Lymphoma & Plasma Cell Disorders

Michelle Fanale, MD

Photo by Larry Young

SAN FRANCISCO—Preclinical and early phase 1 results suggest the aurora A kinase inhibitor alisertib and the histone deacetylase (HDAC) inhibitor romidepsin have synergistic activity against T-cell lymphomas.

In the preclinical study, the drugs showed synergy in cutaneous T-cell lymphoma (CTCL) cell lines and a benefit over monotherapy in vivo.

In the phase 1 study, romidepsin and alisertib produced clinical benefits in patients with peripheral T-cell lymphoma (PTCL).

Unfortunately, there are currently no good markers for predicting which patients might benefit from this type of combination, potentially because the drugs have multivariate mechanisms of action, said Michelle Fanale, MD, of the University of Texas MD Anderson Cancer Center in Houston.

She presented data on romidepsin and alisertib in combination at the 7th Annual T-cell Lymphoma Forum.

Dr Fanale said she was inspired to test the combination (in a phase 1 trial) after researchers reported promising results with the aurora kinase inhibitors MK-0457 and MK-5108 in combination with the HDAC inhibitor vorinostat (Kretzner et al, Cancer Research 2011).

She noted that aurora kinase inhibitors work mainly through actions at the G2-M transition point, while HDAC inhibitors induce G1-S transition. HDAC inhibitors can also degrade aurora A and B kinases, and the drugs modify kinetochore assembly through hyperacetylation of pericentromeric histones.

“When you actually treat with an HDAC inhibitor by itself, you’re basically getting an increase of this sub-G1 population,” Dr Fanale said. “When you treat with your aurora kinase inhibitor by itself, you’re clearly getting an increase of cells that are arresting at G2/M.”

“When you treat with the combination, you’re actually getting a further increase in the sub-G1, denoting dead cells, and then you’re further getting some increase of cells spreading out now through the G2/M portion as well.”

Preclinical research

Dr Fanale presented preclinical results showing that alisertib is highly synergistic with romidepsin in T-cell, but not B-cell, lymphoma. She was not involved in the research, which was also presented at the recent ASH Annual Meeting (Zullo et al, ASH 2014, abst 4493).

The researchers administered romidepsin at IC_10-20 concentrations, with increasing concentrations of alisertib, and incubated cells for 72 hours. A synergy coefficient less than 1 denoted synergy.

The combination demonstrated synergy in the HH (CTCL) cell line when alisertib was given at 100 nM or 1000 nM (0.68 and 0.40, respectively) but not at 50 nM (1.05).

Likewise, the combination demonstrated synergy in the H9 (CTCL) cell line when alisertib was given at 100 nM or 1000 nM (0.66 and 0.46, respectively) but not at 50 nM (1.1).

Romidepsin was shown to cause a mild increase in the percent of cells in G1 compared with alisertib, which significantly increased the percent of cells in G2/M arrest. And live cell imaging showed marked cytokinesis failure following treatment.

“When looking at further markers for apoptosis, when giving the combination, there’s further increase in caspase 3 and PARP cleavage, as well as other pro-apoptotic proteins, including PUMA, and a decrease in the anti-apoptotic protein Bcl-xL,” Dr Fanale noted.

She also pointed out that, in an in vivo xenograft model, alisertib and romidepsin produced significantly better results than those observed with monotherapy or in controls.

Phase 1 trial

The phase 1 trial of romidepsin and alisertib in combination included patients with aggressive B- and T-cell lymphomas (NCT01897012; Fanale et al, ASH 2014, abst 1744).

Twelve patients have been enrolled to date. Ninety-two percent of patients had primary refractory disease, they had a median of 3.5 prior lines of therapy (range, 1 to 7), and none of the patients had received a stem cell transplant.

The patients received treatment as follows:

• Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 6 mg/m² IV on days 1 and 8
• Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 8 mg/m² IV on days 1 and 8
• Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 10 mg/m² IV on days 1 and 8
• Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 10 mg/m² IV on days 1 and 8
• Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 12 mg/m² IV on days 1 and 8
• Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 14 mg/m² IV on days 1 and 8.

The maximum-tolerated dose has not yet been reached. The main side effect was reversible myelosuppression. In the 24 cycles administered, patients experienced grade 3/4 neutropenia (62.5%), anemia (29%), and thrombocytopenia (48%).

Dr Fanale noted that 3 of the 4 patients with T-cell lymphomas had some level of clinical benefit after therapy.

One patient, a heavily pretreated patient with PTCL who was treated at the lowest dose, had a complete response lasting 10 months. The patient had received 7 prior lines of therapy, including romidepsin alone.

Two other patients had stable disease, one with PTCL and one with an overlap diagnosis of B-cell and T-cell lymphoma. The PTCL patient went on to receive a matched, unrelated-donor transplant and is doing well, Dr Fanale said.

“We’ve taken a pause from this clinical trial,” she added. “We plan to reopen it toward T-cell lymphoma patients, potentially exclusively, . . . and also potentially to change a bit of the dosing schema with both romidepsin and alisertib.”

Michelle Fanale, MD

Photo by Larry Young

SAN FRANCISCO—Preclinical and early phase 1 results suggest the aurora A kinase inhibitor alisertib and the histone deacetylase (HDAC) inhibitor romidepsin have synergistic activity against T-cell lymphomas.

In the preclinical study, the drugs showed synergy in cutaneous T-cell lymphoma (CTCL) cell lines and a benefit over monotherapy in vivo.

In the phase 1 study, romidepsin and alisertib produced clinical benefits in patients with peripheral T-cell lymphoma (PTCL).

Unfortunately, there are currently no good markers for predicting which patients might benefit from this type of combination, potentially because the drugs have multivariate mechanisms of action, said Michelle Fanale, MD, of the University of Texas MD Anderson Cancer Center in Houston.

She presented data on romidepsin and alisertib in combination at the 7th Annual T-cell Lymphoma Forum.

Dr Fanale said she was inspired to test the combination (in a phase 1 trial) after researchers reported promising results with the aurora kinase inhibitors MK-0457 and MK-5108 in combination with the HDAC inhibitor vorinostat (Kretzner et al, Cancer Research 2011).

She noted that aurora kinase inhibitors work mainly through actions at the G2-M transition point, while HDAC inhibitors induce G1-S transition. HDAC inhibitors can also degrade aurora A and B kinases, and the drugs modify kinetochore assembly through hyperacetylation of pericentromeric histones.

“When you actually treat with an HDAC inhibitor by itself, you’re basically getting an increase of this sub-G1 population,” Dr Fanale said. “When you treat with your aurora kinase inhibitor by itself, you’re clearly getting an increase of cells that are arresting at G2/M.”

“When you treat with the combination, you’re actually getting a further increase in the sub-G1, denoting dead cells, and then you’re further getting some increase of cells spreading out now through the G2/M portion as well.”

Preclinical research

Dr Fanale presented preclinical results showing that alisertib is highly synergistic with romidepsin in T-cell, but not B-cell, lymphoma. She was not involved in the research, which was also presented at the recent ASH Annual Meeting (Zullo et al, ASH 2014, abst 4493).

The researchers administered romidepsin at IC_10-20 concentrations, with increasing concentrations of alisertib, and incubated cells for 72 hours. A synergy coefficient less than 1 denoted synergy.

The combination demonstrated synergy in the HH (CTCL) cell line when alisertib was given at 100 nM or 1000 nM (0.68 and 0.40, respectively) but not at 50 nM (1.05).

Likewise, the combination demonstrated synergy in the H9 (CTCL) cell line when alisertib was given at 100 nM or 1000 nM (0.66 and 0.46, respectively) but not at 50 nM (1.1).

Romidepsin was shown to cause a mild increase in the percent of cells in G1 compared with alisertib, which significantly increased the percent of cells in G2/M arrest. And live cell imaging showed marked cytokinesis failure following treatment.

“When looking at further markers for apoptosis, when giving the combination, there’s further increase in caspase 3 and PARP cleavage, as well as other pro-apoptotic proteins, including PUMA, and a decrease in the anti-apoptotic protein Bcl-xL,” Dr Fanale noted.

She also pointed out that, in an in vivo xenograft model, alisertib and romidepsin produced significantly better results than those observed with monotherapy or in controls.

Phase 1 trial

The phase 1 trial of romidepsin and alisertib in combination included patients with aggressive B- and T-cell lymphomas (NCT01897012; Fanale et al, ASH 2014, abst 1744).

Twelve patients have been enrolled to date. Ninety-two percent of patients had primary refractory disease, they had a median of 3.5 prior lines of therapy (range, 1 to 7), and none of the patients had received a stem cell transplant.

The patients received treatment as follows:

• Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 6 mg/m² IV on days 1 and 8
• Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 8 mg/m² IV on days 1 and 8
• Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 10 mg/m² IV on days 1 and 8
• Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 10 mg/m² IV on days 1 and 8
• Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 12 mg/m² IV on days 1 and 8
• Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 14 mg/m² IV on days 1 and 8.

The maximum-tolerated dose has not yet been reached. The main side effect was reversible myelosuppression. In the 24 cycles administered, patients experienced grade 3/4 neutropenia (62.5%), anemia (29%), and thrombocytopenia (48%).

Dr Fanale noted that 3 of the 4 patients with T-cell lymphomas had some level of clinical benefit after therapy.

One patient, a heavily pretreated patient with PTCL who was treated at the lowest dose, had a complete response lasting 10 months. The patient had received 7 prior lines of therapy, including romidepsin alone.

Two other patients had stable disease, one with PTCL and one with an overlap diagnosis of B-cell and T-cell lymphoma. The PTCL patient went on to receive a matched, unrelated-donor transplant and is doing well, Dr Fanale said.

“We’ve taken a pause from this clinical trial,” she added. “We plan to reopen it toward T-cell lymphoma patients, potentially exclusively, . . . and also potentially to change a bit of the dosing schema with both romidepsin and alisertib.”

Michelle Fanale, MD

Photo by Larry Young

SAN FRANCISCO—Preclinical and early phase 1 results suggest the aurora A kinase inhibitor alisertib and the histone deacetylase (HDAC) inhibitor romidepsin have synergistic activity against T-cell lymphomas.

In the preclinical study, the drugs showed synergy in cutaneous T-cell lymphoma (CTCL) cell lines and a benefit over monotherapy in vivo.

In the phase 1 study, romidepsin and alisertib produced clinical benefits in patients with peripheral T-cell lymphoma (PTCL).

Unfortunately, there are currently no good markers for predicting which patients might benefit from this type of combination, potentially because the drugs have multivariate mechanisms of action, said Michelle Fanale, MD, of the University of Texas MD Anderson Cancer Center in Houston.

She presented data on romidepsin and alisertib in combination at the 7th Annual T-cell Lymphoma Forum.

Dr Fanale said she was inspired to test the combination (in a phase 1 trial) after researchers reported promising results with the aurora kinase inhibitors MK-0457 and MK-5108 in combination with the HDAC inhibitor vorinostat (Kretzner et al, Cancer Research 2011).

She noted that aurora kinase inhibitors work mainly through actions at the G2-M transition point, while HDAC inhibitors induce G1-S transition. HDAC inhibitors can also degrade aurora A and B kinases, and the drugs modify kinetochore assembly through hyperacetylation of pericentromeric histones.

“When you actually treat with an HDAC inhibitor by itself, you’re basically getting an increase of this sub-G1 population,” Dr Fanale said. “When you treat with your aurora kinase inhibitor by itself, you’re clearly getting an increase of cells that are arresting at G2/M.”

“When you treat with the combination, you’re actually getting a further increase in the sub-G1, denoting dead cells, and then you’re further getting some increase of cells spreading out now through the G2/M portion as well.”

Preclinical research

Dr Fanale presented preclinical results showing that alisertib is highly synergistic with romidepsin in T-cell, but not B-cell, lymphoma. She was not involved in the research, which was also presented at the recent ASH Annual Meeting (Zullo et al, ASH 2014, abst 4493).

The researchers administered romidepsin at IC_10-20 concentrations, with increasing concentrations of alisertib, and incubated cells for 72 hours. A synergy coefficient less than 1 denoted synergy.

The combination demonstrated synergy in the HH (CTCL) cell line when alisertib was given at 100 nM or 1000 nM (0.68 and 0.40, respectively) but not at 50 nM (1.05).

Likewise, the combination demonstrated synergy in the H9 (CTCL) cell line when alisertib was given at 100 nM or 1000 nM (0.66 and 0.46, respectively) but not at 50 nM (1.1).

Romidepsin was shown to cause a mild increase in the percent of cells in G1 compared with alisertib, which significantly increased the percent of cells in G2/M arrest. And live cell imaging showed marked cytokinesis failure following treatment.

“When looking at further markers for apoptosis, when giving the combination, there’s further increase in caspase 3 and PARP cleavage, as well as other pro-apoptotic proteins, including PUMA, and a decrease in the anti-apoptotic protein Bcl-xL,” Dr Fanale noted.

She also pointed out that, in an in vivo xenograft model, alisertib and romidepsin produced significantly better results than those observed with monotherapy or in controls.

Phase 1 trial

The phase 1 trial of romidepsin and alisertib in combination included patients with aggressive B- and T-cell lymphomas (NCT01897012; Fanale et al, ASH 2014, abst 1744).

Twelve patients have been enrolled to date. Ninety-two percent of patients had primary refractory disease, they had a median of 3.5 prior lines of therapy (range, 1 to 7), and none of the patients had received a stem cell transplant.

The patients received treatment as follows:

• Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 6 mg/m² IV on days 1 and 8
• Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 8 mg/m² IV on days 1 and 8
• Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 10 mg/m² IV on days 1 and 8
• Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 10 mg/m² IV on days 1 and 8
• Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 12 mg/m² IV on days 1 and 8
• Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 14 mg/m² IV on days 1 and 8.

The maximum-tolerated dose has not yet been reached. The main side effect was reversible myelosuppression. In the 24 cycles administered, patients experienced grade 3/4 neutropenia (62.5%), anemia (29%), and thrombocytopenia (48%).

Dr Fanale noted that 3 of the 4 patients with T-cell lymphomas had some level of clinical benefit after therapy.

One patient, a heavily pretreated patient with PTCL who was treated at the lowest dose, had a complete response lasting 10 months. The patient had received 7 prior lines of therapy, including romidepsin alone.

Two other patients had stable disease, one with PTCL and one with an overlap diagnosis of B-cell and T-cell lymphoma. The PTCL patient went on to receive a matched, unrelated-donor transplant and is doing well, Dr Fanale said.

“We’ve taken a pause from this clinical trial,” she added. “We plan to reopen it toward T-cell lymphoma patients, potentially exclusively, . . . and also potentially to change a bit of the dosing schema with both romidepsin and alisertib.”

Yuankai Shi, MD, PhD

Photo by Larry Young

SAN FRANCISCO—The histone deacetylase (HDAC) inhibitor chidamide is effective and well-tolerated in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL), results of the phase 2 CHIPEL trial suggest.

The study showed that chidamide can elicit higher response rates than those previously observed with the folate analog metabolic inhibitor pralatrexate and the HDAC inhibitor romidepsin.

Chidamide also prolonged survival and posed a lower risk of toxicity compared to pralatrexate and romidepsin.

Yuankai Shi, MD, PhD, of the Chinese Academy of Medical Science & Peking Union Medical College in  Beijing, China, presented these results at the 7th Annual T-cell Lymphoma Forum. The trial is sponsored by Chipscreen Biosciences Ltd.

He noted that the CHIPEL study was split into two parts: an exploratory trial and a pivotal trial.

Exploratory trial

The exploratory trial included 19 patients who had a median age of 51 and were a median of 1.41 years from diagnosis. Seventeen patients had PTCL unspecified (PTCL-U), and 2 had other subtypes of PTCL.

The patients received chidamide at 30 mg (n=9) or 50 mg (n=10) twice a week for 2 weeks of a 3-week cycle. The overall response rate was 26% (n=5), and 16% of patients (n=3) had a complete response (CR) or unconfirmed CR (CRu).

Pivotal trial

The pivotal trial included 83 patients who had a median age of 53 and were a median of 1.06 years from diagnosis.

The patients had PTCL-U (29.1%, n=23), nasal NK/T-cell lymphoma (20.3%, n=16), anaplastic large-cell lymphoma (ALCL, 20.3%, n=16), angioimmunoblastic T-cell lymphoma (AITL, 11.4%, n=9), enteropathy-type T-cell lymphoma (2.5%, n=2), CD4-positive PTCL (1.3%, n=1), Lennert-type PTCL (1.3%, n=1), transformed mycosis fungoides (1.3%, n=1), and other subtypes of PTCL (12.7%, n=10).

These patients received chidamide at 30 mg twice a week without a drug-free holiday.

The overall response rate was 29% (n=23) according to investigators and 28% (n=22) according to an independent review committee. Fourteen percent of patients (n=11) had a CR/CRu, according to both sources.

The median progression-free survival was 2.1 months for all patients, 14 months for patients who achieved CR/CRus, 7.7 months in patients with partial responses, and 2.5 months in patients with stable disease.

The median overall survival was 21.4 months in all patients and not reached in patients who had a CR/CRu, partial response, or stable disease.

Overall safety

Of all 102 patients (in both the pivotal and exploratory analyses), 80% had at least one adverse event (AE), 37% had grade 3 or higher AEs, 17% had AEs leading to treatment discontinuation, and 8% had severe AEs.

The most common AEs were thrombocytopenia (50%), leukopenia (37%), neutropenia (19%), fatigue (11%), and fever (11%).

Twenty-four percent of patients had grade 3 or higher thrombocytopenia, 13% had grade 3 or higher leukopenia, and 10% had grade 3 or higher neutropenia.

Chidamide vs other agents

Dr Shi compared response rates with chidamide in the pivotal trial to those previously observed with pralatrexate (O’Connor et al, JCO 2011) and romidepsin (Coiffier et al, J Hematol Oncol 2014).

In patients with PTCL-U, response rates were similar for all 3 drugs (≈30%). In ALCL, the response rate with chidamide was higher (≈50%) than with pralatrexate (≈30%) or romidepsin (≈25%). And in AITL, the response rate with chidamide was higher (≈45%) than with pralatrexate (≈8%) or romidepsin (≈30%).

Chidamide also conferred better overall survival than pralatrexate, romidepsin, and other treatments from previous studies.

The median overall survival was 6.5 months with chemotherapy (Mak et al, JCO 2013), 14.5 months with pralatrexate (O’Connor et al, JCO 2011), 11.3 months with romidepsin (Coiffier et al, J Hematol Oncol 2014), 7.9 months with belinostat (Hyon-Zu Lee, Clinical Review 2009), and 21.4 months with chidamide.

Finally, Dr Shi compared the rates of AEs observed in the chidamide pivotal trial to AEs observed in the pralatrexate and romidepsin trials.

At least one AE occurred in 100% of patients treated with pralatrexate, 96% of patients on romidepsin, and 82% of patients on chidamide. Grade 3 or higher AEs occurred in 74%, 66%, and 39% of patients, respectively. And at least one severe AE occurred in 44%, 46%, and 8% of patients, respectively.

The favorable results observed with chidamide support the Chinese Food and Drug Administration’s December decision to approve the drug (under the brand name Epidaza) for use in patients with PTCL.

Yuankai Shi, MD, PhD

Photo by Larry Young

SAN FRANCISCO—The histone deacetylase (HDAC) inhibitor chidamide is effective and well-tolerated in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL), results of the phase 2 CHIPEL trial suggest.

The study showed that chidamide can elicit higher response rates than those previously observed with the folate analog metabolic inhibitor pralatrexate and the HDAC inhibitor romidepsin.

Chidamide also prolonged survival and posed a lower risk of toxicity compared to pralatrexate and romidepsin.

Yuankai Shi, MD, PhD, of the Chinese Academy of Medical Science & Peking Union Medical College in  Beijing, China, presented these results at the 7th Annual T-cell Lymphoma Forum. The trial is sponsored by Chipscreen Biosciences Ltd.

He noted that the CHIPEL study was split into two parts: an exploratory trial and a pivotal trial.

Exploratory trial

The exploratory trial included 19 patients who had a median age of 51 and were a median of 1.41 years from diagnosis. Seventeen patients had PTCL unspecified (PTCL-U), and 2 had other subtypes of PTCL.

The patients received chidamide at 30 mg (n=9) or 50 mg (n=10) twice a week for 2 weeks of a 3-week cycle. The overall response rate was 26% (n=5), and 16% of patients (n=3) had a complete response (CR) or unconfirmed CR (CRu).

Pivotal trial

The pivotal trial included 83 patients who had a median age of 53 and were a median of 1.06 years from diagnosis.

The patients had PTCL-U (29.1%, n=23), nasal NK/T-cell lymphoma (20.3%, n=16), anaplastic large-cell lymphoma (ALCL, 20.3%, n=16), angioimmunoblastic T-cell lymphoma (AITL, 11.4%, n=9), enteropathy-type T-cell lymphoma (2.5%, n=2), CD4-positive PTCL (1.3%, n=1), Lennert-type PTCL (1.3%, n=1), transformed mycosis fungoides (1.3%, n=1), and other subtypes of PTCL (12.7%, n=10).

These patients received chidamide at 30 mg twice a week without a drug-free holiday.

The overall response rate was 29% (n=23) according to investigators and 28% (n=22) according to an independent review committee. Fourteen percent of patients (n=11) had a CR/CRu, according to both sources.

The median progression-free survival was 2.1 months for all patients, 14 months for patients who achieved CR/CRus, 7.7 months in patients with partial responses, and 2.5 months in patients with stable disease.

The median overall survival was 21.4 months in all patients and not reached in patients who had a CR/CRu, partial response, or stable disease.

Overall safety

Of all 102 patients (in both the pivotal and exploratory analyses), 80% had at least one adverse event (AE), 37% had grade 3 or higher AEs, 17% had AEs leading to treatment discontinuation, and 8% had severe AEs.

The most common AEs were thrombocytopenia (50%), leukopenia (37%), neutropenia (19%), fatigue (11%), and fever (11%).

Twenty-four percent of patients had grade 3 or higher thrombocytopenia, 13% had grade 3 or higher leukopenia, and 10% had grade 3 or higher neutropenia.

Chidamide vs other agents

Dr Shi compared response rates with chidamide in the pivotal trial to those previously observed with pralatrexate (O’Connor et al, JCO 2011) and romidepsin (Coiffier et al, J Hematol Oncol 2014).

In patients with PTCL-U, response rates were similar for all 3 drugs (≈30%). In ALCL, the response rate with chidamide was higher (≈50%) than with pralatrexate (≈30%) or romidepsin (≈25%). And in AITL, the response rate with chidamide was higher (≈45%) than with pralatrexate (≈8%) or romidepsin (≈30%).

Chidamide also conferred better overall survival than pralatrexate, romidepsin, and other treatments from previous studies.

The median overall survival was 6.5 months with chemotherapy (Mak et al, JCO 2013), 14.5 months with pralatrexate (O’Connor et al, JCO 2011), 11.3 months with romidepsin (Coiffier et al, J Hematol Oncol 2014), 7.9 months with belinostat (Hyon-Zu Lee, Clinical Review 2009), and 21.4 months with chidamide.

Finally, Dr Shi compared the rates of AEs observed in the chidamide pivotal trial to AEs observed in the pralatrexate and romidepsin trials.

At least one AE occurred in 100% of patients treated with pralatrexate, 96% of patients on romidepsin, and 82% of patients on chidamide. Grade 3 or higher AEs occurred in 74%, 66%, and 39% of patients, respectively. And at least one severe AE occurred in 44%, 46%, and 8% of patients, respectively.

The favorable results observed with chidamide support the Chinese Food and Drug Administration’s December decision to approve the drug (under the brand name Epidaza) for use in patients with PTCL.

Yuankai Shi, MD, PhD

Photo by Larry Young

SAN FRANCISCO—The histone deacetylase (HDAC) inhibitor chidamide is effective and well-tolerated in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL), results of the phase 2 CHIPEL trial suggest.

The study showed that chidamide can elicit higher response rates than those previously observed with the folate analog metabolic inhibitor pralatrexate and the HDAC inhibitor romidepsin.

Chidamide also prolonged survival and posed a lower risk of toxicity compared to pralatrexate and romidepsin.

Yuankai Shi, MD, PhD, of the Chinese Academy of Medical Science & Peking Union Medical College in  Beijing, China, presented these results at the 7th Annual T-cell Lymphoma Forum. The trial is sponsored by Chipscreen Biosciences Ltd.

He noted that the CHIPEL study was split into two parts: an exploratory trial and a pivotal trial.

Exploratory trial

The exploratory trial included 19 patients who had a median age of 51 and were a median of 1.41 years from diagnosis. Seventeen patients had PTCL unspecified (PTCL-U), and 2 had other subtypes of PTCL.

The patients received chidamide at 30 mg (n=9) or 50 mg (n=10) twice a week for 2 weeks of a 3-week cycle. The overall response rate was 26% (n=5), and 16% of patients (n=3) had a complete response (CR) or unconfirmed CR (CRu).

Pivotal trial

The pivotal trial included 83 patients who had a median age of 53 and were a median of 1.06 years from diagnosis.

The patients had PTCL-U (29.1%, n=23), nasal NK/T-cell lymphoma (20.3%, n=16), anaplastic large-cell lymphoma (ALCL, 20.3%, n=16), angioimmunoblastic T-cell lymphoma (AITL, 11.4%, n=9), enteropathy-type T-cell lymphoma (2.5%, n=2), CD4-positive PTCL (1.3%, n=1), Lennert-type PTCL (1.3%, n=1), transformed mycosis fungoides (1.3%, n=1), and other subtypes of PTCL (12.7%, n=10).

These patients received chidamide at 30 mg twice a week without a drug-free holiday.

The overall response rate was 29% (n=23) according to investigators and 28% (n=22) according to an independent review committee. Fourteen percent of patients (n=11) had a CR/CRu, according to both sources.

The median progression-free survival was 2.1 months for all patients, 14 months for patients who achieved CR/CRus, 7.7 months in patients with partial responses, and 2.5 months in patients with stable disease.

The median overall survival was 21.4 months in all patients and not reached in patients who had a CR/CRu, partial response, or stable disease.

Overall safety

Of all 102 patients (in both the pivotal and exploratory analyses), 80% had at least one adverse event (AE), 37% had grade 3 or higher AEs, 17% had AEs leading to treatment discontinuation, and 8% had severe AEs.

The most common AEs were thrombocytopenia (50%), leukopenia (37%), neutropenia (19%), fatigue (11%), and fever (11%).

Twenty-four percent of patients had grade 3 or higher thrombocytopenia, 13% had grade 3 or higher leukopenia, and 10% had grade 3 or higher neutropenia.

Chidamide vs other agents

Dr Shi compared response rates with chidamide in the pivotal trial to those previously observed with pralatrexate (O’Connor et al, JCO 2011) and romidepsin (Coiffier et al, J Hematol Oncol 2014).

In patients with PTCL-U, response rates were similar for all 3 drugs (≈30%). In ALCL, the response rate with chidamide was higher (≈50%) than with pralatrexate (≈30%) or romidepsin (≈25%). And in AITL, the response rate with chidamide was higher (≈45%) than with pralatrexate (≈8%) or romidepsin (≈30%).

Chidamide also conferred better overall survival than pralatrexate, romidepsin, and other treatments from previous studies.

The median overall survival was 6.5 months with chemotherapy (Mak et al, JCO 2013), 14.5 months with pralatrexate (O’Connor et al, JCO 2011), 11.3 months with romidepsin (Coiffier et al, J Hematol Oncol 2014), 7.9 months with belinostat (Hyon-Zu Lee, Clinical Review 2009), and 21.4 months with chidamide.

Finally, Dr Shi compared the rates of AEs observed in the chidamide pivotal trial to AEs observed in the pralatrexate and romidepsin trials.

At least one AE occurred in 100% of patients treated with pralatrexate, 96% of patients on romidepsin, and 82% of patients on chidamide. Grade 3 or higher AEs occurred in 74%, 66%, and 39% of patients, respectively. And at least one severe AE occurred in 44%, 46%, and 8% of patients, respectively.

The favorable results observed with chidamide support the Chinese Food and Drug Administration’s December decision to approve the drug (under the brand name Epidaza) for use in patients with PTCL.

Massimo Federico, MD

Photo by Larry Young

SAN FRANCISCO—Outcomes remain dismal for the majority of patients with peripheral T-cell lymphoma (PTCL), according to a speaker at the 7th Annual T-cell Lymphoma Forum.

Massimo Federico, MD, of the Università di Modena e Reggio Emilia in Italy, presented an analysis of the first 1000 patients enrolled in the prospective T-Cell Project.

The data showed no improvements in survival for these patients compared to patients included in the retrospective International Peripheral T-Cell Lymphoma

Project.

The International Peripheral T-Cell Lymphoma Project included PTCL patients treated at various institutions between 1990 and 2002.

The T-Cell Project was designed to complement this retrospective analysis, providing prospective international data on PTCL patients.

“The main aim was to verify if a prospective collection of data would allow for more accurate information to better define prognosis of the most frequent subtypes of PTCL—PTCL not otherwise specified (NOS) and angioimmunoblastic T-cell lymphoma (AITL)—and improve our knowledge of clinical and biological characteristics and outcomes of the more uncommon subtypes of PTCL,” Dr Federico said.

He reported that, as of January 12, 2015, 73 institutions were recruiting patients for the project, and 6 institutions were active but not yet recruiting.

Of the 1308 patients registered at that point, 46% were from European countries (Italy, UK, Switzerland, Slovakia, Spain, and France), 20% were from the US, 20% were from South America (Argentina, Brazil, Chile, and Uruguay), and 14% were from the Middle East or Far East (South Korea, Hong Kong, and Israel).

Dr Federico went on to present data from the first 1000 patients registered in the project. The final analysis actually included 943 patients, as some patients withdrew consent, some did not have baseline data available, and some diagnoses could not be confirmed.

So of the 943 patients, 37% had PTCL-NOS, 17% had AITL, 15% had ALK-negative anaplastic large-cell lymphoma (ALCL), 7% had ALK-positive ALCL, 11% had natural killer/T-cell lymphoma (NKTCL), 8% had T-cell receptor γδ T-cell lymphoma, and 5% had other histologies.

The patients’ median age was 56 (range, 18-89), and 61% were male. Twenty-four percent of patients had an ECOG status greater than 1, 48% had B symptoms, and 71% had disease-related discomfort. Sixty-seven percent of patients had stage III-IV disease, 27% had nodal-only disease, 6% had bulky disease, 29% had more than 1 extranodal site, and 19% had bone marrow involvement.

The median follow-up was 41 months (range, 1-91). The 5-year overall survival (OS) was 44%, and the median OS was 39 months.

The 5-year OS was 35% for patients with PTCL-NOS, 42% for those with AITL, 45% for those with ALK-negative ALCL, 80% for those with ALK-positive ALCL, 48% for those with NKTCL (56% for nasal and 33% for extranasal), and 39% for those with T-cell receptor γδ T-cell lymphoma.

In comparison, the International Peripheral T-Cell Lymphoma Project showed a 5-year OS of 32% for patients with PTCL-NOS, 70% for patients with ALK-positive ALCL, and 49% for patients with ALK-negative ALCL (K. Savage et al. Blood 2008). The 5-year OS was 40% for patients with nasal NKTCL and 15% for those with extranasal NKTCL (W. Au et al. Blood 2008).

“[T]he outcome of PTCL continues to be dismal in the majority of cases, [with] no improvement in overall survival compared to older series,” Dr Federico summarized. “Treatment remains challenging, and new therapies are welcome.”

He added that the next steps for the T-Cell Project are to continue registration (with the goal of reaching 2000 assessable cases), extend the network to additional sites (particularly in under-represented areas such as Japan, China, India, and Oceania), and expand the collection of tissue.

“In particular, we intend to create an international tissue catalogue—including paraffin-embedded samples and, if possible, frozen ones—accessible to research groups with a solid reputation in investigating PTCLs at the molecular and translation level.”

Massimo Federico, MD

Photo by Larry Young

SAN FRANCISCO—Outcomes remain dismal for the majority of patients with peripheral T-cell lymphoma (PTCL), according to a speaker at the 7th Annual T-cell Lymphoma Forum.

Massimo Federico, MD, of the Università di Modena e Reggio Emilia in Italy, presented an analysis of the first 1000 patients enrolled in the prospective T-Cell Project.

The data showed no improvements in survival for these patients compared to patients included in the retrospective International Peripheral T-Cell Lymphoma

Project.

The International Peripheral T-Cell Lymphoma Project included PTCL patients treated at various institutions between 1990 and 2002.

The T-Cell Project was designed to complement this retrospective analysis, providing prospective international data on PTCL patients.

“The main aim was to verify if a prospective collection of data would allow for more accurate information to better define prognosis of the most frequent subtypes of PTCL—PTCL not otherwise specified (NOS) and angioimmunoblastic T-cell lymphoma (AITL)—and improve our knowledge of clinical and biological characteristics and outcomes of the more uncommon subtypes of PTCL,” Dr Federico said.

He reported that, as of January 12, 2015, 73 institutions were recruiting patients for the project, and 6 institutions were active but not yet recruiting.

Of the 1308 patients registered at that point, 46% were from European countries (Italy, UK, Switzerland, Slovakia, Spain, and France), 20% were from the US, 20% were from South America (Argentina, Brazil, Chile, and Uruguay), and 14% were from the Middle East or Far East (South Korea, Hong Kong, and Israel).

Dr Federico went on to present data from the first 1000 patients registered in the project. The final analysis actually included 943 patients, as some patients withdrew consent, some did not have baseline data available, and some diagnoses could not be confirmed.

So of the 943 patients, 37% had PTCL-NOS, 17% had AITL, 15% had ALK-negative anaplastic large-cell lymphoma (ALCL), 7% had ALK-positive ALCL, 11% had natural killer/T-cell lymphoma (NKTCL), 8% had T-cell receptor γδ T-cell lymphoma, and 5% had other histologies.

The patients’ median age was 56 (range, 18-89), and 61% were male. Twenty-four percent of patients had an ECOG status greater than 1, 48% had B symptoms, and 71% had disease-related discomfort. Sixty-seven percent of patients had stage III-IV disease, 27% had nodal-only disease, 6% had bulky disease, 29% had more than 1 extranodal site, and 19% had bone marrow involvement.

The median follow-up was 41 months (range, 1-91). The 5-year overall survival (OS) was 44%, and the median OS was 39 months.

The 5-year OS was 35% for patients with PTCL-NOS, 42% for those with AITL, 45% for those with ALK-negative ALCL, 80% for those with ALK-positive ALCL, 48% for those with NKTCL (56% for nasal and 33% for extranasal), and 39% for those with T-cell receptor γδ T-cell lymphoma.

In comparison, the International Peripheral T-Cell Lymphoma Project showed a 5-year OS of 32% for patients with PTCL-NOS, 70% for patients with ALK-positive ALCL, and 49% for patients with ALK-negative ALCL (K. Savage et al. Blood 2008). The 5-year OS was 40% for patients with nasal NKTCL and 15% for those with extranasal NKTCL (W. Au et al. Blood 2008).

“[T]he outcome of PTCL continues to be dismal in the majority of cases, [with] no improvement in overall survival compared to older series,” Dr Federico summarized. “Treatment remains challenging, and new therapies are welcome.”

He added that the next steps for the T-Cell Project are to continue registration (with the goal of reaching 2000 assessable cases), extend the network to additional sites (particularly in under-represented areas such as Japan, China, India, and Oceania), and expand the collection of tissue.

“In particular, we intend to create an international tissue catalogue—including paraffin-embedded samples and, if possible, frozen ones—accessible to research groups with a solid reputation in investigating PTCLs at the molecular and translation level.”

Massimo Federico, MD

Photo by Larry Young

SAN FRANCISCO—Outcomes remain dismal for the majority of patients with peripheral T-cell lymphoma (PTCL), according to a speaker at the 7th Annual T-cell Lymphoma Forum.

Massimo Federico, MD, of the Università di Modena e Reggio Emilia in Italy, presented an analysis of the first 1000 patients enrolled in the prospective T-Cell Project.

The data showed no improvements in survival for these patients compared to patients included in the retrospective International Peripheral T-Cell Lymphoma

Project.

The International Peripheral T-Cell Lymphoma Project included PTCL patients treated at various institutions between 1990 and 2002.

The T-Cell Project was designed to complement this retrospective analysis, providing prospective international data on PTCL patients.

“The main aim was to verify if a prospective collection of data would allow for more accurate information to better define prognosis of the most frequent subtypes of PTCL—PTCL not otherwise specified (NOS) and angioimmunoblastic T-cell lymphoma (AITL)—and improve our knowledge of clinical and biological characteristics and outcomes of the more uncommon subtypes of PTCL,” Dr Federico said.

He reported that, as of January 12, 2015, 73 institutions were recruiting patients for the project, and 6 institutions were active but not yet recruiting.

Of the 1308 patients registered at that point, 46% were from European countries (Italy, UK, Switzerland, Slovakia, Spain, and France), 20% were from the US, 20% were from South America (Argentina, Brazil, Chile, and Uruguay), and 14% were from the Middle East or Far East (South Korea, Hong Kong, and Israel).

Dr Federico went on to present data from the first 1000 patients registered in the project. The final analysis actually included 943 patients, as some patients withdrew consent, some did not have baseline data available, and some diagnoses could not be confirmed.

So of the 943 patients, 37% had PTCL-NOS, 17% had AITL, 15% had ALK-negative anaplastic large-cell lymphoma (ALCL), 7% had ALK-positive ALCL, 11% had natural killer/T-cell lymphoma (NKTCL), 8% had T-cell receptor γδ T-cell lymphoma, and 5% had other histologies.

The patients’ median age was 56 (range, 18-89), and 61% were male. Twenty-four percent of patients had an ECOG status greater than 1, 48% had B symptoms, and 71% had disease-related discomfort. Sixty-seven percent of patients had stage III-IV disease, 27% had nodal-only disease, 6% had bulky disease, 29% had more than 1 extranodal site, and 19% had bone marrow involvement.

The median follow-up was 41 months (range, 1-91). The 5-year overall survival (OS) was 44%, and the median OS was 39 months.

The 5-year OS was 35% for patients with PTCL-NOS, 42% for those with AITL, 45% for those with ALK-negative ALCL, 80% for those with ALK-positive ALCL, 48% for those with NKTCL (56% for nasal and 33% for extranasal), and 39% for those with T-cell receptor γδ T-cell lymphoma.

In comparison, the International Peripheral T-Cell Lymphoma Project showed a 5-year OS of 32% for patients with PTCL-NOS, 70% for patients with ALK-positive ALCL, and 49% for patients with ALK-negative ALCL (K. Savage et al. Blood 2008). The 5-year OS was 40% for patients with nasal NKTCL and 15% for those with extranasal NKTCL (W. Au et al. Blood 2008).

“[T]he outcome of PTCL continues to be dismal in the majority of cases, [with] no improvement in overall survival compared to older series,” Dr Federico summarized. “Treatment remains challenging, and new therapies are welcome.”

He added that the next steps for the T-Cell Project are to continue registration (with the goal of reaching 2000 assessable cases), extend the network to additional sites (particularly in under-represented areas such as Japan, China, India, and Oceania), and expand the collection of tissue.

“In particular, we intend to create an international tissue catalogue—including paraffin-embedded samples and, if possible, frozen ones—accessible to research groups with a solid reputation in investigating PTCLs at the molecular and translation level.”

Andrei Shustov, MD

Photo by Larry Young

SAN FRANCISCO—The distribution of peripheral T-cell lymphoma (PTCL) subtypes in the US varies greatly according to race and ethnicity, new research suggests.

The retrospective study showed that the overall incidence of PTCL and its subtypes is lower in American Indians and Alaskan Natives than in other ethnic groups.

And the black population has a significantly higher incidence of PTCL—and the most common subtype, PTCL-not otherwise specified (NOS)—than other populations.

Andrei Shustov, MD, of the University of Washington Medical Center in Seattle, presented these and other findings at the 7th Annual T-cell Lymphoma Forum.

The findings were derived from data collected by the Surveillance, Epidemiology, and End Results (SEER) Cancer Registries, which cover 28% of the US population. The data included patients older than 15 years of age who were treated at 18 centers from 2000 through 2011.

Of all cancer patients registered over the 12-year period, 60% were non-Hispanic whites (n=470,864,199), 17% were Hispanic whites (n=134,464,006), 12% were black (n=92,294,395), 10% were Asian/Pacific Islanders (n=74,973,831), and 1% were American Indian/Alaskan Natives (n=10,802,898).

The overall incidence of PTCL was highest in blacks—2.11 per 100,000 persons per year, compared to 1.63 in non-Hispanic whites, 1.53 in Hispanic whites, 1.46 in Asian/Pacific Islanders, and 0.97 in American Indian/Alaskan Natives.

Although American Indian/Alaskan Natives appear to have the lowest overall rate of PTCLs, some cases may have been misclassified, Dr Shustov noted.

“The data collected for ethnicity in the SEER registry are self-reported, and a lot of American Indian/Alaskan Natives misreport their ethnic background,” he said.

Subtype analyses

PTCL-NOS was the most common subtype among all the racial/ethnic groups. The highest rate of PTCL-NOS (per 100,000 persons per year) was in blacks—at 0.77, compared to 0.47 in non-Hispanic whites, 0.46 in Hispanic whites, 0.45 in Asian/Pacific Islanders, and 0.28 in American Indian/Alaskan Natives.

The proportion of PTCL-NOS cases was 29.5% in non-Hispanic whites, 35.7% in blacks, 29.8% in Asian/Pacific Islanders, 27% in Hispanic whites, and 23.1% in American Indian/Alaskan Natives.

The proportion of angioimmunoblastic T-cell lymphoma cases was 9.9% in non-Hispanic whites, 5.2% in blacks, 15.3% in Asian/Pacific Islanders, 9.9% in Hispanic whites, and 2.6% in American Indian/Alaskan Natives.

The proportion of anaplastic large-cell lymphoma cases was 17.6% in non-Hispanic whites, 17.3% in blacks, 12.4% in Asian/Pacific Islanders, 21.2% in Hispanic whites, and 28.2% in American Indian/Alaskan Natives.

And the proportion of NK/T-cell lymphoma cases was 3.4% in non-Hispanic whites, 2.0% in blacks, 13.9% in Asian/Pacific Islanders, 14.6% in Hispanic whites, and 14.1% in American Indian/Alaskan Natives.

“That data indicates that, given the overall incidence of T-cell lymphoma in Natives is lower than in whites, if you’re a Native American/Alaskan Native [with] T-cell lymphoma, you’re 4 times more likely to have nasal NK-cell lymphoma than non-Hispanic whites,” Dr Shustov said.

He then showed a pairwise comparison of the percentage of PTCL subtypes. All of the racial/ethnic groups were significantly different from one another (P<0.001), except when Hispanic whites were compared to American Indian/Alaskan Natives (P=0.14).

Dr Shustov said this might be explained by the fact that these two groups have similar genetic backgrounds.

Andrei Shustov, MD

Photo by Larry Young

SAN FRANCISCO—The distribution of peripheral T-cell lymphoma (PTCL) subtypes in the US varies greatly according to race and ethnicity, new research suggests.

The retrospective study showed that the overall incidence of PTCL and its subtypes is lower in American Indians and Alaskan Natives than in other ethnic groups.

And the black population has a significantly higher incidence of PTCL—and the most common subtype, PTCL-not otherwise specified (NOS)—than other populations.

Andrei Shustov, MD, of the University of Washington Medical Center in Seattle, presented these and other findings at the 7th Annual T-cell Lymphoma Forum.

The findings were derived from data collected by the Surveillance, Epidemiology, and End Results (SEER) Cancer Registries, which cover 28% of the US population. The data included patients older than 15 years of age who were treated at 18 centers from 2000 through 2011.

Of all cancer patients registered over the 12-year period, 60% were non-Hispanic whites (n=470,864,199), 17% were Hispanic whites (n=134,464,006), 12% were black (n=92,294,395), 10% were Asian/Pacific Islanders (n=74,973,831), and 1% were American Indian/Alaskan Natives (n=10,802,898).

The overall incidence of PTCL was highest in blacks—2.11 per 100,000 persons per year, compared to 1.63 in non-Hispanic whites, 1.53 in Hispanic whites, 1.46 in Asian/Pacific Islanders, and 0.97 in American Indian/Alaskan Natives.

Although American Indian/Alaskan Natives appear to have the lowest overall rate of PTCLs, some cases may have been misclassified, Dr Shustov noted.

“The data collected for ethnicity in the SEER registry are self-reported, and a lot of American Indian/Alaskan Natives misreport their ethnic background,” he said.

Subtype analyses

PTCL-NOS was the most common subtype among all the racial/ethnic groups. The highest rate of PTCL-NOS (per 100,000 persons per year) was in blacks—at 0.77, compared to 0.47 in non-Hispanic whites, 0.46 in Hispanic whites, 0.45 in Asian/Pacific Islanders, and 0.28 in American Indian/Alaskan Natives.

The proportion of PTCL-NOS cases was 29.5% in non-Hispanic whites, 35.7% in blacks, 29.8% in Asian/Pacific Islanders, 27% in Hispanic whites, and 23.1% in American Indian/Alaskan Natives.

The proportion of angioimmunoblastic T-cell lymphoma cases was 9.9% in non-Hispanic whites, 5.2% in blacks, 15.3% in Asian/Pacific Islanders, 9.9% in Hispanic whites, and 2.6% in American Indian/Alaskan Natives.

The proportion of anaplastic large-cell lymphoma cases was 17.6% in non-Hispanic whites, 17.3% in blacks, 12.4% in Asian/Pacific Islanders, 21.2% in Hispanic whites, and 28.2% in American Indian/Alaskan Natives.

And the proportion of NK/T-cell lymphoma cases was 3.4% in non-Hispanic whites, 2.0% in blacks, 13.9% in Asian/Pacific Islanders, 14.6% in Hispanic whites, and 14.1% in American Indian/Alaskan Natives.

“That data indicates that, given the overall incidence of T-cell lymphoma in Natives is lower than in whites, if you’re a Native American/Alaskan Native [with] T-cell lymphoma, you’re 4 times more likely to have nasal NK-cell lymphoma than non-Hispanic whites,” Dr Shustov said.

He then showed a pairwise comparison of the percentage of PTCL subtypes. All of the racial/ethnic groups were significantly different from one another (P<0.001), except when Hispanic whites were compared to American Indian/Alaskan Natives (P=0.14).

Dr Shustov said this might be explained by the fact that these two groups have similar genetic backgrounds.

Andrei Shustov, MD

Photo by Larry Young

SAN FRANCISCO—The distribution of peripheral T-cell lymphoma (PTCL) subtypes in the US varies greatly according to race and ethnicity, new research suggests.

The retrospective study showed that the overall incidence of PTCL and its subtypes is lower in American Indians and Alaskan Natives than in other ethnic groups.

And the black population has a significantly higher incidence of PTCL—and the most common subtype, PTCL-not otherwise specified (NOS)—than other populations.

Andrei Shustov, MD, of the University of Washington Medical Center in Seattle, presented these and other findings at the 7th Annual T-cell Lymphoma Forum.

The findings were derived from data collected by the Surveillance, Epidemiology, and End Results (SEER) Cancer Registries, which cover 28% of the US population. The data included patients older than 15 years of age who were treated at 18 centers from 2000 through 2011.

Of all cancer patients registered over the 12-year period, 60% were non-Hispanic whites (n=470,864,199), 17% were Hispanic whites (n=134,464,006), 12% were black (n=92,294,395), 10% were Asian/Pacific Islanders (n=74,973,831), and 1% were American Indian/Alaskan Natives (n=10,802,898).

The overall incidence of PTCL was highest in blacks—2.11 per 100,000 persons per year, compared to 1.63 in non-Hispanic whites, 1.53 in Hispanic whites, 1.46 in Asian/Pacific Islanders, and 0.97 in American Indian/Alaskan Natives.

Although American Indian/Alaskan Natives appear to have the lowest overall rate of PTCLs, some cases may have been misclassified, Dr Shustov noted.

“The data collected for ethnicity in the SEER registry are self-reported, and a lot of American Indian/Alaskan Natives misreport their ethnic background,” he said.

Subtype analyses

PTCL-NOS was the most common subtype among all the racial/ethnic groups. The highest rate of PTCL-NOS (per 100,000 persons per year) was in blacks—at 0.77, compared to 0.47 in non-Hispanic whites, 0.46 in Hispanic whites, 0.45 in Asian/Pacific Islanders, and 0.28 in American Indian/Alaskan Natives.

The proportion of PTCL-NOS cases was 29.5% in non-Hispanic whites, 35.7% in blacks, 29.8% in Asian/Pacific Islanders, 27% in Hispanic whites, and 23.1% in American Indian/Alaskan Natives.

The proportion of angioimmunoblastic T-cell lymphoma cases was 9.9% in non-Hispanic whites, 5.2% in blacks, 15.3% in Asian/Pacific Islanders, 9.9% in Hispanic whites, and 2.6% in American Indian/Alaskan Natives.

The proportion of anaplastic large-cell lymphoma cases was 17.6% in non-Hispanic whites, 17.3% in blacks, 12.4% in Asian/Pacific Islanders, 21.2% in Hispanic whites, and 28.2% in American Indian/Alaskan Natives.

And the proportion of NK/T-cell lymphoma cases was 3.4% in non-Hispanic whites, 2.0% in blacks, 13.9% in Asian/Pacific Islanders, 14.6% in Hispanic whites, and 14.1% in American Indian/Alaskan Natives.

“That data indicates that, given the overall incidence of T-cell lymphoma in Natives is lower than in whites, if you’re a Native American/Alaskan Native [with] T-cell lymphoma, you’re 4 times more likely to have nasal NK-cell lymphoma than non-Hispanic whites,” Dr Shustov said.

He then showed a pairwise comparison of the percentage of PTCL subtypes. All of the racial/ethnic groups were significantly different from one another (P<0.001), except when Hispanic whites were compared to American Indian/Alaskan Natives (P=0.14).

Dr Shustov said this might be explained by the fact that these two groups have similar genetic backgrounds.

In his monthly podcast for The Journal of Community and Supportive Oncology, Dr David Henry looks at Original Reports on the comparison of atropine-diphenoxylate and hyoscyamine in lowering the rates of irinotecan-related cholinergic syndrome; the effects of age and comorbidities in the management of rectal cancer in elderly patients at an institution in Portugal; the impact of a telehealth intervention on quality of life and symptom distress in patients with head and neck cancer; and the beneficial effects of animal-assisted visits on quality of life during multimodal radiation-chemotherapy regimens. He also discusses a Research Report in which the authors attempt, possibly for the first time, to quantify radiation exposure from diagnostic procedures in patients with newly diagnosed breast cancer, as well as two feature articles – a round-up of some of the presentations at the 2014 San Antonio Breast Cancer Symposium and a Journal Club presentation of therapies for lymphoproliferative disorders.

In his monthly podcast for The Journal of Community and Supportive Oncology, Dr David Henry looks at Original Reports on the comparison of atropine-diphenoxylate and hyoscyamine in lowering the rates of irinotecan-related cholinergic syndrome; the effects of age and comorbidities in the management of rectal cancer in elderly patients at an institution in Portugal; the impact of a telehealth intervention on quality of life and symptom distress in patients with head and neck cancer; and the beneficial effects of animal-assisted visits on quality of life during multimodal radiation-chemotherapy regimens. He also discusses a Research Report in which the authors attempt, possibly for the first time, to quantify radiation exposure from diagnostic procedures in patients with newly diagnosed breast cancer, as well as two feature articles – a round-up of some of the presentations at the 2014 San Antonio Breast Cancer Symposium and a Journal Club presentation of therapies for lymphoproliferative disorders.

In his monthly podcast for The Journal of Community and Supportive Oncology, Dr David Henry looks at Original Reports on the comparison of atropine-diphenoxylate and hyoscyamine in lowering the rates of irinotecan-related cholinergic syndrome; the effects of age and comorbidities in the management of rectal cancer in elderly patients at an institution in Portugal; the impact of a telehealth intervention on quality of life and symptom distress in patients with head and neck cancer; and the beneficial effects of animal-assisted visits on quality of life during multimodal radiation-chemotherapy regimens. He also discusses a Research Report in which the authors attempt, possibly for the first time, to quantify radiation exposure from diagnostic procedures in patients with newly diagnosed breast cancer, as well as two feature articles – a round-up of some of the presentations at the 2014 San Antonio Breast Cancer Symposium and a Journal Club presentation of therapies for lymphoproliferative disorders.

Prescriptions

Credit: CDC

The US Food and Drug Administration (FDA) has granted approval for ibrutinib (Imbruvica) as the first and only treatment for patients with Waldenstrom’s macroglobulinemia (WM).

The drug is now approved as a single agent for use in all lines of therapy.

This is the fourth indication for ibrutinib, which is also FDA-approved to treat patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, CLL patients with del 17p, and patients with mantle cell lymphoma.

Ibrutinib is being jointly developed and commercialized by Pharmacyclics and Janssen Biotech, Inc.

The latest FDA approval is based on results from a multicenter, phase 2 study in which researchers evaluated the efficacy and tolerability of ibrutinib in 63 patients with previously treated WM.

The response rate, according to an independent review committee, was 62%. Eleven percent of patients had a very good partial response rate, and 51% had a partial response rate.

The median duration of response has not been reached, with a range of 2.8 to 18.8 months.

The most commonly occurring adverse events (>20%) were neutropenia, thrombocytopenia, diarrhea, rash, nausea, muscle spasms, and fatigue.

Six percent of patients discontinued treatment due to adverse events. Events leading to dose reduction occurred in 11% of patients.

For more details, see the full prescribing information.

Prescriptions

Credit: CDC

The US Food and Drug Administration (FDA) has granted approval for ibrutinib (Imbruvica) as the first and only treatment for patients with Waldenstrom’s macroglobulinemia (WM).

The drug is now approved as a single agent for use in all lines of therapy.

This is the fourth indication for ibrutinib, which is also FDA-approved to treat patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, CLL patients with del 17p, and patients with mantle cell lymphoma.

Ibrutinib is being jointly developed and commercialized by Pharmacyclics and Janssen Biotech, Inc.

The latest FDA approval is based on results from a multicenter, phase 2 study in which researchers evaluated the efficacy and tolerability of ibrutinib in 63 patients with previously treated WM.

The response rate, according to an independent review committee, was 62%. Eleven percent of patients had a very good partial response rate, and 51% had a partial response rate.

The median duration of response has not been reached, with a range of 2.8 to 18.8 months.

The most commonly occurring adverse events (>20%) were neutropenia, thrombocytopenia, diarrhea, rash, nausea, muscle spasms, and fatigue.

Six percent of patients discontinued treatment due to adverse events. Events leading to dose reduction occurred in 11% of patients.

For more details, see the full prescribing information.

Prescriptions

Credit: CDC

The US Food and Drug Administration (FDA) has granted approval for ibrutinib (Imbruvica) as the first and only treatment for patients with Waldenstrom’s macroglobulinemia (WM).

The drug is now approved as a single agent for use in all lines of therapy.

This is the fourth indication for ibrutinib, which is also FDA-approved to treat patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, CLL patients with del 17p, and patients with mantle cell lymphoma.

Ibrutinib is being jointly developed and commercialized by Pharmacyclics and Janssen Biotech, Inc.

The latest FDA approval is based on results from a multicenter, phase 2 study in which researchers evaluated the efficacy and tolerability of ibrutinib in 63 patients with previously treated WM.

The response rate, according to an independent review committee, was 62%. Eleven percent of patients had a very good partial response rate, and 51% had a partial response rate.

The median duration of response has not been reached, with a range of 2.8 to 18.8 months.

The most commonly occurring adverse events (>20%) were neutropenia, thrombocytopenia, diarrhea, rash, nausea, muscle spasms, and fatigue.

Six percent of patients discontinued treatment due to adverse events. Events leading to dose reduction occurred in 11% of patients.

For more details, see the full prescribing information.

Dimitrios Stamou, PhD

Credit: Jes Andersen/

University of Copenhagen

Researchers say they have discovered how Ras proteins find their proper place in cells, a finding that may aid the development of novel approaches to treat cancers.

The team noted that cancers develop if Ras proteins start to trigger misregulation, and Ras misregulates if it misses its correct location on the cell wall—the membrane.

What the researchers discovered is that Ras cannot reach its designated location if the membrane has the wrong shape.

“If the curvature of the cell is right, Ras goes to the right place,” said Dimitrios Stamou, PhD, of the University of Copenhagen in Denmark.

“If the membrane is too straight or too bent, it does not. And Ras is very much like any other worker. If it never finds the way to its workplace, it is not likely to get any work done.”

Dr Stamou and his colleagues described this discovery in Nature Chemical Biology.

Ras proteins are thought to be misregulated in upwards of 30% of all cancers. For 3 decades, researchers have been searching for ways to quell the killer protein.

Their lack of success has given Ras a reputation as the “undruggable cancer target,” but Dr Stamou believes we can change by moving in a new direction.

“If Ras goes off the rails because of changes in the curvature of the cell, perhaps we should target whatever changes the shape of the cell membrane,” he said.

Looking for a correlation between cell shape and Ras misregulation was unusual, even bordering on controversial, said study author Jannik Bruun Larsen, PhD, of the University of Copenhagen.

The researchers were investigating how Ras proteins attach themselves to the cell wall, and Dr Larsen tried to attach Ras to a variety of simulated cell membranes formed into small spheres or vesicles of varying sizes.

He found that Ras would attach more readily to smaller spheres, which were more curved than the large ones, and Dr Larsen started to see a pattern.

“For more than a decade, people thought that the constituents of the cell wall was the thing that controlled where Ras was localized,” Dr Larson said. “We have shown that at least one other aspect—namely, membrane curvature—governs where Ras ends up in the cell and is therefore likely to be a factor in cancer development.”

All of the research so far has been conducted in vitro. Dr Stamou said the next big challenge is to uncover how these effects play out in living systems.

“It will be 10 times more difficult to uncover these effects in living systems, but it needs to happen,” he said. “We have started, and we really hope others will follow. It may prove complicated to develop a drug that changes the shape of cells, but I am certain that the discovery of the shape/misregulation-correlation will at least lead to new ways to diagnose cancers.”

Dimitrios Stamou, PhD

Credit: Jes Andersen/

University of Copenhagen

Researchers say they have discovered how Ras proteins find their proper place in cells, a finding that may aid the development of novel approaches to treat cancers.

The team noted that cancers develop if Ras proteins start to trigger misregulation, and Ras misregulates if it misses its correct location on the cell wall—the membrane.

What the researchers discovered is that Ras cannot reach its designated location if the membrane has the wrong shape.

“If the curvature of the cell is right, Ras goes to the right place,” said Dimitrios Stamou, PhD, of the University of Copenhagen in Denmark.

“If the membrane is too straight or too bent, it does not. And Ras is very much like any other worker. If it never finds the way to its workplace, it is not likely to get any work done.”

Dr Stamou and his colleagues described this discovery in Nature Chemical Biology.

Ras proteins are thought to be misregulated in upwards of 30% of all cancers. For 3 decades, researchers have been searching for ways to quell the killer protein.

Their lack of success has given Ras a reputation as the “undruggable cancer target,” but Dr Stamou believes we can change by moving in a new direction.

“If Ras goes off the rails because of changes in the curvature of the cell, perhaps we should target whatever changes the shape of the cell membrane,” he said.

Looking for a correlation between cell shape and Ras misregulation was unusual, even bordering on controversial, said study author Jannik Bruun Larsen, PhD, of the University of Copenhagen.

The researchers were investigating how Ras proteins attach themselves to the cell wall, and Dr Larsen tried to attach Ras to a variety of simulated cell membranes formed into small spheres or vesicles of varying sizes.

He found that Ras would attach more readily to smaller spheres, which were more curved than the large ones, and Dr Larsen started to see a pattern.

“For more than a decade, people thought that the constituents of the cell wall was the thing that controlled where Ras was localized,” Dr Larson said. “We have shown that at least one other aspect—namely, membrane curvature—governs where Ras ends up in the cell and is therefore likely to be a factor in cancer development.”

All of the research so far has been conducted in vitro. Dr Stamou said the next big challenge is to uncover how these effects play out in living systems.

“It will be 10 times more difficult to uncover these effects in living systems, but it needs to happen,” he said. “We have started, and we really hope others will follow. It may prove complicated to develop a drug that changes the shape of cells, but I am certain that the discovery of the shape/misregulation-correlation will at least lead to new ways to diagnose cancers.”

Dimitrios Stamou, PhD

Credit: Jes Andersen/

University of Copenhagen

Researchers say they have discovered how Ras proteins find their proper place in cells, a finding that may aid the development of novel approaches to treat cancers.

The team noted that cancers develop if Ras proteins start to trigger misregulation, and Ras misregulates if it misses its correct location on the cell wall—the membrane.

What the researchers discovered is that Ras cannot reach its designated location if the membrane has the wrong shape.

“If the curvature of the cell is right, Ras goes to the right place,” said Dimitrios Stamou, PhD, of the University of Copenhagen in Denmark.

“If the membrane is too straight or too bent, it does not. And Ras is very much like any other worker. If it never finds the way to its workplace, it is not likely to get any work done.”

Dr Stamou and his colleagues described this discovery in Nature Chemical Biology.

Ras proteins are thought to be misregulated in upwards of 30% of all cancers. For 3 decades, researchers have been searching for ways to quell the killer protein.

Their lack of success has given Ras a reputation as the “undruggable cancer target,” but Dr Stamou believes we can change by moving in a new direction.

“If Ras goes off the rails because of changes in the curvature of the cell, perhaps we should target whatever changes the shape of the cell membrane,” he said.

Looking for a correlation between cell shape and Ras misregulation was unusual, even bordering on controversial, said study author Jannik Bruun Larsen, PhD, of the University of Copenhagen.

The researchers were investigating how Ras proteins attach themselves to the cell wall, and Dr Larsen tried to attach Ras to a variety of simulated cell membranes formed into small spheres or vesicles of varying sizes.

He found that Ras would attach more readily to smaller spheres, which were more curved than the large ones, and Dr Larsen started to see a pattern.

“For more than a decade, people thought that the constituents of the cell wall was the thing that controlled where Ras was localized,” Dr Larson said. “We have shown that at least one other aspect—namely, membrane curvature—governs where Ras ends up in the cell and is therefore likely to be a factor in cancer development.”

All of the research so far has been conducted in vitro. Dr Stamou said the next big challenge is to uncover how these effects play out in living systems.

“It will be 10 times more difficult to uncover these effects in living systems, but it needs to happen,” he said. “We have started, and we really hope others will follow. It may prove complicated to develop a drug that changes the shape of cells, but I am certain that the discovery of the shape/misregulation-correlation will at least lead to new ways to diagnose cancers.”

Burkitt lymphoma cells

Credit: Ed Uthman

New research has revealed how Epstein Barr virus (EBV) and other herpes viruses outwit the body’s immune response.

It seems these viruses carry microRNAs (miRNAs) that block the interferon (IFN) response—when immune cells release IFN to prevent viral replication, which often kills or slows the growth of infected host cells.

This appears to explain why patients with EBV-positive lymphomas and other viral cancers may resist treatment with IFN.

Jennifer Cox, a graduate student at the University of Texas Austin, and her colleagues recounted these findings in PNAS.

The team noted that many viruses, including EBV, carry miRNAs they use to hijack natural processes in a host’s cells during an infection.

Viral miRNAs are known to prevent host cell death, promote host cell growth, and dampen the host cell’s viral defenses. However, scientists don’t yet know which viral miRNAs perform which functions.

To gain some insight, Cox and her colleagues screened a library of more than 70 human viral miRNAs. This revealed 3 unrelated miRNAs from distantly related herpes viruses that significantly inhibited IFN signaling.

The 5’ and 3’ derivatives from EBV-encoded miR-BART-18 precursor miRNA and the orthologous precursor miRNA from Rhesus lymphocryptovirus all reduced expression of the cyclic AMP-responsive element-binding protein (CBP), which, as part of the p300-CBP complex, mediates IFN signaling.

When the researchers restored miR-BART-18 to cells infected with an EBV miRNA mutant, they observed a cellular growth advantage upon IFN treatment. And they found that miRNAs from other herpes viruses were able to complement this activity.

The team also showed that blocking miR-BART-18 function in an EBV-positive tumor cell line rendered cells more susceptible to IFN-mediated effects.

“[These findings] could explain the variability seen in the success of previous interferon-based cancer treatments,” Cox said. “While this work does not immediately identify new drugs, the fact that such different tumor viruses have converged on the same strategy makes this an exciting pursuit for future therapies against viral cancers.”

Burkitt lymphoma cells

Credit: Ed Uthman

New research has revealed how Epstein Barr virus (EBV) and other herpes viruses outwit the body’s immune response.

It seems these viruses carry microRNAs (miRNAs) that block the interferon (IFN) response—when immune cells release IFN to prevent viral replication, which often kills or slows the growth of infected host cells.

This appears to explain why patients with EBV-positive lymphomas and other viral cancers may resist treatment with IFN.

Jennifer Cox, a graduate student at the University of Texas Austin, and her colleagues recounted these findings in PNAS.

The team noted that many viruses, including EBV, carry miRNAs they use to hijack natural processes in a host’s cells during an infection.

Viral miRNAs are known to prevent host cell death, promote host cell growth, and dampen the host cell’s viral defenses. However, scientists don’t yet know which viral miRNAs perform which functions.

To gain some insight, Cox and her colleagues screened a library of more than 70 human viral miRNAs. This revealed 3 unrelated miRNAs from distantly related herpes viruses that significantly inhibited IFN signaling.

The 5’ and 3’ derivatives from EBV-encoded miR-BART-18 precursor miRNA and the orthologous precursor miRNA from Rhesus lymphocryptovirus all reduced expression of the cyclic AMP-responsive element-binding protein (CBP), which, as part of the p300-CBP complex, mediates IFN signaling.

When the researchers restored miR-BART-18 to cells infected with an EBV miRNA mutant, they observed a cellular growth advantage upon IFN treatment. And they found that miRNAs from other herpes viruses were able to complement this activity.

The team also showed that blocking miR-BART-18 function in an EBV-positive tumor cell line rendered cells more susceptible to IFN-mediated effects.

“[These findings] could explain the variability seen in the success of previous interferon-based cancer treatments,” Cox said. “While this work does not immediately identify new drugs, the fact that such different tumor viruses have converged on the same strategy makes this an exciting pursuit for future therapies against viral cancers.”

Burkitt lymphoma cells

Credit: Ed Uthman

New research has revealed how Epstein Barr virus (EBV) and other herpes viruses outwit the body’s immune response.

It seems these viruses carry microRNAs (miRNAs) that block the interferon (IFN) response—when immune cells release IFN to prevent viral replication, which often kills or slows the growth of infected host cells.

This appears to explain why patients with EBV-positive lymphomas and other viral cancers may resist treatment with IFN.

Jennifer Cox, a graduate student at the University of Texas Austin, and her colleagues recounted these findings in PNAS.

The team noted that many viruses, including EBV, carry miRNAs they use to hijack natural processes in a host’s cells during an infection.

Viral miRNAs are known to prevent host cell death, promote host cell growth, and dampen the host cell’s viral defenses. However, scientists don’t yet know which viral miRNAs perform which functions.

To gain some insight, Cox and her colleagues screened a library of more than 70 human viral miRNAs. This revealed 3 unrelated miRNAs from distantly related herpes viruses that significantly inhibited IFN signaling.

The 5’ and 3’ derivatives from EBV-encoded miR-BART-18 precursor miRNA and the orthologous precursor miRNA from Rhesus lymphocryptovirus all reduced expression of the cyclic AMP-responsive element-binding protein (CBP), which, as part of the p300-CBP complex, mediates IFN signaling.

When the researchers restored miR-BART-18 to cells infected with an EBV miRNA mutant, they observed a cellular growth advantage upon IFN treatment. And they found that miRNAs from other herpes viruses were able to complement this activity.

The team also showed that blocking miR-BART-18 function in an EBV-positive tumor cell line rendered cells more susceptible to IFN-mediated effects.

“[These findings] could explain the variability seen in the success of previous interferon-based cancer treatments,” Cox said. “While this work does not immediately identify new drugs, the fact that such different tumor viruses have converged on the same strategy makes this an exciting pursuit for future therapies against viral cancers.”

Prescription medications

Credit: Steven Harbour

The European Medicines Agency (EMA) has recommended suspending a number of drugs that were approved in the European Union (EU) based on clinical studies conducted at GVK Biosciences in Hyderabad, India.

An inspection of the site suggested GVK Bio employees may have manipulated data from trials that took place there.

So the EMA compiled a list of drugs—which includes clopidogrel, dexamethasone, and tacrolimus, among others—that should be suspended.

However, the EMA said there is no evidence of harm or lack of effectiveness linked to the conduct of studies by GVK Bio, and patients should continue taking their medicines as prescribed.

The EMA’s opinion has been forwarded to the European Commission (EC), which will adopt a legally binding decision.

It was at the request of the EC that the EMA’s Committee for Medicinal Products for Human Use (CHMP) reviewed the drugs set to be suspended.

An inspection by the French medicines agency, Agence nationale de sécurité du médicament et des produits de santé (ANSM), in May 2014 uncovered “non-compliance with good clinical practice” at the GVK Bio site in Hyderabad.

The ANSM inspector analyzed 9 studies conducted there from 2008 to 2013 and found evidence suggesting that data from electrocardiograms (ECGs) had been manipulated. It appeared that GVK Bio employees were taking multiple ECGs of one volunteer and presenting them as ECGs of other volunteers.

The EMA said the systematic nature of these data manipulations, the extended period of time during which they took place, and the number of staff members involved casts doubt on the integrity of the way trials were performed at the Hyderabad facility and on the reliability of data generated there.

With this in mind, the CHMP looked at more than 1000 pharmaceutical forms and strengths of medicines studied at the site. For more than 300 of the medications, there was sufficient data from other sources to support the drugs’ authorization, so these will remain on the market in the EU.

For drugs that lack data from other studies, the CHMP recommended suspension unless they are of critical importance for patients because alternatives will not be able to meet patients’ needs.

Whether a medicine is critical for patients will be determined by the national authorities of EU member states, depending on the situation in their country. For drugs that are considered critical, companies developing those drugs will be given 12 months to submit additional data.

The CHMP’s recommendation will be sent to the EC for a legally binding decision that will apply to all EU member states whether or not they have taken interim measures to suspend medicines.

GVK Bio responds

GVK Bio said an internal audit conducted following the ANSM inspection suggested that standard operating procedures were followed for the 9 trials analyzed. The organization also sought the opinion of 4 independent cardiologists, who said it was difficult to determine if the ECGs belong to the same volunteer or more than one person.

GVK Bio presented this information to the ANSM, but the agency concluded that the studies did not meet good clinical practice guidelines and should be rejected.

Following subsequent meetings and analyses, the EMA came to a similar conclusion—that the overall findings cast doubt on the results of trials conducted at the Hyderabad facility from 2008 to 2014.

GVK Bio said it respects the EMA’s decision, but their recommended suspension of drugs is “unprecedented and highly disproportional” for a few reasons.

First, the ANSM said the ECGs in question were not essential to demonstrate the bioequivalence of the drugs tested, and the agency’s recommendation to reject the 9 studies was a “precautionary” measure.

The ANSM also said the observations made during the inspection should not be extrapolated to other trial-related activities at the Hyderabad site or GVK Bio’s other site in Ahmedabad.

And finally, the EMA itself said there is no evidence proving that the drugs in question are ineffective or pose a risk to human health.

Prescription medications

Credit: Steven Harbour

The European Medicines Agency (EMA) has recommended suspending a number of drugs that were approved in the European Union (EU) based on clinical studies conducted at GVK Biosciences in Hyderabad, India.

An inspection of the site suggested GVK Bio employees may have manipulated data from trials that took place there.

So the EMA compiled a list of drugs—which includes clopidogrel, dexamethasone, and tacrolimus, among others—that should be suspended.

However, the EMA said there is no evidence of harm or lack of effectiveness linked to the conduct of studies by GVK Bio, and patients should continue taking their medicines as prescribed.

The EMA’s opinion has been forwarded to the European Commission (EC), which will adopt a legally binding decision.

It was at the request of the EC that the EMA’s Committee for Medicinal Products for Human Use (CHMP) reviewed the drugs set to be suspended.

An inspection by the French medicines agency, Agence nationale de sécurité du médicament et des produits de santé (ANSM), in May 2014 uncovered “non-compliance with good clinical practice” at the GVK Bio site in Hyderabad.

The ANSM inspector analyzed 9 studies conducted there from 2008 to 2013 and found evidence suggesting that data from electrocardiograms (ECGs) had been manipulated. It appeared that GVK Bio employees were taking multiple ECGs of one volunteer and presenting them as ECGs of other volunteers.

The EMA said the systematic nature of these data manipulations, the extended period of time during which they took place, and the number of staff members involved casts doubt on the integrity of the way trials were performed at the Hyderabad facility and on the reliability of data generated there.

With this in mind, the CHMP looked at more than 1000 pharmaceutical forms and strengths of medicines studied at the site. For more than 300 of the medications, there was sufficient data from other sources to support the drugs’ authorization, so these will remain on the market in the EU.

For drugs that lack data from other studies, the CHMP recommended suspension unless they are of critical importance for patients because alternatives will not be able to meet patients’ needs.

Whether a medicine is critical for patients will be determined by the national authorities of EU member states, depending on the situation in their country. For drugs that are considered critical, companies developing those drugs will be given 12 months to submit additional data.

The CHMP’s recommendation will be sent to the EC for a legally binding decision that will apply to all EU member states whether or not they have taken interim measures to suspend medicines.

GVK Bio responds

GVK Bio said an internal audit conducted following the ANSM inspection suggested that standard operating procedures were followed for the 9 trials analyzed. The organization also sought the opinion of 4 independent cardiologists, who said it was difficult to determine if the ECGs belong to the same volunteer or more than one person.

GVK Bio presented this information to the ANSM, but the agency concluded that the studies did not meet good clinical practice guidelines and should be rejected.

Following subsequent meetings and analyses, the EMA came to a similar conclusion—that the overall findings cast doubt on the results of trials conducted at the Hyderabad facility from 2008 to 2014.

GVK Bio said it respects the EMA’s decision, but their recommended suspension of drugs is “unprecedented and highly disproportional” for a few reasons.

First, the ANSM said the ECGs in question were not essential to demonstrate the bioequivalence of the drugs tested, and the agency’s recommendation to reject the 9 studies was a “precautionary” measure.

The ANSM also said the observations made during the inspection should not be extrapolated to other trial-related activities at the Hyderabad site or GVK Bio’s other site in Ahmedabad.

And finally, the EMA itself said there is no evidence proving that the drugs in question are ineffective or pose a risk to human health.

Prescription medications

Credit: Steven Harbour

The European Medicines Agency (EMA) has recommended suspending a number of drugs that were approved in the European Union (EU) based on clinical studies conducted at GVK Biosciences in Hyderabad, India.

An inspection of the site suggested GVK Bio employees may have manipulated data from trials that took place there.

So the EMA compiled a list of drugs—which includes clopidogrel, dexamethasone, and tacrolimus, among others—that should be suspended.

However, the EMA said there is no evidence of harm or lack of effectiveness linked to the conduct of studies by GVK Bio, and patients should continue taking their medicines as prescribed.

The EMA’s opinion has been forwarded to the European Commission (EC), which will adopt a legally binding decision.

It was at the request of the EC that the EMA’s Committee for Medicinal Products for Human Use (CHMP) reviewed the drugs set to be suspended.

An inspection by the French medicines agency, Agence nationale de sécurité du médicament et des produits de santé (ANSM), in May 2014 uncovered “non-compliance with good clinical practice” at the GVK Bio site in Hyderabad.

The ANSM inspector analyzed 9 studies conducted there from 2008 to 2013 and found evidence suggesting that data from electrocardiograms (ECGs) had been manipulated. It appeared that GVK Bio employees were taking multiple ECGs of one volunteer and presenting them as ECGs of other volunteers.

The EMA said the systematic nature of these data manipulations, the extended period of time during which they took place, and the number of staff members involved casts doubt on the integrity of the way trials were performed at the Hyderabad facility and on the reliability of data generated there.

With this in mind, the CHMP looked at more than 1000 pharmaceutical forms and strengths of medicines studied at the site. For more than 300 of the medications, there was sufficient data from other sources to support the drugs’ authorization, so these will remain on the market in the EU.

For drugs that lack data from other studies, the CHMP recommended suspension unless they are of critical importance for patients because alternatives will not be able to meet patients’ needs.

Whether a medicine is critical for patients will be determined by the national authorities of EU member states, depending on the situation in their country. For drugs that are considered critical, companies developing those drugs will be given 12 months to submit additional data.

The CHMP’s recommendation will be sent to the EC for a legally binding decision that will apply to all EU member states whether or not they have taken interim measures to suspend medicines.

GVK Bio responds

GVK Bio said an internal audit conducted following the ANSM inspection suggested that standard operating procedures were followed for the 9 trials analyzed. The organization also sought the opinion of 4 independent cardiologists, who said it was difficult to determine if the ECGs belong to the same volunteer or more than one person.

GVK Bio presented this information to the ANSM, but the agency concluded that the studies did not meet good clinical practice guidelines and should be rejected.

Following subsequent meetings and analyses, the EMA came to a similar conclusion—that the overall findings cast doubt on the results of trials conducted at the Hyderabad facility from 2008 to 2014.

GVK Bio said it respects the EMA’s decision, but their recommended suspension of drugs is “unprecedented and highly disproportional” for a few reasons.

First, the ANSM said the ECGs in question were not essential to demonstrate the bioequivalence of the drugs tested, and the agency’s recommendation to reject the 9 studies was a “precautionary” measure.

The ANSM also said the observations made during the inspection should not be extrapolated to other trial-related activities at the Hyderabad site or GVK Bio’s other site in Ahmedabad.

And finally, the EMA itself said there is no evidence proving that the drugs in question are ineffective or pose a risk to human health.