TCLF 2015

Bertrand Coiffier, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Adding romidepsin to CHOP can enhance the regimen’s efficacy against peripheral T-cell lymphoma (PTCL), but the combination can also induce severe toxicity, results of a phase 1b/2 study have shown.

In patients with previously untreated PTCL, romidepsin plus CHOP elicited an overall response rate of about 69%.

But all patients experienced adverse events, a median of 49 per patient. In addition, rates of hematologic toxicities were high, and 3 patients experienced acute cardiac toxicity.

Bertrand Coiffier, MD, PhD, of CHU Lyon Sud in Pierre Benite, France, presented these findings at the 7th Annual T-cell Lymphoma Forum. Dr Coiffier and other researchers involved in this study receive funds from Celgene, the company developing romidepsin.

“CHOP is widely accepted,” Dr Coiffier noted. “It’s the most-used regimen for peripheral T-cell lymphoma, but it’s not the best one, and we certainly have regimens that do produce more [complete responses] and longer responses.”

He said researchers decided to test romidepsin in combination with CHOP because studies have suggested that romidepsin has very good efficacy in relapsed/refractory peripheral T-cell lymphoma, and the toxicities associated with romidepsin and CHOP alone have been managable.

So the researchers tested the combination in 37 patients with untreated PTCL, most of whom were male (n=20). The median age was 57, and 37.8% were older than 60. About 95% of patients had stage III/IV disease, and about 89% had an ECOG performance status less than 2.

Most patients had angioimmunoblastic T-cell lymphoma (n=17), followed by PTCL not otherwise specified (n=13), ALK- anaplastic large-cell lymphoma (n=3), enteropathy-associated T-cell lymphoma (n=1), hepatosplenic T-cell lymphoma (n=1), primary cutaneous CD4⁺ small/medium T-cell lymphoma (n=1), and “other” (n=1).

Early DLTs

The researchers used a standard “3+3” dose-escalation scheme, starting with a romidepsin dose of 10 mg/m² given on days 1 and 8.

In the first 2 cycles, there were 3 dose-limiting toxicities (DLTs)—1 case  of grade 3 syncope, 1 case of grade 3 general status alteration, and 1 case of grade 3 hematologic toxicity (neutropenia and thrombocytopenia) lasting longer than 7 days.

“So we looked at the definition of the criteria for DLT, and we thought that, this time, they were too severe,” Dr Coiffier said. “After a lot of discussion between all the investigators, we decided to modify the criteria for DLT regarding neutropenia or thrombocytopenia and to allow a little more toxicity before saying it’s a DLT.”

A DLT was initially defined as grade 3/4 non-hematologic toxicity, grade 3 hematologic toxicity lasting more than 7 days, or grade 4 hematologic toxicity lasting more than 3 days. The researchers modified the criteria so that hematologic toxicities would not be considered DLTs if they lasted less than 10 days for grade 3 or less than 7 days for grade 4.

When the team decreased the romidepsin dose to 8 mg/m², they did not observe any DLTs according to the new criteria. The same was true when they raised the dose back up to 10 mg/m².

There were, however, DLTs when the dose was increased to 12 mg/m². In cohort 5, there was a case of grade 3 cardiac failure, and in cohort 6, there were 2 cases of grade 3 nausea.

Nevertheless, 12 mg/m² became the phase 2 dose. In all, 25 patients received romidepsin at that dose.

Safety data

Twenty-six of 37 patients completed the 8 planned cycles of treatment. Five patients discontinued treatment due to progression and 6 due to toxicity (5 due to thrombocytopenia).

“One hundred percent of patients experienced at least one adverse event, but most of them were grade 1 or 2 [84%] and occurred during the first 2 cycles [38%],” Dr Coiffier said. “There were no deaths related to adverse events.”

Severe toxicities occurred during the expansion phase. There was a case of severe peripheral sensory neuropathy that led to treatment discontinuation, and there were 3 cases of acute cardiac toxicity. They all occurred after the first cycle, and none were fatal.

The rate of hematologic toxicity was high. Neutropenia occurred in all patients, thrombocytopenia in 94%, and anemia in 89%.

Grade 3/4 adverse events included neutropenia (85%), thrombocytopenia (35%), febrile neutropenia (19%), general status deterioration (13%), nausea/vomiting (10%), anemia (8%), hypophosphatemia (8%), fatigue (5%), mucositis (5%), decreased appetite (5%), hypocalcemia (3%), hyponatremia (3%), hypokalemia (3%), hypomagnesemia (3%), dysgeusia (3%), and peripheral sensory neuropathy (3%).

Response, survival, and next steps

About 51% of patients (18/35) achieved a complete response, and 17% (n=6) had a partial response. Twenty-six percent of patients (n=9) progressed.

The median follow-up was 30 months. The estimated 1-year progression-free survival was 57%, and the estimated 1-year overall survival was 82%.

“The [overall survival] curve is certainly much better than you would expect with just standard CHOP,” Dr Coiffier noted.

He added that this research has progressed to a phase 3 study comparing romidepsin and CHOP in combination to CHOP alone. There are 7 countries participating (France, Belgium, South Korea, Spain, Italy, Germany, and Portugal), and 100 patients have been enrolled thus far.

Bertrand Coiffier, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Adding romidepsin to CHOP can enhance the regimen’s efficacy against peripheral T-cell lymphoma (PTCL), but the combination can also induce severe toxicity, results of a phase 1b/2 study have shown.

In patients with previously untreated PTCL, romidepsin plus CHOP elicited an overall response rate of about 69%.

But all patients experienced adverse events, a median of 49 per patient. In addition, rates of hematologic toxicities were high, and 3 patients experienced acute cardiac toxicity.

Bertrand Coiffier, MD, PhD, of CHU Lyon Sud in Pierre Benite, France, presented these findings at the 7th Annual T-cell Lymphoma Forum. Dr Coiffier and other researchers involved in this study receive funds from Celgene, the company developing romidepsin.

“CHOP is widely accepted,” Dr Coiffier noted. “It’s the most-used regimen for peripheral T-cell lymphoma, but it’s not the best one, and we certainly have regimens that do produce more [complete responses] and longer responses.”

He said researchers decided to test romidepsin in combination with CHOP because studies have suggested that romidepsin has very good efficacy in relapsed/refractory peripheral T-cell lymphoma, and the toxicities associated with romidepsin and CHOP alone have been managable.

So the researchers tested the combination in 37 patients with untreated PTCL, most of whom were male (n=20). The median age was 57, and 37.8% were older than 60. About 95% of patients had stage III/IV disease, and about 89% had an ECOG performance status less than 2.

Most patients had angioimmunoblastic T-cell lymphoma (n=17), followed by PTCL not otherwise specified (n=13), ALK- anaplastic large-cell lymphoma (n=3), enteropathy-associated T-cell lymphoma (n=1), hepatosplenic T-cell lymphoma (n=1), primary cutaneous CD4⁺ small/medium T-cell lymphoma (n=1), and “other” (n=1).

Early DLTs

The researchers used a standard “3+3” dose-escalation scheme, starting with a romidepsin dose of 10 mg/m² given on days 1 and 8.

In the first 2 cycles, there were 3 dose-limiting toxicities (DLTs)—1 case  of grade 3 syncope, 1 case of grade 3 general status alteration, and 1 case of grade 3 hematologic toxicity (neutropenia and thrombocytopenia) lasting longer than 7 days.

“So we looked at the definition of the criteria for DLT, and we thought that, this time, they were too severe,” Dr Coiffier said. “After a lot of discussion between all the investigators, we decided to modify the criteria for DLT regarding neutropenia or thrombocytopenia and to allow a little more toxicity before saying it’s a DLT.”

A DLT was initially defined as grade 3/4 non-hematologic toxicity, grade 3 hematologic toxicity lasting more than 7 days, or grade 4 hematologic toxicity lasting more than 3 days. The researchers modified the criteria so that hematologic toxicities would not be considered DLTs if they lasted less than 10 days for grade 3 or less than 7 days for grade 4.

When the team decreased the romidepsin dose to 8 mg/m², they did not observe any DLTs according to the new criteria. The same was true when they raised the dose back up to 10 mg/m².

There were, however, DLTs when the dose was increased to 12 mg/m². In cohort 5, there was a case of grade 3 cardiac failure, and in cohort 6, there were 2 cases of grade 3 nausea.

Nevertheless, 12 mg/m² became the phase 2 dose. In all, 25 patients received romidepsin at that dose.

Safety data

Twenty-six of 37 patients completed the 8 planned cycles of treatment. Five patients discontinued treatment due to progression and 6 due to toxicity (5 due to thrombocytopenia).

“One hundred percent of patients experienced at least one adverse event, but most of them were grade 1 or 2 [84%] and occurred during the first 2 cycles [38%],” Dr Coiffier said. “There were no deaths related to adverse events.”

Severe toxicities occurred during the expansion phase. There was a case of severe peripheral sensory neuropathy that led to treatment discontinuation, and there were 3 cases of acute cardiac toxicity. They all occurred after the first cycle, and none were fatal.

The rate of hematologic toxicity was high. Neutropenia occurred in all patients, thrombocytopenia in 94%, and anemia in 89%.

Grade 3/4 adverse events included neutropenia (85%), thrombocytopenia (35%), febrile neutropenia (19%), general status deterioration (13%), nausea/vomiting (10%), anemia (8%), hypophosphatemia (8%), fatigue (5%), mucositis (5%), decreased appetite (5%), hypocalcemia (3%), hyponatremia (3%), hypokalemia (3%), hypomagnesemia (3%), dysgeusia (3%), and peripheral sensory neuropathy (3%).

Response, survival, and next steps

About 51% of patients (18/35) achieved a complete response, and 17% (n=6) had a partial response. Twenty-six percent of patients (n=9) progressed.

The median follow-up was 30 months. The estimated 1-year progression-free survival was 57%, and the estimated 1-year overall survival was 82%.

“The [overall survival] curve is certainly much better than you would expect with just standard CHOP,” Dr Coiffier noted.

He added that this research has progressed to a phase 3 study comparing romidepsin and CHOP in combination to CHOP alone. There are 7 countries participating (France, Belgium, South Korea, Spain, Italy, Germany, and Portugal), and 100 patients have been enrolled thus far.

Bertrand Coiffier, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Adding romidepsin to CHOP can enhance the regimen’s efficacy against peripheral T-cell lymphoma (PTCL), but the combination can also induce severe toxicity, results of a phase 1b/2 study have shown.

In patients with previously untreated PTCL, romidepsin plus CHOP elicited an overall response rate of about 69%.

But all patients experienced adverse events, a median of 49 per patient. In addition, rates of hematologic toxicities were high, and 3 patients experienced acute cardiac toxicity.

Bertrand Coiffier, MD, PhD, of CHU Lyon Sud in Pierre Benite, France, presented these findings at the 7th Annual T-cell Lymphoma Forum. Dr Coiffier and other researchers involved in this study receive funds from Celgene, the company developing romidepsin.

“CHOP is widely accepted,” Dr Coiffier noted. “It’s the most-used regimen for peripheral T-cell lymphoma, but it’s not the best one, and we certainly have regimens that do produce more [complete responses] and longer responses.”

He said researchers decided to test romidepsin in combination with CHOP because studies have suggested that romidepsin has very good efficacy in relapsed/refractory peripheral T-cell lymphoma, and the toxicities associated with romidepsin and CHOP alone have been managable.

So the researchers tested the combination in 37 patients with untreated PTCL, most of whom were male (n=20). The median age was 57, and 37.8% were older than 60. About 95% of patients had stage III/IV disease, and about 89% had an ECOG performance status less than 2.

Most patients had angioimmunoblastic T-cell lymphoma (n=17), followed by PTCL not otherwise specified (n=13), ALK- anaplastic large-cell lymphoma (n=3), enteropathy-associated T-cell lymphoma (n=1), hepatosplenic T-cell lymphoma (n=1), primary cutaneous CD4⁺ small/medium T-cell lymphoma (n=1), and “other” (n=1).

Early DLTs

The researchers used a standard “3+3” dose-escalation scheme, starting with a romidepsin dose of 10 mg/m² given on days 1 and 8.

In the first 2 cycles, there were 3 dose-limiting toxicities (DLTs)—1 case  of grade 3 syncope, 1 case of grade 3 general status alteration, and 1 case of grade 3 hematologic toxicity (neutropenia and thrombocytopenia) lasting longer than 7 days.

“So we looked at the definition of the criteria for DLT, and we thought that, this time, they were too severe,” Dr Coiffier said. “After a lot of discussion between all the investigators, we decided to modify the criteria for DLT regarding neutropenia or thrombocytopenia and to allow a little more toxicity before saying it’s a DLT.”

A DLT was initially defined as grade 3/4 non-hematologic toxicity, grade 3 hematologic toxicity lasting more than 7 days, or grade 4 hematologic toxicity lasting more than 3 days. The researchers modified the criteria so that hematologic toxicities would not be considered DLTs if they lasted less than 10 days for grade 3 or less than 7 days for grade 4.

When the team decreased the romidepsin dose to 8 mg/m², they did not observe any DLTs according to the new criteria. The same was true when they raised the dose back up to 10 mg/m².

There were, however, DLTs when the dose was increased to 12 mg/m². In cohort 5, there was a case of grade 3 cardiac failure, and in cohort 6, there were 2 cases of grade 3 nausea.

Nevertheless, 12 mg/m² became the phase 2 dose. In all, 25 patients received romidepsin at that dose.

Safety data

Twenty-six of 37 patients completed the 8 planned cycles of treatment. Five patients discontinued treatment due to progression and 6 due to toxicity (5 due to thrombocytopenia).

“One hundred percent of patients experienced at least one adverse event, but most of them were grade 1 or 2 [84%] and occurred during the first 2 cycles [38%],” Dr Coiffier said. “There were no deaths related to adverse events.”

Severe toxicities occurred during the expansion phase. There was a case of severe peripheral sensory neuropathy that led to treatment discontinuation, and there were 3 cases of acute cardiac toxicity. They all occurred after the first cycle, and none were fatal.

The rate of hematologic toxicity was high. Neutropenia occurred in all patients, thrombocytopenia in 94%, and anemia in 89%.

Grade 3/4 adverse events included neutropenia (85%), thrombocytopenia (35%), febrile neutropenia (19%), general status deterioration (13%), nausea/vomiting (10%), anemia (8%), hypophosphatemia (8%), fatigue (5%), mucositis (5%), decreased appetite (5%), hypocalcemia (3%), hyponatremia (3%), hypokalemia (3%), hypomagnesemia (3%), dysgeusia (3%), and peripheral sensory neuropathy (3%).

Response, survival, and next steps

About 51% of patients (18/35) achieved a complete response, and 17% (n=6) had a partial response. Twenty-six percent of patients (n=9) progressed.

The median follow-up was 30 months. The estimated 1-year progression-free survival was 57%, and the estimated 1-year overall survival was 82%.

“The [overall survival] curve is certainly much better than you would expect with just standard CHOP,” Dr Coiffier noted.

He added that this research has progressed to a phase 3 study comparing romidepsin and CHOP in combination to CHOP alone. There are 7 countries participating (France, Belgium, South Korea, Spain, Italy, Germany, and Portugal), and 100 patients have been enrolled thus far.

Pier Luigi Zinzani, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Two phase 2 studies testing mogamulizumab in peripheral T-cell lymphomas (PTCLs) suggest that higher response rates don’t necessarily translate to an improvement in progression-free survival (PFS).

The anti-CCR4 antibody produced a higher overall response rate (ORR) in a Japanese study than in a European study—34% and 11%, respectively.

However, median PFS times were similar—about 2 months in both studies.

This similarity is all the more interesting because the studies enrolled different types of patients and followed different dosing schedules, according to Pier Luigi Zinzani, MD, PhD, of the University of Bologna in Italy.

Dr Zinzani discussed details of the European experience testing mogamulizumab in PTCL, comparing it to the Japanese experience, in a presentation at the 7th Annual T-cell Lymphoma Forum.

Kensei Tobinai, MD, PhD, of the National Cancer Center Hospital in Tokyo, Japan, also reviewed the Japanese experience (TCLF 2013, JCO 2014) during the meeting’s keynote address and presented data from an ancillary analysis of this study (which is unpublished).

All of the research was sponsored by Kyowa Hakko Kirin Co., Ltd., the company developing mogamulizumab.

The Japanese experience

The Japanese study included 29 patients with PTCL and 8 with cutaneous T-cell lymphoma (CTCL). All patients had relapsed after their last chemotherapy regimen, and none had received an allogeneic stem cell transplant (allo-SCT). The PTCL patients had a median age of 67, and 69% were male.

All patients received mogamulizumab at 1.0 mg/kg/day weekly for 8 weeks. The ORR was 35%—34% for PTCL patients and 38% for CTCL patients.

Among PTCL patients, there were 5 complete responses (CRs) and 5 partial responses (PRs). Nine patients had stable disease (SD), and 10 progressed.

Of the 16 patients with PTCL-not otherwise specified (PTCL-NOS), 1 had a CR, 2 had a PR, 6 had SD, and 7 progressed. Of the 12 patients with angioimmunoblastic T-cell lymphoma (AITL), 3 had a CR, 3 had a PR, 3 had SD, and 3 progressed. The only patient with ALK- anaplastic large-cell lymphoma (ALCL) had an unconfirmed CR.

The ancillary analysis showed that tumor shrinkage of the target lesions occurred in 72% (21/29) of patients with PTCL. The patients’ median duration of response was 6.4 months, and the median time to response was 1.9 months.

Overall, the median PFS was 3.0 months—2.0 months in patients with PTCL and 3.4 months in patients with CTCL.

Common adverse events (for both PTCL and CTCL patients) included lymphopenia (81%), skin disorders (51%), leukopenia (43%), neutropenia (38%), thrombocytopenia (38%), pyrexia (30%), acute infusion reactions (24%), and anemia (14%).

Dr Tobinai noted that these results are not as favorable as those observed when patients with adult T-cell leukemia-lymphoma receive mogamulizumab.

“But compared to the efficacy rate of other approved agents—pralatrexate and romidepsin—this antibody has promising efficacy,” he said.

In fact, the results of this study prompted the December approval of mogamulizumab to treat PTCL and CTCL patients in Japan.

The European experience

The European study differed from the Japanese study in a few ways, Dr Zinzani pointed out. The European study only enrolled patients with PTCL. And it included patients with relapsed (49%) or refractory (51%) disease, whereas the Japanese study only included relapsed patients.

Furthermore, the Japanese study did not include any patients with an ECOG performance status of 2, while the European study did (39%). And the dosing schedule differed between the 2 studies.

In the European study, patients received mogamulizumab at 1 mg/kg once weekly for 4 weeks and then once every 2 weeks until they progressed or developed unacceptable toxicity.

There were 38 patients in the safety analysis. They had a median age of 58.5 years, and 61% were male.

Thirty-five of these patients were included in the efficacy analysis. They had a median of 2 prior treatments (range, 1-8), and 17 patients (49%) had responded to their last therapy.

The patients had PTCL-NOS (43%, 15/35), AITL (34%, 12), transformed mycosis fungoides (9%, 3), ALK- ALCL (11%, 4), and ALK+ ALCL (3%, 1).

The ORR was 11% (n=4), and 46% of patients (n=16) had SD or better. Two patients with PTCL-NOS responded, as did 2 with AITL.

Six patients with PTCL-NOS had SD, as did 3 with AITL, 1 with transformed mycosis fungoides, and 2 with ALK- ALCL.

The median duration of response (including SD) was 2.9 months. And the median PFS was 2.1 months. Two patients (1 with ALK- ALCL and 1 with PTCL-NOS) went on to allo-SCT.

The most frequent adverse events (occurring in at least 10% of patients) were drug eruption (n=12), pyrexia (n=9), pruritus (n=7), diarrhea (n=7), cough (n=6), vomiting (n=6), thrombocytopenia (n=6), hypotension (n=4), headache (n=4), peripheral edema (n=4), asthenia (n=4), nausea (n=4), anemia (n=4), and neutropenia (n=4).

“For the European experience, there were some differences from the Japanese experience,” Dr Zinzani said in closing. “It was worse in terms of overall response rate—only 11%—but roughly 50% of patients attained at least stable disease. And there was an acceptable safety profile in these really heavily pretreated, relapsed/refractory PTCL patients.”

Pier Luigi Zinzani, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Two phase 2 studies testing mogamulizumab in peripheral T-cell lymphomas (PTCLs) suggest that higher response rates don’t necessarily translate to an improvement in progression-free survival (PFS).

The anti-CCR4 antibody produced a higher overall response rate (ORR) in a Japanese study than in a European study—34% and 11%, respectively.

However, median PFS times were similar—about 2 months in both studies.

This similarity is all the more interesting because the studies enrolled different types of patients and followed different dosing schedules, according to Pier Luigi Zinzani, MD, PhD, of the University of Bologna in Italy.

Dr Zinzani discussed details of the European experience testing mogamulizumab in PTCL, comparing it to the Japanese experience, in a presentation at the 7th Annual T-cell Lymphoma Forum.

Kensei Tobinai, MD, PhD, of the National Cancer Center Hospital in Tokyo, Japan, also reviewed the Japanese experience (TCLF 2013, JCO 2014) during the meeting’s keynote address and presented data from an ancillary analysis of this study (which is unpublished).

All of the research was sponsored by Kyowa Hakko Kirin Co., Ltd., the company developing mogamulizumab.

The Japanese experience

The Japanese study included 29 patients with PTCL and 8 with cutaneous T-cell lymphoma (CTCL). All patients had relapsed after their last chemotherapy regimen, and none had received an allogeneic stem cell transplant (allo-SCT). The PTCL patients had a median age of 67, and 69% were male.

All patients received mogamulizumab at 1.0 mg/kg/day weekly for 8 weeks. The ORR was 35%—34% for PTCL patients and 38% for CTCL patients.

Among PTCL patients, there were 5 complete responses (CRs) and 5 partial responses (PRs). Nine patients had stable disease (SD), and 10 progressed.

Of the 16 patients with PTCL-not otherwise specified (PTCL-NOS), 1 had a CR, 2 had a PR, 6 had SD, and 7 progressed. Of the 12 patients with angioimmunoblastic T-cell lymphoma (AITL), 3 had a CR, 3 had a PR, 3 had SD, and 3 progressed. The only patient with ALK- anaplastic large-cell lymphoma (ALCL) had an unconfirmed CR.

The ancillary analysis showed that tumor shrinkage of the target lesions occurred in 72% (21/29) of patients with PTCL. The patients’ median duration of response was 6.4 months, and the median time to response was 1.9 months.

Overall, the median PFS was 3.0 months—2.0 months in patients with PTCL and 3.4 months in patients with CTCL.

Common adverse events (for both PTCL and CTCL patients) included lymphopenia (81%), skin disorders (51%), leukopenia (43%), neutropenia (38%), thrombocytopenia (38%), pyrexia (30%), acute infusion reactions (24%), and anemia (14%).

Dr Tobinai noted that these results are not as favorable as those observed when patients with adult T-cell leukemia-lymphoma receive mogamulizumab.

“But compared to the efficacy rate of other approved agents—pralatrexate and romidepsin—this antibody has promising efficacy,” he said.

In fact, the results of this study prompted the December approval of mogamulizumab to treat PTCL and CTCL patients in Japan.

The European experience

The European study differed from the Japanese study in a few ways, Dr Zinzani pointed out. The European study only enrolled patients with PTCL. And it included patients with relapsed (49%) or refractory (51%) disease, whereas the Japanese study only included relapsed patients.

Furthermore, the Japanese study did not include any patients with an ECOG performance status of 2, while the European study did (39%). And the dosing schedule differed between the 2 studies.

In the European study, patients received mogamulizumab at 1 mg/kg once weekly for 4 weeks and then once every 2 weeks until they progressed or developed unacceptable toxicity.

There were 38 patients in the safety analysis. They had a median age of 58.5 years, and 61% were male.

Thirty-five of these patients were included in the efficacy analysis. They had a median of 2 prior treatments (range, 1-8), and 17 patients (49%) had responded to their last therapy.

The patients had PTCL-NOS (43%, 15/35), AITL (34%, 12), transformed mycosis fungoides (9%, 3), ALK- ALCL (11%, 4), and ALK+ ALCL (3%, 1).

The ORR was 11% (n=4), and 46% of patients (n=16) had SD or better. Two patients with PTCL-NOS responded, as did 2 with AITL.

Six patients with PTCL-NOS had SD, as did 3 with AITL, 1 with transformed mycosis fungoides, and 2 with ALK- ALCL.

The median duration of response (including SD) was 2.9 months. And the median PFS was 2.1 months. Two patients (1 with ALK- ALCL and 1 with PTCL-NOS) went on to allo-SCT.

The most frequent adverse events (occurring in at least 10% of patients) were drug eruption (n=12), pyrexia (n=9), pruritus (n=7), diarrhea (n=7), cough (n=6), vomiting (n=6), thrombocytopenia (n=6), hypotension (n=4), headache (n=4), peripheral edema (n=4), asthenia (n=4), nausea (n=4), anemia (n=4), and neutropenia (n=4).

“For the European experience, there were some differences from the Japanese experience,” Dr Zinzani said in closing. “It was worse in terms of overall response rate—only 11%—but roughly 50% of patients attained at least stable disease. And there was an acceptable safety profile in these really heavily pretreated, relapsed/refractory PTCL patients.”

Pier Luigi Zinzani, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Two phase 2 studies testing mogamulizumab in peripheral T-cell lymphomas (PTCLs) suggest that higher response rates don’t necessarily translate to an improvement in progression-free survival (PFS).

The anti-CCR4 antibody produced a higher overall response rate (ORR) in a Japanese study than in a European study—34% and 11%, respectively.

However, median PFS times were similar—about 2 months in both studies.

This similarity is all the more interesting because the studies enrolled different types of patients and followed different dosing schedules, according to Pier Luigi Zinzani, MD, PhD, of the University of Bologna in Italy.

Dr Zinzani discussed details of the European experience testing mogamulizumab in PTCL, comparing it to the Japanese experience, in a presentation at the 7th Annual T-cell Lymphoma Forum.

Kensei Tobinai, MD, PhD, of the National Cancer Center Hospital in Tokyo, Japan, also reviewed the Japanese experience (TCLF 2013, JCO 2014) during the meeting’s keynote address and presented data from an ancillary analysis of this study (which is unpublished).

All of the research was sponsored by Kyowa Hakko Kirin Co., Ltd., the company developing mogamulizumab.

The Japanese experience

The Japanese study included 29 patients with PTCL and 8 with cutaneous T-cell lymphoma (CTCL). All patients had relapsed after their last chemotherapy regimen, and none had received an allogeneic stem cell transplant (allo-SCT). The PTCL patients had a median age of 67, and 69% were male.

All patients received mogamulizumab at 1.0 mg/kg/day weekly for 8 weeks. The ORR was 35%—34% for PTCL patients and 38% for CTCL patients.

Among PTCL patients, there were 5 complete responses (CRs) and 5 partial responses (PRs). Nine patients had stable disease (SD), and 10 progressed.

Of the 16 patients with PTCL-not otherwise specified (PTCL-NOS), 1 had a CR, 2 had a PR, 6 had SD, and 7 progressed. Of the 12 patients with angioimmunoblastic T-cell lymphoma (AITL), 3 had a CR, 3 had a PR, 3 had SD, and 3 progressed. The only patient with ALK- anaplastic large-cell lymphoma (ALCL) had an unconfirmed CR.

The ancillary analysis showed that tumor shrinkage of the target lesions occurred in 72% (21/29) of patients with PTCL. The patients’ median duration of response was 6.4 months, and the median time to response was 1.9 months.

Overall, the median PFS was 3.0 months—2.0 months in patients with PTCL and 3.4 months in patients with CTCL.

Common adverse events (for both PTCL and CTCL patients) included lymphopenia (81%), skin disorders (51%), leukopenia (43%), neutropenia (38%), thrombocytopenia (38%), pyrexia (30%), acute infusion reactions (24%), and anemia (14%).

Dr Tobinai noted that these results are not as favorable as those observed when patients with adult T-cell leukemia-lymphoma receive mogamulizumab.

“But compared to the efficacy rate of other approved agents—pralatrexate and romidepsin—this antibody has promising efficacy,” he said.

In fact, the results of this study prompted the December approval of mogamulizumab to treat PTCL and CTCL patients in Japan.

The European experience

The European study differed from the Japanese study in a few ways, Dr Zinzani pointed out. The European study only enrolled patients with PTCL. And it included patients with relapsed (49%) or refractory (51%) disease, whereas the Japanese study only included relapsed patients.

Furthermore, the Japanese study did not include any patients with an ECOG performance status of 2, while the European study did (39%). And the dosing schedule differed between the 2 studies.

In the European study, patients received mogamulizumab at 1 mg/kg once weekly for 4 weeks and then once every 2 weeks until they progressed or developed unacceptable toxicity.

There were 38 patients in the safety analysis. They had a median age of 58.5 years, and 61% were male.

Thirty-five of these patients were included in the efficacy analysis. They had a median of 2 prior treatments (range, 1-8), and 17 patients (49%) had responded to their last therapy.

The patients had PTCL-NOS (43%, 15/35), AITL (34%, 12), transformed mycosis fungoides (9%, 3), ALK- ALCL (11%, 4), and ALK+ ALCL (3%, 1).

The ORR was 11% (n=4), and 46% of patients (n=16) had SD or better. Two patients with PTCL-NOS responded, as did 2 with AITL.

Six patients with PTCL-NOS had SD, as did 3 with AITL, 1 with transformed mycosis fungoides, and 2 with ALK- ALCL.

The median duration of response (including SD) was 2.9 months. And the median PFS was 2.1 months. Two patients (1 with ALK- ALCL and 1 with PTCL-NOS) went on to allo-SCT.

The most frequent adverse events (occurring in at least 10% of patients) were drug eruption (n=12), pyrexia (n=9), pruritus (n=7), diarrhea (n=7), cough (n=6), vomiting (n=6), thrombocytopenia (n=6), hypotension (n=4), headache (n=4), peripheral edema (n=4), asthenia (n=4), nausea (n=4), anemia (n=4), and neutropenia (n=4).

“For the European experience, there were some differences from the Japanese experience,” Dr Zinzani said in closing. “It was worse in terms of overall response rate—only 11%—but roughly 50% of patients attained at least stable disease. And there was an acceptable safety profile in these really heavily pretreated, relapsed/refractory PTCL patients.”

Philipp Staber, MD, PhD

Photo by Larry Young

SAN FRANCISCO—MicroRNA-155 (miR-155) can act as an oncogenic driver in ALK− anaplastic large-cell lymphoma (ALCL) and may therefore be a therapeutic target for the disease, according to a presentation at the 7th Annual T-cell Lymphoma Forum.

Analyzing patient samples and cell lines, researchers discovered that miR-155 is highly expressed in ALK− ALCL but is nearly absent in ALK+ ALCL.

They also found evidence suggesting that miR-155 drives tumor growth in mouse models of ALK− ALCL.

Philipp Staber, MD, PhD, of the Medical University of Vienna in Austria, presented these findings at the meeting.

Dr Staber and his colleagues previously found (Merkel et al, PNAS 2010) that miR-155 was highly expressed in ALK− ALCL. So they decided to take a closer look at the phenomenon.

They assessed miR-155 expression in samples from patients with ALK+ or ALK− ALCL, as well as 6 ALCL cell lines.

miR-155 expression was significantly higher in the ALK− patient samples than in the ALK+ samples (P<0.001). And it was significantly higher (P<0.001) in the ALK− cell lines (DL-40, Mac1, and Mac2a) than in the ALK+ cell lines (K299, SR789, and SUP-M2).

Dr Staber and his colleagues then overexpressed miR-155 in ALK+ ALCL cell lines (K299 and SR789). And they observed a decrease in known target genes of miR-155—C/EBPβ, SOCS1, and SHIP1.

The researchers also observed an inverse correlation between miR-155 host gene promoter methylation and miR-155 expression in an ALCL+ cell line, which suggested that ALK activity has no direct effect on miR-155 levels.

The team treated the K299 cell line with the ALK inhibitor crizotinib at 100 nM, 200 nM, and 400 nM doses and found that miR-155 did not increase at any dose. Dr Staber noted, however, that the researchers were only able to treat cells for a maximum of 24 hours.

The group then discovered that anti-miR-155 mimics could reduce tumor growth in mouse models of ALK- ALCL. Mice were injected with Mac1 or Mac2a cells transfected with anti-miR-155, control RNA, or pre-miR-155 oligos.

In both Mac1 and Mac2 models, tumors were substantially smaller in the anti-mir-155 mice than in the pre-miR-155 mice (P=0.038 and P=0.006, respectively). But tumor growth was not significantly reduced compared to controls.

“Immunohistochemistry in these tumors shows quite a clear picture,” Dr Staber said. “The C/EBPβ target gene is overexpressed when using anti-miR-155, and [expression is decreased] with overexpression of miR-155. And the same is true for SOCS1. STAT3 signaling is increased through overexpression of miR-155.”

The researchers observed the same effect in ALK− ALCL patient samples.

Using ALK+ cell lines (K299 and SR789), the team went on to show that miR-155 suppresses IL-8 expression and induces IL-22 expression, a finding they verified in mice.

“IL-8 is a direct target of C/EBPβ, and C/EBPβ, as shown before, is a target of miR-155, so this makes sense,” Dr Staber said. “On the other hand, IL-22 is a strong inducer of STAT3 signaling, which is strongly induced when we increase miR-155 expression.”

Dr Staber and his colleagues concluded that these findings, when taken together, suggest that miR-155 could be a therapeutic target for ALK− ALCL.

Philipp Staber, MD, PhD

Photo by Larry Young

SAN FRANCISCO—MicroRNA-155 (miR-155) can act as an oncogenic driver in ALK− anaplastic large-cell lymphoma (ALCL) and may therefore be a therapeutic target for the disease, according to a presentation at the 7th Annual T-cell Lymphoma Forum.

Analyzing patient samples and cell lines, researchers discovered that miR-155 is highly expressed in ALK− ALCL but is nearly absent in ALK+ ALCL.

They also found evidence suggesting that miR-155 drives tumor growth in mouse models of ALK− ALCL.

Philipp Staber, MD, PhD, of the Medical University of Vienna in Austria, presented these findings at the meeting.

Dr Staber and his colleagues previously found (Merkel et al, PNAS 2010) that miR-155 was highly expressed in ALK− ALCL. So they decided to take a closer look at the phenomenon.

They assessed miR-155 expression in samples from patients with ALK+ or ALK− ALCL, as well as 6 ALCL cell lines.

miR-155 expression was significantly higher in the ALK− patient samples than in the ALK+ samples (P<0.001). And it was significantly higher (P<0.001) in the ALK− cell lines (DL-40, Mac1, and Mac2a) than in the ALK+ cell lines (K299, SR789, and SUP-M2).

Dr Staber and his colleagues then overexpressed miR-155 in ALK+ ALCL cell lines (K299 and SR789). And they observed a decrease in known target genes of miR-155—C/EBPβ, SOCS1, and SHIP1.

The researchers also observed an inverse correlation between miR-155 host gene promoter methylation and miR-155 expression in an ALCL+ cell line, which suggested that ALK activity has no direct effect on miR-155 levels.

The team treated the K299 cell line with the ALK inhibitor crizotinib at 100 nM, 200 nM, and 400 nM doses and found that miR-155 did not increase at any dose. Dr Staber noted, however, that the researchers were only able to treat cells for a maximum of 24 hours.

The group then discovered that anti-miR-155 mimics could reduce tumor growth in mouse models of ALK- ALCL. Mice were injected with Mac1 or Mac2a cells transfected with anti-miR-155, control RNA, or pre-miR-155 oligos.

In both Mac1 and Mac2 models, tumors were substantially smaller in the anti-mir-155 mice than in the pre-miR-155 mice (P=0.038 and P=0.006, respectively). But tumor growth was not significantly reduced compared to controls.

“Immunohistochemistry in these tumors shows quite a clear picture,” Dr Staber said. “The C/EBPβ target gene is overexpressed when using anti-miR-155, and [expression is decreased] with overexpression of miR-155. And the same is true for SOCS1. STAT3 signaling is increased through overexpression of miR-155.”

The researchers observed the same effect in ALK− ALCL patient samples.

Using ALK+ cell lines (K299 and SR789), the team went on to show that miR-155 suppresses IL-8 expression and induces IL-22 expression, a finding they verified in mice.

“IL-8 is a direct target of C/EBPβ, and C/EBPβ, as shown before, is a target of miR-155, so this makes sense,” Dr Staber said. “On the other hand, IL-22 is a strong inducer of STAT3 signaling, which is strongly induced when we increase miR-155 expression.”

Dr Staber and his colleagues concluded that these findings, when taken together, suggest that miR-155 could be a therapeutic target for ALK− ALCL.

Philipp Staber, MD, PhD

Photo by Larry Young

SAN FRANCISCO—MicroRNA-155 (miR-155) can act as an oncogenic driver in ALK− anaplastic large-cell lymphoma (ALCL) and may therefore be a therapeutic target for the disease, according to a presentation at the 7th Annual T-cell Lymphoma Forum.

Analyzing patient samples and cell lines, researchers discovered that miR-155 is highly expressed in ALK− ALCL but is nearly absent in ALK+ ALCL.

They also found evidence suggesting that miR-155 drives tumor growth in mouse models of ALK− ALCL.

Philipp Staber, MD, PhD, of the Medical University of Vienna in Austria, presented these findings at the meeting.

Dr Staber and his colleagues previously found (Merkel et al, PNAS 2010) that miR-155 was highly expressed in ALK− ALCL. So they decided to take a closer look at the phenomenon.

They assessed miR-155 expression in samples from patients with ALK+ or ALK− ALCL, as well as 6 ALCL cell lines.

miR-155 expression was significantly higher in the ALK− patient samples than in the ALK+ samples (P<0.001). And it was significantly higher (P<0.001) in the ALK− cell lines (DL-40, Mac1, and Mac2a) than in the ALK+ cell lines (K299, SR789, and SUP-M2).

Dr Staber and his colleagues then overexpressed miR-155 in ALK+ ALCL cell lines (K299 and SR789). And they observed a decrease in known target genes of miR-155—C/EBPβ, SOCS1, and SHIP1.

The researchers also observed an inverse correlation between miR-155 host gene promoter methylation and miR-155 expression in an ALCL+ cell line, which suggested that ALK activity has no direct effect on miR-155 levels.

The team treated the K299 cell line with the ALK inhibitor crizotinib at 100 nM, 200 nM, and 400 nM doses and found that miR-155 did not increase at any dose. Dr Staber noted, however, that the researchers were only able to treat cells for a maximum of 24 hours.

The group then discovered that anti-miR-155 mimics could reduce tumor growth in mouse models of ALK- ALCL. Mice were injected with Mac1 or Mac2a cells transfected with anti-miR-155, control RNA, or pre-miR-155 oligos.

In both Mac1 and Mac2 models, tumors were substantially smaller in the anti-mir-155 mice than in the pre-miR-155 mice (P=0.038 and P=0.006, respectively). But tumor growth was not significantly reduced compared to controls.

“Immunohistochemistry in these tumors shows quite a clear picture,” Dr Staber said. “The C/EBPβ target gene is overexpressed when using anti-miR-155, and [expression is decreased] with overexpression of miR-155. And the same is true for SOCS1. STAT3 signaling is increased through overexpression of miR-155.”

The researchers observed the same effect in ALK− ALCL patient samples.

Using ALK+ cell lines (K299 and SR789), the team went on to show that miR-155 suppresses IL-8 expression and induces IL-22 expression, a finding they verified in mice.

“IL-8 is a direct target of C/EBPβ, and C/EBPβ, as shown before, is a target of miR-155, so this makes sense,” Dr Staber said. “On the other hand, IL-22 is a strong inducer of STAT3 signaling, which is strongly induced when we increase miR-155 expression.”

Dr Staber and his colleagues concluded that these findings, when taken together, suggest that miR-155 could be a therapeutic target for ALK− ALCL.

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.