AVAHO

Altered mental status (AMS) is a common presentation to the emergency department (ED) for older patients and is often due to underlying drug-associated adverse effects (AEs), medical or psychiatric illness, or neurologic disease. EDs often have protocols for diagnosing and managing AMS to assess the underlying etiology. A formal assessment with a full history and physical examination is paramount to diagnosing the cause of AMS.

Oral metronidazole is a commonly used antibiotic for anaerobic bacterial infections and Clostridium difficile-associated diarrhea and colitis.¹Metronidazole produces cytotoxic intermediates that cause DNA strand breakage and destabilization, resulting in bactericidal activity in host cells.²Common AEs include gastrointestinal symptoms such as nausea, vomiting, and diarrhea; less common AEs can involve the nervous system and include seizures, peripheral neuropathy, dizziness, ataxia, and encephalopathy.^3,4A pattern of magnetic resonance image (MRI) abnormalities typically located at the cerebellar dentate nucleus midbrain, dorsal pons, medulla, and splenium of the corpus callosum have been associated with metronidazole usage.⁵

Hyperbaric oxygen therapy (HBOT) is a treatment modality used as the primary therapy for decompression sickness, arterial gas embolism, and carbon monoxide poisoning. HBOT is used as adjuvant therapy for osteonecrosis caused by radiation or bisphosphonate use.^6,7 HBOT increases the partial pressure of oxygen in plasma and increases the amount of oxygen delivered to tissues throughout the body.⁸Hyperoxia, defined as an elevated partial pressure of oxygen leading to excess oxygenation to tissues and organs, increases production of reactive oxygen and nitrogen species, which are signaling factors in a variety of pathways that stimulate angiogenesis.⁸ AEs of HBOT include barotrauma-related injuries and oxygen toxicity, such as respiratory distress or central nervous system (CNS) symptoms.⁹ Severe CNS AEs occur in 1% to 2% of patients undergoing therapy and manifest as generalized tonic-clonic seizures, typically in patients with preexisting neurologic disorders, brain injury, or lowered seizure threshold.^7,8,10 There have been no documented incidences of HBOT inducing acute encephalopathy.

Case Presentation

A 63-year-old male smoker with no history of alcohol use presented to the ED with an acute onset of lightheadedness, confusion, and poor coordination following his second HBOT for radiation-induced osteonecrosis of the mandible. The patient reported chronic, slowly progressive pain and numbness of the feet that began 4 years earlier. He noted marked worsening of pain and difficulty standing and walking 3 to 4 months prior to presentation.

Ten years prior, the patient was diagnosed with cancer of the right tonsil. A tonsillectomy with wide margins was performed, followed by 35 rounds of radiation treatment and 2 rounds of chemotherapy with cisplatin.

In May 2017, the patient presented with a lump in the right cheek that was diagnosed as osteonecrosis of the mandible. An oral surgeon prescribed metronidazole 500 mg qid and amoxicillin 500 mg tid. The patient was adherent until presentation in November 2017. Following lack of improvement of the osteonecrosis from antibiotic therapy, oral surgery was planned, and the patient was referred for HBOT with a planned 20 HBOT preoperative treatments and 10 postoperative treatments.

Following his first 2-hour HBOT treatment on November 13, 2017, the patient complained of light-headedness, confusion, and incoordination. While driving on a familiar route to his home, he collided with a tree that was 6 feet from the curb. The patient attempted to drive another vehicle later that day, resulting in a second motor vehicle accident. There was no significant injury reported in either accident.

His partner described the patient’s episode of disorientation lasting 6 to 8 hours, during which he “looked drunk” and was unable to sit in a chair without falling. The following morning, the patient had improved mental status but had not returned to baseline. His second HBOT treatment took place that day, and again, the patient acutely experienced light-headedness and confusion following completion. Therapy was suspended, and the patient was referred to the ED for further evaluation. Mild facial asymmetry without weakness, decreased sensation from toes to knees bilaterally, and absent Achilles reflexes bilaterally were found on neurologic examination. He exhibited past-pointing on finger-to-nose testing bilaterally. He was able to ambulate independently, but he could not perform tandem gait.

An MRI of the brain showed abnormal T2 hyperintensity found bilaterally at the dentate nuclei and inferior colliculi. The splenium of the corpus callosum also showed mild involvement with hyperintense lesions. Laboratory tests of the patient’s complete blood count; comprehensive metabolic panel; vitamins B₁, B₆, B₁₂; and folic acid levels had no notable abnormalities and were within normal limits.

Metronidazole and HBOT therapy were discontinued, and all of the patient’s symptoms resolved within 2 weeks. A repeat examination and MRI performed 1 month later showed resolution of all the patient’s clinical findings and MRI abnormalities. HBOT was resumed without the recurrence of previously described symptoms.

Discussion

This patient’s encephalopathic symptoms correlate temporally with the onset of HBOT. There is no medical literature suggesting a relationship between HBOT and encephalopathic symptoms with MRI abnormalities, and in fact, some studies suggest HBOT as a treatment for hypoxic-ischemic encephalopathy in neonates.¹¹ This led us to believe that the HBOT may have exacerbated some underlying condition, evidenced by the specific MRI findings of T2 fluid-attenuated inversion recovery (FLAIR) hyperintensities in the dentate nuclei and inferior colliculi (Figures 1 and 2). 

Differential diagnoses for T2 hyperintense lesions in the dentate nuclei include metronidazole toxicity, acute Wernicke encephalopathy (WE), and methyl bromide intoxication. Diseases that would have presented in infancy with similar MRI findings (Canavan disease, maple-syrup urine disease, and glutaric aciduria type 1) were not considered plausible.^12-14 

Despite his denial of alcohol use, the patient was at risk for malnutrition secondary to his mandibular lesion and difficulty eating. Clinically, he presented with episodes of confusion and ataxia, consistent with 2 of the classic triad of symptoms of WE (no ocular abnormalities noted on exam). Typical MRI findings in WE include signal intensity alterations (including T2 hyperintensities) in the medial thalami, mammillary bodies, collicular bodies, and periaqueductal and periventricular regions.^14,15 Atypical MRI findings in WE include symmetric signal intensity changes in the cerebellum, dentate nuclei, caudate nuclei, red nuclei, cranial nerve nuclei, and splenium.¹⁴ Of note, atypical MRI findings were more common in patients without alcohol use disorders and WE, and typical MRI findings were more common in patients with alcohol use disorders.¹⁴ However, this patient’s report of no alcohol use and the serum thiamine level being within normal limits (173 nmol/L; range 78-185 nmol/L) made acute WE less likely than metronidonazale-induced encephalopathy (MIE).

The most common neurologic AE of metronidazole is distal symmetric sensory polyneuropathy, which also can have motor or autonomic features.^16,17 While our patient had a history of peripheral neuropathy, he noted marked worsening of foot pain 3 months after initiating metronidazole therapy. A potential mechanism involves metronidazole or its cytotoxic intermediates binding neuronal ribonucleic acids, thus inhibiting protein synthesis and resulting in degenerative neuronal changes and reversible axonal swelling (as opposed to the DNA interference attributed to the drug’s mechanism of bactericidal action).¹⁸ Neuropathies may result from prolonged high-dose metronidazole therapy (cumulative dose > 42 g),³ but they also have been seen in short-term use of high dosages.¹⁷

CNS AEs are much rarer and are thought to be associated with metronidazole’s ability to cross the blood-brain barrier. These patients present as a toxic encephalopathy with cerebellar dysfunction (dysarthria, ataxia) as the most common presentation, followed by AMS and seizures.⁴ Our patient presented with acute confusion and ataxia. Animal studies suggest that γ-aminobutyric acid (GABA) receptor modulation in the cerebellar and vestibular systems may contribute to this neurotoxicity, but no definitive mechanism of injury has been found.¹⁹

On MRI, MIE most commonly presents with hyperintense lesions in the bilateral cerebellar dentate nucleus on T2-weighted and FLAIR images.^5,20 The midbrain, dorsal pons, medulla, and corpus callosum also can show increased signal intensity.⁵ This AE does not seem to be dose- or duration-dependent, and most cases report complete or partial resolution of symptoms following discontinuation of the drug, though this is not absolute.^4,13,21 The patient’s MRI findings were highly consistent with MIE (Figure 2).

Conclusion

This patient’s highly specific MRI findings, neurologic examination consistent with confusion, ataxia, length-dependent sensory neuropathy, and 360-g cumulative dose of metronidazole over the previous 6 months suggest he experienced MIE. The mechanism of how HBOT precipitated the patient’s altered mental status, incoordination, and worsening of peripheral neuropathy is unknown. Although encephalopathy with MRI abnormalities as described is not a reported AE of HBOT, it may be unrecognized. It is possible that without HBOT the patient would have remained asymptomatic apart from his peripheral neuropathy.

We propose HBOT may exacerbate or increase the risk of a patient developing MIE. Our patient was able to safely resume HBOT after metronidazole was discontinued, suggesting that the combination was the causation for the development of encephalopathy. We do not believe any similar cases have been reported.

Altered mental status (AMS) is a common presentation to the emergency department (ED) for older patients and is often due to underlying drug-associated adverse effects (AEs), medical or psychiatric illness, or neurologic disease. EDs often have protocols for diagnosing and managing AMS to assess the underlying etiology. A formal assessment with a full history and physical examination is paramount to diagnosing the cause of AMS.

Oral metronidazole is a commonly used antibiotic for anaerobic bacterial infections and Clostridium difficile-associated diarrhea and colitis.¹Metronidazole produces cytotoxic intermediates that cause DNA strand breakage and destabilization, resulting in bactericidal activity in host cells.²Common AEs include gastrointestinal symptoms such as nausea, vomiting, and diarrhea; less common AEs can involve the nervous system and include seizures, peripheral neuropathy, dizziness, ataxia, and encephalopathy.^3,4A pattern of magnetic resonance image (MRI) abnormalities typically located at the cerebellar dentate nucleus midbrain, dorsal pons, medulla, and splenium of the corpus callosum have been associated with metronidazole usage.⁵

Hyperbaric oxygen therapy (HBOT) is a treatment modality used as the primary therapy for decompression sickness, arterial gas embolism, and carbon monoxide poisoning. HBOT is used as adjuvant therapy for osteonecrosis caused by radiation or bisphosphonate use.^6,7 HBOT increases the partial pressure of oxygen in plasma and increases the amount of oxygen delivered to tissues throughout the body.⁸Hyperoxia, defined as an elevated partial pressure of oxygen leading to excess oxygenation to tissues and organs, increases production of reactive oxygen and nitrogen species, which are signaling factors in a variety of pathways that stimulate angiogenesis.⁸ AEs of HBOT include barotrauma-related injuries and oxygen toxicity, such as respiratory distress or central nervous system (CNS) symptoms.⁹ Severe CNS AEs occur in 1% to 2% of patients undergoing therapy and manifest as generalized tonic-clonic seizures, typically in patients with preexisting neurologic disorders, brain injury, or lowered seizure threshold.^7,8,10 There have been no documented incidences of HBOT inducing acute encephalopathy.

Case Presentation

A 63-year-old male smoker with no history of alcohol use presented to the ED with an acute onset of lightheadedness, confusion, and poor coordination following his second HBOT for radiation-induced osteonecrosis of the mandible. The patient reported chronic, slowly progressive pain and numbness of the feet that began 4 years earlier. He noted marked worsening of pain and difficulty standing and walking 3 to 4 months prior to presentation.

Ten years prior, the patient was diagnosed with cancer of the right tonsil. A tonsillectomy with wide margins was performed, followed by 35 rounds of radiation treatment and 2 rounds of chemotherapy with cisplatin.

In May 2017, the patient presented with a lump in the right cheek that was diagnosed as osteonecrosis of the mandible. An oral surgeon prescribed metronidazole 500 mg qid and amoxicillin 500 mg tid. The patient was adherent until presentation in November 2017. Following lack of improvement of the osteonecrosis from antibiotic therapy, oral surgery was planned, and the patient was referred for HBOT with a planned 20 HBOT preoperative treatments and 10 postoperative treatments.

Following his first 2-hour HBOT treatment on November 13, 2017, the patient complained of light-headedness, confusion, and incoordination. While driving on a familiar route to his home, he collided with a tree that was 6 feet from the curb. The patient attempted to drive another vehicle later that day, resulting in a second motor vehicle accident. There was no significant injury reported in either accident.

His partner described the patient’s episode of disorientation lasting 6 to 8 hours, during which he “looked drunk” and was unable to sit in a chair without falling. The following morning, the patient had improved mental status but had not returned to baseline. His second HBOT treatment took place that day, and again, the patient acutely experienced light-headedness and confusion following completion. Therapy was suspended, and the patient was referred to the ED for further evaluation. Mild facial asymmetry without weakness, decreased sensation from toes to knees bilaterally, and absent Achilles reflexes bilaterally were found on neurologic examination. He exhibited past-pointing on finger-to-nose testing bilaterally. He was able to ambulate independently, but he could not perform tandem gait.

An MRI of the brain showed abnormal T2 hyperintensity found bilaterally at the dentate nuclei and inferior colliculi. The splenium of the corpus callosum also showed mild involvement with hyperintense lesions. Laboratory tests of the patient’s complete blood count; comprehensive metabolic panel; vitamins B₁, B₆, B₁₂; and folic acid levels had no notable abnormalities and were within normal limits.

Metronidazole and HBOT therapy were discontinued, and all of the patient’s symptoms resolved within 2 weeks. A repeat examination and MRI performed 1 month later showed resolution of all the patient’s clinical findings and MRI abnormalities. HBOT was resumed without the recurrence of previously described symptoms.

Discussion

This patient’s encephalopathic symptoms correlate temporally with the onset of HBOT. There is no medical literature suggesting a relationship between HBOT and encephalopathic symptoms with MRI abnormalities, and in fact, some studies suggest HBOT as a treatment for hypoxic-ischemic encephalopathy in neonates.¹¹ This led us to believe that the HBOT may have exacerbated some underlying condition, evidenced by the specific MRI findings of T2 fluid-attenuated inversion recovery (FLAIR) hyperintensities in the dentate nuclei and inferior colliculi (Figures 1 and 2). 

Differential diagnoses for T2 hyperintense lesions in the dentate nuclei include metronidazole toxicity, acute Wernicke encephalopathy (WE), and methyl bromide intoxication. Diseases that would have presented in infancy with similar MRI findings (Canavan disease, maple-syrup urine disease, and glutaric aciduria type 1) were not considered plausible.^12-14 

Despite his denial of alcohol use, the patient was at risk for malnutrition secondary to his mandibular lesion and difficulty eating. Clinically, he presented with episodes of confusion and ataxia, consistent with 2 of the classic triad of symptoms of WE (no ocular abnormalities noted on exam). Typical MRI findings in WE include signal intensity alterations (including T2 hyperintensities) in the medial thalami, mammillary bodies, collicular bodies, and periaqueductal and periventricular regions.^14,15 Atypical MRI findings in WE include symmetric signal intensity changes in the cerebellum, dentate nuclei, caudate nuclei, red nuclei, cranial nerve nuclei, and splenium.¹⁴ Of note, atypical MRI findings were more common in patients without alcohol use disorders and WE, and typical MRI findings were more common in patients with alcohol use disorders.¹⁴ However, this patient’s report of no alcohol use and the serum thiamine level being within normal limits (173 nmol/L; range 78-185 nmol/L) made acute WE less likely than metronidonazale-induced encephalopathy (MIE).

The most common neurologic AE of metronidazole is distal symmetric sensory polyneuropathy, which also can have motor or autonomic features.^16,17 While our patient had a history of peripheral neuropathy, he noted marked worsening of foot pain 3 months after initiating metronidazole therapy. A potential mechanism involves metronidazole or its cytotoxic intermediates binding neuronal ribonucleic acids, thus inhibiting protein synthesis and resulting in degenerative neuronal changes and reversible axonal swelling (as opposed to the DNA interference attributed to the drug’s mechanism of bactericidal action).¹⁸ Neuropathies may result from prolonged high-dose metronidazole therapy (cumulative dose > 42 g),³ but they also have been seen in short-term use of high dosages.¹⁷

CNS AEs are much rarer and are thought to be associated with metronidazole’s ability to cross the blood-brain barrier. These patients present as a toxic encephalopathy with cerebellar dysfunction (dysarthria, ataxia) as the most common presentation, followed by AMS and seizures.⁴ Our patient presented with acute confusion and ataxia. Animal studies suggest that γ-aminobutyric acid (GABA) receptor modulation in the cerebellar and vestibular systems may contribute to this neurotoxicity, but no definitive mechanism of injury has been found.¹⁹

On MRI, MIE most commonly presents with hyperintense lesions in the bilateral cerebellar dentate nucleus on T2-weighted and FLAIR images.^5,20 The midbrain, dorsal pons, medulla, and corpus callosum also can show increased signal intensity.⁵ This AE does not seem to be dose- or duration-dependent, and most cases report complete or partial resolution of symptoms following discontinuation of the drug, though this is not absolute.^4,13,21 The patient’s MRI findings were highly consistent with MIE (Figure 2).

Conclusion

This patient’s highly specific MRI findings, neurologic examination consistent with confusion, ataxia, length-dependent sensory neuropathy, and 360-g cumulative dose of metronidazole over the previous 6 months suggest he experienced MIE. The mechanism of how HBOT precipitated the patient’s altered mental status, incoordination, and worsening of peripheral neuropathy is unknown. Although encephalopathy with MRI abnormalities as described is not a reported AE of HBOT, it may be unrecognized. It is possible that without HBOT the patient would have remained asymptomatic apart from his peripheral neuropathy.

We propose HBOT may exacerbate or increase the risk of a patient developing MIE. Our patient was able to safely resume HBOT after metronidazole was discontinued, suggesting that the combination was the causation for the development of encephalopathy. We do not believe any similar cases have been reported.

Altered mental status (AMS) is a common presentation to the emergency department (ED) for older patients and is often due to underlying drug-associated adverse effects (AEs), medical or psychiatric illness, or neurologic disease. EDs often have protocols for diagnosing and managing AMS to assess the underlying etiology. A formal assessment with a full history and physical examination is paramount to diagnosing the cause of AMS.

Oral metronidazole is a commonly used antibiotic for anaerobic bacterial infections and Clostridium difficile-associated diarrhea and colitis.¹Metronidazole produces cytotoxic intermediates that cause DNA strand breakage and destabilization, resulting in bactericidal activity in host cells.²Common AEs include gastrointestinal symptoms such as nausea, vomiting, and diarrhea; less common AEs can involve the nervous system and include seizures, peripheral neuropathy, dizziness, ataxia, and encephalopathy.^3,4A pattern of magnetic resonance image (MRI) abnormalities typically located at the cerebellar dentate nucleus midbrain, dorsal pons, medulla, and splenium of the corpus callosum have been associated with metronidazole usage.⁵

Hyperbaric oxygen therapy (HBOT) is a treatment modality used as the primary therapy for decompression sickness, arterial gas embolism, and carbon monoxide poisoning. HBOT is used as adjuvant therapy for osteonecrosis caused by radiation or bisphosphonate use.^6,7 HBOT increases the partial pressure of oxygen in plasma and increases the amount of oxygen delivered to tissues throughout the body.⁸Hyperoxia, defined as an elevated partial pressure of oxygen leading to excess oxygenation to tissues and organs, increases production of reactive oxygen and nitrogen species, which are signaling factors in a variety of pathways that stimulate angiogenesis.⁸ AEs of HBOT include barotrauma-related injuries and oxygen toxicity, such as respiratory distress or central nervous system (CNS) symptoms.⁹ Severe CNS AEs occur in 1% to 2% of patients undergoing therapy and manifest as generalized tonic-clonic seizures, typically in patients with preexisting neurologic disorders, brain injury, or lowered seizure threshold.^7,8,10 There have been no documented incidences of HBOT inducing acute encephalopathy.

Case Presentation

A 63-year-old male smoker with no history of alcohol use presented to the ED with an acute onset of lightheadedness, confusion, and poor coordination following his second HBOT for radiation-induced osteonecrosis of the mandible. The patient reported chronic, slowly progressive pain and numbness of the feet that began 4 years earlier. He noted marked worsening of pain and difficulty standing and walking 3 to 4 months prior to presentation.

Ten years prior, the patient was diagnosed with cancer of the right tonsil. A tonsillectomy with wide margins was performed, followed by 35 rounds of radiation treatment and 2 rounds of chemotherapy with cisplatin.

In May 2017, the patient presented with a lump in the right cheek that was diagnosed as osteonecrosis of the mandible. An oral surgeon prescribed metronidazole 500 mg qid and amoxicillin 500 mg tid. The patient was adherent until presentation in November 2017. Following lack of improvement of the osteonecrosis from antibiotic therapy, oral surgery was planned, and the patient was referred for HBOT with a planned 20 HBOT preoperative treatments and 10 postoperative treatments.

Following his first 2-hour HBOT treatment on November 13, 2017, the patient complained of light-headedness, confusion, and incoordination. While driving on a familiar route to his home, he collided with a tree that was 6 feet from the curb. The patient attempted to drive another vehicle later that day, resulting in a second motor vehicle accident. There was no significant injury reported in either accident.

His partner described the patient’s episode of disorientation lasting 6 to 8 hours, during which he “looked drunk” and was unable to sit in a chair without falling. The following morning, the patient had improved mental status but had not returned to baseline. His second HBOT treatment took place that day, and again, the patient acutely experienced light-headedness and confusion following completion. Therapy was suspended, and the patient was referred to the ED for further evaluation. Mild facial asymmetry without weakness, decreased sensation from toes to knees bilaterally, and absent Achilles reflexes bilaterally were found on neurologic examination. He exhibited past-pointing on finger-to-nose testing bilaterally. He was able to ambulate independently, but he could not perform tandem gait.

An MRI of the brain showed abnormal T2 hyperintensity found bilaterally at the dentate nuclei and inferior colliculi. The splenium of the corpus callosum also showed mild involvement with hyperintense lesions. Laboratory tests of the patient’s complete blood count; comprehensive metabolic panel; vitamins B₁, B₆, B₁₂; and folic acid levels had no notable abnormalities and were within normal limits.

Metronidazole and HBOT therapy were discontinued, and all of the patient’s symptoms resolved within 2 weeks. A repeat examination and MRI performed 1 month later showed resolution of all the patient’s clinical findings and MRI abnormalities. HBOT was resumed without the recurrence of previously described symptoms.

Discussion

This patient’s encephalopathic symptoms correlate temporally with the onset of HBOT. There is no medical literature suggesting a relationship between HBOT and encephalopathic symptoms with MRI abnormalities, and in fact, some studies suggest HBOT as a treatment for hypoxic-ischemic encephalopathy in neonates.¹¹ This led us to believe that the HBOT may have exacerbated some underlying condition, evidenced by the specific MRI findings of T2 fluid-attenuated inversion recovery (FLAIR) hyperintensities in the dentate nuclei and inferior colliculi (Figures 1 and 2). 

Differential diagnoses for T2 hyperintense lesions in the dentate nuclei include metronidazole toxicity, acute Wernicke encephalopathy (WE), and methyl bromide intoxication. Diseases that would have presented in infancy with similar MRI findings (Canavan disease, maple-syrup urine disease, and glutaric aciduria type 1) were not considered plausible.^12-14 

Despite his denial of alcohol use, the patient was at risk for malnutrition secondary to his mandibular lesion and difficulty eating. Clinically, he presented with episodes of confusion and ataxia, consistent with 2 of the classic triad of symptoms of WE (no ocular abnormalities noted on exam). Typical MRI findings in WE include signal intensity alterations (including T2 hyperintensities) in the medial thalami, mammillary bodies, collicular bodies, and periaqueductal and periventricular regions.^14,15 Atypical MRI findings in WE include symmetric signal intensity changes in the cerebellum, dentate nuclei, caudate nuclei, red nuclei, cranial nerve nuclei, and splenium.¹⁴ Of note, atypical MRI findings were more common in patients without alcohol use disorders and WE, and typical MRI findings were more common in patients with alcohol use disorders.¹⁴ However, this patient’s report of no alcohol use and the serum thiamine level being within normal limits (173 nmol/L; range 78-185 nmol/L) made acute WE less likely than metronidonazale-induced encephalopathy (MIE).

The most common neurologic AE of metronidazole is distal symmetric sensory polyneuropathy, which also can have motor or autonomic features.^16,17 While our patient had a history of peripheral neuropathy, he noted marked worsening of foot pain 3 months after initiating metronidazole therapy. A potential mechanism involves metronidazole or its cytotoxic intermediates binding neuronal ribonucleic acids, thus inhibiting protein synthesis and resulting in degenerative neuronal changes and reversible axonal swelling (as opposed to the DNA interference attributed to the drug’s mechanism of bactericidal action).¹⁸ Neuropathies may result from prolonged high-dose metronidazole therapy (cumulative dose > 42 g),³ but they also have been seen in short-term use of high dosages.¹⁷

CNS AEs are much rarer and are thought to be associated with metronidazole’s ability to cross the blood-brain barrier. These patients present as a toxic encephalopathy with cerebellar dysfunction (dysarthria, ataxia) as the most common presentation, followed by AMS and seizures.⁴ Our patient presented with acute confusion and ataxia. Animal studies suggest that γ-aminobutyric acid (GABA) receptor modulation in the cerebellar and vestibular systems may contribute to this neurotoxicity, but no definitive mechanism of injury has been found.¹⁹

On MRI, MIE most commonly presents with hyperintense lesions in the bilateral cerebellar dentate nucleus on T2-weighted and FLAIR images.^5,20 The midbrain, dorsal pons, medulla, and corpus callosum also can show increased signal intensity.⁵ This AE does not seem to be dose- or duration-dependent, and most cases report complete or partial resolution of symptoms following discontinuation of the drug, though this is not absolute.^4,13,21 The patient’s MRI findings were highly consistent with MIE (Figure 2).

Conclusion

This patient’s highly specific MRI findings, neurologic examination consistent with confusion, ataxia, length-dependent sensory neuropathy, and 360-g cumulative dose of metronidazole over the previous 6 months suggest he experienced MIE. The mechanism of how HBOT precipitated the patient’s altered mental status, incoordination, and worsening of peripheral neuropathy is unknown. Although encephalopathy with MRI abnormalities as described is not a reported AE of HBOT, it may be unrecognized. It is possible that without HBOT the patient would have remained asymptomatic apart from his peripheral neuropathy.

We propose HBOT may exacerbate or increase the risk of a patient developing MIE. Our patient was able to safely resume HBOT after metronidazole was discontinued, suggesting that the combination was the causation for the development of encephalopathy. We do not believe any similar cases have been reported.

ATLANTA – Lynch syndrome serves as an excellent platform for the development of immunoprevention cancer vaccines, and findings from a preclinical Lynch syndrome mouse model support ongoing research, according to Steven M. Lipkin, MD, PhD.

A novel vaccine, which included peptides encoding four intestinal cancer frameshift peptide (FSP) neoantigens derived from coding microsatellite (cMS) mutations in the genes Nacad, Maz, Xirp1, and Senp6 elicited strong antigen-specific cellular immune responses in the model, Dr. Lipkin, the Gladys and Roland Harriman Professor of Medicine and vice chair for research in the Sanford and Joan Weill Department of Medicine, Weill Cornell Medical College, New York, reported at the annual meeting of the American Association for Cancer Research.

CD4-specific T cell responses were detected for Maz, Nacad, and Senp6, and CD8-positive T cells were detected for Xirp1 and Nacad, he noted, explaining that the findings come in the wake of a recently completed clinical phase 1/2a trial that successfully demonstrated safety and immunogenicity of an FSP neoantigen-based vaccine in microsatellite unstable (MSI) colorectal cancer patients.

The current effort to further develop a cancer preventive vaccine against MSI cancers in Lynch syndrome using a preclinical mouse model involved a systematic database search to identify cMS sequences in the murine genome. Intestinal tumors obtained from Lynch syndrome mice were evaluated for mutations affecting these candidate cMS, and of 13 with a mutation frequency of 15% or higher, the 4 FSP neoantigens ultimately included in the vaccine elicited strong antigen-specific cellular immune responses.

Vaccination with peptides encoding these four intestinal cancer FSP neoantigens promoted antineoantigen immunity, reduced intestinal tumorigenicity, and prolonged overall survival, Dr. Lipkin said.

Further, based on preclinical data suggesting that naproxen in this setting might provide better risk-reducing effects, compared with aspirin (which has previously been shown to reduce colorectal cancer risk in Lynch syndrome patients), its addition to the vaccine did, indeed, improve response, he noted, explaining that naproxen worked as “sort of a super-aspirin,” that improved overall survival, compared with vaccine alone or nonsteroidal anti-inflammatory agents alone.

In a video interview, Dr. Lipkin describes his research and its potential implications for the immunoprevention of Lynch syndrome and other cancers.

Vaccination with as few as four mutations that occur across Lynch syndrome tumors induced complete cures in some mice and delays in disease onset in others, he said.

“[This is] a very simple approach, very effective,” he added, noting that the T cells are now being studied to better understand the biology of the effects. “The idea of immunoprevention ... is actually very exciting and ... can be expanded beyond this.”

Lynch syndrome is a “great place to start,” because of the high rate of mutations, which are the most immunogenic types of mutations, he said.

“If we can get this basic paradigm to work, I think we can expand it to other types of mutations – for example, KRAS or BRAF, which are seen frequently in lung cancers, colon cancers, stomach cancers, pancreatic cancers, and others,” he said, noting that a proposal for a phase 1 clinical trial has been submitted.
 

ATLANTA – Lynch syndrome serves as an excellent platform for the development of immunoprevention cancer vaccines, and findings from a preclinical Lynch syndrome mouse model support ongoing research, according to Steven M. Lipkin, MD, PhD.

A novel vaccine, which included peptides encoding four intestinal cancer frameshift peptide (FSP) neoantigens derived from coding microsatellite (cMS) mutations in the genes Nacad, Maz, Xirp1, and Senp6 elicited strong antigen-specific cellular immune responses in the model, Dr. Lipkin, the Gladys and Roland Harriman Professor of Medicine and vice chair for research in the Sanford and Joan Weill Department of Medicine, Weill Cornell Medical College, New York, reported at the annual meeting of the American Association for Cancer Research.

CD4-specific T cell responses were detected for Maz, Nacad, and Senp6, and CD8-positive T cells were detected for Xirp1 and Nacad, he noted, explaining that the findings come in the wake of a recently completed clinical phase 1/2a trial that successfully demonstrated safety and immunogenicity of an FSP neoantigen-based vaccine in microsatellite unstable (MSI) colorectal cancer patients.

The current effort to further develop a cancer preventive vaccine against MSI cancers in Lynch syndrome using a preclinical mouse model involved a systematic database search to identify cMS sequences in the murine genome. Intestinal tumors obtained from Lynch syndrome mice were evaluated for mutations affecting these candidate cMS, and of 13 with a mutation frequency of 15% or higher, the 4 FSP neoantigens ultimately included in the vaccine elicited strong antigen-specific cellular immune responses.

Vaccination with peptides encoding these four intestinal cancer FSP neoantigens promoted antineoantigen immunity, reduced intestinal tumorigenicity, and prolonged overall survival, Dr. Lipkin said.

Further, based on preclinical data suggesting that naproxen in this setting might provide better risk-reducing effects, compared with aspirin (which has previously been shown to reduce colorectal cancer risk in Lynch syndrome patients), its addition to the vaccine did, indeed, improve response, he noted, explaining that naproxen worked as “sort of a super-aspirin,” that improved overall survival, compared with vaccine alone or nonsteroidal anti-inflammatory agents alone.

In a video interview, Dr. Lipkin describes his research and its potential implications for the immunoprevention of Lynch syndrome and other cancers.

Vaccination with as few as four mutations that occur across Lynch syndrome tumors induced complete cures in some mice and delays in disease onset in others, he said.

“[This is] a very simple approach, very effective,” he added, noting that the T cells are now being studied to better understand the biology of the effects. “The idea of immunoprevention ... is actually very exciting and ... can be expanded beyond this.”

Lynch syndrome is a “great place to start,” because of the high rate of mutations, which are the most immunogenic types of mutations, he said.

“If we can get this basic paradigm to work, I think we can expand it to other types of mutations – for example, KRAS or BRAF, which are seen frequently in lung cancers, colon cancers, stomach cancers, pancreatic cancers, and others,” he said, noting that a proposal for a phase 1 clinical trial has been submitted.
 

ATLANTA – Lynch syndrome serves as an excellent platform for the development of immunoprevention cancer vaccines, and findings from a preclinical Lynch syndrome mouse model support ongoing research, according to Steven M. Lipkin, MD, PhD.

A novel vaccine, which included peptides encoding four intestinal cancer frameshift peptide (FSP) neoantigens derived from coding microsatellite (cMS) mutations in the genes Nacad, Maz, Xirp1, and Senp6 elicited strong antigen-specific cellular immune responses in the model, Dr. Lipkin, the Gladys and Roland Harriman Professor of Medicine and vice chair for research in the Sanford and Joan Weill Department of Medicine, Weill Cornell Medical College, New York, reported at the annual meeting of the American Association for Cancer Research.

CD4-specific T cell responses were detected for Maz, Nacad, and Senp6, and CD8-positive T cells were detected for Xirp1 and Nacad, he noted, explaining that the findings come in the wake of a recently completed clinical phase 1/2a trial that successfully demonstrated safety and immunogenicity of an FSP neoantigen-based vaccine in microsatellite unstable (MSI) colorectal cancer patients.

The current effort to further develop a cancer preventive vaccine against MSI cancers in Lynch syndrome using a preclinical mouse model involved a systematic database search to identify cMS sequences in the murine genome. Intestinal tumors obtained from Lynch syndrome mice were evaluated for mutations affecting these candidate cMS, and of 13 with a mutation frequency of 15% or higher, the 4 FSP neoantigens ultimately included in the vaccine elicited strong antigen-specific cellular immune responses.

Vaccination with peptides encoding these four intestinal cancer FSP neoantigens promoted antineoantigen immunity, reduced intestinal tumorigenicity, and prolonged overall survival, Dr. Lipkin said.

Further, based on preclinical data suggesting that naproxen in this setting might provide better risk-reducing effects, compared with aspirin (which has previously been shown to reduce colorectal cancer risk in Lynch syndrome patients), its addition to the vaccine did, indeed, improve response, he noted, explaining that naproxen worked as “sort of a super-aspirin,” that improved overall survival, compared with vaccine alone or nonsteroidal anti-inflammatory agents alone.

In a video interview, Dr. Lipkin describes his research and its potential implications for the immunoprevention of Lynch syndrome and other cancers.

Vaccination with as few as four mutations that occur across Lynch syndrome tumors induced complete cures in some mice and delays in disease onset in others, he said.

“[This is] a very simple approach, very effective,” he added, noting that the T cells are now being studied to better understand the biology of the effects. “The idea of immunoprevention ... is actually very exciting and ... can be expanded beyond this.”

Lynch syndrome is a “great place to start,” because of the high rate of mutations, which are the most immunogenic types of mutations, he said.

“If we can get this basic paradigm to work, I think we can expand it to other types of mutations – for example, KRAS or BRAF, which are seen frequently in lung cancers, colon cancers, stomach cancers, pancreatic cancers, and others,” he said, noting that a proposal for a phase 1 clinical trial has been submitted.
 

ATLANTA – A novel chimeric antigen receptor (CAR) T-cell construct centered on HER2 as the target antigen was safe and showed early promise in the treatment of advanced sarcomas of bone and soft tissues in a phase I trial.

Neil Osterweil/MDedge News

One patient, a 16-year-old girl with advanced osteosarcoma metastatic to her lungs, had a complete response to the therapy that is ongoing out to nearly 3 years, reported Shoba A. Navai, MD, from Baylor College of Medicine in Houston.

A second patient, an 8-year-old boy with rhabdomyosarcoma metastatic to bone marrow, had a complete response lasting 12 months. Upon relapse he was re-enrolled, received additional CAR T-cell infusions, and had a second complete response that has been ongoing for 17 months.

“HER2 CAR T cells can induce objective clinical responses in some patients with sarcoma, and engagement of endogenous immunity may aid in generation of tumor responses. We are currently working to validate these findings in other patients who were treated,” she said at a briefing at the annual meeting of the American Association for Cancer Research.

HER2 is a member of the human epidermal growth factor receptor family that is primarily expressed on the surface of tumor cells but is largely absent from nonmalignant tissues. HER2 can be expressed in a variety of sarcomas, including osteosarcoma, and HER2 expression in osteosarcoma correlates with worse overall survival.

Unlike HER2-positive breast cancers, however, HER2 expression levels in osteosarcoma are too low to be effectively targeted by anti-HER2 agents such as trastuzumab (Hereceptin).

But as Dr. Navai and colleagues have found, HER2 appears to be a valid target for CAR T-cell therapy in otherwise antigenically “cold” tumors – that is, tumors with few targetable antigens.
 

Old target, new weapon

They have developed a CAR T-cell construct using a HER2-directed antibody coupled with CD28 as the costimulatory molecule. As with other CAR T therapies, the patient’s T cells or selected T cell subsets are collected, transfected to express the antigen, and are then expanded and returned to the patient following lymphodepletion with either fludarabine alone or with cyclophosphamide.

Each patient received up to three infusions of autologous CAR T cells at a dose of 1 x 108 cells/m², and eligible patients received up to five additional infusions without additional lymphodepletion.

Dr. Navai presented data on 10 patients treated to date, including the two mentioned before; the boy with rhabdomyosarcoma was counted as two separate patients for the purpose of the efficacy analysis.

All patients had metastatic disease, including five with osteosarcoma, three with rhabdomyosarcoma, one with Ewing sarcoma, and one with synovial sarcoma.

The lymphodepletion regimens did their job, inducing neutropenia (defined as an absolute neutrophil count less than 500 per milliliter ) for up to 14 days.

Eight patients developed grade 1 or 2 cytokine release syndrome within 24 hours of CAR T-cell infusion, and all cases completely resolved with supportive care within 5 days of onset.

In nine patients, T cells were successfully expanded, with a median peak expansion on day 7.

In all 10 patients, CAR T cells were detected by quantitative polymerase chain reaction 6 weeks after infusion.

In addition to the two patients with complete remissions already described, three patients had stable disease. The remaining patients had disease progression. At the most recent analysis, five patients were still alive, and five had died.

The infusions were safe, with no dose-limiting toxicities reported. No patient required a transfusion, and there were no opportunistic, infections, no neurotoxicities, and no lasting pulmonary or cardiac toxicities, Dr. Navai reported.
 

Some fare better than others

Nilofer S. Azad, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, who moderated the briefing, commented that the study had “very small numbers, but is still very exciting.”

She noted that the patients who benefited most from the therapy either had minimal residual disease or bone marrow disease without visceral disease; she asked Dr. Navai how this could be addressed going forward.

“The patients who seemed to have had responses both in this trial, as well as in our previous trial without lymphodepletion, tended to have less disease or more accessible disease. So we hypothesized that disease that’s in the bone marrow because it’s more accessible, or in the lungs, where also CAR T cells go after they are first infused, may be more amenable to treatment,” Dr. Navai said.

In contrast, larger tumors and more invasive disease may emit immune inhibitory signals that dampen the efficacy of CAR T cells, she added.

Development of the CAR T-cell construct is supported by the Cancer Prevention & Research Institute of Texas, Stand Up to Cancer, the St. Baldrick’s Foundation, Cookies for Kids’ Cancer, Alex’s Lemonade Stand, and a grant from the National Institutes of Health. Dr. Navai and Dr. Azad reported having no disclosures relevant to the work.

SOURCE: Navai SA et al. AACR 2019, Abstract LB-147.

ATLANTA – A novel chimeric antigen receptor (CAR) T-cell construct centered on HER2 as the target antigen was safe and showed early promise in the treatment of advanced sarcomas of bone and soft tissues in a phase I trial.

Neil Osterweil/MDedge News

One patient, a 16-year-old girl with advanced osteosarcoma metastatic to her lungs, had a complete response to the therapy that is ongoing out to nearly 3 years, reported Shoba A. Navai, MD, from Baylor College of Medicine in Houston.

A second patient, an 8-year-old boy with rhabdomyosarcoma metastatic to bone marrow, had a complete response lasting 12 months. Upon relapse he was re-enrolled, received additional CAR T-cell infusions, and had a second complete response that has been ongoing for 17 months.

“HER2 CAR T cells can induce objective clinical responses in some patients with sarcoma, and engagement of endogenous immunity may aid in generation of tumor responses. We are currently working to validate these findings in other patients who were treated,” she said at a briefing at the annual meeting of the American Association for Cancer Research.

HER2 is a member of the human epidermal growth factor receptor family that is primarily expressed on the surface of tumor cells but is largely absent from nonmalignant tissues. HER2 can be expressed in a variety of sarcomas, including osteosarcoma, and HER2 expression in osteosarcoma correlates with worse overall survival.

Unlike HER2-positive breast cancers, however, HER2 expression levels in osteosarcoma are too low to be effectively targeted by anti-HER2 agents such as trastuzumab (Hereceptin).

But as Dr. Navai and colleagues have found, HER2 appears to be a valid target for CAR T-cell therapy in otherwise antigenically “cold” tumors – that is, tumors with few targetable antigens.
 

Old target, new weapon

They have developed a CAR T-cell construct using a HER2-directed antibody coupled with CD28 as the costimulatory molecule. As with other CAR T therapies, the patient’s T cells or selected T cell subsets are collected, transfected to express the antigen, and are then expanded and returned to the patient following lymphodepletion with either fludarabine alone or with cyclophosphamide.

Each patient received up to three infusions of autologous CAR T cells at a dose of 1 x 108 cells/m², and eligible patients received up to five additional infusions without additional lymphodepletion.

Dr. Navai presented data on 10 patients treated to date, including the two mentioned before; the boy with rhabdomyosarcoma was counted as two separate patients for the purpose of the efficacy analysis.

All patients had metastatic disease, including five with osteosarcoma, three with rhabdomyosarcoma, one with Ewing sarcoma, and one with synovial sarcoma.

The lymphodepletion regimens did their job, inducing neutropenia (defined as an absolute neutrophil count less than 500 per milliliter ) for up to 14 days.

Eight patients developed grade 1 or 2 cytokine release syndrome within 24 hours of CAR T-cell infusion, and all cases completely resolved with supportive care within 5 days of onset.

In nine patients, T cells were successfully expanded, with a median peak expansion on day 7.

In all 10 patients, CAR T cells were detected by quantitative polymerase chain reaction 6 weeks after infusion.

In addition to the two patients with complete remissions already described, three patients had stable disease. The remaining patients had disease progression. At the most recent analysis, five patients were still alive, and five had died.

The infusions were safe, with no dose-limiting toxicities reported. No patient required a transfusion, and there were no opportunistic, infections, no neurotoxicities, and no lasting pulmonary or cardiac toxicities, Dr. Navai reported.
 

Some fare better than others

Nilofer S. Azad, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, who moderated the briefing, commented that the study had “very small numbers, but is still very exciting.”

She noted that the patients who benefited most from the therapy either had minimal residual disease or bone marrow disease without visceral disease; she asked Dr. Navai how this could be addressed going forward.

“The patients who seemed to have had responses both in this trial, as well as in our previous trial without lymphodepletion, tended to have less disease or more accessible disease. So we hypothesized that disease that’s in the bone marrow because it’s more accessible, or in the lungs, where also CAR T cells go after they are first infused, may be more amenable to treatment,” Dr. Navai said.

In contrast, larger tumors and more invasive disease may emit immune inhibitory signals that dampen the efficacy of CAR T cells, she added.

Development of the CAR T-cell construct is supported by the Cancer Prevention & Research Institute of Texas, Stand Up to Cancer, the St. Baldrick’s Foundation, Cookies for Kids’ Cancer, Alex’s Lemonade Stand, and a grant from the National Institutes of Health. Dr. Navai and Dr. Azad reported having no disclosures relevant to the work.

SOURCE: Navai SA et al. AACR 2019, Abstract LB-147.

ATLANTA – A novel chimeric antigen receptor (CAR) T-cell construct centered on HER2 as the target antigen was safe and showed early promise in the treatment of advanced sarcomas of bone and soft tissues in a phase I trial.

Neil Osterweil/MDedge News

One patient, a 16-year-old girl with advanced osteosarcoma metastatic to her lungs, had a complete response to the therapy that is ongoing out to nearly 3 years, reported Shoba A. Navai, MD, from Baylor College of Medicine in Houston.

A second patient, an 8-year-old boy with rhabdomyosarcoma metastatic to bone marrow, had a complete response lasting 12 months. Upon relapse he was re-enrolled, received additional CAR T-cell infusions, and had a second complete response that has been ongoing for 17 months.

“HER2 CAR T cells can induce objective clinical responses in some patients with sarcoma, and engagement of endogenous immunity may aid in generation of tumor responses. We are currently working to validate these findings in other patients who were treated,” she said at a briefing at the annual meeting of the American Association for Cancer Research.

HER2 is a member of the human epidermal growth factor receptor family that is primarily expressed on the surface of tumor cells but is largely absent from nonmalignant tissues. HER2 can be expressed in a variety of sarcomas, including osteosarcoma, and HER2 expression in osteosarcoma correlates with worse overall survival.

Unlike HER2-positive breast cancers, however, HER2 expression levels in osteosarcoma are too low to be effectively targeted by anti-HER2 agents such as trastuzumab (Hereceptin).

But as Dr. Navai and colleagues have found, HER2 appears to be a valid target for CAR T-cell therapy in otherwise antigenically “cold” tumors – that is, tumors with few targetable antigens.
 

Old target, new weapon

They have developed a CAR T-cell construct using a HER2-directed antibody coupled with CD28 as the costimulatory molecule. As with other CAR T therapies, the patient’s T cells or selected T cell subsets are collected, transfected to express the antigen, and are then expanded and returned to the patient following lymphodepletion with either fludarabine alone or with cyclophosphamide.

Each patient received up to three infusions of autologous CAR T cells at a dose of 1 x 108 cells/m², and eligible patients received up to five additional infusions without additional lymphodepletion.

Dr. Navai presented data on 10 patients treated to date, including the two mentioned before; the boy with rhabdomyosarcoma was counted as two separate patients for the purpose of the efficacy analysis.

All patients had metastatic disease, including five with osteosarcoma, three with rhabdomyosarcoma, one with Ewing sarcoma, and one with synovial sarcoma.

The lymphodepletion regimens did their job, inducing neutropenia (defined as an absolute neutrophil count less than 500 per milliliter ) for up to 14 days.

Eight patients developed grade 1 or 2 cytokine release syndrome within 24 hours of CAR T-cell infusion, and all cases completely resolved with supportive care within 5 days of onset.

In nine patients, T cells were successfully expanded, with a median peak expansion on day 7.

In all 10 patients, CAR T cells were detected by quantitative polymerase chain reaction 6 weeks after infusion.

In addition to the two patients with complete remissions already described, three patients had stable disease. The remaining patients had disease progression. At the most recent analysis, five patients were still alive, and five had died.

The infusions were safe, with no dose-limiting toxicities reported. No patient required a transfusion, and there were no opportunistic, infections, no neurotoxicities, and no lasting pulmonary or cardiac toxicities, Dr. Navai reported.
 

Some fare better than others

Nilofer S. Azad, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, who moderated the briefing, commented that the study had “very small numbers, but is still very exciting.”

She noted that the patients who benefited most from the therapy either had minimal residual disease or bone marrow disease without visceral disease; she asked Dr. Navai how this could be addressed going forward.

“The patients who seemed to have had responses both in this trial, as well as in our previous trial without lymphodepletion, tended to have less disease or more accessible disease. So we hypothesized that disease that’s in the bone marrow because it’s more accessible, or in the lungs, where also CAR T cells go after they are first infused, may be more amenable to treatment,” Dr. Navai said.

In contrast, larger tumors and more invasive disease may emit immune inhibitory signals that dampen the efficacy of CAR T cells, she added.

Development of the CAR T-cell construct is supported by the Cancer Prevention & Research Institute of Texas, Stand Up to Cancer, the St. Baldrick’s Foundation, Cookies for Kids’ Cancer, Alex’s Lemonade Stand, and a grant from the National Institutes of Health. Dr. Navai and Dr. Azad reported having no disclosures relevant to the work.

SOURCE: Navai SA et al. AACR 2019, Abstract LB-147.

Favorable results from a phase 2 trial have prompted further development of polatuzumab vedotin in non-Hodgkin lymphoma.

In the ROMULUS trial, polatuzumab vedotin plus rituximab (R-pola) produced more durable responses than did pinatuzumab vedotin plus rituximab (R-pina) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL).

Researchers also observed a more favorable benefit-risk profile with R-pola.

Franck Morschhauser, MD, of Centre Hospitalier Régional Universitaire de Lille, France, and his colleagues described these findings in the Lancet Haematology.

The ROMULUS trial included 81 DLBCL patients and 42 FL patients. They were randomized to receive R-pola or R-pina (rituximab at 375 mg/m² plus either antibody-drug conjugate at 2.4 mg/kg) every 21 days until disease progression or unacceptable toxicity for up to 1 year.

Among DLBCL patients, the median age was 69 years in the R-pina arm and 68 years in the R-pola arm. Among FL patients, the median age was 59 years in the R-pina arm and 67 years in the R-pola arm.

Seventy-six percent of DLBCL patients randomized to R-pina were refractory to their last treatment, as were 80% of DLBCL patients assigned to R-pola, 52% of FL patients assigned to R-pina, and 35% of FL patients assigned to R-pola.

The median number of prior systemic therapies was three in the R-pina DLBCL arm, the R-pola DLBCL arm, and the R-pina FL arm. The median number of prior therapies was two in the R-pola FL arm.

Response and survival

Among the DLBCL patients, R-pina produced an objective response rate (ORR) of 60% and a complete response (CR) rate of 26%. R-pola produced an ORR of 54% and a CR rate of 21%. The median duration of response was 6.2 months in the R-pina arm and 13.4 months in the R-pola arm.

The median progression-free survival in the DLBCL cohort was 5.4 months for the R-pina arm and 5.6 months for the R-pola arm. The median overall survival was 16.5 months and 20.1 months, respectively.

In the FL cohort, R-pina produced an ORR of 62% and a CR rate of 5%. R-pola produced an ORR of 70% and a CR rate of 45%. The median duration of response was 6.5 months in the R-pina arm and 9.4 months in the R-pola arm.

The median progression-free survival in the FL cohort was 12.7 months for the R-pina arm and 15.3 months for the R-pola arm. The 2-year overall survival rate was 90.5% and 87.8%, respectively. The median overall survival was not reached in either arm.

“Patients treated with R-pola tended to have longer durations of response than those receiving R-pina (particularly those with relapsed or refractory diffuse large B-cell lymphoma), and the results for R-pola compared favorably with other novel antilymphoma agents,” Dr. Morschhauser and his colleagues wrote.

Safety

Among DLBCL patients, serious adverse events (AEs) occurred in 50.0% of those in the R-pina arm and 35.9% of those in the R-pola arm. Among FL patients, serious AEs occurred in 28.6% of those the R-pina arm and 35.0% of those in the R-pola arm.

Ten grade 5 AEs occurred in nine DLBCL patients who received R-pina (21.4%). These events included two cases of sepsis, influenza and pneumonia in the same patient, general physical health deterioration including one death attributed to disease progression, and one case each of Clostridium difficile sepsis, respiratory failure, urosepsis, and sudden death.

There was one grade 5 AE in a FL patient who received R-pola. The 84-year-old patient died of pulmonary congestion 64 days after the last of 12 cycles of treatment.

There were no fatal AEs in the other arms.

“These findings make pola a promising novel candidate for further clinical evaluation in combination regimens in treatment-refractory patients and also in a first-line setting in B-cell non-Hodgkin lymphoma,” Dr. Morschhauser and his colleagues wrote.

Polatuzumab vedotin was chosen by the study funder for further development in non-Hodgkin lymphoma, partly because of longer durations of response, compared with pinatuzumab vedotin.

Polatuzumab vedotin is currently under investigation in the phase 3 POLARIX study. The drug is being combined with rituximab, cyclophosphamide, doxorubicin, and prednisone and compared to rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with DLBCL.

The ROMULUS study was funded by F Hoffmann-La Roche. The study authors reported relationships with Roche and other companies.

jensmith@mdedge.com

SOURCE: Morschhauser F et al. Lancet Haematol. 2019 Mar 29. doi: 10.1016/S2352-3026(19)30026-2.

Favorable results from a phase 2 trial have prompted further development of polatuzumab vedotin in non-Hodgkin lymphoma.

In the ROMULUS trial, polatuzumab vedotin plus rituximab (R-pola) produced more durable responses than did pinatuzumab vedotin plus rituximab (R-pina) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL).

Researchers also observed a more favorable benefit-risk profile with R-pola.

Franck Morschhauser, MD, of Centre Hospitalier Régional Universitaire de Lille, France, and his colleagues described these findings in the Lancet Haematology.

The ROMULUS trial included 81 DLBCL patients and 42 FL patients. They were randomized to receive R-pola or R-pina (rituximab at 375 mg/m² plus either antibody-drug conjugate at 2.4 mg/kg) every 21 days until disease progression or unacceptable toxicity for up to 1 year.

Among DLBCL patients, the median age was 69 years in the R-pina arm and 68 years in the R-pola arm. Among FL patients, the median age was 59 years in the R-pina arm and 67 years in the R-pola arm.

Seventy-six percent of DLBCL patients randomized to R-pina were refractory to their last treatment, as were 80% of DLBCL patients assigned to R-pola, 52% of FL patients assigned to R-pina, and 35% of FL patients assigned to R-pola.

The median number of prior systemic therapies was three in the R-pina DLBCL arm, the R-pola DLBCL arm, and the R-pina FL arm. The median number of prior therapies was two in the R-pola FL arm.

Response and survival

Among the DLBCL patients, R-pina produced an objective response rate (ORR) of 60% and a complete response (CR) rate of 26%. R-pola produced an ORR of 54% and a CR rate of 21%. The median duration of response was 6.2 months in the R-pina arm and 13.4 months in the R-pola arm.

The median progression-free survival in the DLBCL cohort was 5.4 months for the R-pina arm and 5.6 months for the R-pola arm. The median overall survival was 16.5 months and 20.1 months, respectively.

In the FL cohort, R-pina produced an ORR of 62% and a CR rate of 5%. R-pola produced an ORR of 70% and a CR rate of 45%. The median duration of response was 6.5 months in the R-pina arm and 9.4 months in the R-pola arm.

The median progression-free survival in the FL cohort was 12.7 months for the R-pina arm and 15.3 months for the R-pola arm. The 2-year overall survival rate was 90.5% and 87.8%, respectively. The median overall survival was not reached in either arm.

“Patients treated with R-pola tended to have longer durations of response than those receiving R-pina (particularly those with relapsed or refractory diffuse large B-cell lymphoma), and the results for R-pola compared favorably with other novel antilymphoma agents,” Dr. Morschhauser and his colleagues wrote.

Safety

Among DLBCL patients, serious adverse events (AEs) occurred in 50.0% of those in the R-pina arm and 35.9% of those in the R-pola arm. Among FL patients, serious AEs occurred in 28.6% of those the R-pina arm and 35.0% of those in the R-pola arm.

Ten grade 5 AEs occurred in nine DLBCL patients who received R-pina (21.4%). These events included two cases of sepsis, influenza and pneumonia in the same patient, general physical health deterioration including one death attributed to disease progression, and one case each of Clostridium difficile sepsis, respiratory failure, urosepsis, and sudden death.

There was one grade 5 AE in a FL patient who received R-pola. The 84-year-old patient died of pulmonary congestion 64 days after the last of 12 cycles of treatment.

There were no fatal AEs in the other arms.

“These findings make pola a promising novel candidate for further clinical evaluation in combination regimens in treatment-refractory patients and also in a first-line setting in B-cell non-Hodgkin lymphoma,” Dr. Morschhauser and his colleagues wrote.

Polatuzumab vedotin was chosen by the study funder for further development in non-Hodgkin lymphoma, partly because of longer durations of response, compared with pinatuzumab vedotin.

Polatuzumab vedotin is currently under investigation in the phase 3 POLARIX study. The drug is being combined with rituximab, cyclophosphamide, doxorubicin, and prednisone and compared to rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with DLBCL.

The ROMULUS study was funded by F Hoffmann-La Roche. The study authors reported relationships with Roche and other companies.

jensmith@mdedge.com

SOURCE: Morschhauser F et al. Lancet Haematol. 2019 Mar 29. doi: 10.1016/S2352-3026(19)30026-2.

Favorable results from a phase 2 trial have prompted further development of polatuzumab vedotin in non-Hodgkin lymphoma.

In the ROMULUS trial, polatuzumab vedotin plus rituximab (R-pola) produced more durable responses than did pinatuzumab vedotin plus rituximab (R-pina) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL).

Researchers also observed a more favorable benefit-risk profile with R-pola.

Franck Morschhauser, MD, of Centre Hospitalier Régional Universitaire de Lille, France, and his colleagues described these findings in the Lancet Haematology.

The ROMULUS trial included 81 DLBCL patients and 42 FL patients. They were randomized to receive R-pola or R-pina (rituximab at 375 mg/m² plus either antibody-drug conjugate at 2.4 mg/kg) every 21 days until disease progression or unacceptable toxicity for up to 1 year.

Among DLBCL patients, the median age was 69 years in the R-pina arm and 68 years in the R-pola arm. Among FL patients, the median age was 59 years in the R-pina arm and 67 years in the R-pola arm.

Seventy-six percent of DLBCL patients randomized to R-pina were refractory to their last treatment, as were 80% of DLBCL patients assigned to R-pola, 52% of FL patients assigned to R-pina, and 35% of FL patients assigned to R-pola.

The median number of prior systemic therapies was three in the R-pina DLBCL arm, the R-pola DLBCL arm, and the R-pina FL arm. The median number of prior therapies was two in the R-pola FL arm.

Response and survival

Among the DLBCL patients, R-pina produced an objective response rate (ORR) of 60% and a complete response (CR) rate of 26%. R-pola produced an ORR of 54% and a CR rate of 21%. The median duration of response was 6.2 months in the R-pina arm and 13.4 months in the R-pola arm.

The median progression-free survival in the DLBCL cohort was 5.4 months for the R-pina arm and 5.6 months for the R-pola arm. The median overall survival was 16.5 months and 20.1 months, respectively.

In the FL cohort, R-pina produced an ORR of 62% and a CR rate of 5%. R-pola produced an ORR of 70% and a CR rate of 45%. The median duration of response was 6.5 months in the R-pina arm and 9.4 months in the R-pola arm.

The median progression-free survival in the FL cohort was 12.7 months for the R-pina arm and 15.3 months for the R-pola arm. The 2-year overall survival rate was 90.5% and 87.8%, respectively. The median overall survival was not reached in either arm.

“Patients treated with R-pola tended to have longer durations of response than those receiving R-pina (particularly those with relapsed or refractory diffuse large B-cell lymphoma), and the results for R-pola compared favorably with other novel antilymphoma agents,” Dr. Morschhauser and his colleagues wrote.

Safety

Among DLBCL patients, serious adverse events (AEs) occurred in 50.0% of those in the R-pina arm and 35.9% of those in the R-pola arm. Among FL patients, serious AEs occurred in 28.6% of those the R-pina arm and 35.0% of those in the R-pola arm.

Ten grade 5 AEs occurred in nine DLBCL patients who received R-pina (21.4%). These events included two cases of sepsis, influenza and pneumonia in the same patient, general physical health deterioration including one death attributed to disease progression, and one case each of Clostridium difficile sepsis, respiratory failure, urosepsis, and sudden death.

There was one grade 5 AE in a FL patient who received R-pola. The 84-year-old patient died of pulmonary congestion 64 days after the last of 12 cycles of treatment.

There were no fatal AEs in the other arms.

“These findings make pola a promising novel candidate for further clinical evaluation in combination regimens in treatment-refractory patients and also in a first-line setting in B-cell non-Hodgkin lymphoma,” Dr. Morschhauser and his colleagues wrote.

Polatuzumab vedotin was chosen by the study funder for further development in non-Hodgkin lymphoma, partly because of longer durations of response, compared with pinatuzumab vedotin.

Polatuzumab vedotin is currently under investigation in the phase 3 POLARIX study. The drug is being combined with rituximab, cyclophosphamide, doxorubicin, and prednisone and compared to rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with DLBCL.

The ROMULUS study was funded by F Hoffmann-La Roche. The study authors reported relationships with Roche and other companies.

jensmith@mdedge.com

SOURCE: Morschhauser F et al. Lancet Haematol. 2019 Mar 29. doi: 10.1016/S2352-3026(19)30026-2.

New clinical practice guidelines, jointly released by two leading cancer organizations, provide nearly 50 specific recommendations for the management of newly diagnosed and relapsed multiple myeloma patients.

The guidelines from the American Society of Clinical Oncology (ASCO) and Cancer Care Ontario (CCO) were authored by a panel of 21 experts in medical oncology, surgery, radiation oncology, and advocacy who reviewed 124 relevant studies published between 2005 and 2018.

“The treatment of multiple myeloma has changed significantly in the last 5 years. Since 2015, four new drugs have been approved, thus providing more options and adding to the complexity of treatment options,” the expert panel wrote in the Journal of Clinical Oncology.

The recommendations are intended to put in context recent randomized trials and drug advances, according to the experts, led by cochairs Joseph Mikhael, MD, of City of Hope Cancer Center, Phoenix, and the International Myeloma Foundation, North Hollywood, Calif., and Tom Martin, MD, of the University of California, San Francisco.

Specifically, the recently approved agents include the proteasome inhibitor ixazomib, the histone deacetylase inhibitor panobinostat, and the monoclonal antibodies daratumumab and elotuzumab, directed at CD38 and SLAMF7, respectively.

There are 20 specific recommendations for newly diagnosed, transplant-eligible patients with multiple myeloma; 10 recommendations for newly diagnosed, transplant-ineligible patients; and 16 recommendations related to relapsed disease in the ASCO/CCO guidelines.

All transplant-eligible patients should be offered up-front autologous stem cell transplant (ASCT), according to the guidelines. By contrast, allogeneic transplant is not routinely recommended but “may be considered” in select high-risk patients, and tandem transplant “should not be routinely recommended,” the expert panelists said in their report.

Lenalidomide maintenance therapy should be routinely offered to standard-risk, transplant-eligible patients, according to the panel, whereas bortezomib maintenance could be considered in those who are intolerant of lenalidomide or can’t receive that immunomodulatory drug.

“Evidence is emerging for the use of ixazomib as maintenance therapy and may also be considered,” the panel members said, citing the TOURMALINE-MM3 study results presented at the 2018 annual meeting of the American Society of Hematology and recently published in the Lancet.

Although minimal residual disease (MRD)–negative status is linked to improved outcomes, there is insufficient evidence that MRD can be used today to modify maintenance therapy based on depth of response in transplant-eligible patients, according to the guidelines. Likewise, in transplant-ineligible patients, MRD shouldn’t be used to guide treatment goals in clinical practice, the authors said.

Triplet therapies such as bortezomib, lenalidomide, and dexamethasone (VRd) can be considered for transplant ineligible patients, as can the combination of daratumumab and bortezomib plus melphalan and prednisone that was approved by the Food and Drug Administration in May 2018.

For patients with biochemically relapsed myeloma and high-risk disease – defined as early relapse and presence of high-risk cytogenetics – treatment should begin immediately, whereas close observation may be appropriate for patients with asymptomatic, slowly progressive relapse.

Triplets containing two novel therapies should be administered on first relapse, and should continue until disease progression, the expert panel advised.

If it was not already done after primary induction, ASCT should be offered to relapsed, transplant-eligible myeloma patients.

The expert panel reported numerous financial relationships with industry, including Celgene, Sanofi, AbbVie, TeneoBio, Roche, June Therapeutics, and others.

SOURCE: Mikhael J et al. J Clin Oncol. 2019 Apr 1. doi: 10.1200/JCO.18.02096.

New clinical practice guidelines, jointly released by two leading cancer organizations, provide nearly 50 specific recommendations for the management of newly diagnosed and relapsed multiple myeloma patients.

The guidelines from the American Society of Clinical Oncology (ASCO) and Cancer Care Ontario (CCO) were authored by a panel of 21 experts in medical oncology, surgery, radiation oncology, and advocacy who reviewed 124 relevant studies published between 2005 and 2018.

“The treatment of multiple myeloma has changed significantly in the last 5 years. Since 2015, four new drugs have been approved, thus providing more options and adding to the complexity of treatment options,” the expert panel wrote in the Journal of Clinical Oncology.

The recommendations are intended to put in context recent randomized trials and drug advances, according to the experts, led by cochairs Joseph Mikhael, MD, of City of Hope Cancer Center, Phoenix, and the International Myeloma Foundation, North Hollywood, Calif., and Tom Martin, MD, of the University of California, San Francisco.

Specifically, the recently approved agents include the proteasome inhibitor ixazomib, the histone deacetylase inhibitor panobinostat, and the monoclonal antibodies daratumumab and elotuzumab, directed at CD38 and SLAMF7, respectively.

There are 20 specific recommendations for newly diagnosed, transplant-eligible patients with multiple myeloma; 10 recommendations for newly diagnosed, transplant-ineligible patients; and 16 recommendations related to relapsed disease in the ASCO/CCO guidelines.

All transplant-eligible patients should be offered up-front autologous stem cell transplant (ASCT), according to the guidelines. By contrast, allogeneic transplant is not routinely recommended but “may be considered” in select high-risk patients, and tandem transplant “should not be routinely recommended,” the expert panelists said in their report.

Lenalidomide maintenance therapy should be routinely offered to standard-risk, transplant-eligible patients, according to the panel, whereas bortezomib maintenance could be considered in those who are intolerant of lenalidomide or can’t receive that immunomodulatory drug.

“Evidence is emerging for the use of ixazomib as maintenance therapy and may also be considered,” the panel members said, citing the TOURMALINE-MM3 study results presented at the 2018 annual meeting of the American Society of Hematology and recently published in the Lancet.

Although minimal residual disease (MRD)–negative status is linked to improved outcomes, there is insufficient evidence that MRD can be used today to modify maintenance therapy based on depth of response in transplant-eligible patients, according to the guidelines. Likewise, in transplant-ineligible patients, MRD shouldn’t be used to guide treatment goals in clinical practice, the authors said.

Triplet therapies such as bortezomib, lenalidomide, and dexamethasone (VRd) can be considered for transplant ineligible patients, as can the combination of daratumumab and bortezomib plus melphalan and prednisone that was approved by the Food and Drug Administration in May 2018.

For patients with biochemically relapsed myeloma and high-risk disease – defined as early relapse and presence of high-risk cytogenetics – treatment should begin immediately, whereas close observation may be appropriate for patients with asymptomatic, slowly progressive relapse.

Triplets containing two novel therapies should be administered on first relapse, and should continue until disease progression, the expert panel advised.

If it was not already done after primary induction, ASCT should be offered to relapsed, transplant-eligible myeloma patients.

The expert panel reported numerous financial relationships with industry, including Celgene, Sanofi, AbbVie, TeneoBio, Roche, June Therapeutics, and others.

SOURCE: Mikhael J et al. J Clin Oncol. 2019 Apr 1. doi: 10.1200/JCO.18.02096.

New clinical practice guidelines, jointly released by two leading cancer organizations, provide nearly 50 specific recommendations for the management of newly diagnosed and relapsed multiple myeloma patients.

The guidelines from the American Society of Clinical Oncology (ASCO) and Cancer Care Ontario (CCO) were authored by a panel of 21 experts in medical oncology, surgery, radiation oncology, and advocacy who reviewed 124 relevant studies published between 2005 and 2018.

“The treatment of multiple myeloma has changed significantly in the last 5 years. Since 2015, four new drugs have been approved, thus providing more options and adding to the complexity of treatment options,” the expert panel wrote in the Journal of Clinical Oncology.

The recommendations are intended to put in context recent randomized trials and drug advances, according to the experts, led by cochairs Joseph Mikhael, MD, of City of Hope Cancer Center, Phoenix, and the International Myeloma Foundation, North Hollywood, Calif., and Tom Martin, MD, of the University of California, San Francisco.

Specifically, the recently approved agents include the proteasome inhibitor ixazomib, the histone deacetylase inhibitor panobinostat, and the monoclonal antibodies daratumumab and elotuzumab, directed at CD38 and SLAMF7, respectively.

There are 20 specific recommendations for newly diagnosed, transplant-eligible patients with multiple myeloma; 10 recommendations for newly diagnosed, transplant-ineligible patients; and 16 recommendations related to relapsed disease in the ASCO/CCO guidelines.

All transplant-eligible patients should be offered up-front autologous stem cell transplant (ASCT), according to the guidelines. By contrast, allogeneic transplant is not routinely recommended but “may be considered” in select high-risk patients, and tandem transplant “should not be routinely recommended,” the expert panelists said in their report.

Lenalidomide maintenance therapy should be routinely offered to standard-risk, transplant-eligible patients, according to the panel, whereas bortezomib maintenance could be considered in those who are intolerant of lenalidomide or can’t receive that immunomodulatory drug.

“Evidence is emerging for the use of ixazomib as maintenance therapy and may also be considered,” the panel members said, citing the TOURMALINE-MM3 study results presented at the 2018 annual meeting of the American Society of Hematology and recently published in the Lancet.

Although minimal residual disease (MRD)–negative status is linked to improved outcomes, there is insufficient evidence that MRD can be used today to modify maintenance therapy based on depth of response in transplant-eligible patients, according to the guidelines. Likewise, in transplant-ineligible patients, MRD shouldn’t be used to guide treatment goals in clinical practice, the authors said.

Triplet therapies such as bortezomib, lenalidomide, and dexamethasone (VRd) can be considered for transplant ineligible patients, as can the combination of daratumumab and bortezomib plus melphalan and prednisone that was approved by the Food and Drug Administration in May 2018.

For patients with biochemically relapsed myeloma and high-risk disease – defined as early relapse and presence of high-risk cytogenetics – treatment should begin immediately, whereas close observation may be appropriate for patients with asymptomatic, slowly progressive relapse.

Triplets containing two novel therapies should be administered on first relapse, and should continue until disease progression, the expert panel advised.

If it was not already done after primary induction, ASCT should be offered to relapsed, transplant-eligible myeloma patients.

The expert panel reported numerous financial relationships with industry, including Celgene, Sanofi, AbbVie, TeneoBio, Roche, June Therapeutics, and others.

SOURCE: Mikhael J et al. J Clin Oncol. 2019 Apr 1. doi: 10.1200/JCO.18.02096.

ATLANTA – The current standard of care for patients with advanced pancreatic cancer is chemotherapy continued until patients experience disease progression, unacceptable toxicities, clinical decline, or death.

But a subset of patients with pancreatic cancer – approximately 5%-8% – have pathogenic mutations in homologous recombination genes such as BRCA1, BRCA2, or PALB2. The resulting homologous recombination deficiencies (HRD) make their cancers especially sensitive to platinum-based chemotherapy and, potentially, to poly (ADP-ribose) polymerase (PARP) inhibitors.

Now, investigators at the University of Pennsylvania, Philadelphia, are proposing to upend the conventional approach by treating patients with advanced pancreatic cancer and HRD with a novel strategy consisting of induction chemotherapy, followed by maintenance with the PARP inhibitor rucaparib (Rubraca).

In a video interview at the annual meeting of the American Society for Cancer Research, Kim A. Reiss Binder, MD, of the University of Pennsylvania, describes the rationale for treating this subset of patients with this novel strategy, outlines the promising progression-free and overall survival results in a clinical study, and discusses the potential for chemotherapy and PARP inhibitors in neoadjuvant or adjuvant settings for some patients with pancreatic cancer.

The study is sponsored by the Abramson Cancer Center and is funded by Clovis Oncology. Dr. Reiss Binder receives research funding from Clovis Oncology, Tesaro, Bristol-Myers Squibb, and Lilly Oncology.

ATLANTA – The current standard of care for patients with advanced pancreatic cancer is chemotherapy continued until patients experience disease progression, unacceptable toxicities, clinical decline, or death.

But a subset of patients with pancreatic cancer – approximately 5%-8% – have pathogenic mutations in homologous recombination genes such as BRCA1, BRCA2, or PALB2. The resulting homologous recombination deficiencies (HRD) make their cancers especially sensitive to platinum-based chemotherapy and, potentially, to poly (ADP-ribose) polymerase (PARP) inhibitors.

Now, investigators at the University of Pennsylvania, Philadelphia, are proposing to upend the conventional approach by treating patients with advanced pancreatic cancer and HRD with a novel strategy consisting of induction chemotherapy, followed by maintenance with the PARP inhibitor rucaparib (Rubraca).

In a video interview at the annual meeting of the American Society for Cancer Research, Kim A. Reiss Binder, MD, of the University of Pennsylvania, describes the rationale for treating this subset of patients with this novel strategy, outlines the promising progression-free and overall survival results in a clinical study, and discusses the potential for chemotherapy and PARP inhibitors in neoadjuvant or adjuvant settings for some patients with pancreatic cancer.

The study is sponsored by the Abramson Cancer Center and is funded by Clovis Oncology. Dr. Reiss Binder receives research funding from Clovis Oncology, Tesaro, Bristol-Myers Squibb, and Lilly Oncology.

ATLANTA – The current standard of care for patients with advanced pancreatic cancer is chemotherapy continued until patients experience disease progression, unacceptable toxicities, clinical decline, or death.

But a subset of patients with pancreatic cancer – approximately 5%-8% – have pathogenic mutations in homologous recombination genes such as BRCA1, BRCA2, or PALB2. The resulting homologous recombination deficiencies (HRD) make their cancers especially sensitive to platinum-based chemotherapy and, potentially, to poly (ADP-ribose) polymerase (PARP) inhibitors.

Now, investigators at the University of Pennsylvania, Philadelphia, are proposing to upend the conventional approach by treating patients with advanced pancreatic cancer and HRD with a novel strategy consisting of induction chemotherapy, followed by maintenance with the PARP inhibitor rucaparib (Rubraca).

In a video interview at the annual meeting of the American Society for Cancer Research, Kim A. Reiss Binder, MD, of the University of Pennsylvania, describes the rationale for treating this subset of patients with this novel strategy, outlines the promising progression-free and overall survival results in a clinical study, and discusses the potential for chemotherapy and PARP inhibitors in neoadjuvant or adjuvant settings for some patients with pancreatic cancer.

The study is sponsored by the Abramson Cancer Center and is funded by Clovis Oncology. Dr. Reiss Binder receives research funding from Clovis Oncology, Tesaro, Bristol-Myers Squibb, and Lilly Oncology.

ATLANTA – The phosphoinositide 3-kinase (PI3K) delta inhibitor umbralisib is active and well tolerated as single-agent therapy in patients with relapsed or refractory marginal zone lymphoma, according to findings from the ongoing phase 2 UNITY-NHL study.

The best overall response rate (ORR) among 42 study participants with at least 9 months of follow-up was 52% by both independent review committee (IRC) and investigator assessment, and the complete response rate was 19%, Nathan H. Fowler, MD, reported at the annual meeting of the American Association for Cancer Research.

The ORR by IRC assessment for those with extranodal, nodal, and splenic disease was 57%, 42%, and 43%, respectively, and for those with prior chemo-immunotherapy and those refractory to their last line of therapy, the ORR was 53% and 38%, respectively, said Dr. Fowler of MD Anderson Cancer Center, Houston.

The clinical benefit rate was 88%, and the median duration of response and progression-free survival (PFS) have not been reached; 12-month PFS is estimated at 66%, he added.

Patients in the marginal zone lymphoma cohort of the multicohort trial, which is evaluating umbralisib both as monotherapy and as part of various combinations in patients with previously treated non-Hodgkin’s lymphoma, received single agent umbralisib at a dose of 800 mg daily until disease progression or unacceptable toxicity.

“Most patients who have responded continue on drug,” he said in a video interview.

Dr. Fowler also further discussed the findings to date with respect to response, adverse events, and future directions in the wake of the breakthrough therapy designation recently granted by the Food and Drug Administration for umbralisib based on these findings.

“Despite the fact that a lot of things work in the front line, when patients relapse, especially when they become refractory to rituximab, there are limited options available,” he said, noting that currently used treatments are associated with significant adverse event and short remission times. “We still need better options.”

sworcester@mdedge.com

ATLANTA – The phosphoinositide 3-kinase (PI3K) delta inhibitor umbralisib is active and well tolerated as single-agent therapy in patients with relapsed or refractory marginal zone lymphoma, according to findings from the ongoing phase 2 UNITY-NHL study.

The best overall response rate (ORR) among 42 study participants with at least 9 months of follow-up was 52% by both independent review committee (IRC) and investigator assessment, and the complete response rate was 19%, Nathan H. Fowler, MD, reported at the annual meeting of the American Association for Cancer Research.

The ORR by IRC assessment for those with extranodal, nodal, and splenic disease was 57%, 42%, and 43%, respectively, and for those with prior chemo-immunotherapy and those refractory to their last line of therapy, the ORR was 53% and 38%, respectively, said Dr. Fowler of MD Anderson Cancer Center, Houston.

The clinical benefit rate was 88%, and the median duration of response and progression-free survival (PFS) have not been reached; 12-month PFS is estimated at 66%, he added.

Patients in the marginal zone lymphoma cohort of the multicohort trial, which is evaluating umbralisib both as monotherapy and as part of various combinations in patients with previously treated non-Hodgkin’s lymphoma, received single agent umbralisib at a dose of 800 mg daily until disease progression or unacceptable toxicity.

“Most patients who have responded continue on drug,” he said in a video interview.

Dr. Fowler also further discussed the findings to date with respect to response, adverse events, and future directions in the wake of the breakthrough therapy designation recently granted by the Food and Drug Administration for umbralisib based on these findings.

“Despite the fact that a lot of things work in the front line, when patients relapse, especially when they become refractory to rituximab, there are limited options available,” he said, noting that currently used treatments are associated with significant adverse event and short remission times. “We still need better options.”

sworcester@mdedge.com

ATLANTA – The phosphoinositide 3-kinase (PI3K) delta inhibitor umbralisib is active and well tolerated as single-agent therapy in patients with relapsed or refractory marginal zone lymphoma, according to findings from the ongoing phase 2 UNITY-NHL study.

The best overall response rate (ORR) among 42 study participants with at least 9 months of follow-up was 52% by both independent review committee (IRC) and investigator assessment, and the complete response rate was 19%, Nathan H. Fowler, MD, reported at the annual meeting of the American Association for Cancer Research.

The ORR by IRC assessment for those with extranodal, nodal, and splenic disease was 57%, 42%, and 43%, respectively, and for those with prior chemo-immunotherapy and those refractory to their last line of therapy, the ORR was 53% and 38%, respectively, said Dr. Fowler of MD Anderson Cancer Center, Houston.

The clinical benefit rate was 88%, and the median duration of response and progression-free survival (PFS) have not been reached; 12-month PFS is estimated at 66%, he added.

Patients in the marginal zone lymphoma cohort of the multicohort trial, which is evaluating umbralisib both as monotherapy and as part of various combinations in patients with previously treated non-Hodgkin’s lymphoma, received single agent umbralisib at a dose of 800 mg daily until disease progression or unacceptable toxicity.

“Most patients who have responded continue on drug,” he said in a video interview.

Dr. Fowler also further discussed the findings to date with respect to response, adverse events, and future directions in the wake of the breakthrough therapy designation recently granted by the Food and Drug Administration for umbralisib based on these findings.

“Despite the fact that a lot of things work in the front line, when patients relapse, especially when they become refractory to rituximab, there are limited options available,” he said, noting that currently used treatments are associated with significant adverse event and short remission times. “We still need better options.”

sworcester@mdedge.com

ATLANTA – Adult survivors of childhood cancers are at significantly greater risk than the general population for late-term complications related to therapy, including secondary cancers, cardiovascular disease, and cerebrovascular complications, including ischemic and hemorrhagic strokes.

In particular, childhood cancer survivors have an approximately eightfold higher risk for stroke, compared with their siblings, with a history of cranial irradiation being a strong, dose-dependent risk factor for stroke.

Researchers at St. Jude Children’s Research Hospital in Memphis, Tenn., are conducting a retrospective cohort study with prospective clinical follow-up and ongoing enrollment of childhood cancer survivors who are 5 or more years out of therapy.

The study includes publicly available, whole-genome sequencing data on 4,500 participants. Sifting through these data, Yadav Sapkota, PhD, a clinical research scientist at St. Jude, and his colleagues have identified a genetic variant strongly associated with stroke risk in survivors of European ancestry, and they have replicated the finding in survivors of African ancestry.

In a video interview at the annual meeting of the American Association for Cancer Research, Dr. Sapkota describes his group’s findings and potential research and clinical implications.

The study was sponsored by the National Cancer Institute and ALSAC, the fundraising and awareness organization of St. Jude. Dr. Sapkota declared no conflict of interest.

ATLANTA – Adult survivors of childhood cancers are at significantly greater risk than the general population for late-term complications related to therapy, including secondary cancers, cardiovascular disease, and cerebrovascular complications, including ischemic and hemorrhagic strokes.

In particular, childhood cancer survivors have an approximately eightfold higher risk for stroke, compared with their siblings, with a history of cranial irradiation being a strong, dose-dependent risk factor for stroke.

Researchers at St. Jude Children’s Research Hospital in Memphis, Tenn., are conducting a retrospective cohort study with prospective clinical follow-up and ongoing enrollment of childhood cancer survivors who are 5 or more years out of therapy.

The study includes publicly available, whole-genome sequencing data on 4,500 participants. Sifting through these data, Yadav Sapkota, PhD, a clinical research scientist at St. Jude, and his colleagues have identified a genetic variant strongly associated with stroke risk in survivors of European ancestry, and they have replicated the finding in survivors of African ancestry.

In a video interview at the annual meeting of the American Association for Cancer Research, Dr. Sapkota describes his group’s findings and potential research and clinical implications.

The study was sponsored by the National Cancer Institute and ALSAC, the fundraising and awareness organization of St. Jude. Dr. Sapkota declared no conflict of interest.

ATLANTA – Adult survivors of childhood cancers are at significantly greater risk than the general population for late-term complications related to therapy, including secondary cancers, cardiovascular disease, and cerebrovascular complications, including ischemic and hemorrhagic strokes.

In particular, childhood cancer survivors have an approximately eightfold higher risk for stroke, compared with their siblings, with a history of cranial irradiation being a strong, dose-dependent risk factor for stroke.

Researchers at St. Jude Children’s Research Hospital in Memphis, Tenn., are conducting a retrospective cohort study with prospective clinical follow-up and ongoing enrollment of childhood cancer survivors who are 5 or more years out of therapy.

The study includes publicly available, whole-genome sequencing data on 4,500 participants. Sifting through these data, Yadav Sapkota, PhD, a clinical research scientist at St. Jude, and his colleagues have identified a genetic variant strongly associated with stroke risk in survivors of European ancestry, and they have replicated the finding in survivors of African ancestry.

In a video interview at the annual meeting of the American Association for Cancer Research, Dr. Sapkota describes his group’s findings and potential research and clinical implications.

The study was sponsored by the National Cancer Institute and ALSAC, the fundraising and awareness organization of St. Jude. Dr. Sapkota declared no conflict of interest.

ATLANTA – Sarcomas of bone and soft tissues are considered to be “antigenically cold” tumors, with few identifiable mutations that may be susceptible to targeted therapies.

Some sarcoma subtypes such as osteosarcoma and rhabomyosarcoma, however, frequently express the human epidermal growth factor receptor 2 on tumor surfaces. Although HER2 expression in these tumors is at too low a level for HER2-targeted therapies such as trastuzumab (Herceptin), HER2 appears to be an opportunistic target for chimeric antigen receptor (CAR) T-cell therapy, according to Shoba Navai, MD, from Baylor College of Medicine, Houston.

In a video interview at the 2019 annual meeting of the American Association for Cancer Research, Dr. Navai describes her team’s early experience using a HER2-targeted CAR-T cell construct and preinfusion lymphodepletion in patients with advanced sarcomas.

Development of the CAR-T cell construct is supported by the Cancer Prevention & Research Institute of Texas, Stand Up to Cancer, the St. Baldrick’s Foundation, Cookies for Kids’ Cancer, Alex’s Lemonade Stand, and a grant from the National Institutes of Health. Dr. Navai reported having no disclosures.

ATLANTA – Sarcomas of bone and soft tissues are considered to be “antigenically cold” tumors, with few identifiable mutations that may be susceptible to targeted therapies.

Some sarcoma subtypes such as osteosarcoma and rhabomyosarcoma, however, frequently express the human epidermal growth factor receptor 2 on tumor surfaces. Although HER2 expression in these tumors is at too low a level for HER2-targeted therapies such as trastuzumab (Herceptin), HER2 appears to be an opportunistic target for chimeric antigen receptor (CAR) T-cell therapy, according to Shoba Navai, MD, from Baylor College of Medicine, Houston.

In a video interview at the 2019 annual meeting of the American Association for Cancer Research, Dr. Navai describes her team’s early experience using a HER2-targeted CAR-T cell construct and preinfusion lymphodepletion in patients with advanced sarcomas.

Development of the CAR-T cell construct is supported by the Cancer Prevention & Research Institute of Texas, Stand Up to Cancer, the St. Baldrick’s Foundation, Cookies for Kids’ Cancer, Alex’s Lemonade Stand, and a grant from the National Institutes of Health. Dr. Navai reported having no disclosures.

ATLANTA – Sarcomas of bone and soft tissues are considered to be “antigenically cold” tumors, with few identifiable mutations that may be susceptible to targeted therapies.

Some sarcoma subtypes such as osteosarcoma and rhabomyosarcoma, however, frequently express the human epidermal growth factor receptor 2 on tumor surfaces. Although HER2 expression in these tumors is at too low a level for HER2-targeted therapies such as trastuzumab (Herceptin), HER2 appears to be an opportunistic target for chimeric antigen receptor (CAR) T-cell therapy, according to Shoba Navai, MD, from Baylor College of Medicine, Houston.

In a video interview at the 2019 annual meeting of the American Association for Cancer Research, Dr. Navai describes her team’s early experience using a HER2-targeted CAR-T cell construct and preinfusion lymphodepletion in patients with advanced sarcomas.

Development of the CAR-T cell construct is supported by the Cancer Prevention & Research Institute of Texas, Stand Up to Cancer, the St. Baldrick’s Foundation, Cookies for Kids’ Cancer, Alex’s Lemonade Stand, and a grant from the National Institutes of Health. Dr. Navai reported having no disclosures.

Proposed changes to federal mammography regulations aim to provide more information for doctors and patients, as well as standardize patient information on breast density’s impact on screening.

The Food and Drug Administration posted a new proposed rule online March 27 that would “expand the information mammography facilities must provide to patients and health care professionals, allowing for more informed medical decision making,” the agency said in a statement. “It would also modernize mammography quality standards and better position the FDA to enforce regulations that apply to the safety and quality of mammography services.”

Key among the proposed changes is the addition of breast density information to the summary letter provided to patients and to the medical report provided to referring health care professionals.

“The FDA is proposing specific language that would explain how breast density can influence the accuracy of mammography and would recommend patients with dense breasts talk to their health care provider about high breast density and how it relates to breast cancer risk and their individual situation,” the agency said in a statement.

Laurie Margolies, MD, section chief of breast imaging at Mount Sinai Health System in New York, said the regulations would bring some uniformity to the communication process.

“It builds on the experience of the 37 states and the District of Columbia, all of whom have passed dense breast notification laws, and can serve to unify those disparate regulations into one that would be uniform throughout the country to give one clear message to women and health care providers,” Dr. Margolies said in an interview.

She noted that dense breasts are very common and communicating issues that are related to them, including the potential need for supplemental screening, are important.

“Almost half of American women have dense breasts and why that is significant is because the dense breast issue not only increases one’s risk of getting breast cancer, but it also can hide small breast cancers on the mammogram,” she said.

If you take 1,000 women with dense breasts and then do a breast ultrasound as a supplemental screening measure, “you will find three more small node-negative breast cancers that would not have come to light if you didn’t do the extra supplemental screening,” underscoring the importance of communicating dense breast information, she continued.

FDA also is seeking to enhance information provided to health care professionals by codifying three additional categories for mammogram assessments, including the addition of the “known biopsy proven malignancy” category, which the agency says would help identify which scans were being used to evaluate treatment of already diagnosed cancers.

Both patients and health care professionals would receive more detailed information about the mammography facility under the proposed rule.

FDA is proposing modernization of quality standards to help the agency enforce regulations, including giving the agency the authority to notify patients and health care professionals directly if a mammography facility does not meet quality standards and that a reevaluation or repeat of the exam at a different facility may be needed. The proposed amendments also include requiring that only digital accessory components specifically FDA approved or cleared for mammography be used or that facilities use components that otherwise meet the requirements, and stronger record-keeping requirements.

Dr. Margolies did note one potential deficiency in the proposed rule – the lack of any information on health insurance coverage of supplemental screening for women with dense breasts, though she noted this may not fall under the FDA’s authority.

“It would do the most good if everybody could get the supplemental screening without regards to their ability to pay for it out of pocket,” she said.

The proposal amends regulations issued under the Mammography Quality Standards Act of 1992, which gives FDA oversight authority over mammography facilities, including accreditation, certification, annual inspection, and enforcement of standards.

Comments on the proposal are due 90 days after the proposed rule is published in the Federal Register, which is scheduled for March 28.

gtwachtman@mdedge.com

Proposed changes to federal mammography regulations aim to provide more information for doctors and patients, as well as standardize patient information on breast density’s impact on screening.

The Food and Drug Administration posted a new proposed rule online March 27 that would “expand the information mammography facilities must provide to patients and health care professionals, allowing for more informed medical decision making,” the agency said in a statement. “It would also modernize mammography quality standards and better position the FDA to enforce regulations that apply to the safety and quality of mammography services.”

Key among the proposed changes is the addition of breast density information to the summary letter provided to patients and to the medical report provided to referring health care professionals.

“The FDA is proposing specific language that would explain how breast density can influence the accuracy of mammography and would recommend patients with dense breasts talk to their health care provider about high breast density and how it relates to breast cancer risk and their individual situation,” the agency said in a statement.

Laurie Margolies, MD, section chief of breast imaging at Mount Sinai Health System in New York, said the regulations would bring some uniformity to the communication process.

“It builds on the experience of the 37 states and the District of Columbia, all of whom have passed dense breast notification laws, and can serve to unify those disparate regulations into one that would be uniform throughout the country to give one clear message to women and health care providers,” Dr. Margolies said in an interview.

She noted that dense breasts are very common and communicating issues that are related to them, including the potential need for supplemental screening, are important.

“Almost half of American women have dense breasts and why that is significant is because the dense breast issue not only increases one’s risk of getting breast cancer, but it also can hide small breast cancers on the mammogram,” she said.

If you take 1,000 women with dense breasts and then do a breast ultrasound as a supplemental screening measure, “you will find three more small node-negative breast cancers that would not have come to light if you didn’t do the extra supplemental screening,” underscoring the importance of communicating dense breast information, she continued.

FDA also is seeking to enhance information provided to health care professionals by codifying three additional categories for mammogram assessments, including the addition of the “known biopsy proven malignancy” category, which the agency says would help identify which scans were being used to evaluate treatment of already diagnosed cancers.

Both patients and health care professionals would receive more detailed information about the mammography facility under the proposed rule.

FDA is proposing modernization of quality standards to help the agency enforce regulations, including giving the agency the authority to notify patients and health care professionals directly if a mammography facility does not meet quality standards and that a reevaluation or repeat of the exam at a different facility may be needed. The proposed amendments also include requiring that only digital accessory components specifically FDA approved or cleared for mammography be used or that facilities use components that otherwise meet the requirements, and stronger record-keeping requirements.

Dr. Margolies did note one potential deficiency in the proposed rule – the lack of any information on health insurance coverage of supplemental screening for women with dense breasts, though she noted this may not fall under the FDA’s authority.

“It would do the most good if everybody could get the supplemental screening without regards to their ability to pay for it out of pocket,” she said.

The proposal amends regulations issued under the Mammography Quality Standards Act of 1992, which gives FDA oversight authority over mammography facilities, including accreditation, certification, annual inspection, and enforcement of standards.

Comments on the proposal are due 90 days after the proposed rule is published in the Federal Register, which is scheduled for March 28.

gtwachtman@mdedge.com

Proposed changes to federal mammography regulations aim to provide more information for doctors and patients, as well as standardize patient information on breast density’s impact on screening.

The Food and Drug Administration posted a new proposed rule online March 27 that would “expand the information mammography facilities must provide to patients and health care professionals, allowing for more informed medical decision making,” the agency said in a statement. “It would also modernize mammography quality standards and better position the FDA to enforce regulations that apply to the safety and quality of mammography services.”

Key among the proposed changes is the addition of breast density information to the summary letter provided to patients and to the medical report provided to referring health care professionals.

“The FDA is proposing specific language that would explain how breast density can influence the accuracy of mammography and would recommend patients with dense breasts talk to their health care provider about high breast density and how it relates to breast cancer risk and their individual situation,” the agency said in a statement.

Laurie Margolies, MD, section chief of breast imaging at Mount Sinai Health System in New York, said the regulations would bring some uniformity to the communication process.

“It builds on the experience of the 37 states and the District of Columbia, all of whom have passed dense breast notification laws, and can serve to unify those disparate regulations into one that would be uniform throughout the country to give one clear message to women and health care providers,” Dr. Margolies said in an interview.

She noted that dense breasts are very common and communicating issues that are related to them, including the potential need for supplemental screening, are important.

“Almost half of American women have dense breasts and why that is significant is because the dense breast issue not only increases one’s risk of getting breast cancer, but it also can hide small breast cancers on the mammogram,” she said.

If you take 1,000 women with dense breasts and then do a breast ultrasound as a supplemental screening measure, “you will find three more small node-negative breast cancers that would not have come to light if you didn’t do the extra supplemental screening,” underscoring the importance of communicating dense breast information, she continued.

FDA also is seeking to enhance information provided to health care professionals by codifying three additional categories for mammogram assessments, including the addition of the “known biopsy proven malignancy” category, which the agency says would help identify which scans were being used to evaluate treatment of already diagnosed cancers.

Both patients and health care professionals would receive more detailed information about the mammography facility under the proposed rule.

FDA is proposing modernization of quality standards to help the agency enforce regulations, including giving the agency the authority to notify patients and health care professionals directly if a mammography facility does not meet quality standards and that a reevaluation or repeat of the exam at a different facility may be needed. The proposed amendments also include requiring that only digital accessory components specifically FDA approved or cleared for mammography be used or that facilities use components that otherwise meet the requirements, and stronger record-keeping requirements.

Dr. Margolies did note one potential deficiency in the proposed rule – the lack of any information on health insurance coverage of supplemental screening for women with dense breasts, though she noted this may not fall under the FDA’s authority.

“It would do the most good if everybody could get the supplemental screening without regards to their ability to pay for it out of pocket,” she said.

The proposal amends regulations issued under the Mammography Quality Standards Act of 1992, which gives FDA oversight authority over mammography facilities, including accreditation, certification, annual inspection, and enforcement of standards.

Comments on the proposal are due 90 days after the proposed rule is published in the Federal Register, which is scheduled for March 28.

gtwachtman@mdedge.com