stem cell source.^2-4 In IMFS patients, the donor cell type may affect the choice of conditioning regimen.^5,6 Reduced-intensity conditioning in lieu of myeloablative conditioning without total body irradiation has proved feasible in patients with Fanconi anemia, and is associated with a reduced risk of secondary malignancies.^5,6 Incorporation of fludarabine in the conditioning regimen of patients without a matched sibling donor is associated with superior engraftment and survival^2,5,7 compared to cyclophosphamide conditioning, which was historically used in matched related donors.^6,8 The addition of fludarabine appears to be especially beneficial in older patients, in whom its use is associated with lower rates of graft failure, likely due to increased immunosuppression at the time of engraftment.^7,9 Fludarabine has also been incorporated into conditioning regimens for patients with a telomere biology disorder, but outcomes data is limited.⁵

For patients presenting with acute myeloid leukemia (AML) or a high-risk myelodysplastic syndrome (MDS) who are subsequently diagnosed with an IMFS, treatment can be more complex, as these patients are at high risk for toxicity from standard chemotherapy. Limited data suggests that induction therapy and transplantation are feasible in this group of patients, and this approach is associated with increased overall survival (OS) despite lower OS rates than those of IMFS patients who present prior to the development of MDS or AML.^10,11 Further work is needed to determine the optimal induction regimen that balances the risks of treatment-related mortality and complications associated with conditioning regimens, risk of relapse, and risk of secondary malignancies, especially in the cohort of patients diagnosed at an older age.

Acquired Aplastic Anemia

Supportive Care

While the workup and treatment plan is being established, attention should be directed at supportive care for prevention of complications. The most common complications leading to death in patients with significant pancytopenia and neutropenia are opportunistic infections and hemorrhagic complications.¹²

Transfusion support is critical to avoid symptomatic anemia and hemorrhagic complications related to thrombocytopenia, which typically occur with platelet counts lower than 10,000 cells/µL. However, transfusion carries the risk of alloimmunization (which may persist for years following transfusion) and transfusion-related graft versus host disease (trGVHD), and thus use of transfusion should be minimized when possible.^13,14 Transfusion support is often required to prevent complications associated with thrombocytopenia and anemia; all blood products given to patients with aplastic anemia should be irradiated and leukoreduced to reduce the risk of both alloimmunization and trGVHD. Guidelines from the British Society for Haematology recommend routine screening for Rh and Kell antibodies to reduce the risk of alloimmunization.¹⁵ Infectious complications remain a common cause of morbidity and mortality in patients with aplastic anemia who have prolonged neutropenia (defined as an absolute neutrophil count [ANC] < 500 cells/µL).^16-19 Therefore, patients should receive broad-spectrum antibiotics with antipseudomonal coverage. In a study by Tichelli and colleagues evaluating the role of granulocyte-colony stimulating factor (G-CSF) in patients with SAA receiving immunosuppressive therapy, 55% of all patient deaths were secondary to infection.²⁰ There was no OS benefit seen in patients who received G-CSF, though a significantly lower rate of infection was observed in the G-CSF arm compared to those not receiving G-CSF (56% versus 81%, P = 0.006).This difference was largely driven by a decrease in infectious episodes in patients with very severe aplastic anemia (VSAA) treated with G-CSF as compared to those who did not receive this therapy (22% versus 48%, P = 0.014).²⁰

Angio-invasive pulmonary aspergillosis and Zygomycetes (eg, Rhizopus, Mucor species) remain major causes of mortality related to opportunistic mycotic infections in patients with aplastic anemia.¹⁸ The infectious risk is directly related to the duration and severity of neutropenia, with one study demonstrating a significant increase in risk in AML patients with neutropenia lasting longer than 3 weeks.²¹ Invasive fungal infections carry a high mortality in patients with severe neutropenia, though due to earlier recognition and empiric antifungal therapy with extended-spectrum azoles, overall mortality secondary to invasive fungal infections is declining.^19,22

While neutropenia related to cytotoxic chemotherapy is commonly associated with gram-negative bacteria due to disruption of mucosal barriers, patients with aplastic anemia have an increased incidence of gram-positive bacteremia with staphylococcal species compared to other neutropenic populations.^18,19 This appears to be changing with time. Valdez and colleagues demonstrated a decrease in prevalence of coagulase-negative staphylococcal infections, increased prevalence of gram-positive bacilli bacteremia, and no change in prevalence of gram-negative bacteremia in patients with aplastic anemia treated between 1989 and 2008.²² Gram-negative bacteremia caused by Stenotrophomonas maltophila, Escherichia coli, Klebsiella pneumoniae, Citrobacter, and Proteus has also been reported.¹⁹ Despite a lack of clinical trials investigating the role of antifungal and antibacterial prophylaxis for patients with aplastic anemia, most centers initiate antifungal prophylaxis in patients with severe aplastic anema (SAA) or VSAA with an anti-mold agent such as voriconazole or posaconazole (which has the additional benefit compared to voriconazole of covering Mucor species).^17,23 This is especially true for patients who have received ATG or undergone HSCT. For antimicrobial prophylaxis, a fluoroquinolone antibiotic with a spectrum of activity against Pseudomonas should be considered for patients with an ANC < 500 cells/µL.¹⁷ Acyclovir or valacyclovir prophylaxis is recommended for varicella-zoster virus and herpes simplex virus. Cytomegalovirus reactivation is minimal in patients with aplastic anemia, unless multiple courses of ATG are used.

Iron overload is another complication the provider must be aware of in the setting of increased transfusions in aplastic anemia patients. Lee and colleagues demonstrated that iron chelation therapy using deferasirox is effective at reducing serum ferritin levels in patients with aplastic anemia (median ferritin level: 3254 ng/mL prior to therapy, 1854 ng/mL following), and is associated with no serious adverse events (most common adverse events included nausea, diarrhea, vomiting, and rash).²⁴ Approximately 25% of patients in this trial demonstrated an increase in creatinine, with patients taking concomitant cyclosporine more affected than those on chelation therapy alone.²⁴ For patients following HSCT or with improved hematopoiesis following immunosuppressive therapy, phlebotomy can be used to treat iron overload in lieu of chelation therapy.¹⁵

Approach to Therapy

The main treatment options for SAA and VSAA include allogeneic bone marrow transplant and immunosuppression. The deciding factors as to which treatment is best initially depends on the availability of HLA-matched related donors and age (Figure 1 and Figure 2). Survival is decreased in patients with SAA or VSAA who delay initiation of therapy, and therefore prompt referral for HLA typing and evaluation for bone marrow transplant is a very important first step in managing aplastic anemia.

Matched Sibling Donor Transplant

Current standards of care recommend HLA-matched sibling donor transplant for patients with SAA or VSAA who are younger than 50 years of age, with the caveat that integration of fludarabine and reduced cyclophosphamide dosing along with ATG shows the best overall outcomes. Locasciulli and colleagues examined outcomes in patients given either immunosuppressive therapy or sibling HSCT between 1991-1996 and 1997-2002, respectively, and found that sibling HSCT was associated with a superior 10-year OS compared to immunosuppressive therapy (73% versus 68%).²⁵ Interestingly in this study, there was no OS improvement seen with immunosuppressive therapy alone (69% versus 73%) between the 2 time periods, despite increased OS in both sibling HSCT (74% and 80%) and matched unrelated donor HSCT (38% and 65%).²⁵ Though total body irradiation has been used in the past, it is typically not included in current conditioning regimens for matched related donor transplants.²⁶

Current conditioning regimens typically use a combination of cyclophosphamide and ATG^27,28 with or without fludarabine. Fludarabine-based conditioning regimens have shown promise in patients undergoing sibling HSCT. Maury and colleagues evaluated the role of fludarabine in addition to low-dose cyclophosphamide and ATG compared to cyclophosphamide alone or in combination with ATG in patients over age 30 undergoing sibling HSCT.⁹ There was a nonsignificant improvement in 5-year OS in the fludarabine arm compared to controls (77% ± 8% versus 60% ± 3%, P = 0.14) in the pooled analysis, but when adjusted for age the fludarabine arm had a significantly lower relative risk (RR) of death (RR, 0.44; P = 0.04) compared to the control arm. Shin et al reported outcomes with fludarabine/cyclophosphamide/ATG, with excellent overall outcomes and no difference in patients older or younger than 40 years.²⁹ In addition, Kim et al evaluated their experience with patients older than 40 years of age receiving matched related donors, finding comparable outcomes in those aged 41 to 50 years compared to younger patients. Outcomes did decline in those over the age of 50 years.³⁰ Long-term data for matched related donor transplant for aplastic anemia shows excellent long-term outcomes, with minimal chronic GVHD and good performance status.³¹ Hence, these factors support the role of matched related donor transplant as the initial treatment in SAA and VSAA.

Regarding the role of transplant for patients who lack a matched related donor, a growing body of literature demonstrating identical outcomes between matched related and matched unrelated donor (MUD) transplants for pediatric patients^32,33 supports recent recommendations for upfront unrelated donor transplantation for aplastic anemia.^34,35

Immunosuppressive Therapy

For patients without an HLA-matched sibling donor or those who are older than 50 years of age, immunosuppressive therapy is the first-line therapy. ATG and cyclosporine A are the treatments of choice.³⁶ The potential effectiveness of immunosuppressive therapy in treating aplastic anemia was initially observed in patients in whom autologous transplant failed but who still experienced hematopoietic reconstitution despite the failed graft; this observation led to the hypothesis that the conditioning regimen may have an effect on hematopoiesis.^16,36,37

Anti-thymocyte globulin. Immunosuppressive therapy with ATG has been used for the treatment of aplastic anemia since the 1980s.³⁸ Historically, rabbit ATG had been used, but a 2011 study of horse ATG demonstrated superior hematological response at 6 months compared to rabbit ATG (68% versus 37%).¹⁶ Superior survival was also seen with horse ATG compared to rabbit ATG (3-year OS: 96% versus 76%). Due to these results, horse ATG is preferred over rabbit ATG. ATG should be used in combination with cyclosporine A to optimize outcomes.

Cyclosporine A. Early studies also demonstrated the efficacy of cyclosporine A in the treatment of aplastic anemia, with response rates equivalent to that of ATG monotherapy.³⁹ Recent publications still note the efficacy of cyclosporine A in the treatment of aplastic anemia. Its role as an affordable option for single-agent therapy in developing countries is intriguing.³⁹

The combination of the ATG and cyclosporine A was proven superior to either agent alone in a study by Frickhofen et al.³⁷ In this study patients were randomly assigned to a control arm that received ATG plus methylprednisolone or to an arm that received ATG plus cyclosporine A and methylprednisolone. At 6 months, 70% of patients in the cyclosporine A arm had a complete remission (CR) or partial remission compared to 46% in the control arm.⁴⁰ Further work confirmed the long-term efficacy of this regimen, reporting a 7-year OS of 55%.⁴¹ Among a pediatric population, immunosuppressive therapy was associated with an 83% 10-year OS.⁴²

It is recommended that patients remain on cyclosporine therapy for a minimum of 6 months, after which a gradual taper may be considered, although there is variation among practitioners, with some continuing immunosuppressive therapy for a minimum of 12 months due to a proportion of patients being cyclosporine dependent.^42,43 A study found that within a population of patients who responded to immunosuppressive therapy, 18% became cyclosporine dependent.⁴² The median duration of cyclosporine A treatment at full dose was 12 months, with tapering completed over a median of 19 months after patients had been in a stable CR for a minimum of 3 months. Relapse occurred more often when patients were tapered quickly (decrease ≥ 0.8 mg/kg/month) compared to slowly (0.4-0.7 mg/kg/month) or very slowly (< 0.3 mg/kg/month).

Immunosuppressive therapy plus eltrombopag. Townsley and colleagues recently investigated incorporating the use of the thrombopoietin receptor agonist eltrombopag with immunosuppressive therapy as first-line therapy in aplastic anemia.⁴⁴ When given at a dose of 150 mg daily in patients aged 12 years and older or 75 mg daily in patients younger than 12 years, in conjunction with cyclosporine A and ATG, patients demonstrated markedly improved hematological response compared to historical treatment with standard immunosuppressive therapy alone.⁴⁴ In the patient cohort administered eltrombopag starting on day 1 and continuing for 6 months, the complete response rate was 58%. Eltrombopag led to improvement in all cell lines among all treatment subgroups, and OS (censored for patients who proceeded to transplant) was 99% at 2 years.⁴⁵ Overall, toxicities associated with this therapy were low, with liver enzyme elevations most commonly observed.⁴⁴ Recently, a phase 2 trial of immunosuppressive therapy with or without eltrombopag was reported. Of the 38 patients enrolled, overall response, complete response, and time to response were not statistically different.⁴⁶ With this recent finding, the role of eltrombopag in addition to immunosuppressive therapy is not clearly defined, and further studies are warranted.

OS for patients who do not respond to immunosuppressive therapy is approximately 57% at 5 years, largely due to improved supportive measures among this patient population.^4,22 Therefore, it is important to recognize those patients who have a low chance of response so that second-line therapy can be pursued to improve outcomes.

Matched Unrelated Donor Transplant

For patients with refractory disease following immunosuppressive therapy who lack a matched sibling donor, MUD HSCT is considered standard therapy given the marked improvement in overall outcomes with modulating conditioning regimens and high-resolution HLA typing. A European Society for Blood and Marrow Transplantation analysis comparing matched sibling HSCT to MUD HSCT noted significantly higher rates of acute grade II-IV and grade III-V GVHD (grade II-IV 13% versus 25%, grade III-IV 5% versus 10%) among patients undergoing MUD transplant.⁴⁷ Chronic GVHD rates were 14% in the sibling group, as compared to 26% in the MUD group. Additional benefits seen in this analysis included improved survival when transplanted under age 20 years (84% versus 72%), when transplanted within 6 months of diagnosis (85% versus 72%), the use of ATG in the conditioning regimen (81% versus 73%), and when the donor and recipient were cytomegalovirus-negative compared to other combinations (82% versus 76%).⁴⁷ Interestingly, this study demonstrated that OS was not significantly increased when using a sibling HSCT compared to a MUD HSCT, likely as a result of improved understanding of conditioning regimens, GVHD prophylaxis, and supportive care.

Additional studies of MUD HSCT have shown outcomes similar to those seen in sibling HSCT.^4,43 A French study found a significant increase in survival in patients undergoing MUD HSCT compared to historical cohorts (2000-2005: OS 52%; 2006-2012: OS 74%).³³ The majority of patients underwent conditioning with cyclophosphamide or a combination of busulfan and cyclophosphamide, with or without fludarabine; 81% of patients included underwent in vivo T-cell depletion, and a bone marrow donor source was utilized. OS was significantly lower in patients over age 30 years undergoing MUD HSCT (57%) compared to those under age 30 years (70%). Improved OS was also seen when patients underwent transplant within 1 year of diagnosis and when a 10/10 matched donor (compared to a 9/10 mismatched donor) was utilized.⁴ A 2015 study investigated the role of MUD HSCT as frontline therapy instead of immunosuppressive therapy in patients without a matched sibling donor.³³ The 2-year OS was 96% in the MUD HSCT cohort compared to 91%, 94%, and 74% in historical cohorts of sibling HSCT, frontline immunosuppressive therapy, and second-line MUD HSCT following failed immunosuppressive therapy, respectively. Additionally, event-free survival in the MUD HSCT cohort (defined by the authors as death, lack of response, relapse, occurrence of clonal evolution/clinical paroxysmal nocturnal hemoglobinuria, malignancies developing over follow‐up, and transplant for patients receiving immunosuppressive therapy frontline) was similar compared to sibling HSCT and superior to frontline immunosuppressive therapy and second-line MUD HSCT. Furthermore, Samarasinghe et al highlighted the importance of in vivo T-cell depletion with either ATG or alemtuzumab (anti-CD52 monoclonal antibody) in the prevention of acute and chronic GVHD in both sibling HSCT and MUD HSCT.⁴⁸

With continued improvement of less toxic and more immunomodulating conditioning regimens, utilization of bone marrow as a donor cell source, in vivo T-cell depletion, and use of GVHD and antimicrobial prophylaxis, more clinical evidence supports elevating MUD HSCT in the treatment plan for patients without a matched sibling donor.⁴⁹ However, there is still a large population of patients without matched sibling or unrelated donor options. In an effort to expand the transplant pool and thus avoid clonal hematopoiesis, clinically significant paroxysmal nocturnal hemoglobinuria, and relapsed aplastic anemia, more work continues to recognize the expanding role of alternative donor transplants (cord blood and haploidentical) as another viable treatment strategy for aplastic anemia after immunosuppressive therapy failure.⁵⁰

Summary

Aplastic anemia is a rare but potentially life-threatening disorder characterized by pancytopenia and a marked reduction in the hematopoietic stem cell compartment. Treatment should be instituted as soon as the dignosis of aplastic anemia is established. Treatment outcomes are excellent with modern supportive care and the current approach to allogeneic transplantation, and therefore referral to a bone marrow transplant program to evaluate for early transplantation is the new standard of care.