Aggressive Lymphomas

follicular lymphoma

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products has recommended orphan designation for G100 for the treatment of follicular lymphoma (FL).

G100 contains the synthetic small molecule toll-like receptor-4 agonist glucopyranosyl lipid A.

G100 works by activating innate and adaptive immunity in the tumor microenvironment to generate an immune response against the tumor’s pre-existing antigens.

Clinical and preclinical data have demonstrated G100’s ability to activate tumor-infiltrating lymphocytes, macrophages, and dendritic cells, and promote antigen-presentation and the recruitment of T cells to the tumor.

The induction of local and systemic immune responses has been shown in preclinical studies to result in local and abscopal tumor control.

Immune Design, the company developing G100, is currently evaluating G100 plus local radiation, with or without pembrolizumab, in a phase 1/2 trial of FL patients.

Results from this trial were presented at the 2017 ASCO Annual Meeting (abstract 7537). Nine patients who received G100 (3 patients each at the 5, 10, or 20 μg dose) with radiation (but not pembrolizumab) were evaluable for safety and efficacy.

The overall response rate was 44%, and all of these were partial responses (n=4). Thirty-three percent of patients had stable disease (n=3).

Among the responders, tumor regression ranged from 58% to 89%, which included up to 56% shrinkage of abscopal sites. Tumor biopsies showed increased inflammatory responses and T-cell infiltrates in abscopal tumors.

An additional 13 patients treated at the 10 μg dose were evaluable for safety.  There were no dose-limiting toxicities, serious adverse events (AEs), or grade 3/4 AEs observed.

Common AEs included injection site disorders, abdominal pain/discomfort, nausea, pruritus, and decrease in lymphocytes.

Immune Design said that, if this trial produces a sufficiently robust clinical benefit for patients, the company may pursue FL as the first indication for regulatory approval of G100.

About orphan designation

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval.

The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The commission typically makes a decision within 30 days of the submission. 

follicular lymphoma

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products has recommended orphan designation for G100 for the treatment of follicular lymphoma (FL).

G100 contains the synthetic small molecule toll-like receptor-4 agonist glucopyranosyl lipid A.

G100 works by activating innate and adaptive immunity in the tumor microenvironment to generate an immune response against the tumor’s pre-existing antigens.

Clinical and preclinical data have demonstrated G100’s ability to activate tumor-infiltrating lymphocytes, macrophages, and dendritic cells, and promote antigen-presentation and the recruitment of T cells to the tumor.

The induction of local and systemic immune responses has been shown in preclinical studies to result in local and abscopal tumor control.

Immune Design, the company developing G100, is currently evaluating G100 plus local radiation, with or without pembrolizumab, in a phase 1/2 trial of FL patients.

Results from this trial were presented at the 2017 ASCO Annual Meeting (abstract 7537). Nine patients who received G100 (3 patients each at the 5, 10, or 20 μg dose) with radiation (but not pembrolizumab) were evaluable for safety and efficacy.

The overall response rate was 44%, and all of these were partial responses (n=4). Thirty-three percent of patients had stable disease (n=3).

Among the responders, tumor regression ranged from 58% to 89%, which included up to 56% shrinkage of abscopal sites. Tumor biopsies showed increased inflammatory responses and T-cell infiltrates in abscopal tumors.

An additional 13 patients treated at the 10 μg dose were evaluable for safety.  There were no dose-limiting toxicities, serious adverse events (AEs), or grade 3/4 AEs observed.

Common AEs included injection site disorders, abdominal pain/discomfort, nausea, pruritus, and decrease in lymphocytes.

Immune Design said that, if this trial produces a sufficiently robust clinical benefit for patients, the company may pursue FL as the first indication for regulatory approval of G100.

About orphan designation

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval.

The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The commission typically makes a decision within 30 days of the submission. 

follicular lymphoma

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products has recommended orphan designation for G100 for the treatment of follicular lymphoma (FL).

G100 contains the synthetic small molecule toll-like receptor-4 agonist glucopyranosyl lipid A.

G100 works by activating innate and adaptive immunity in the tumor microenvironment to generate an immune response against the tumor’s pre-existing antigens.

Clinical and preclinical data have demonstrated G100’s ability to activate tumor-infiltrating lymphocytes, macrophages, and dendritic cells, and promote antigen-presentation and the recruitment of T cells to the tumor.

The induction of local and systemic immune responses has been shown in preclinical studies to result in local and abscopal tumor control.

Immune Design, the company developing G100, is currently evaluating G100 plus local radiation, with or without pembrolizumab, in a phase 1/2 trial of FL patients.

Results from this trial were presented at the 2017 ASCO Annual Meeting (abstract 7537). Nine patients who received G100 (3 patients each at the 5, 10, or 20 μg dose) with radiation (but not pembrolizumab) were evaluable for safety and efficacy.

The overall response rate was 44%, and all of these were partial responses (n=4). Thirty-three percent of patients had stable disease (n=3).

Among the responders, tumor regression ranged from 58% to 89%, which included up to 56% shrinkage of abscopal sites. Tumor biopsies showed increased inflammatory responses and T-cell infiltrates in abscopal tumors.

An additional 13 patients treated at the 10 μg dose were evaluable for safety.  There were no dose-limiting toxicities, serious adverse events (AEs), or grade 3/4 AEs observed.

Common AEs included injection site disorders, abdominal pain/discomfort, nausea, pruritus, and decrease in lymphocytes.

Immune Design said that, if this trial produces a sufficiently robust clinical benefit for patients, the company may pursue FL as the first indication for regulatory approval of G100.

About orphan designation

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval.

The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The commission typically makes a decision within 30 days of the submission. 

In elderly patients with aggressive B-cell lymphomas who experience treatment failure after CHOP or rituximab-CHOP (R-CHOP), the outcomes of subsequent salvage therapy were improved when rituximab was included, results of a retrospective analysis suggest.

“Survival after rituximab-containing salvage therapy was better in all patient groups, supporting the repeated administration of rituximab to all patients needing salvage therapy,” wrote investigator Bertram Glass, MD, of the department of hematology and stem cell transplantation at Helios Klinikum Berlin-Buch, Berlin, and his coauthors (Ann Oncol. 2017 Oct 6. doi: 10.1093/annonc/mdx556).

Dr. Glass and colleagues reviewed data from the randomized RICOVER-60 trial, which included 1,222 patients aged 61-80 years with aggressive B-cell lymphomas who received CHOP or R-CHOP for six or eight cycles. Based on survival outcomes, six cycles of R-CHOP every 2 weeks should be the preferred regimen, investigators wrote when the study results were published in 2008 (Lancet Oncol. 2008;9[2]:105-16. doi: 10.1016/S1470-2045(08)70002-0).

Of 1,222 patients in the RICOVER-60 trial, 301 (24.6%) had treatment failure, of whom 297 could be included in the present analysis.

Rituximab, included in salvage therapy for 57.4% of those evaluable patients, was found to improve the 2-year survival rate from 20.7% to 46.8% (P less than .001), Dr. Glass and his coinvestigators reported.

The benefit of rituximab in the salvage setting was apparent regardless of whether patients received R-CHOP or CHOP as part of their initial therapy in RICOVER-60, they added.

Among patients who had received CHOP as first-line therapy, 2-year overall survival was 49.6% for those who received rituximab in the salvage setting, compared with 19.1% for those who did not (P less than .001), according to the published data. Likewise, in the initial R-CHOP group, 2-year overall survival was 33.1% for rituximab in salvage and 22.5% for no rituximab in salvage (P = .034).

The investigators also looked for differences in prognosis according to specific patient characteristics, including presence of MYC rearrangements and MYC expression by immunohistochemistry.

In patients with MYC translocation at diagnosis, use of rituximab reduced risk of initial treatment failure from 58.8% to 26.3%, according to the investigators. After treatment failure, patients who initially received CHOP had significantly improved 2-year survival if they had MYC translocations or negative MYC immunohistochemistry, though no such association was found for patients who initially received R-CHOP, they wrote.

Dr. Glass and colleagues concluded that new treatment strategies are needed.

“Overall, the outcome of second-line treatment of elderly patients with refractory and relapsed aggressive B-cell lymphoma is disappointing and worse than in younger patients regardless of the modality chosen,” they wrote. “New drugs and treatment modalities with the potential to change the dismal outlook for elderly patients with aggressive B-cell lymphomas are eagerly awaited.”

Dr. Glass and several coauthors reported honoraria, research funding, and consultancies with Roche.

In elderly patients with aggressive B-cell lymphomas who experience treatment failure after CHOP or rituximab-CHOP (R-CHOP), the outcomes of subsequent salvage therapy were improved when rituximab was included, results of a retrospective analysis suggest.

“Survival after rituximab-containing salvage therapy was better in all patient groups, supporting the repeated administration of rituximab to all patients needing salvage therapy,” wrote investigator Bertram Glass, MD, of the department of hematology and stem cell transplantation at Helios Klinikum Berlin-Buch, Berlin, and his coauthors (Ann Oncol. 2017 Oct 6. doi: 10.1093/annonc/mdx556).

Dr. Glass and colleagues reviewed data from the randomized RICOVER-60 trial, which included 1,222 patients aged 61-80 years with aggressive B-cell lymphomas who received CHOP or R-CHOP for six or eight cycles. Based on survival outcomes, six cycles of R-CHOP every 2 weeks should be the preferred regimen, investigators wrote when the study results were published in 2008 (Lancet Oncol. 2008;9[2]:105-16. doi: 10.1016/S1470-2045(08)70002-0).

Of 1,222 patients in the RICOVER-60 trial, 301 (24.6%) had treatment failure, of whom 297 could be included in the present analysis.

Rituximab, included in salvage therapy for 57.4% of those evaluable patients, was found to improve the 2-year survival rate from 20.7% to 46.8% (P less than .001), Dr. Glass and his coinvestigators reported.

The benefit of rituximab in the salvage setting was apparent regardless of whether patients received R-CHOP or CHOP as part of their initial therapy in RICOVER-60, they added.

Among patients who had received CHOP as first-line therapy, 2-year overall survival was 49.6% for those who received rituximab in the salvage setting, compared with 19.1% for those who did not (P less than .001), according to the published data. Likewise, in the initial R-CHOP group, 2-year overall survival was 33.1% for rituximab in salvage and 22.5% for no rituximab in salvage (P = .034).

The investigators also looked for differences in prognosis according to specific patient characteristics, including presence of MYC rearrangements and MYC expression by immunohistochemistry.

In patients with MYC translocation at diagnosis, use of rituximab reduced risk of initial treatment failure from 58.8% to 26.3%, according to the investigators. After treatment failure, patients who initially received CHOP had significantly improved 2-year survival if they had MYC translocations or negative MYC immunohistochemistry, though no such association was found for patients who initially received R-CHOP, they wrote.

Dr. Glass and colleagues concluded that new treatment strategies are needed.

“Overall, the outcome of second-line treatment of elderly patients with refractory and relapsed aggressive B-cell lymphoma is disappointing and worse than in younger patients regardless of the modality chosen,” they wrote. “New drugs and treatment modalities with the potential to change the dismal outlook for elderly patients with aggressive B-cell lymphomas are eagerly awaited.”

Dr. Glass and several coauthors reported honoraria, research funding, and consultancies with Roche.

In elderly patients with aggressive B-cell lymphomas who experience treatment failure after CHOP or rituximab-CHOP (R-CHOP), the outcomes of subsequent salvage therapy were improved when rituximab was included, results of a retrospective analysis suggest.

“Survival after rituximab-containing salvage therapy was better in all patient groups, supporting the repeated administration of rituximab to all patients needing salvage therapy,” wrote investigator Bertram Glass, MD, of the department of hematology and stem cell transplantation at Helios Klinikum Berlin-Buch, Berlin, and his coauthors (Ann Oncol. 2017 Oct 6. doi: 10.1093/annonc/mdx556).

Dr. Glass and colleagues reviewed data from the randomized RICOVER-60 trial, which included 1,222 patients aged 61-80 years with aggressive B-cell lymphomas who received CHOP or R-CHOP for six or eight cycles. Based on survival outcomes, six cycles of R-CHOP every 2 weeks should be the preferred regimen, investigators wrote when the study results were published in 2008 (Lancet Oncol. 2008;9[2]:105-16. doi: 10.1016/S1470-2045(08)70002-0).

Of 1,222 patients in the RICOVER-60 trial, 301 (24.6%) had treatment failure, of whom 297 could be included in the present analysis.

Rituximab, included in salvage therapy for 57.4% of those evaluable patients, was found to improve the 2-year survival rate from 20.7% to 46.8% (P less than .001), Dr. Glass and his coinvestigators reported.

The benefit of rituximab in the salvage setting was apparent regardless of whether patients received R-CHOP or CHOP as part of their initial therapy in RICOVER-60, they added.

Among patients who had received CHOP as first-line therapy, 2-year overall survival was 49.6% for those who received rituximab in the salvage setting, compared with 19.1% for those who did not (P less than .001), according to the published data. Likewise, in the initial R-CHOP group, 2-year overall survival was 33.1% for rituximab in salvage and 22.5% for no rituximab in salvage (P = .034).

The investigators also looked for differences in prognosis according to specific patient characteristics, including presence of MYC rearrangements and MYC expression by immunohistochemistry.

In patients with MYC translocation at diagnosis, use of rituximab reduced risk of initial treatment failure from 58.8% to 26.3%, according to the investigators. After treatment failure, patients who initially received CHOP had significantly improved 2-year survival if they had MYC translocations or negative MYC immunohistochemistry, though no such association was found for patients who initially received R-CHOP, they wrote.

Dr. Glass and colleagues concluded that new treatment strategies are needed.

“Overall, the outcome of second-line treatment of elderly patients with refractory and relapsed aggressive B-cell lymphoma is disappointing and worse than in younger patients regardless of the modality chosen,” they wrote. “New drugs and treatment modalities with the potential to change the dismal outlook for elderly patients with aggressive B-cell lymphomas are eagerly awaited.”

Dr. Glass and several coauthors reported honoraria, research funding, and consultancies with Roche.

Micrograph showing DLBCL

A new assay may help improve the diagnosis and treatment of diffuse large B-cell lymphoma (DLBCL), according to researchers.

The gene expression signature assay can be used to classify subtypes of DLBCL and may enhance disease management by helping to match tumors with the appropriate targeted therapy.

Researchers described the assay in the Journal of Molecular Diagnostics.

The assay is a novel gene expression profiling DLBCL classifier based on reverse transcriptase multiplex ligation-dependent probe amplification (RT-MLPA).

It can simultaneously evaluate the expression of 21 markers, allowing differentiation of the 3 subtypes of DLBCL—germinal center B-cell-like (GCB), activated B-cell-like (ABC), and primary mediastinal B-cell lymphoma (PMBL)—as well as other individualized disease characteristics, such as Epstein-Barr infection status.

Researchers used the RT-MLPA assay to test 150 samples from DLBCL patients. Forty-two percent of the samples were the ABC subtype, 37% the GCB subtype, and 10% molecular PMBL. Eleven percent of the samples could not be classified.

Overall, the RT-MLPA assay correctly assigned 85.0% of the cases into the expected subtypes, compared to 78.8% of samples assigned via immunohistochemistry.

The RT-MLPA assay was also able to detect the MYD88 L265P mutation, one of the most common genetic abnormalities found in ABC DLBCLs. This information can influence treatment, since the presence of the mutation is thought to be predictive of ibrutinib sensitivity.

The researchers said RT-MLPA is a robust, efficient, rapid, and cost-effective alternative to current methods used in the clinic to establish the cell-of-origin classification of DLBCLs.

RT-MLPA requires only common laboratory equipment and can be applied to formalin-fixed, paraffin-embedded samples. Other types of diagnostic methods may not provide the level of detail needed and may also be limited by poor reproducibility and lack of adaptability to routine use in standard laboratories.

“Because we have provided the classification algorithms, other laboratories will be able to verify our results and adjust the procedures to suit their environment,” said study author Philippe Ruminy, PhD, of the Henri Becquerel Cancer Treatment Center, INSERM U1245 in Rouen, France.

“It is our hope that the assay we have developed, which addresses an important recommendation of the recent WHO classifications, will contribute to better management of these tumors and improved patient outcomes.”

Micrograph showing DLBCL

A new assay may help improve the diagnosis and treatment of diffuse large B-cell lymphoma (DLBCL), according to researchers.

The gene expression signature assay can be used to classify subtypes of DLBCL and may enhance disease management by helping to match tumors with the appropriate targeted therapy.

Researchers described the assay in the Journal of Molecular Diagnostics.

The assay is a novel gene expression profiling DLBCL classifier based on reverse transcriptase multiplex ligation-dependent probe amplification (RT-MLPA).

It can simultaneously evaluate the expression of 21 markers, allowing differentiation of the 3 subtypes of DLBCL—germinal center B-cell-like (GCB), activated B-cell-like (ABC), and primary mediastinal B-cell lymphoma (PMBL)—as well as other individualized disease characteristics, such as Epstein-Barr infection status.

Researchers used the RT-MLPA assay to test 150 samples from DLBCL patients. Forty-two percent of the samples were the ABC subtype, 37% the GCB subtype, and 10% molecular PMBL. Eleven percent of the samples could not be classified.

Overall, the RT-MLPA assay correctly assigned 85.0% of the cases into the expected subtypes, compared to 78.8% of samples assigned via immunohistochemistry.

The RT-MLPA assay was also able to detect the MYD88 L265P mutation, one of the most common genetic abnormalities found in ABC DLBCLs. This information can influence treatment, since the presence of the mutation is thought to be predictive of ibrutinib sensitivity.

The researchers said RT-MLPA is a robust, efficient, rapid, and cost-effective alternative to current methods used in the clinic to establish the cell-of-origin classification of DLBCLs.

RT-MLPA requires only common laboratory equipment and can be applied to formalin-fixed, paraffin-embedded samples. Other types of diagnostic methods may not provide the level of detail needed and may also be limited by poor reproducibility and lack of adaptability to routine use in standard laboratories.

“Because we have provided the classification algorithms, other laboratories will be able to verify our results and adjust the procedures to suit their environment,” said study author Philippe Ruminy, PhD, of the Henri Becquerel Cancer Treatment Center, INSERM U1245 in Rouen, France.

“It is our hope that the assay we have developed, which addresses an important recommendation of the recent WHO classifications, will contribute to better management of these tumors and improved patient outcomes.”

Micrograph showing DLBCL

A new assay may help improve the diagnosis and treatment of diffuse large B-cell lymphoma (DLBCL), according to researchers.

The gene expression signature assay can be used to classify subtypes of DLBCL and may enhance disease management by helping to match tumors with the appropriate targeted therapy.

Researchers described the assay in the Journal of Molecular Diagnostics.

The assay is a novel gene expression profiling DLBCL classifier based on reverse transcriptase multiplex ligation-dependent probe amplification (RT-MLPA).

It can simultaneously evaluate the expression of 21 markers, allowing differentiation of the 3 subtypes of DLBCL—germinal center B-cell-like (GCB), activated B-cell-like (ABC), and primary mediastinal B-cell lymphoma (PMBL)—as well as other individualized disease characteristics, such as Epstein-Barr infection status.

Researchers used the RT-MLPA assay to test 150 samples from DLBCL patients. Forty-two percent of the samples were the ABC subtype, 37% the GCB subtype, and 10% molecular PMBL. Eleven percent of the samples could not be classified.

Overall, the RT-MLPA assay correctly assigned 85.0% of the cases into the expected subtypes, compared to 78.8% of samples assigned via immunohistochemistry.

The RT-MLPA assay was also able to detect the MYD88 L265P mutation, one of the most common genetic abnormalities found in ABC DLBCLs. This information can influence treatment, since the presence of the mutation is thought to be predictive of ibrutinib sensitivity.

The researchers said RT-MLPA is a robust, efficient, rapid, and cost-effective alternative to current methods used in the clinic to establish the cell-of-origin classification of DLBCLs.

RT-MLPA requires only common laboratory equipment and can be applied to formalin-fixed, paraffin-embedded samples. Other types of diagnostic methods may not provide the level of detail needed and may also be limited by poor reproducibility and lack of adaptability to routine use in standard laboratories.

“Because we have provided the classification algorithms, other laboratories will be able to verify our results and adjust the procedures to suit their environment,” said study author Philippe Ruminy, PhD, of the Henri Becquerel Cancer Treatment Center, INSERM U1245 in Rouen, France.

“It is our hope that the assay we have developed, which addresses an important recommendation of the recent WHO classifications, will contribute to better management of these tumors and improved patient outcomes.”

A second chimeric antigen receptor (CAR) T-cell therapy has gained FDA approval, this time for the treatment of large B-cell lymphoma in adults.

“Today marks another milestone in the development of a whole new scientific paradigm for the treatment of serious diseases,” FDA Commissioner Scott Gottlieb, MD, said in a statement. “This approval demonstrates the continued momentum of this promising new area of medicine, and we’re committed to supporting and helping expedite the development of these products.”

[email protected]

On Twitter @denisefulton

A second chimeric antigen receptor (CAR) T-cell therapy has gained FDA approval, this time for the treatment of large B-cell lymphoma in adults.

“Today marks another milestone in the development of a whole new scientific paradigm for the treatment of serious diseases,” FDA Commissioner Scott Gottlieb, MD, said in a statement. “This approval demonstrates the continued momentum of this promising new area of medicine, and we’re committed to supporting and helping expedite the development of these products.”

[email protected]

On Twitter @denisefulton

A second chimeric antigen receptor (CAR) T-cell therapy has gained FDA approval, this time for the treatment of large B-cell lymphoma in adults.

“Today marks another milestone in the development of a whole new scientific paradigm for the treatment of serious diseases,” FDA Commissioner Scott Gottlieb, MD, said in a statement. “This approval demonstrates the continued momentum of this promising new area of medicine, and we’re committed to supporting and helping expedite the development of these products.”

[email protected]

On Twitter @denisefulton

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/.

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.

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.

In a head-to-head trial of anti-CD20 monoclonal antibodies in first-line therapy for follicular lymphoma, obinutuzumab-based chemotherapy was associated with slightly but significantly better progression-free survival than rituximab-based therapy, but at the cost of higher toxicities, including severe adverse events.

Among 1,202 patients with follicular lymphoma followed for a median of 34.5 months, the estimated 3-year rate of progression-free survival (PFS) for patients randomized to obinutuzumab-based chemotherapy and maintenance was 80%, compared with 73.3% for patients randomized to rituximab chemotherapy and maintenance. Response rates and overall survival were similar between the treatment groups, Robert Marcus, MB, BS, of King’s College Hospital, London, and his coinvestigators reported in the GALLIUM trial.

In a head-to-head trial of anti-CD20 monoclonal antibodies in first-line therapy for follicular lymphoma, obinutuzumab-based chemotherapy was associated with slightly but significantly better progression-free survival than rituximab-based therapy, but at the cost of higher toxicities, including severe adverse events.

Among 1,202 patients with follicular lymphoma followed for a median of 34.5 months, the estimated 3-year rate of progression-free survival (PFS) for patients randomized to obinutuzumab-based chemotherapy and maintenance was 80%, compared with 73.3% for patients randomized to rituximab chemotherapy and maintenance. Response rates and overall survival were similar between the treatment groups, Robert Marcus, MB, BS, of King’s College Hospital, London, and his coinvestigators reported in the GALLIUM trial.

In a head-to-head trial of anti-CD20 monoclonal antibodies in first-line therapy for follicular lymphoma, obinutuzumab-based chemotherapy was associated with slightly but significantly better progression-free survival than rituximab-based therapy, but at the cost of higher toxicities, including severe adverse events.

Among 1,202 patients with follicular lymphoma followed for a median of 34.5 months, the estimated 3-year rate of progression-free survival (PFS) for patients randomized to obinutuzumab-based chemotherapy and maintenance was 80%, compared with 73.3% for patients randomized to rituximab chemotherapy and maintenance. Response rates and overall survival were similar between the treatment groups, Robert Marcus, MB, BS, of King’s College Hospital, London, and his coinvestigators reported in the GALLIUM trial.