Lymphoma & Plasma Cell Disorders

Photo courtesy of FDA

Results of a systematic review suggest a need for more research and long-term follow-up of patients with breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL).

Although data suggest BIA-ALCL is likely associated with textured implants and may result from chronic inflammation, neither of these theories has been confirmed.

Furthermore, researchers have yet to establish optimal prognostic and treatment guidelines for BIA-ALCL.

Dino Ravnic, DO, of Penn State Health Milton S. Hershey Medical Center in Hershey, Pennsylvania, and his colleagues highlighted these areas of need in an article published in JAMA Surgery.

The team conducted a literature review to learn more about the development, risk factors, diagnosis, and treatment of BIA-ALCL. They reviewed data from 115 articles and 95 patients.

The researchers noted that the incidence of BIA-ALCL is unknown. The Association of Breast Surgery estimates an incidence of 1 in 300,000 breast implants, while the Australian Therapeutic Goods Administration estimates BIA-ALCL could affect between 1 in 1000 and 1 in 10,000 women with breast implants.

“We’re seeing that this cancer is likely very underreported, and, as more information on this type of cancer comes to light, the number of cases is likely to increase in the coming years,” Dr Ravnic said.

He and his colleagues noted that almost all documented cases of BIA-ALCL have been associated with textured implants. These implants rose in popularity in the 1990s, and the first case of BIA-ALCL was documented in 1997.

The researchers said that because they could find no incidents of BIA-ALCL prior to the introduction of textured implants, this suggests a causal relationship, but more research is needed to confirm this theory.

“We’re still exploring the exact causes, but according to current knowledge, this cancer only really started to appear after textured implants came on the market in the 1990s,” Dr Ravnic said.

“All manufacturers of textured implants have had cases linked to this type of lymphoma, and we haven’t seen cases linked to smooth implants. But, in many of these cases, the implant was removed without testing the surrounding fluid and tissue for lymphoma cells, so it’s difficult to definitively correlate the two.”

The researchers also said the evidence suggests BIA-ALCL may occur as a result of inflammation surrounding the breast implant, and tissue that grows into pores in the textured implant may prolong inflammation.

Chronic inflammation may lead to malignant transformation of T cells that are anaplastic lymphoma kinase-negative and CD30-positive.

The data also suggest BIA-ALCL tends to develop slowly. The mean time to BIA-ALCL presentation in the 95 patients analyzed was about 10 years after the patients received their implants.

The researchers said treatment of BIA-ALCL must include removal of the implant and surrounding capsule. However, patients with advanced disease—including a tumor mass (stage II), lymph node involvement (stage II/III), or distant disease (stage IV)—may require chemotherapy, radiotherapy, or both. Brentuximab vedotin has also been used.

Overall, the patients included in this review appeared to have a good prognosis, with only 5 patients experiencing disease recurrence and dying of BIA-ALCL.

However, the researchers noted that it was difficult to calculate the mean overall survival and disease-free survival of these patients due to a lack of data and inadequate follow-up.

Photo courtesy of FDA

Results of a systematic review suggest a need for more research and long-term follow-up of patients with breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL).

Although data suggest BIA-ALCL is likely associated with textured implants and may result from chronic inflammation, neither of these theories has been confirmed.

Furthermore, researchers have yet to establish optimal prognostic and treatment guidelines for BIA-ALCL.

Dino Ravnic, DO, of Penn State Health Milton S. Hershey Medical Center in Hershey, Pennsylvania, and his colleagues highlighted these areas of need in an article published in JAMA Surgery.

The team conducted a literature review to learn more about the development, risk factors, diagnosis, and treatment of BIA-ALCL. They reviewed data from 115 articles and 95 patients.

The researchers noted that the incidence of BIA-ALCL is unknown. The Association of Breast Surgery estimates an incidence of 1 in 300,000 breast implants, while the Australian Therapeutic Goods Administration estimates BIA-ALCL could affect between 1 in 1000 and 1 in 10,000 women with breast implants.

“We’re seeing that this cancer is likely very underreported, and, as more information on this type of cancer comes to light, the number of cases is likely to increase in the coming years,” Dr Ravnic said.

He and his colleagues noted that almost all documented cases of BIA-ALCL have been associated with textured implants. These implants rose in popularity in the 1990s, and the first case of BIA-ALCL was documented in 1997.

The researchers said that because they could find no incidents of BIA-ALCL prior to the introduction of textured implants, this suggests a causal relationship, but more research is needed to confirm this theory.

“We’re still exploring the exact causes, but according to current knowledge, this cancer only really started to appear after textured implants came on the market in the 1990s,” Dr Ravnic said.

“All manufacturers of textured implants have had cases linked to this type of lymphoma, and we haven’t seen cases linked to smooth implants. But, in many of these cases, the implant was removed without testing the surrounding fluid and tissue for lymphoma cells, so it’s difficult to definitively correlate the two.”

The researchers also said the evidence suggests BIA-ALCL may occur as a result of inflammation surrounding the breast implant, and tissue that grows into pores in the textured implant may prolong inflammation.

Chronic inflammation may lead to malignant transformation of T cells that are anaplastic lymphoma kinase-negative and CD30-positive.

The data also suggest BIA-ALCL tends to develop slowly. The mean time to BIA-ALCL presentation in the 95 patients analyzed was about 10 years after the patients received their implants.

The researchers said treatment of BIA-ALCL must include removal of the implant and surrounding capsule. However, patients with advanced disease—including a tumor mass (stage II), lymph node involvement (stage II/III), or distant disease (stage IV)—may require chemotherapy, radiotherapy, or both. Brentuximab vedotin has also been used.

Overall, the patients included in this review appeared to have a good prognosis, with only 5 patients experiencing disease recurrence and dying of BIA-ALCL.

However, the researchers noted that it was difficult to calculate the mean overall survival and disease-free survival of these patients due to a lack of data and inadequate follow-up.

Photo courtesy of FDA

Results of a systematic review suggest a need for more research and long-term follow-up of patients with breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL).

Although data suggest BIA-ALCL is likely associated with textured implants and may result from chronic inflammation, neither of these theories has been confirmed.

Furthermore, researchers have yet to establish optimal prognostic and treatment guidelines for BIA-ALCL.

Dino Ravnic, DO, of Penn State Health Milton S. Hershey Medical Center in Hershey, Pennsylvania, and his colleagues highlighted these areas of need in an article published in JAMA Surgery.

The team conducted a literature review to learn more about the development, risk factors, diagnosis, and treatment of BIA-ALCL. They reviewed data from 115 articles and 95 patients.

The researchers noted that the incidence of BIA-ALCL is unknown. The Association of Breast Surgery estimates an incidence of 1 in 300,000 breast implants, while the Australian Therapeutic Goods Administration estimates BIA-ALCL could affect between 1 in 1000 and 1 in 10,000 women with breast implants.

“We’re seeing that this cancer is likely very underreported, and, as more information on this type of cancer comes to light, the number of cases is likely to increase in the coming years,” Dr Ravnic said.

He and his colleagues noted that almost all documented cases of BIA-ALCL have been associated with textured implants. These implants rose in popularity in the 1990s, and the first case of BIA-ALCL was documented in 1997.

The researchers said that because they could find no incidents of BIA-ALCL prior to the introduction of textured implants, this suggests a causal relationship, but more research is needed to confirm this theory.

“We’re still exploring the exact causes, but according to current knowledge, this cancer only really started to appear after textured implants came on the market in the 1990s,” Dr Ravnic said.

“All manufacturers of textured implants have had cases linked to this type of lymphoma, and we haven’t seen cases linked to smooth implants. But, in many of these cases, the implant was removed without testing the surrounding fluid and tissue for lymphoma cells, so it’s difficult to definitively correlate the two.”

The researchers also said the evidence suggests BIA-ALCL may occur as a result of inflammation surrounding the breast implant, and tissue that grows into pores in the textured implant may prolong inflammation.

Chronic inflammation may lead to malignant transformation of T cells that are anaplastic lymphoma kinase-negative and CD30-positive.

The data also suggest BIA-ALCL tends to develop slowly. The mean time to BIA-ALCL presentation in the 95 patients analyzed was about 10 years after the patients received their implants.

The researchers said treatment of BIA-ALCL must include removal of the implant and surrounding capsule. However, patients with advanced disease—including a tumor mass (stage II), lymph node involvement (stage II/III), or distant disease (stage IV)—may require chemotherapy, radiotherapy, or both. Brentuximab vedotin has also been used.

Overall, the patients included in this review appeared to have a good prognosis, with only 5 patients experiencing disease recurrence and dying of BIA-ALCL.

However, the researchers noted that it was difficult to calculate the mean overall survival and disease-free survival of these patients due to a lack of data and inadequate follow-up.

Diffuse large B-cell lymphoma

The US Food and Drug Administration (FDA) has approved axicabtagene ciloleucel (Yescarta™, formerly KTE-C19) for use in adults with relapsed or refractory large B-cell lymphoma who have received 2 or more lines of systemic therapy.

Axicabtagene ciloleucel is the first chimeric antigen receptor (CAR) T-cell therapy approved to treat lymphomas.

The approval encompasses diffuse large B-cell lymphoma not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and transformed follicular lymphoma.

Axicabtagene ciloleucel is not approved to treat primary central nervous system lymphoma.

The FDA’s approval of axicabtagene ciloleucel was based on results from the phase 2 ZUMA-1 trial. Updated results from this trial were presented at the AACR Annual Meeting 2017.

Risks

Axicabtagene ciloleucel has a Boxed Warning in its product label noting that the therapy can cause cytokine release syndrome (CRS) and neurologic toxicities. Full prescribing information for axicabtagene ciloleucel is available at https://www.yescarta.com/.

Because of the risk of CRS and neurologic toxicities, axicabtagene ciloleucel was approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use. The FDA is requiring that hospitals and clinics that dispense axicabtagene ciloleucel be specially certified.

As part of that certification, staff who prescribe, dispense, or administer axicabtagene ciloleucel are required to be trained to recognize and manage CRS and nervous system toxicities. In addition, patients must be informed of the potential serious side effects associated with axicabtagene ciloleucel and of the importance of promptly returning to the treatment site if side effects develop.

Additional information about the REMS program can be found at https://www.yescartarems.com/.

To further evaluate the long-term safety of axicabtagene ciloleucel, the FDA is requiring the manufacturer—Kite, a Gilead company—to conduct a post-marketing observational study of patients treated with axicabtagene ciloleucel.

Access and cost

The list price of axicabtagene ciloleucel is $373,000.

The product will be manufactured in Kite’s commercial manufacturing facility in El Segundo, California.

In 2017, Kite established a multi-disciplinary field team focused on providing education and logistics training for medical centers. Now, this team has provided final site certification to 16 centers, enabling them to make axicabtagene ciloleucel available to appropriate patients.

Kite is working to train staff at more than 30 additional centers, with an eventual target of 70 to 90 centers across the US. The latest information on authorized centers is available at https://www.yescarta.com/authorized-treatment-centers/.

Diffuse large B-cell lymphoma

The US Food and Drug Administration (FDA) has approved axicabtagene ciloleucel (Yescarta™, formerly KTE-C19) for use in adults with relapsed or refractory large B-cell lymphoma who have received 2 or more lines of systemic therapy.

Axicabtagene ciloleucel is the first chimeric antigen receptor (CAR) T-cell therapy approved to treat lymphomas.

The approval encompasses diffuse large B-cell lymphoma not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and transformed follicular lymphoma.

Axicabtagene ciloleucel is not approved to treat primary central nervous system lymphoma.

The FDA’s approval of axicabtagene ciloleucel was based on results from the phase 2 ZUMA-1 trial. Updated results from this trial were presented at the AACR Annual Meeting 2017.

Risks

Axicabtagene ciloleucel has a Boxed Warning in its product label noting that the therapy can cause cytokine release syndrome (CRS) and neurologic toxicities. Full prescribing information for axicabtagene ciloleucel is available at https://www.yescarta.com/.

Because of the risk of CRS and neurologic toxicities, axicabtagene ciloleucel was approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use. The FDA is requiring that hospitals and clinics that dispense axicabtagene ciloleucel be specially certified.

As part of that certification, staff who prescribe, dispense, or administer axicabtagene ciloleucel are required to be trained to recognize and manage CRS and nervous system toxicities. In addition, patients must be informed of the potential serious side effects associated with axicabtagene ciloleucel and of the importance of promptly returning to the treatment site if side effects develop.

Additional information about the REMS program can be found at https://www.yescartarems.com/.

To further evaluate the long-term safety of axicabtagene ciloleucel, the FDA is requiring the manufacturer—Kite, a Gilead company—to conduct a post-marketing observational study of patients treated with axicabtagene ciloleucel.

Access and cost

The list price of axicabtagene ciloleucel is $373,000.

The product will be manufactured in Kite’s commercial manufacturing facility in El Segundo, California.

In 2017, Kite established a multi-disciplinary field team focused on providing education and logistics training for medical centers. Now, this team has provided final site certification to 16 centers, enabling them to make axicabtagene ciloleucel available to appropriate patients.

Kite is working to train staff at more than 30 additional centers, with an eventual target of 70 to 90 centers across the US. The latest information on authorized centers is available at https://www.yescarta.com/authorized-treatment-centers/.

Diffuse large B-cell lymphoma

The US Food and Drug Administration (FDA) has approved axicabtagene ciloleucel (Yescarta™, formerly KTE-C19) for use in adults with relapsed or refractory large B-cell lymphoma who have received 2 or more lines of systemic therapy.

Axicabtagene ciloleucel is the first chimeric antigen receptor (CAR) T-cell therapy approved to treat lymphomas.

The approval encompasses diffuse large B-cell lymphoma not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and transformed follicular lymphoma.

Axicabtagene ciloleucel is not approved to treat primary central nervous system lymphoma.

The FDA’s approval of axicabtagene ciloleucel was based on results from the phase 2 ZUMA-1 trial. Updated results from this trial were presented at the AACR Annual Meeting 2017.

Risks

Axicabtagene ciloleucel has a Boxed Warning in its product label noting that the therapy can cause cytokine release syndrome (CRS) and neurologic toxicities. Full prescribing information for axicabtagene ciloleucel is available at https://www.yescarta.com/.

Because of the risk of CRS and neurologic toxicities, axicabtagene ciloleucel was approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use. The FDA is requiring that hospitals and clinics that dispense axicabtagene ciloleucel be specially certified.

As part of that certification, staff who prescribe, dispense, or administer axicabtagene ciloleucel are required to be trained to recognize and manage CRS and nervous system toxicities. In addition, patients must be informed of the potential serious side effects associated with axicabtagene ciloleucel and of the importance of promptly returning to the treatment site if side effects develop.

Additional information about the REMS program can be found at https://www.yescartarems.com/.

To further evaluate the long-term safety of axicabtagene ciloleucel, the FDA is requiring the manufacturer—Kite, a Gilead company—to conduct a post-marketing observational study of patients treated with axicabtagene ciloleucel.

Access and cost

The list price of axicabtagene ciloleucel is $373,000.

The product will be manufactured in Kite’s commercial manufacturing facility in El Segundo, California.

In 2017, Kite established a multi-disciplinary field team focused on providing education and logistics training for medical centers. Now, this team has provided final site certification to 16 centers, enabling them to make axicabtagene ciloleucel available to appropriate patients.

Kite is working to train staff at more than 30 additional centers, with an eventual target of 70 to 90 centers across the US. The latest information on authorized centers is available at https://www.yescarta.com/authorized-treatment-centers/.

mycosis fungoides

LONDON—Results of a phase 2 trial suggest the topical histone deacetylase (HDAC) inhibitor remetinostat can elicit responses in patients with early stage mycosis fungoides (MF).

At the highest dose level tested, remetinostat gel reduced the severity of skin lesions in 40% of patients and reduced the severity of pruritus in 80% of patients.

In addition, the HDAC inhibitor was considered well tolerated and did not produce systemic adverse effects.

These results were presented at the European Organization for Research and Treatment of Cancer Cutaneous Lymphoma Task Force meeting, which took place October 13-15.

The study was sponsored by Medivir AB, which purchased remetinostat from TetraLogic Pharmaceuticals last year.

The trial of remetinostat enrolled 60 patients with stage IA-IIA MF across 5 clinical sites in the US. Patients were randomized to receive remetinostat gel 0.5% twice daily, remetinostat gel 1% once daily, or remetinostat gel 1% twice daily for up to 12 months.

The study’s primary endpoint was the proportion of patients with a confirmed response to therapy, assessed using the Composite Assessment of Index Lesion Severity.

The researchers observed a dose response, with patients in the 1% twice-daily arm having the highest proportion of confirmed responses.

Based on an intent-to-treat analysis, confirmed response rates were as follows:

The researchers also assessed the effect of remetinostat gel on the severity of pruritus. This was assessed monthly for the duration of the study using the visual analogue scale.

Among patients with clinically significant pruritus at baseline, those who received remetinostat gel 1% twice daily were most likely to have a clinically significant reduction in pruritus. This was defined as at least a 30 mm reduction in the visual analogue scale score sustained for more than 4 weeks.

The proportion of patients who had confirmed, clinically significant reductions in pruritus from baseline was 80% in the 1% twice-daily arm, 50% in the 0.5% twice-daily arm, and 37.5% in the 1% once-daily arm.

The researchers said remetinostat was generally well tolerated, with adverse events evenly distributed across the treatment arms. The most common adverse events were skin-related and mostly grade 1-2.

There were no signs of systemic adverse effects related to remetinostat, including those associated with systemic HDAC inhibitors.

Most patients remained on study for the maximum possible duration, and the median treatment time was 350 days.

Based on the outcomes of this study, Medivir expects to meet with regulatory authorities to discuss the design of a pivotal clinical program for remetinostat in MF.

mycosis fungoides

LONDON—Results of a phase 2 trial suggest the topical histone deacetylase (HDAC) inhibitor remetinostat can elicit responses in patients with early stage mycosis fungoides (MF).

At the highest dose level tested, remetinostat gel reduced the severity of skin lesions in 40% of patients and reduced the severity of pruritus in 80% of patients.

In addition, the HDAC inhibitor was considered well tolerated and did not produce systemic adverse effects.

These results were presented at the European Organization for Research and Treatment of Cancer Cutaneous Lymphoma Task Force meeting, which took place October 13-15.

The study was sponsored by Medivir AB, which purchased remetinostat from TetraLogic Pharmaceuticals last year.

The trial of remetinostat enrolled 60 patients with stage IA-IIA MF across 5 clinical sites in the US. Patients were randomized to receive remetinostat gel 0.5% twice daily, remetinostat gel 1% once daily, or remetinostat gel 1% twice daily for up to 12 months.

The study’s primary endpoint was the proportion of patients with a confirmed response to therapy, assessed using the Composite Assessment of Index Lesion Severity.

The researchers observed a dose response, with patients in the 1% twice-daily arm having the highest proportion of confirmed responses.

Based on an intent-to-treat analysis, confirmed response rates were as follows:

The researchers also assessed the effect of remetinostat gel on the severity of pruritus. This was assessed monthly for the duration of the study using the visual analogue scale.

Among patients with clinically significant pruritus at baseline, those who received remetinostat gel 1% twice daily were most likely to have a clinically significant reduction in pruritus. This was defined as at least a 30 mm reduction in the visual analogue scale score sustained for more than 4 weeks.

The proportion of patients who had confirmed, clinically significant reductions in pruritus from baseline was 80% in the 1% twice-daily arm, 50% in the 0.5% twice-daily arm, and 37.5% in the 1% once-daily arm.

The researchers said remetinostat was generally well tolerated, with adverse events evenly distributed across the treatment arms. The most common adverse events were skin-related and mostly grade 1-2.

There were no signs of systemic adverse effects related to remetinostat, including those associated with systemic HDAC inhibitors.

Most patients remained on study for the maximum possible duration, and the median treatment time was 350 days.

Based on the outcomes of this study, Medivir expects to meet with regulatory authorities to discuss the design of a pivotal clinical program for remetinostat in MF.

mycosis fungoides

LONDON—Results of a phase 2 trial suggest the topical histone deacetylase (HDAC) inhibitor remetinostat can elicit responses in patients with early stage mycosis fungoides (MF).

At the highest dose level tested, remetinostat gel reduced the severity of skin lesions in 40% of patients and reduced the severity of pruritus in 80% of patients.

In addition, the HDAC inhibitor was considered well tolerated and did not produce systemic adverse effects.

These results were presented at the European Organization for Research and Treatment of Cancer Cutaneous Lymphoma Task Force meeting, which took place October 13-15.

The study was sponsored by Medivir AB, which purchased remetinostat from TetraLogic Pharmaceuticals last year.

The trial of remetinostat enrolled 60 patients with stage IA-IIA MF across 5 clinical sites in the US. Patients were randomized to receive remetinostat gel 0.5% twice daily, remetinostat gel 1% once daily, or remetinostat gel 1% twice daily for up to 12 months.

The study’s primary endpoint was the proportion of patients with a confirmed response to therapy, assessed using the Composite Assessment of Index Lesion Severity.

The researchers observed a dose response, with patients in the 1% twice-daily arm having the highest proportion of confirmed responses.

Based on an intent-to-treat analysis, confirmed response rates were as follows:

The researchers also assessed the effect of remetinostat gel on the severity of pruritus. This was assessed monthly for the duration of the study using the visual analogue scale.

Among patients with clinically significant pruritus at baseline, those who received remetinostat gel 1% twice daily were most likely to have a clinically significant reduction in pruritus. This was defined as at least a 30 mm reduction in the visual analogue scale score sustained for more than 4 weeks.

The proportion of patients who had confirmed, clinically significant reductions in pruritus from baseline was 80% in the 1% twice-daily arm, 50% in the 0.5% twice-daily arm, and 37.5% in the 1% once-daily arm.

The researchers said remetinostat was generally well tolerated, with adverse events evenly distributed across the treatment arms. The most common adverse events were skin-related and mostly grade 1-2.

There were no signs of systemic adverse effects related to remetinostat, including those associated with systemic HDAC inhibitors.

Most patients remained on study for the maximum possible duration, and the median treatment time was 350 days.

Based on the outcomes of this study, Medivir expects to meet with regulatory authorities to discuss the design of a pivotal clinical program for remetinostat in MF.

Photo by Rhoda Baer

A new study suggests cryotherapy can reduce symptoms of chemotherapy-induced peripheral neuropathy (CIPN).

Researchers found that having chemotherapy patients wear frozen gloves and socks for 90-minute periods significantly reduced the incidence of CIPN symptoms.

Hiroshi Ishiguro, MD, PhD, of International University of Health and Welfare Hospital in Tochigi, Japan, and colleagues reported these findings in the Journal of the National Cancer Institute.

The researchers prospectively evaluated the efficacy of cryotherapy for preventing CIPN. Breast cancer patients treated weekly with paclitaxel (80 mg/m² for 1 hour) wore frozen gloves and socks on one side of their bodies for 90 minutes, including the entire duration of drug infusion.

The researchers then compared symptoms on the treated sides with those on the untreated sides.

The primary endpoint was CIPN incidence assessed by changes in tactile sensitivity from a pretreatment baseline. The researchers also assessed subjective symptoms, as reported in the Patient Neuropathy Questionnaire, and patients' manual dexterity.

Among the 40 patients studied, 4 did not reach the cumulative dose due to the occurrence of pneumonia, severe fatigue, liver dysfunction, and macular edema. Of the 36 remaining patients, none dropped out due to cold intolerance.

The incidence of objective and subjective signs of CIPN was clinically and statistically significantly lower on the intervention side than on the control side for most measurements, which includes (among other measures):

• Hand tactile sensitivity—27.8% and 80.6%, respectively (odds ratio[OR]= 20.00, P<0.001)
• Foot tactile sensitivity—25.0% and 63.9%, respectively (OR=infinite, P<0.001)
• Hand warm sense—8.8% and 32.4%, respectively (OR=9.00, P=0.02)
• Foot warm sense—33.4% and 57.6%, respectively (OR=5.00, P=0.04)
• Hand cold sense—2.8% and 13.9%, respectively (OR=infinite, P=0.13)
• Foot cold sense—12.6% and 18.8%, respectively (OR=2.00, P=0.69)
• Severe CIPN in the hand according to the Patient Neuropathy Questionnaire—2.8% and 41.7%, respectively (OR=infinite, P<0.001)
• Severe CIPN in the foot according to the Patient Neuropathy Questionnaire—2.8% and 36.1%, respectively (OR=infinite, P<0.001).
  

Photo by Rhoda Baer

A new study suggests cryotherapy can reduce symptoms of chemotherapy-induced peripheral neuropathy (CIPN).

Researchers found that having chemotherapy patients wear frozen gloves and socks for 90-minute periods significantly reduced the incidence of CIPN symptoms.

Hiroshi Ishiguro, MD, PhD, of International University of Health and Welfare Hospital in Tochigi, Japan, and colleagues reported these findings in the Journal of the National Cancer Institute.

The researchers prospectively evaluated the efficacy of cryotherapy for preventing CIPN. Breast cancer patients treated weekly with paclitaxel (80 mg/m² for 1 hour) wore frozen gloves and socks on one side of their bodies for 90 minutes, including the entire duration of drug infusion.

The researchers then compared symptoms on the treated sides with those on the untreated sides.

The primary endpoint was CIPN incidence assessed by changes in tactile sensitivity from a pretreatment baseline. The researchers also assessed subjective symptoms, as reported in the Patient Neuropathy Questionnaire, and patients' manual dexterity.

Among the 40 patients studied, 4 did not reach the cumulative dose due to the occurrence of pneumonia, severe fatigue, liver dysfunction, and macular edema. Of the 36 remaining patients, none dropped out due to cold intolerance.

The incidence of objective and subjective signs of CIPN was clinically and statistically significantly lower on the intervention side than on the control side for most measurements, which includes (among other measures):

• Hand tactile sensitivity—27.8% and 80.6%, respectively (odds ratio[OR]= 20.00, P<0.001)
• Foot tactile sensitivity—25.0% and 63.9%, respectively (OR=infinite, P<0.001)
• Hand warm sense—8.8% and 32.4%, respectively (OR=9.00, P=0.02)
• Foot warm sense—33.4% and 57.6%, respectively (OR=5.00, P=0.04)
• Hand cold sense—2.8% and 13.9%, respectively (OR=infinite, P=0.13)
• Foot cold sense—12.6% and 18.8%, respectively (OR=2.00, P=0.69)
• Severe CIPN in the hand according to the Patient Neuropathy Questionnaire—2.8% and 41.7%, respectively (OR=infinite, P<0.001)
• Severe CIPN in the foot according to the Patient Neuropathy Questionnaire—2.8% and 36.1%, respectively (OR=infinite, P<0.001).
  

Photo by Rhoda Baer

A new study suggests cryotherapy can reduce symptoms of chemotherapy-induced peripheral neuropathy (CIPN).

Researchers found that having chemotherapy patients wear frozen gloves and socks for 90-minute periods significantly reduced the incidence of CIPN symptoms.

Hiroshi Ishiguro, MD, PhD, of International University of Health and Welfare Hospital in Tochigi, Japan, and colleagues reported these findings in the Journal of the National Cancer Institute.

The researchers prospectively evaluated the efficacy of cryotherapy for preventing CIPN. Breast cancer patients treated weekly with paclitaxel (80 mg/m² for 1 hour) wore frozen gloves and socks on one side of their bodies for 90 minutes, including the entire duration of drug infusion.

The researchers then compared symptoms on the treated sides with those on the untreated sides.

The primary endpoint was CIPN incidence assessed by changes in tactile sensitivity from a pretreatment baseline. The researchers also assessed subjective symptoms, as reported in the Patient Neuropathy Questionnaire, and patients' manual dexterity.

Among the 40 patients studied, 4 did not reach the cumulative dose due to the occurrence of pneumonia, severe fatigue, liver dysfunction, and macular edema. Of the 36 remaining patients, none dropped out due to cold intolerance.

The incidence of objective and subjective signs of CIPN was clinically and statistically significantly lower on the intervention side than on the control side for most measurements, which includes (among other measures):

• Hand tactile sensitivity—27.8% and 80.6%, respectively (odds ratio[OR]= 20.00, P<0.001)
• Foot tactile sensitivity—25.0% and 63.9%, respectively (OR=infinite, P<0.001)
• Hand warm sense—8.8% and 32.4%, respectively (OR=9.00, P=0.02)
• Foot warm sense—33.4% and 57.6%, respectively (OR=5.00, P=0.04)
• Hand cold sense—2.8% and 13.9%, respectively (OR=infinite, P=0.13)
• Foot cold sense—12.6% and 18.8%, respectively (OR=2.00, P=0.69)
• Severe CIPN in the hand according to the Patient Neuropathy Questionnaire—2.8% and 41.7%, respectively (OR=infinite, P<0.001)
• Severe CIPN in the foot according to the Patient Neuropathy Questionnaire—2.8% and 36.1%, respectively (OR=infinite, P<0.001).
  

Photo by Rhoda Baer

Countries with the lowest opportunities for natural selection have higher cancer rates than countries with the highest opportunities for natural selection, according to a study published in Evolutionary Applications.

Researchers said this is because modern medicine is enabling people to survive cancers, and their genetic backgrounds are passing from one generation to the next.

The team said the rate of some cancers has doubled and even quadrupled over the past 100 to 150 years, and human evolution has moved away from “survival of the fittest.”

“Modern medicine has enabled the human species to live much longer than would otherwise be expected in the natural world,” said study author Maciej Henneberg, PhD, DSc, of the University of Adelaide in South Australia.

“Besides the obvious benefits that modern medicine gives, it also brings with it an unexpected side-effect—allowing genetic material to be passed from one generation to the next that predisposes people to have poor health, such as type 1 diabetes or cancer.”

“Because of the quality of our healthcare in western society, we have almost removed natural selection as the ‘janitor of the gene pool.’ Unfortunately, the accumulation of genetic mutations over time and across multiple generations is like a delayed death sentence.”

Country comparison

The researchers studied global cancer data from the World Health Organization as well as other health and socioeconomic data from the United Nations and the World Bank of 173 countries. The team compared the top 10 countries with the highest opportunities for natural selection to the 10 countries with the lowest opportunities for natural selection.

“We looked at countries that offered the greatest opportunity to survive cancer compared with those that didn’t,” said study author Wenpeng You, a PhD student at the University of Adelaide. “This does not only take into account factors such as socioeconomic status, urbanization, and quality of medical services but also low mortality and fertility rates, which are the 2 distinguishing features in the ‘better’ world.”

“Countries with low mortality rates may allow more people with cancer genetic background to reproduce and pass cancer genes/mutations to the next generation. Meanwhile, low fertility rates in these countries may not be able to have diverse biological variations to provide the opportunity for selecting a naturally fit population—for example, people without or with less cancer genetic background. Low mortality rate and low fertility rate in the ‘better’ world may have formed a self-reinforcing cycle which has accumulated cancer genetic background at a greater rate than previously thought.”

Based on the researchers’ analysis, the 20 countries are:

Cancer incidence

The researchers found the rates of most cancers were higher in the 10 countries with the lowest opportunities for natural selection. The incidence of all cancers was 2.326 times higher in the low-opportunity countries than the high-opportunity ones.

The increased incidences of hematologic malignancies were as follows:

• Non-Hodgkin lymphoma—2.019 times higher in the low-opportunity countries
• Hodgkin lymphoma—3.314 times higher in the low-opportunity countries
• Leukemia—3.574 times higher in the low-opportunity countries
• Multiple myeloma—4.257 times higher in the low-opportunity countries .

Dr Henneberg said that, having removed natural selection as the “janitor of the gene pool,” our modern society is faced with a controversial issue.

“It may be that the only way humankind can be rid of cancer once and for all is through genetic engineering—to repair our genes and take cancer out of the equation,” he said.

Photo by Rhoda Baer

Countries with the lowest opportunities for natural selection have higher cancer rates than countries with the highest opportunities for natural selection, according to a study published in Evolutionary Applications.

Researchers said this is because modern medicine is enabling people to survive cancers, and their genetic backgrounds are passing from one generation to the next.

The team said the rate of some cancers has doubled and even quadrupled over the past 100 to 150 years, and human evolution has moved away from “survival of the fittest.”

“Modern medicine has enabled the human species to live much longer than would otherwise be expected in the natural world,” said study author Maciej Henneberg, PhD, DSc, of the University of Adelaide in South Australia.

“Besides the obvious benefits that modern medicine gives, it also brings with it an unexpected side-effect—allowing genetic material to be passed from one generation to the next that predisposes people to have poor health, such as type 1 diabetes or cancer.”

“Because of the quality of our healthcare in western society, we have almost removed natural selection as the ‘janitor of the gene pool.’ Unfortunately, the accumulation of genetic mutations over time and across multiple generations is like a delayed death sentence.”

Country comparison

The researchers studied global cancer data from the World Health Organization as well as other health and socioeconomic data from the United Nations and the World Bank of 173 countries. The team compared the top 10 countries with the highest opportunities for natural selection to the 10 countries with the lowest opportunities for natural selection.

“We looked at countries that offered the greatest opportunity to survive cancer compared with those that didn’t,” said study author Wenpeng You, a PhD student at the University of Adelaide. “This does not only take into account factors such as socioeconomic status, urbanization, and quality of medical services but also low mortality and fertility rates, which are the 2 distinguishing features in the ‘better’ world.”

“Countries with low mortality rates may allow more people with cancer genetic background to reproduce and pass cancer genes/mutations to the next generation. Meanwhile, low fertility rates in these countries may not be able to have diverse biological variations to provide the opportunity for selecting a naturally fit population—for example, people without or with less cancer genetic background. Low mortality rate and low fertility rate in the ‘better’ world may have formed a self-reinforcing cycle which has accumulated cancer genetic background at a greater rate than previously thought.”

Based on the researchers’ analysis, the 20 countries are:

Cancer incidence

The researchers found the rates of most cancers were higher in the 10 countries with the lowest opportunities for natural selection. The incidence of all cancers was 2.326 times higher in the low-opportunity countries than the high-opportunity ones.

The increased incidences of hematologic malignancies were as follows:

• Non-Hodgkin lymphoma—2.019 times higher in the low-opportunity countries
• Hodgkin lymphoma—3.314 times higher in the low-opportunity countries
• Leukemia—3.574 times higher in the low-opportunity countries
• Multiple myeloma—4.257 times higher in the low-opportunity countries .

Dr Henneberg said that, having removed natural selection as the “janitor of the gene pool,” our modern society is faced with a controversial issue.

“It may be that the only way humankind can be rid of cancer once and for all is through genetic engineering—to repair our genes and take cancer out of the equation,” he said.

Photo by Rhoda Baer

Countries with the lowest opportunities for natural selection have higher cancer rates than countries with the highest opportunities for natural selection, according to a study published in Evolutionary Applications.

Researchers said this is because modern medicine is enabling people to survive cancers, and their genetic backgrounds are passing from one generation to the next.

The team said the rate of some cancers has doubled and even quadrupled over the past 100 to 150 years, and human evolution has moved away from “survival of the fittest.”

“Modern medicine has enabled the human species to live much longer than would otherwise be expected in the natural world,” said study author Maciej Henneberg, PhD, DSc, of the University of Adelaide in South Australia.

“Besides the obvious benefits that modern medicine gives, it also brings with it an unexpected side-effect—allowing genetic material to be passed from one generation to the next that predisposes people to have poor health, such as type 1 diabetes or cancer.”

“Because of the quality of our healthcare in western society, we have almost removed natural selection as the ‘janitor of the gene pool.’ Unfortunately, the accumulation of genetic mutations over time and across multiple generations is like a delayed death sentence.”

Country comparison

The researchers studied global cancer data from the World Health Organization as well as other health and socioeconomic data from the United Nations and the World Bank of 173 countries. The team compared the top 10 countries with the highest opportunities for natural selection to the 10 countries with the lowest opportunities for natural selection.

“We looked at countries that offered the greatest opportunity to survive cancer compared with those that didn’t,” said study author Wenpeng You, a PhD student at the University of Adelaide. “This does not only take into account factors such as socioeconomic status, urbanization, and quality of medical services but also low mortality and fertility rates, which are the 2 distinguishing features in the ‘better’ world.”

“Countries with low mortality rates may allow more people with cancer genetic background to reproduce and pass cancer genes/mutations to the next generation. Meanwhile, low fertility rates in these countries may not be able to have diverse biological variations to provide the opportunity for selecting a naturally fit population—for example, people without or with less cancer genetic background. Low mortality rate and low fertility rate in the ‘better’ world may have formed a self-reinforcing cycle which has accumulated cancer genetic background at a greater rate than previously thought.”

Based on the researchers’ analysis, the 20 countries are:

Cancer incidence

The researchers found the rates of most cancers were higher in the 10 countries with the lowest opportunities for natural selection. The incidence of all cancers was 2.326 times higher in the low-opportunity countries than the high-opportunity ones.

The increased incidences of hematologic malignancies were as follows:

• Non-Hodgkin lymphoma—2.019 times higher in the low-opportunity countries
• Hodgkin lymphoma—3.314 times higher in the low-opportunity countries
• Leukemia—3.574 times higher in the low-opportunity countries
• Multiple myeloma—4.257 times higher in the low-opportunity countries .

Dr Henneberg said that, having removed natural selection as the “janitor of the gene pool,” our modern society is faced with a controversial issue.

“It may be that the only way humankind can be rid of cancer once and for all is through genetic engineering—to repair our genes and take cancer out of the equation,” he said.

Photo by Rhoda Baer

The National Comprehensive Cancer Network® (NCCN) has announced the release of the newly completed NCCN Radiation Therapy Compendium™.

This resource includes information designed to support clinical decision-making regarding the use of radiation therapy in cancer patients.

The content is based on the NCCN Clinical Practice Guidelines in Oncology and includes information from the 41 guidelines that reference radiation therapy.

“By compiling every recommendation for radiation therapy in one place, we’ve made it significantly easier for specialists . . .  to stay up-to-date on the very latest recommendations, regardless of how many different cancer types they treat,” said Robert W. Carlson, MD, chief executive officer of NCCN.

“This targeted content provides radiation oncologists with the specific, cutting-edge information they need, without forcing them to sift through any extraneous information. It’s part of our ongoing effort to always provide the most pertinent data on emerging treatment practices in the clearest, most efficient way possible.”

The NCCN Radiation Therapy Compendium includes a full complement of radiation therapy recommendations found in the current NCCN guidelines, including specific treatment modalities such as 2D/3D conformal external beam radiation therapy, intensity modulated radiation therapy, intra-operative radiation therapy, stereotactic radiosurgery/stereotactic body radiotherapy/stereotactic ablative body radiotherapy, image-guided radiation therapy, low dose-rate/high dose-rate brachytherapy, radioisotope, and particle therapy.

NCCN first announced the launch of the Radiation Therapy Compendium in March at the NCCN Annual Conference: Improving the Quality, Effectiveness, and Efficiency of Cancer Care.

At the time, the NCCN released a preliminary version of the compendium featuring 24 cancer types. The newly completed version now contains all 41 disease sites that are currently being treated using radiation therapy.

The compendium will be updated on a continual basis in conjunction with the library of clinical guidelines.

For more information and to access the NCCN Radiation Therapy Compendium, visit NCCN.org/RTCompendium. The compendium is available free-of-charge through March 2018.

Photo by Rhoda Baer

The National Comprehensive Cancer Network® (NCCN) has announced the release of the newly completed NCCN Radiation Therapy Compendium™.

This resource includes information designed to support clinical decision-making regarding the use of radiation therapy in cancer patients.

The content is based on the NCCN Clinical Practice Guidelines in Oncology and includes information from the 41 guidelines that reference radiation therapy.

“By compiling every recommendation for radiation therapy in one place, we’ve made it significantly easier for specialists . . .  to stay up-to-date on the very latest recommendations, regardless of how many different cancer types they treat,” said Robert W. Carlson, MD, chief executive officer of NCCN.

“This targeted content provides radiation oncologists with the specific, cutting-edge information they need, without forcing them to sift through any extraneous information. It’s part of our ongoing effort to always provide the most pertinent data on emerging treatment practices in the clearest, most efficient way possible.”

The NCCN Radiation Therapy Compendium includes a full complement of radiation therapy recommendations found in the current NCCN guidelines, including specific treatment modalities such as 2D/3D conformal external beam radiation therapy, intensity modulated radiation therapy, intra-operative radiation therapy, stereotactic radiosurgery/stereotactic body radiotherapy/stereotactic ablative body radiotherapy, image-guided radiation therapy, low dose-rate/high dose-rate brachytherapy, radioisotope, and particle therapy.

NCCN first announced the launch of the Radiation Therapy Compendium in March at the NCCN Annual Conference: Improving the Quality, Effectiveness, and Efficiency of Cancer Care.

At the time, the NCCN released a preliminary version of the compendium featuring 24 cancer types. The newly completed version now contains all 41 disease sites that are currently being treated using radiation therapy.

The compendium will be updated on a continual basis in conjunction with the library of clinical guidelines.

For more information and to access the NCCN Radiation Therapy Compendium, visit NCCN.org/RTCompendium. The compendium is available free-of-charge through March 2018.

Photo by Rhoda Baer

The National Comprehensive Cancer Network® (NCCN) has announced the release of the newly completed NCCN Radiation Therapy Compendium™.

This resource includes information designed to support clinical decision-making regarding the use of radiation therapy in cancer patients.

The content is based on the NCCN Clinical Practice Guidelines in Oncology and includes information from the 41 guidelines that reference radiation therapy.

“By compiling every recommendation for radiation therapy in one place, we’ve made it significantly easier for specialists . . .  to stay up-to-date on the very latest recommendations, regardless of how many different cancer types they treat,” said Robert W. Carlson, MD, chief executive officer of NCCN.

“This targeted content provides radiation oncologists with the specific, cutting-edge information they need, without forcing them to sift through any extraneous information. It’s part of our ongoing effort to always provide the most pertinent data on emerging treatment practices in the clearest, most efficient way possible.”

The NCCN Radiation Therapy Compendium includes a full complement of radiation therapy recommendations found in the current NCCN guidelines, including specific treatment modalities such as 2D/3D conformal external beam radiation therapy, intensity modulated radiation therapy, intra-operative radiation therapy, stereotactic radiosurgery/stereotactic body radiotherapy/stereotactic ablative body radiotherapy, image-guided radiation therapy, low dose-rate/high dose-rate brachytherapy, radioisotope, and particle therapy.

NCCN first announced the launch of the Radiation Therapy Compendium in March at the NCCN Annual Conference: Improving the Quality, Effectiveness, and Efficiency of Cancer Care.

At the time, the NCCN released a preliminary version of the compendium featuring 24 cancer types. The newly completed version now contains all 41 disease sites that are currently being treated using radiation therapy.

The compendium will be updated on a continual basis in conjunction with the library of clinical guidelines.

For more information and to access the NCCN Radiation Therapy Compendium, visit NCCN.org/RTCompendium. The compendium is available free-of-charge through March 2018.

Fred Hutch News Service

Researchers say they have identified potential biomarkers that may be used to help identify patients at an increased risk of neurotoxicity after chimeric antigen receptor (CAR) T-cell therapy.

The team also created an algorithm intended to identify patients whose symptoms were most likely to be life-threatening.

The researchers discovered the biomarkers and developed the algorithm based on data from a trial of JCAR014, an anti-CD19 CAR T-cell therapy, in patients with B-cell malignancies.

Cameron J. Turtle, MBBS, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues described this research in Cancer Discovery.

“It’s essential that we understand the potential side effects of CAR T therapies” Dr Turtle said. “While use of these cell therapies is likely to dramatically increase because they’ve been so effective in patients with resistant or refractory B-cell malignancies, there is still much to learn.”

Dr Turtle and his colleagues sought to provide a detailed clinical, radiological, and pathological characterization of neurotoxicity arising from anti-CD19 CAR T-cell therapy.

So the team analyzed data from a phase 1/2 trial of 133 adults with relapsed and/or refractory CD19+ B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma, or chronic lymphocytic leukemia.

The patients received lymphodepleting chemotherapy followed by an infusion of JCAR014.

Neurotoxicity

Within 28 days of treatment, 53 patients (40%) developed grade 1 or higher neurologic adverse events (AEs), 28 patients (21%) had grade 3 or higher neurotoxicity, and 4 patients (3%) developed fatal neurotoxicity.

Of the 53 patients with any neurologic AE, 48 (91%) also had cytokine release syndrome (CRS). All neurologic AEs in the 5 patients who did not have CRS were mild (grade 1) and transient.

Neurologic AEs included delirium with preserved alertness (66%), headache (55%), language disturbance (34%), decreased level of consciousness (25%), seizures (8%), and macroscopic intracranial hemorrhage (2%).

For most patients, neurotoxicity resolved by day 28 after CAR T-cell infusion. The exceptions were 1 patient in whom a grade 1 neurologic AE resolved 2 months after CAR T-cell infusion and the 4 patients who died of neurotoxicity.

The 4 neurotoxicity-related deaths were due to:

• Acute cerebral edema (n=2)
• Multifocal brainstem hemorrhage and edema associated with disseminated intravascular coagulation (n=1)
• Cortical laminar necrosis with a persistent minimally conscious state until death (n=1).

Potential biomarkers

In a univariate analysis, neurotoxicity was significantly more frequent in patients who:

• Had CRS (P<0.0001)
• Received a high CAR T-cell dose (P<0.0001)
• Had pre-existing neurologic comorbidities at baseline (P=0.0059).

In a multivariable analysis (which did not include CRS as a variable), patients had an increased risk of neurotoxicity if they:

• Had pre-existing neurologic comorbidities (P=0.0023)
• Received cyclophosphamide and fludarabine lymphodepletion (P=0.0259)
• Received a higher CAR T-cell dose (P=0.0009)
• Had a higher burden of malignant CD19+ B cells in the bone marrow (P=0.0165).

The researchers noted that patients who developed grade 3 or higher neurotoxicity had more severe CRS (P<0.0001).

“It appears that cytokine release syndrome is probably necessary for most cases of severe neurotoxicity, but, in terms of what triggers a person with cytokine release syndrome to get neurotoxicity, that’s something we need to investigate further,” said study author Kevin Hay, MD, of Fred Hutchinson Cancer Research Center.

Dr Hay and his colleagues also found that patients with severe neurotoxicity exhibited evidence of endothelial activation, which could contribute to manifestations such as capillary leak, disseminated intravascular coagulation, and disruption of the blood-brain barrier.

Algorithm

The researchers developed a predictive classification tree algorithm to identify patients who have an increased risk of severe neurotoxicity.

The algorithm suggests patients who meet the following criteria in the first 36 hours after CAR T-cell infusion have a high risk of grade 4-5 neurotoxicity:

• Fever of 38.9°C or greater
• Serum levels of IL6 at 16 pg/mL or higher
• Serum levels of MCP1 at 1343.5 pg/mL or higher.

This algorithm predicted severe neurotoxicity with 100% sensitivity and 94% specificity. Eight patients were misclassified, 1 of whom did not subsequently develop grade 2-3 neurotoxicity and/or grade 2 or higher CRS.

Funding

This research was funded by Juno Therapeutics Inc. (the company developing JCAR014), the National Cancer Institute, Life Science Discovery Fund, the Bezos family, the University of British Columbia Clinical Investigator Program, and via institutional funds from Bloodworks Northwest.

Dr Turtle receives research funding from Juno Therapeutics, holds patents licensed by Juno, and has pending patent applications that could be licensed by nonprofit institutions and for-profit companies, including Juno.

The Fred Hutchinson Cancer Research Center has a financial interest in Juno and receives licensing and other payments from the company.

Fred Hutch News Service

Researchers say they have identified potential biomarkers that may be used to help identify patients at an increased risk of neurotoxicity after chimeric antigen receptor (CAR) T-cell therapy.

The team also created an algorithm intended to identify patients whose symptoms were most likely to be life-threatening.

The researchers discovered the biomarkers and developed the algorithm based on data from a trial of JCAR014, an anti-CD19 CAR T-cell therapy, in patients with B-cell malignancies.

Cameron J. Turtle, MBBS, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues described this research in Cancer Discovery.

“It’s essential that we understand the potential side effects of CAR T therapies” Dr Turtle said. “While use of these cell therapies is likely to dramatically increase because they’ve been so effective in patients with resistant or refractory B-cell malignancies, there is still much to learn.”

Dr Turtle and his colleagues sought to provide a detailed clinical, radiological, and pathological characterization of neurotoxicity arising from anti-CD19 CAR T-cell therapy.

So the team analyzed data from a phase 1/2 trial of 133 adults with relapsed and/or refractory CD19+ B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma, or chronic lymphocytic leukemia.

The patients received lymphodepleting chemotherapy followed by an infusion of JCAR014.

Neurotoxicity

Within 28 days of treatment, 53 patients (40%) developed grade 1 or higher neurologic adverse events (AEs), 28 patients (21%) had grade 3 or higher neurotoxicity, and 4 patients (3%) developed fatal neurotoxicity.

Of the 53 patients with any neurologic AE, 48 (91%) also had cytokine release syndrome (CRS). All neurologic AEs in the 5 patients who did not have CRS were mild (grade 1) and transient.

Neurologic AEs included delirium with preserved alertness (66%), headache (55%), language disturbance (34%), decreased level of consciousness (25%), seizures (8%), and macroscopic intracranial hemorrhage (2%).

For most patients, neurotoxicity resolved by day 28 after CAR T-cell infusion. The exceptions were 1 patient in whom a grade 1 neurologic AE resolved 2 months after CAR T-cell infusion and the 4 patients who died of neurotoxicity.

The 4 neurotoxicity-related deaths were due to:

• Acute cerebral edema (n=2)
• Multifocal brainstem hemorrhage and edema associated with disseminated intravascular coagulation (n=1)
• Cortical laminar necrosis with a persistent minimally conscious state until death (n=1).

Potential biomarkers

In a univariate analysis, neurotoxicity was significantly more frequent in patients who:

• Had CRS (P<0.0001)
• Received a high CAR T-cell dose (P<0.0001)
• Had pre-existing neurologic comorbidities at baseline (P=0.0059).

In a multivariable analysis (which did not include CRS as a variable), patients had an increased risk of neurotoxicity if they:

• Had pre-existing neurologic comorbidities (P=0.0023)
• Received cyclophosphamide and fludarabine lymphodepletion (P=0.0259)
• Received a higher CAR T-cell dose (P=0.0009)
• Had a higher burden of malignant CD19+ B cells in the bone marrow (P=0.0165).

The researchers noted that patients who developed grade 3 or higher neurotoxicity had more severe CRS (P<0.0001).

“It appears that cytokine release syndrome is probably necessary for most cases of severe neurotoxicity, but, in terms of what triggers a person with cytokine release syndrome to get neurotoxicity, that’s something we need to investigate further,” said study author Kevin Hay, MD, of Fred Hutchinson Cancer Research Center.

Dr Hay and his colleagues also found that patients with severe neurotoxicity exhibited evidence of endothelial activation, which could contribute to manifestations such as capillary leak, disseminated intravascular coagulation, and disruption of the blood-brain barrier.

Algorithm

The researchers developed a predictive classification tree algorithm to identify patients who have an increased risk of severe neurotoxicity.

The algorithm suggests patients who meet the following criteria in the first 36 hours after CAR T-cell infusion have a high risk of grade 4-5 neurotoxicity:

• Fever of 38.9°C or greater
• Serum levels of IL6 at 16 pg/mL or higher
• Serum levels of MCP1 at 1343.5 pg/mL or higher.

This algorithm predicted severe neurotoxicity with 100% sensitivity and 94% specificity. Eight patients were misclassified, 1 of whom did not subsequently develop grade 2-3 neurotoxicity and/or grade 2 or higher CRS.

Funding

This research was funded by Juno Therapeutics Inc. (the company developing JCAR014), the National Cancer Institute, Life Science Discovery Fund, the Bezos family, the University of British Columbia Clinical Investigator Program, and via institutional funds from Bloodworks Northwest.

Dr Turtle receives research funding from Juno Therapeutics, holds patents licensed by Juno, and has pending patent applications that could be licensed by nonprofit institutions and for-profit companies, including Juno.

The Fred Hutchinson Cancer Research Center has a financial interest in Juno and receives licensing and other payments from the company.

Fred Hutch News Service

Researchers say they have identified potential biomarkers that may be used to help identify patients at an increased risk of neurotoxicity after chimeric antigen receptor (CAR) T-cell therapy.

The team also created an algorithm intended to identify patients whose symptoms were most likely to be life-threatening.

The researchers discovered the biomarkers and developed the algorithm based on data from a trial of JCAR014, an anti-CD19 CAR T-cell therapy, in patients with B-cell malignancies.

Cameron J. Turtle, MBBS, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues described this research in Cancer Discovery.

“It’s essential that we understand the potential side effects of CAR T therapies” Dr Turtle said. “While use of these cell therapies is likely to dramatically increase because they’ve been so effective in patients with resistant or refractory B-cell malignancies, there is still much to learn.”

Dr Turtle and his colleagues sought to provide a detailed clinical, radiological, and pathological characterization of neurotoxicity arising from anti-CD19 CAR T-cell therapy.

So the team analyzed data from a phase 1/2 trial of 133 adults with relapsed and/or refractory CD19+ B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma, or chronic lymphocytic leukemia.

The patients received lymphodepleting chemotherapy followed by an infusion of JCAR014.

Neurotoxicity

Within 28 days of treatment, 53 patients (40%) developed grade 1 or higher neurologic adverse events (AEs), 28 patients (21%) had grade 3 or higher neurotoxicity, and 4 patients (3%) developed fatal neurotoxicity.

Of the 53 patients with any neurologic AE, 48 (91%) also had cytokine release syndrome (CRS). All neurologic AEs in the 5 patients who did not have CRS were mild (grade 1) and transient.

Neurologic AEs included delirium with preserved alertness (66%), headache (55%), language disturbance (34%), decreased level of consciousness (25%), seizures (8%), and macroscopic intracranial hemorrhage (2%).

For most patients, neurotoxicity resolved by day 28 after CAR T-cell infusion. The exceptions were 1 patient in whom a grade 1 neurologic AE resolved 2 months after CAR T-cell infusion and the 4 patients who died of neurotoxicity.

The 4 neurotoxicity-related deaths were due to:

• Acute cerebral edema (n=2)
• Multifocal brainstem hemorrhage and edema associated with disseminated intravascular coagulation (n=1)
• Cortical laminar necrosis with a persistent minimally conscious state until death (n=1).

Potential biomarkers

In a univariate analysis, neurotoxicity was significantly more frequent in patients who:

• Had CRS (P<0.0001)
• Received a high CAR T-cell dose (P<0.0001)
• Had pre-existing neurologic comorbidities at baseline (P=0.0059).

In a multivariable analysis (which did not include CRS as a variable), patients had an increased risk of neurotoxicity if they:

• Had pre-existing neurologic comorbidities (P=0.0023)
• Received cyclophosphamide and fludarabine lymphodepletion (P=0.0259)
• Received a higher CAR T-cell dose (P=0.0009)
• Had a higher burden of malignant CD19+ B cells in the bone marrow (P=0.0165).

The researchers noted that patients who developed grade 3 or higher neurotoxicity had more severe CRS (P<0.0001).

“It appears that cytokine release syndrome is probably necessary for most cases of severe neurotoxicity, but, in terms of what triggers a person with cytokine release syndrome to get neurotoxicity, that’s something we need to investigate further,” said study author Kevin Hay, MD, of Fred Hutchinson Cancer Research Center.

Dr Hay and his colleagues also found that patients with severe neurotoxicity exhibited evidence of endothelial activation, which could contribute to manifestations such as capillary leak, disseminated intravascular coagulation, and disruption of the blood-brain barrier.

Algorithm

The researchers developed a predictive classification tree algorithm to identify patients who have an increased risk of severe neurotoxicity.

The algorithm suggests patients who meet the following criteria in the first 36 hours after CAR T-cell infusion have a high risk of grade 4-5 neurotoxicity:

• Fever of 38.9°C or greater
• Serum levels of IL6 at 16 pg/mL or higher
• Serum levels of MCP1 at 1343.5 pg/mL or higher.

This algorithm predicted severe neurotoxicity with 100% sensitivity and 94% specificity. Eight patients were misclassified, 1 of whom did not subsequently develop grade 2-3 neurotoxicity and/or grade 2 or higher CRS.

Funding

This research was funded by Juno Therapeutics Inc. (the company developing JCAR014), the National Cancer Institute, Life Science Discovery Fund, the Bezos family, the University of British Columbia Clinical Investigator Program, and via institutional funds from Bloodworks Northwest.

Dr Turtle receives research funding from Juno Therapeutics, holds patents licensed by Juno, and has pending patent applications that could be licensed by nonprofit institutions and for-profit companies, including Juno.

The Fred Hutchinson Cancer Research Center has a financial interest in Juno and receives licensing and other payments from the company.

Image by Joshua Stokes

Researchers have reported successful inhibition of the phosphatase SHIP1, which may be an effective approach for treating T-cell lymphoma.

The team found that intermittent treatment with a SHIP1 inhibitor prevented the immune exhaustion observed with SHIP1 deletion.

Intermittent SHIP1 inhibition enhanced the antitumor activity of natural killer (NK) cells and T cells in a mouse model of T-cell lymphoma.

The treatment also appeared to have a direct chemotherapeutic effect and induced immunological memory against lymphoma cells.

Matthew Gumbleton, MD, of SUNY Upstate Medical University in Syracuse, New York, and his colleagues reported these results in Science Signaling.

The researchers noted that previous efforts to inhibit SHIP1 have yielded disappointing results. Mice engineered to lack the SHIP1 gene had poorly responsive immune systems, potentially because overactivated cells became exhausted.

Dr Gumbleton and his colleagues found they could overcome this problem by administering a SHIP1 inhibitor—3-a-aminocholestane (3AC)—in a pulsed regimen of 2 consecutive treatment days per week.

The team tested this regimen in mouse models of colorectal cancer and T-cell lymphoma (RMA-Rae1).

In the lymphoma model, intermittent 3AC treatment increased the responsiveness of T cells and NK cells.

The treatment significantly increased the number of NK cells at the tumor site and the terminal maturation of the peripheral NK-cell compartment.

3AC also enhanced FasL-Fas–mediated killing of lymphoma cells. (NK cells induce apoptosis of target cells via Fas-FasL signaling.)

However, 3AC treatment reduced lymphoma burden in NK-cell-deficient mice as well. Therefore, the researchers believe 3AC may have a direct chemotherapeutic effect.

The team also found that intermittent 3AC treatment increased survival in lymphoma-bearing mice.

Treated mice had significantly longer survival than control mice. And some of the treated mice had long-term survival with no evidence of tumor burden, which suggests the treatment could be curative.

Additional experiments revealed that both NK cells and T cells were required to induce long-term survival in the lymphoma-bearing mice.

Finally, the researchers found evidence to suggest that 3AC treatment triggered “immunological memory capable of sustained and protective antitumor response that prevents relapse.”

The team infused hematolymphoid cells from either a naïve donor mouse or a lymphoma-challenged, 3AC-treated, long-term-surviving donor mouse into naïve host mice. The host mice were then challenged with RMA-Rae1 cells but didn’t receive 3AC.

Mice that received cells from the 3AC-treated donors had significantly better survival than mice that received cells from naive donors.

Based on these results, the researchers concluded that intermittent SHIP1 inhibition may be effective for treating and preventing relapse of T-cell lymphoma and other cancers.

Image by Joshua Stokes

Researchers have reported successful inhibition of the phosphatase SHIP1, which may be an effective approach for treating T-cell lymphoma.

The team found that intermittent treatment with a SHIP1 inhibitor prevented the immune exhaustion observed with SHIP1 deletion.

Intermittent SHIP1 inhibition enhanced the antitumor activity of natural killer (NK) cells and T cells in a mouse model of T-cell lymphoma.

The treatment also appeared to have a direct chemotherapeutic effect and induced immunological memory against lymphoma cells.

Matthew Gumbleton, MD, of SUNY Upstate Medical University in Syracuse, New York, and his colleagues reported these results in Science Signaling.

The researchers noted that previous efforts to inhibit SHIP1 have yielded disappointing results. Mice engineered to lack the SHIP1 gene had poorly responsive immune systems, potentially because overactivated cells became exhausted.

Dr Gumbleton and his colleagues found they could overcome this problem by administering a SHIP1 inhibitor—3-a-aminocholestane (3AC)—in a pulsed regimen of 2 consecutive treatment days per week.

The team tested this regimen in mouse models of colorectal cancer and T-cell lymphoma (RMA-Rae1).

In the lymphoma model, intermittent 3AC treatment increased the responsiveness of T cells and NK cells.

The treatment significantly increased the number of NK cells at the tumor site and the terminal maturation of the peripheral NK-cell compartment.

3AC also enhanced FasL-Fas–mediated killing of lymphoma cells. (NK cells induce apoptosis of target cells via Fas-FasL signaling.)

However, 3AC treatment reduced lymphoma burden in NK-cell-deficient mice as well. Therefore, the researchers believe 3AC may have a direct chemotherapeutic effect.

The team also found that intermittent 3AC treatment increased survival in lymphoma-bearing mice.

Treated mice had significantly longer survival than control mice. And some of the treated mice had long-term survival with no evidence of tumor burden, which suggests the treatment could be curative.

Additional experiments revealed that both NK cells and T cells were required to induce long-term survival in the lymphoma-bearing mice.

Finally, the researchers found evidence to suggest that 3AC treatment triggered “immunological memory capable of sustained and protective antitumor response that prevents relapse.”

The team infused hematolymphoid cells from either a naïve donor mouse or a lymphoma-challenged, 3AC-treated, long-term-surviving donor mouse into naïve host mice. The host mice were then challenged with RMA-Rae1 cells but didn’t receive 3AC.

Mice that received cells from the 3AC-treated donors had significantly better survival than mice that received cells from naive donors.

Based on these results, the researchers concluded that intermittent SHIP1 inhibition may be effective for treating and preventing relapse of T-cell lymphoma and other cancers.

Image by Joshua Stokes

Researchers have reported successful inhibition of the phosphatase SHIP1, which may be an effective approach for treating T-cell lymphoma.

The team found that intermittent treatment with a SHIP1 inhibitor prevented the immune exhaustion observed with SHIP1 deletion.

Intermittent SHIP1 inhibition enhanced the antitumor activity of natural killer (NK) cells and T cells in a mouse model of T-cell lymphoma.

The treatment also appeared to have a direct chemotherapeutic effect and induced immunological memory against lymphoma cells.

Matthew Gumbleton, MD, of SUNY Upstate Medical University in Syracuse, New York, and his colleagues reported these results in Science Signaling.

The researchers noted that previous efforts to inhibit SHIP1 have yielded disappointing results. Mice engineered to lack the SHIP1 gene had poorly responsive immune systems, potentially because overactivated cells became exhausted.

Dr Gumbleton and his colleagues found they could overcome this problem by administering a SHIP1 inhibitor—3-a-aminocholestane (3AC)—in a pulsed regimen of 2 consecutive treatment days per week.

The team tested this regimen in mouse models of colorectal cancer and T-cell lymphoma (RMA-Rae1).

In the lymphoma model, intermittent 3AC treatment increased the responsiveness of T cells and NK cells.

The treatment significantly increased the number of NK cells at the tumor site and the terminal maturation of the peripheral NK-cell compartment.

3AC also enhanced FasL-Fas–mediated killing of lymphoma cells. (NK cells induce apoptosis of target cells via Fas-FasL signaling.)

However, 3AC treatment reduced lymphoma burden in NK-cell-deficient mice as well. Therefore, the researchers believe 3AC may have a direct chemotherapeutic effect.

The team also found that intermittent 3AC treatment increased survival in lymphoma-bearing mice.

Treated mice had significantly longer survival than control mice. And some of the treated mice had long-term survival with no evidence of tumor burden, which suggests the treatment could be curative.

Additional experiments revealed that both NK cells and T cells were required to induce long-term survival in the lymphoma-bearing mice.

Finally, the researchers found evidence to suggest that 3AC treatment triggered “immunological memory capable of sustained and protective antitumor response that prevents relapse.”

The team infused hematolymphoid cells from either a naïve donor mouse or a lymphoma-challenged, 3AC-treated, long-term-surviving donor mouse into naïve host mice. The host mice were then challenged with RMA-Rae1 cells but didn’t receive 3AC.

Mice that received cells from the 3AC-treated donors had significantly better survival than mice that received cells from naive donors.

Based on these results, the researchers concluded that intermittent SHIP1 inhibition may be effective for treating and preventing relapse of T-cell lymphoma and other cancers.

Photo by Rhoda Baer

The US Food and Drug Administration (FDA) has issued a complete response letter saying the agency cannot approve MYL-1401H, a proposed biosimilar of pegfilgrastim (Neulasta).

Biocon and Mylan are seeking approval of MYL-1401H to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults receiving chemotherapy to treat non-myeloid malignancies.

Biocon and Mylan filed the biologics license application for MYL-1401H in February.

The FDA had planned to issue a decision on the application by October 9.

Biocon and Mylan said the FDA’s complete response letter relates to a pending update to the application. The update involves chemistry manufacturing and control data from facility requalification activities after recent plant modifications.

The complete response letter did not raise any questions on the biosimilarity of MYL-1401H, pharmacokinetic/pharmacodynamic data, clinical data, or immunogenicity. (Results of a phase 3 study presented at ESMO 2016 Congress suggested MYL-1401H is equivalent to Neulasta.)

Biocon and Mylan said they do not expect the complete response letter for MYL-1401H to impact the commercial launch timing of the drug in the US. The companies said they are committed to working with the FDA to resolve the issues outlined in the letter.

Photo by Rhoda Baer

The US Food and Drug Administration (FDA) has issued a complete response letter saying the agency cannot approve MYL-1401H, a proposed biosimilar of pegfilgrastim (Neulasta).

Biocon and Mylan are seeking approval of MYL-1401H to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults receiving chemotherapy to treat non-myeloid malignancies.

Biocon and Mylan filed the biologics license application for MYL-1401H in February.

The FDA had planned to issue a decision on the application by October 9.

Biocon and Mylan said the FDA’s complete response letter relates to a pending update to the application. The update involves chemistry manufacturing and control data from facility requalification activities after recent plant modifications.

The complete response letter did not raise any questions on the biosimilarity of MYL-1401H, pharmacokinetic/pharmacodynamic data, clinical data, or immunogenicity. (Results of a phase 3 study presented at ESMO 2016 Congress suggested MYL-1401H is equivalent to Neulasta.)

Biocon and Mylan said they do not expect the complete response letter for MYL-1401H to impact the commercial launch timing of the drug in the US. The companies said they are committed to working with the FDA to resolve the issues outlined in the letter.

Photo by Rhoda Baer

The US Food and Drug Administration (FDA) has issued a complete response letter saying the agency cannot approve MYL-1401H, a proposed biosimilar of pegfilgrastim (Neulasta).

Biocon and Mylan are seeking approval of MYL-1401H to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults receiving chemotherapy to treat non-myeloid malignancies.

Biocon and Mylan filed the biologics license application for MYL-1401H in February.

The FDA had planned to issue a decision on the application by October 9.

Biocon and Mylan said the FDA’s complete response letter relates to a pending update to the application. The update involves chemistry manufacturing and control data from facility requalification activities after recent plant modifications.

The complete response letter did not raise any questions on the biosimilarity of MYL-1401H, pharmacokinetic/pharmacodynamic data, clinical data, or immunogenicity. (Results of a phase 3 study presented at ESMO 2016 Congress suggested MYL-1401H is equivalent to Neulasta.)

Biocon and Mylan said they do not expect the complete response letter for MYL-1401H to impact the commercial launch timing of the drug in the US. The companies said they are committed to working with the FDA to resolve the issues outlined in the letter.

Photo by Larry Young

Research published in Cell has revealed 150 genetic drivers of diffuse large B-cell lymphoma (DLBCL).

Among these drivers are 27 genes newly implicated in DLBCL, 35 functional oncogenes, and 9 genes that can be targeted with existing drugs.

Researchers used these findings to create a prognostic model that, they say, outperformed existing risk predictors in DLBCL.

“This work provides a comprehensive road map in terms of research and clinical priorities,” said study author Sandeep Dave, MD, of Duke University in Durham, North Carolina.

“We have very good data now to pursue new and existing therapies that might target the genetic mutations we identified. Additionally, this data could also be used to develop genetic markers that steer patients to therapies that would be most effective.”

Dr Dave and his colleagues began this research by analyzing tumor samples from 1001 patients who had been diagnosed with DLBCL over the past decade and were treated at 12 institutions around the world. There were 313 patients with ABC DLBCL, 331 with GCB DLBCL, and the rest were unclassified DLBCLs.

Using whole-exome sequencing, the researchers pinpointed 150 driver genes that were recurrently mutated in the DLBCL patients. This included 27 genes that, the researchers believe, had never before been implicated in DLBCL.

The team also found that ABC and GCB DLBCLs “shared the vast majority of driver genes at statistically indistinguishable frequencies.”

However, there were 20 genes that were differentially mutated between the 2 groups. For instance, EZH2, SGK1, GNA13, SOCS1, STAT6, and TNFRSF14 were more frequently mutated in GCB DLBCLs. And ETV6, MYD88, PIM1, and TBL1XR1 were more frequently mutated in ABC DLBCLs.

Essential genes

To identify genes essential to the development and maintenance of DLBCL, the researchers used CRISPR. The team knocked out genes in 6 cell lines—3 ABC DLBCLs (LY3, TMD8, and HBL1), 2 GCB DLBCLs (SUDHL4 and Pfeiffer), and 1 Burkitt lymphoma (BJAB) that phenotypically resembles GCB DLBCL.

This revealed 1956 essential genes. Knocking out these genes resulted in a significant decrease in cell fitness in at least 1 cell line.

The work also revealed 35 driver genes that, when knocked out, resulted in decreased viability of DLBCL cells, which classified them as functional oncogenes.

The researchers found that knockout of EBF1, IRF4, CARD11, MYD88, and IKBKB was selectively lethal in ABC DLBCL. And knockout of ZBTB7A, XPO1, TGFBR2, and PTPN6 was selectively lethal in GCB DLBCL.

In addition, the team noted that 9 of the driver genes are direct targets of drugs that are already approved or under investigation in clinical trials—MTOR, BCL2, SF3B1, SYK, PIM2, PIK3R1, XPO1, MCL1, and BTK.

Patient outcomes

The researchers also looked at the driver genes in the context of patient outcomes. The team found that mutations in MYC, CD79B, and ZFAT were strongly associated with poorer survival, while mutations in NF1 and SGK1 were associated with more favorable survival.

Mutations in KLHL14, BTG1, PAX5, and CDKN2A were associated with significantly poorer survival in ABC DLBCL, while mutations in CREBBP were associated with favorable survival in ABC DLBCL.

In GCB DLBCL, mutations in NFKBIA and NCOR1 were associated with poorer prognosis, while mutations in EZH2, MYD88, and ARID5B were associated with better prognosis.

Finally, the researchers developed a prognostic model based on combinations of genetic markers (the 150 driver genes) and gene expression markers (cell of origin, MYC, and BCL2).

The team found their prognostic model could predict survival more effectively than the International Prognostic Index, cell of origin alone, and MYC and BCL2 expression alone or together.

Photo by Larry Young

Research published in Cell has revealed 150 genetic drivers of diffuse large B-cell lymphoma (DLBCL).

Among these drivers are 27 genes newly implicated in DLBCL, 35 functional oncogenes, and 9 genes that can be targeted with existing drugs.

Researchers used these findings to create a prognostic model that, they say, outperformed existing risk predictors in DLBCL.

“This work provides a comprehensive road map in terms of research and clinical priorities,” said study author Sandeep Dave, MD, of Duke University in Durham, North Carolina.

“We have very good data now to pursue new and existing therapies that might target the genetic mutations we identified. Additionally, this data could also be used to develop genetic markers that steer patients to therapies that would be most effective.”

Dr Dave and his colleagues began this research by analyzing tumor samples from 1001 patients who had been diagnosed with DLBCL over the past decade and were treated at 12 institutions around the world. There were 313 patients with ABC DLBCL, 331 with GCB DLBCL, and the rest were unclassified DLBCLs.

Using whole-exome sequencing, the researchers pinpointed 150 driver genes that were recurrently mutated in the DLBCL patients. This included 27 genes that, the researchers believe, had never before been implicated in DLBCL.

The team also found that ABC and GCB DLBCLs “shared the vast majority of driver genes at statistically indistinguishable frequencies.”

However, there were 20 genes that were differentially mutated between the 2 groups. For instance, EZH2, SGK1, GNA13, SOCS1, STAT6, and TNFRSF14 were more frequently mutated in GCB DLBCLs. And ETV6, MYD88, PIM1, and TBL1XR1 were more frequently mutated in ABC DLBCLs.

Essential genes

To identify genes essential to the development and maintenance of DLBCL, the researchers used CRISPR. The team knocked out genes in 6 cell lines—3 ABC DLBCLs (LY3, TMD8, and HBL1), 2 GCB DLBCLs (SUDHL4 and Pfeiffer), and 1 Burkitt lymphoma (BJAB) that phenotypically resembles GCB DLBCL.

This revealed 1956 essential genes. Knocking out these genes resulted in a significant decrease in cell fitness in at least 1 cell line.

The work also revealed 35 driver genes that, when knocked out, resulted in decreased viability of DLBCL cells, which classified them as functional oncogenes.

The researchers found that knockout of EBF1, IRF4, CARD11, MYD88, and IKBKB was selectively lethal in ABC DLBCL. And knockout of ZBTB7A, XPO1, TGFBR2, and PTPN6 was selectively lethal in GCB DLBCL.

In addition, the team noted that 9 of the driver genes are direct targets of drugs that are already approved or under investigation in clinical trials—MTOR, BCL2, SF3B1, SYK, PIM2, PIK3R1, XPO1, MCL1, and BTK.

Patient outcomes

The researchers also looked at the driver genes in the context of patient outcomes. The team found that mutations in MYC, CD79B, and ZFAT were strongly associated with poorer survival, while mutations in NF1 and SGK1 were associated with more favorable survival.

Mutations in KLHL14, BTG1, PAX5, and CDKN2A were associated with significantly poorer survival in ABC DLBCL, while mutations in CREBBP were associated with favorable survival in ABC DLBCL.

In GCB DLBCL, mutations in NFKBIA and NCOR1 were associated with poorer prognosis, while mutations in EZH2, MYD88, and ARID5B were associated with better prognosis.

Finally, the researchers developed a prognostic model based on combinations of genetic markers (the 150 driver genes) and gene expression markers (cell of origin, MYC, and BCL2).

The team found their prognostic model could predict survival more effectively than the International Prognostic Index, cell of origin alone, and MYC and BCL2 expression alone or together.

Photo by Larry Young

Research published in Cell has revealed 150 genetic drivers of diffuse large B-cell lymphoma (DLBCL).

Among these drivers are 27 genes newly implicated in DLBCL, 35 functional oncogenes, and 9 genes that can be targeted with existing drugs.

Researchers used these findings to create a prognostic model that, they say, outperformed existing risk predictors in DLBCL.

“This work provides a comprehensive road map in terms of research and clinical priorities,” said study author Sandeep Dave, MD, of Duke University in Durham, North Carolina.

“We have very good data now to pursue new and existing therapies that might target the genetic mutations we identified. Additionally, this data could also be used to develop genetic markers that steer patients to therapies that would be most effective.”

Dr Dave and his colleagues began this research by analyzing tumor samples from 1001 patients who had been diagnosed with DLBCL over the past decade and were treated at 12 institutions around the world. There were 313 patients with ABC DLBCL, 331 with GCB DLBCL, and the rest were unclassified DLBCLs.

Using whole-exome sequencing, the researchers pinpointed 150 driver genes that were recurrently mutated in the DLBCL patients. This included 27 genes that, the researchers believe, had never before been implicated in DLBCL.

The team also found that ABC and GCB DLBCLs “shared the vast majority of driver genes at statistically indistinguishable frequencies.”

However, there were 20 genes that were differentially mutated between the 2 groups. For instance, EZH2, SGK1, GNA13, SOCS1, STAT6, and TNFRSF14 were more frequently mutated in GCB DLBCLs. And ETV6, MYD88, PIM1, and TBL1XR1 were more frequently mutated in ABC DLBCLs.

Essential genes

To identify genes essential to the development and maintenance of DLBCL, the researchers used CRISPR. The team knocked out genes in 6 cell lines—3 ABC DLBCLs (LY3, TMD8, and HBL1), 2 GCB DLBCLs (SUDHL4 and Pfeiffer), and 1 Burkitt lymphoma (BJAB) that phenotypically resembles GCB DLBCL.

This revealed 1956 essential genes. Knocking out these genes resulted in a significant decrease in cell fitness in at least 1 cell line.

The work also revealed 35 driver genes that, when knocked out, resulted in decreased viability of DLBCL cells, which classified them as functional oncogenes.

The researchers found that knockout of EBF1, IRF4, CARD11, MYD88, and IKBKB was selectively lethal in ABC DLBCL. And knockout of ZBTB7A, XPO1, TGFBR2, and PTPN6 was selectively lethal in GCB DLBCL.

In addition, the team noted that 9 of the driver genes are direct targets of drugs that are already approved or under investigation in clinical trials—MTOR, BCL2, SF3B1, SYK, PIM2, PIK3R1, XPO1, MCL1, and BTK.

Patient outcomes

The researchers also looked at the driver genes in the context of patient outcomes. The team found that mutations in MYC, CD79B, and ZFAT were strongly associated with poorer survival, while mutations in NF1 and SGK1 were associated with more favorable survival.

Mutations in KLHL14, BTG1, PAX5, and CDKN2A were associated with significantly poorer survival in ABC DLBCL, while mutations in CREBBP were associated with favorable survival in ABC DLBCL.

In GCB DLBCL, mutations in NFKBIA and NCOR1 were associated with poorer prognosis, while mutations in EZH2, MYD88, and ARID5B were associated with better prognosis.

Finally, the researchers developed a prognostic model based on combinations of genetic markers (the 150 driver genes) and gene expression markers (cell of origin, MYC, and BCL2).

The team found their prognostic model could predict survival more effectively than the International Prognostic Index, cell of origin alone, and MYC and BCL2 expression alone or together.