Hodgkin Lymphoma

Burkitt lymphoma cells

Credit: Ed Uthman

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

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

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

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

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

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

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

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

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

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

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

Burkitt lymphoma cells

Credit: Ed Uthman

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

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

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

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

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

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

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

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

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

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

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

Burkitt lymphoma cells

Credit: Ed Uthman

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

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

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

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

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

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

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

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

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

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

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

HIV budding from

a cultured lymphocyte

Credit: CDC

SAN FRANCISCO—Patients with HIV-related lymphoma (HRL) should not be excluded from clinical trials of autologous stem cell transplant (ASCT) due to their HIV status, new research suggests.

Investigators found no significant difference in rates of treatment failure, disease progression, or survival between transplant-treated historical controls who had lymphoma but not HIV and patients with HRL who received the modified BEAM regimen followed by ASCT on a phase 2 trial.

This suggests patients with chemotherapy-sensitive, relapsed/refractory HRL can be treated successfully with the modified BEAM regimen, said study investigator Joseph Alvarnas, MD, of City of Hope National Medical Center in Duarte, California.

“Patients with treatment-responsive HIV infection and HIV-related lymphoma should be considered candidates for autologous transplant if they meet standard transplant criteria,” he added. “And we would argue that exclusion from clinical trials on the basis of HIV infection alone is no longer justified.”

Dr Alvarnas presented this viewpoint and the research to support it at the 2014 ASH Annual Meeting as abstract 674.

The trial enrolled 43 patients with treatable HIV-1 infection, adequate organ function, and aggressive lymphoma. Three patients were excluded because they could not undergo transplant due to lymphoma progression.

Of the 40 remaining patients, 5 were female, and their median age was 46.9 years (range, 22.5-62.2). They had diffuse large B-cell lymphoma (n=16), plasmablastic lymphoma (n=2), Burkitt/Burkitt-like lymphoma (n=7), and Hodgkin lymphoma (n=15).

The pre-ASCT HIV viral load was undetectable in 31 patients. In the patients with detectable HIV, the median viral load pre-ASCT was 84 copies/μL (range, 50-17,455). The median CD4 count was 250.5/µL (range, 39-797).

Before transplant, 30 patients (75%) were in complete remission, 8 (20%) were in partial remission, and 2 (5%) had relapsed/progressive disease.

The patients underwent ASCT after conditioning with the modified BEAM regimen—carmustine at 300 mg/m² (day -6), etoposide at 100 mg/m² twice daily (days -5 to -2), cytarabine at 100 mg/m² (days -5 to -2), and melphalan at 140 mg/m² (day -1).

Combination antiretroviral therapy (cART) was held during the preparative regimen and resumed after the resolution of gastrointestinal toxicity. The investigators switched efavirenz to an alternative agent 2 or more weeks prior to the planned interruption of cART, as the drug has a long half-life. And AZT was prohibited due to its myelosuppressive effects.

Treatment results

The median follow-up was 24 months. At 100 days post-transplant, the investigators assessed 39 patients for response. One patient was not evaluable due to early death.

Thirty-six of the patients (92.3%) were in complete remission, 1 (2.6%) was in partial remission, and 2 (5.1%) had relapsed or progressive disease.

Fifteen patients reported grade 3 or higher toxicities within a year of transplant. Of the 13 unexpected grade 3-5 adverse events (reported in 9 patients), 5 were infection/sepsis, 1 was acute appendicitis, 1 was acute coronary syndrome, 2 were deep vein thromboses, 2 were gastrointestinal toxicities, and 2 were metabolic abnormalities.

Seventeen patients reported at least 1 infectious episode, 42 events in total, 9 of which were severe. Fourteen patients required readmission to the hospital after transplant.

Within a year of transplant, 5 patients had died—3 from recurrent/persistent disease, 1 due to a fungal infection, and 1 from cardiac arrest. Two additional patients died after the 1-year mark—1 of recurrent/persistent disease and 1 of heart failure.

At 12 months, the rate of overall survival was 86.6%, progression-free survival was 82.3%, progression was 12.5%, and non-relapse mortality was 5.2%.

“In order to place this within context, we had the opportunity to compare our patient experience with 151 matched controls [without HIV] from CIBMTR,” Dr Alvarnas said. “Ninety-three percent of these patients were actually transplanted within 2 years so that they were the time-concordant group, and they were matched for performance score, disease, and disease stage.”

The investigators found no significant difference between their patient group and the HIV-free controls with regard to overall mortality (P=0.56), treatment failure (P=0.10), progression (P=0.06), and treatment-related mortality (P=0.97).

Likewise, there was no significant difference in overall survival between the HRL patients and controls—86.6% and 87.7%, respectively (P=0.56). And the same was true of progression-free survival—82.3% and 69.5%, respectively (P=0.10).

HIV budding from

a cultured lymphocyte

Credit: CDC

SAN FRANCISCO—Patients with HIV-related lymphoma (HRL) should not be excluded from clinical trials of autologous stem cell transplant (ASCT) due to their HIV status, new research suggests.

Investigators found no significant difference in rates of treatment failure, disease progression, or survival between transplant-treated historical controls who had lymphoma but not HIV and patients with HRL who received the modified BEAM regimen followed by ASCT on a phase 2 trial.

This suggests patients with chemotherapy-sensitive, relapsed/refractory HRL can be treated successfully with the modified BEAM regimen, said study investigator Joseph Alvarnas, MD, of City of Hope National Medical Center in Duarte, California.

“Patients with treatment-responsive HIV infection and HIV-related lymphoma should be considered candidates for autologous transplant if they meet standard transplant criteria,” he added. “And we would argue that exclusion from clinical trials on the basis of HIV infection alone is no longer justified.”

Dr Alvarnas presented this viewpoint and the research to support it at the 2014 ASH Annual Meeting as abstract 674.

The trial enrolled 43 patients with treatable HIV-1 infection, adequate organ function, and aggressive lymphoma. Three patients were excluded because they could not undergo transplant due to lymphoma progression.

Of the 40 remaining patients, 5 were female, and their median age was 46.9 years (range, 22.5-62.2). They had diffuse large B-cell lymphoma (n=16), plasmablastic lymphoma (n=2), Burkitt/Burkitt-like lymphoma (n=7), and Hodgkin lymphoma (n=15).

The pre-ASCT HIV viral load was undetectable in 31 patients. In the patients with detectable HIV, the median viral load pre-ASCT was 84 copies/μL (range, 50-17,455). The median CD4 count was 250.5/µL (range, 39-797).

Before transplant, 30 patients (75%) were in complete remission, 8 (20%) were in partial remission, and 2 (5%) had relapsed/progressive disease.

The patients underwent ASCT after conditioning with the modified BEAM regimen—carmustine at 300 mg/m² (day -6), etoposide at 100 mg/m² twice daily (days -5 to -2), cytarabine at 100 mg/m² (days -5 to -2), and melphalan at 140 mg/m² (day -1).

Combination antiretroviral therapy (cART) was held during the preparative regimen and resumed after the resolution of gastrointestinal toxicity. The investigators switched efavirenz to an alternative agent 2 or more weeks prior to the planned interruption of cART, as the drug has a long half-life. And AZT was prohibited due to its myelosuppressive effects.

Treatment results

The median follow-up was 24 months. At 100 days post-transplant, the investigators assessed 39 patients for response. One patient was not evaluable due to early death.

Thirty-six of the patients (92.3%) were in complete remission, 1 (2.6%) was in partial remission, and 2 (5.1%) had relapsed or progressive disease.

Fifteen patients reported grade 3 or higher toxicities within a year of transplant. Of the 13 unexpected grade 3-5 adverse events (reported in 9 patients), 5 were infection/sepsis, 1 was acute appendicitis, 1 was acute coronary syndrome, 2 were deep vein thromboses, 2 were gastrointestinal toxicities, and 2 were metabolic abnormalities.

Seventeen patients reported at least 1 infectious episode, 42 events in total, 9 of which were severe. Fourteen patients required readmission to the hospital after transplant.

Within a year of transplant, 5 patients had died—3 from recurrent/persistent disease, 1 due to a fungal infection, and 1 from cardiac arrest. Two additional patients died after the 1-year mark—1 of recurrent/persistent disease and 1 of heart failure.

At 12 months, the rate of overall survival was 86.6%, progression-free survival was 82.3%, progression was 12.5%, and non-relapse mortality was 5.2%.

“In order to place this within context, we had the opportunity to compare our patient experience with 151 matched controls [without HIV] from CIBMTR,” Dr Alvarnas said. “Ninety-three percent of these patients were actually transplanted within 2 years so that they were the time-concordant group, and they were matched for performance score, disease, and disease stage.”

The investigators found no significant difference between their patient group and the HIV-free controls with regard to overall mortality (P=0.56), treatment failure (P=0.10), progression (P=0.06), and treatment-related mortality (P=0.97).

Likewise, there was no significant difference in overall survival between the HRL patients and controls—86.6% and 87.7%, respectively (P=0.56). And the same was true of progression-free survival—82.3% and 69.5%, respectively (P=0.10).

HIV budding from

a cultured lymphocyte

Credit: CDC

SAN FRANCISCO—Patients with HIV-related lymphoma (HRL) should not be excluded from clinical trials of autologous stem cell transplant (ASCT) due to their HIV status, new research suggests.

Investigators found no significant difference in rates of treatment failure, disease progression, or survival between transplant-treated historical controls who had lymphoma but not HIV and patients with HRL who received the modified BEAM regimen followed by ASCT on a phase 2 trial.

This suggests patients with chemotherapy-sensitive, relapsed/refractory HRL can be treated successfully with the modified BEAM regimen, said study investigator Joseph Alvarnas, MD, of City of Hope National Medical Center in Duarte, California.

“Patients with treatment-responsive HIV infection and HIV-related lymphoma should be considered candidates for autologous transplant if they meet standard transplant criteria,” he added. “And we would argue that exclusion from clinical trials on the basis of HIV infection alone is no longer justified.”

Dr Alvarnas presented this viewpoint and the research to support it at the 2014 ASH Annual Meeting as abstract 674.

The trial enrolled 43 patients with treatable HIV-1 infection, adequate organ function, and aggressive lymphoma. Three patients were excluded because they could not undergo transplant due to lymphoma progression.

Of the 40 remaining patients, 5 were female, and their median age was 46.9 years (range, 22.5-62.2). They had diffuse large B-cell lymphoma (n=16), plasmablastic lymphoma (n=2), Burkitt/Burkitt-like lymphoma (n=7), and Hodgkin lymphoma (n=15).

The pre-ASCT HIV viral load was undetectable in 31 patients. In the patients with detectable HIV, the median viral load pre-ASCT was 84 copies/μL (range, 50-17,455). The median CD4 count was 250.5/µL (range, 39-797).

Before transplant, 30 patients (75%) were in complete remission, 8 (20%) were in partial remission, and 2 (5%) had relapsed/progressive disease.

The patients underwent ASCT after conditioning with the modified BEAM regimen—carmustine at 300 mg/m² (day -6), etoposide at 100 mg/m² twice daily (days -5 to -2), cytarabine at 100 mg/m² (days -5 to -2), and melphalan at 140 mg/m² (day -1).

Combination antiretroviral therapy (cART) was held during the preparative regimen and resumed after the resolution of gastrointestinal toxicity. The investigators switched efavirenz to an alternative agent 2 or more weeks prior to the planned interruption of cART, as the drug has a long half-life. And AZT was prohibited due to its myelosuppressive effects.

Treatment results

The median follow-up was 24 months. At 100 days post-transplant, the investigators assessed 39 patients for response. One patient was not evaluable due to early death.

Thirty-six of the patients (92.3%) were in complete remission, 1 (2.6%) was in partial remission, and 2 (5.1%) had relapsed or progressive disease.

Fifteen patients reported grade 3 or higher toxicities within a year of transplant. Of the 13 unexpected grade 3-5 adverse events (reported in 9 patients), 5 were infection/sepsis, 1 was acute appendicitis, 1 was acute coronary syndrome, 2 were deep vein thromboses, 2 were gastrointestinal toxicities, and 2 were metabolic abnormalities.

Seventeen patients reported at least 1 infectious episode, 42 events in total, 9 of which were severe. Fourteen patients required readmission to the hospital after transplant.

Within a year of transplant, 5 patients had died—3 from recurrent/persistent disease, 1 due to a fungal infection, and 1 from cardiac arrest. Two additional patients died after the 1-year mark—1 of recurrent/persistent disease and 1 of heart failure.

At 12 months, the rate of overall survival was 86.6%, progression-free survival was 82.3%, progression was 12.5%, and non-relapse mortality was 5.2%.

“In order to place this within context, we had the opportunity to compare our patient experience with 151 matched controls [without HIV] from CIBMTR,” Dr Alvarnas said. “Ninety-three percent of these patients were actually transplanted within 2 years so that they were the time-concordant group, and they were matched for performance score, disease, and disease stage.”

The investigators found no significant difference between their patient group and the HIV-free controls with regard to overall mortality (P=0.56), treatment failure (P=0.10), progression (P=0.06), and treatment-related mortality (P=0.97).

Likewise, there was no significant difference in overall survival between the HRL patients and controls—86.6% and 87.7%, respectively (P=0.56). And the same was true of progression-free survival—82.3% and 69.5%, respectively (P=0.10).

Doctor and patient

Credit: NIH

SAN FRANCISCO—Younger patients with Hodgkin lymphoma fare well on brentuximab vedotin, experiencing an overall objective response rate (ORR) of 75% and a complete response (CR) rate of 34% in the pivotal phase 2 study of patients with relapsed/refractory disease.

And a retrospective study of patients older than 60 years showed that single-agent therapy was well tolerated, prompting an ORR of 53% and a CR rate of 40% in a relapsed or refractory population.

So investigators decided to explore in a prospective study whether patients 60 years or older could benefit from up-front treatment with brentuximab as a single agent or in combination.

Andres Forero-Torres, MD, of the University of Alabama in Birmingham, presented the results of this trial at the 2014 ASH Annual Meeting (abstract 294).*

Enrolled patients had classic Hodgkin lymphoma, were treatment-naïve, and were ineligible for or declined conventional front-line treatment. The primary endpoint was ORR.

The study is being conducted in 3 parts—brentuximab as a single agent, brentuximab plus dacarbazine, and brentuximab plus bendamustine. At the time of the ASH presentation, data for the brentuximab-bendamustine combination were not available.

Single-agent brentuximab

Twenty-seven patients on the single-agent arm were evaluable for efficacy and safety. They were a median age of 78 (range, 64 to 92). About half (52%) were male, and 78% had an ECOG performance status of grade 0 or 1.

Forty-four percent had moderate renal function impairment with a creatinine clearance between 30 and 60 mL/min. Thirty percent had B symptoms, 22% had bulky disease, and 52% had extra-nodal involvement.

Patients received 1.8 mg/kg of brentuximab intravenously on day 1 of a 21-day cycle. Response was assessed by CT scan during cycles 2, 4, 8, and 16, and by CT plus PET scan during cycles 2 and 8.

The median follow-up was 8.7 months. Dr Forero-Torres pointed out that, initially, “there were no progressions,” and all patients achieved tumor reduction.

The ORR was 93%, the CR rate was 70%, the partial response rate was 22%, and the rate of stable disease was 7%.

The median duration of response was 9.1 months (range, 0.03 to 13.14), and the median progression-free survival was 10.5 months (range, 2.6 to 14.3). For patients who had a CR, the median progression-free survival was about 12 months, Dr Forero-Torres said.

The median number of treatment cycles administered per patient was 8 (range, 3 to 23). Patients discontinued treatment primarily because of progressive disease (41%) or adverse events (AEs, 37%).

AEs occurring in 20% or more of patients were constipation, decreased appetite, diarrhea, peripheral edema, nausea, fatigue, and peripheral sensory neuropathy. All were grade 1 or 2, except for peripheral sensory neuropathy, which also had about 20% grade 3 events.

Grade 3 or higher treatment-related AEs included peripheral sensory neuropathy (n=7), peripheral motor neuropathy (n=2), rash (n=2), and 1 patient each with anemia, increased aspartate aminotransferase, asthenia, neutropenia, orthostatic hypotension, generalized rash, and maculopapular rash.

Serious AEs (SAEs) were minimal, Dr Forero-Torres said, and included 1 patient each with pyrexia, orthostatic hypotension, asthenia and rash, and deep vein thrombosis.

Seven patients discontinued treatment due to peripheral sensory neuropathy, 2 due to peripheral motor neuropathy, and 1 due to orthostatic hypotension.

Dr Forero-Torres emphasized that there were no grade 4 AEs, no AE-related deaths, and no deaths within 30 days of the last dose of medication.

Brentuximab plus dacarbazine

Fourteen of 18 patients in the combination arm were evaluable for efficacy and safety. Their median age was 72.5 (range, 62 to 87), 72% were male, 67% had an ECOG status of grade 0 or 1, and 56% had normal renal function with a creatinine clearance greater than 80 mL/min.

Forty-four percent exhibited B symptoms, 11% had bulky disease, and 50% had extra-nodal involvement.

They received brentuximab at 1.8 mg/kg plus dacarbazine at 375 mg/m² for cycles 1-12, followed by monotherapy for cycles 13-16.

At the time of the interim analysis, 83% of patients were still on treatment, “so this is very early preliminary data,” Dr Forero-Torres noted.

All of the patients achieved tumor reduction, and 4 patients achieved a CR.

They had a median treatment duration of 16.7 weeks (range, 3 to 36), received a median of 5.5 cycles (range, 1 to 12), and had a median follow-up time of 19.1 weeks (range, 6.1 to 36.1).

The most common grade 1 or 2 AEs were peripheral sensory neuropathy (33%), nausea (33%), diarrhea (28%), constipation (28%), fatigue (22%), alopecia (22%), arthralgia (22%), and headache (22%).

Grade 3 AEs or SAEs, with 1 patient each, were C difficile colitis (SAE), hypotension (SAE), and hyperglycemia.

Dr Forero-Torres noted that investigators observed “robust antitumor activity” among these older patients receiving front-line brentuximab.

The cohort combining brentuximab with bendamustine is currently enrolling patients.

The study is sponsored by Seattle Genetics, Inc., developer of brentuximab vedotin (Adcetris).

*Information in the abstract differs from that presented at the meeting.

Doctor and patient

Credit: NIH

SAN FRANCISCO—Younger patients with Hodgkin lymphoma fare well on brentuximab vedotin, experiencing an overall objective response rate (ORR) of 75% and a complete response (CR) rate of 34% in the pivotal phase 2 study of patients with relapsed/refractory disease.

And a retrospective study of patients older than 60 years showed that single-agent therapy was well tolerated, prompting an ORR of 53% and a CR rate of 40% in a relapsed or refractory population.

So investigators decided to explore in a prospective study whether patients 60 years or older could benefit from up-front treatment with brentuximab as a single agent or in combination.

Andres Forero-Torres, MD, of the University of Alabama in Birmingham, presented the results of this trial at the 2014 ASH Annual Meeting (abstract 294).*

Enrolled patients had classic Hodgkin lymphoma, were treatment-naïve, and were ineligible for or declined conventional front-line treatment. The primary endpoint was ORR.

The study is being conducted in 3 parts—brentuximab as a single agent, brentuximab plus dacarbazine, and brentuximab plus bendamustine. At the time of the ASH presentation, data for the brentuximab-bendamustine combination were not available.

Single-agent brentuximab

Twenty-seven patients on the single-agent arm were evaluable for efficacy and safety. They were a median age of 78 (range, 64 to 92). About half (52%) were male, and 78% had an ECOG performance status of grade 0 or 1.

Forty-four percent had moderate renal function impairment with a creatinine clearance between 30 and 60 mL/min. Thirty percent had B symptoms, 22% had bulky disease, and 52% had extra-nodal involvement.

Patients received 1.8 mg/kg of brentuximab intravenously on day 1 of a 21-day cycle. Response was assessed by CT scan during cycles 2, 4, 8, and 16, and by CT plus PET scan during cycles 2 and 8.

The median follow-up was 8.7 months. Dr Forero-Torres pointed out that, initially, “there were no progressions,” and all patients achieved tumor reduction.

The ORR was 93%, the CR rate was 70%, the partial response rate was 22%, and the rate of stable disease was 7%.

The median duration of response was 9.1 months (range, 0.03 to 13.14), and the median progression-free survival was 10.5 months (range, 2.6 to 14.3). For patients who had a CR, the median progression-free survival was about 12 months, Dr Forero-Torres said.

The median number of treatment cycles administered per patient was 8 (range, 3 to 23). Patients discontinued treatment primarily because of progressive disease (41%) or adverse events (AEs, 37%).

AEs occurring in 20% or more of patients were constipation, decreased appetite, diarrhea, peripheral edema, nausea, fatigue, and peripheral sensory neuropathy. All were grade 1 or 2, except for peripheral sensory neuropathy, which also had about 20% grade 3 events.

Grade 3 or higher treatment-related AEs included peripheral sensory neuropathy (n=7), peripheral motor neuropathy (n=2), rash (n=2), and 1 patient each with anemia, increased aspartate aminotransferase, asthenia, neutropenia, orthostatic hypotension, generalized rash, and maculopapular rash.

Serious AEs (SAEs) were minimal, Dr Forero-Torres said, and included 1 patient each with pyrexia, orthostatic hypotension, asthenia and rash, and deep vein thrombosis.

Seven patients discontinued treatment due to peripheral sensory neuropathy, 2 due to peripheral motor neuropathy, and 1 due to orthostatic hypotension.

Dr Forero-Torres emphasized that there were no grade 4 AEs, no AE-related deaths, and no deaths within 30 days of the last dose of medication.

Brentuximab plus dacarbazine

Fourteen of 18 patients in the combination arm were evaluable for efficacy and safety. Their median age was 72.5 (range, 62 to 87), 72% were male, 67% had an ECOG status of grade 0 or 1, and 56% had normal renal function with a creatinine clearance greater than 80 mL/min.

Forty-four percent exhibited B symptoms, 11% had bulky disease, and 50% had extra-nodal involvement.

They received brentuximab at 1.8 mg/kg plus dacarbazine at 375 mg/m² for cycles 1-12, followed by monotherapy for cycles 13-16.

At the time of the interim analysis, 83% of patients were still on treatment, “so this is very early preliminary data,” Dr Forero-Torres noted.

All of the patients achieved tumor reduction, and 4 patients achieved a CR.

They had a median treatment duration of 16.7 weeks (range, 3 to 36), received a median of 5.5 cycles (range, 1 to 12), and had a median follow-up time of 19.1 weeks (range, 6.1 to 36.1).

The most common grade 1 or 2 AEs were peripheral sensory neuropathy (33%), nausea (33%), diarrhea (28%), constipation (28%), fatigue (22%), alopecia (22%), arthralgia (22%), and headache (22%).

Grade 3 AEs or SAEs, with 1 patient each, were C difficile colitis (SAE), hypotension (SAE), and hyperglycemia.

Dr Forero-Torres noted that investigators observed “robust antitumor activity” among these older patients receiving front-line brentuximab.

The cohort combining brentuximab with bendamustine is currently enrolling patients.

The study is sponsored by Seattle Genetics, Inc., developer of brentuximab vedotin (Adcetris).

*Information in the abstract differs from that presented at the meeting.

Doctor and patient

Credit: NIH

SAN FRANCISCO—Younger patients with Hodgkin lymphoma fare well on brentuximab vedotin, experiencing an overall objective response rate (ORR) of 75% and a complete response (CR) rate of 34% in the pivotal phase 2 study of patients with relapsed/refractory disease.

And a retrospective study of patients older than 60 years showed that single-agent therapy was well tolerated, prompting an ORR of 53% and a CR rate of 40% in a relapsed or refractory population.

So investigators decided to explore in a prospective study whether patients 60 years or older could benefit from up-front treatment with brentuximab as a single agent or in combination.

Andres Forero-Torres, MD, of the University of Alabama in Birmingham, presented the results of this trial at the 2014 ASH Annual Meeting (abstract 294).*

Enrolled patients had classic Hodgkin lymphoma, were treatment-naïve, and were ineligible for or declined conventional front-line treatment. The primary endpoint was ORR.

The study is being conducted in 3 parts—brentuximab as a single agent, brentuximab plus dacarbazine, and brentuximab plus bendamustine. At the time of the ASH presentation, data for the brentuximab-bendamustine combination were not available.

Single-agent brentuximab

Twenty-seven patients on the single-agent arm were evaluable for efficacy and safety. They were a median age of 78 (range, 64 to 92). About half (52%) were male, and 78% had an ECOG performance status of grade 0 or 1.

Forty-four percent had moderate renal function impairment with a creatinine clearance between 30 and 60 mL/min. Thirty percent had B symptoms, 22% had bulky disease, and 52% had extra-nodal involvement.

Patients received 1.8 mg/kg of brentuximab intravenously on day 1 of a 21-day cycle. Response was assessed by CT scan during cycles 2, 4, 8, and 16, and by CT plus PET scan during cycles 2 and 8.

The median follow-up was 8.7 months. Dr Forero-Torres pointed out that, initially, “there were no progressions,” and all patients achieved tumor reduction.

The ORR was 93%, the CR rate was 70%, the partial response rate was 22%, and the rate of stable disease was 7%.

The median duration of response was 9.1 months (range, 0.03 to 13.14), and the median progression-free survival was 10.5 months (range, 2.6 to 14.3). For patients who had a CR, the median progression-free survival was about 12 months, Dr Forero-Torres said.

The median number of treatment cycles administered per patient was 8 (range, 3 to 23). Patients discontinued treatment primarily because of progressive disease (41%) or adverse events (AEs, 37%).

AEs occurring in 20% or more of patients were constipation, decreased appetite, diarrhea, peripheral edema, nausea, fatigue, and peripheral sensory neuropathy. All were grade 1 or 2, except for peripheral sensory neuropathy, which also had about 20% grade 3 events.

Grade 3 or higher treatment-related AEs included peripheral sensory neuropathy (n=7), peripheral motor neuropathy (n=2), rash (n=2), and 1 patient each with anemia, increased aspartate aminotransferase, asthenia, neutropenia, orthostatic hypotension, generalized rash, and maculopapular rash.

Serious AEs (SAEs) were minimal, Dr Forero-Torres said, and included 1 patient each with pyrexia, orthostatic hypotension, asthenia and rash, and deep vein thrombosis.

Seven patients discontinued treatment due to peripheral sensory neuropathy, 2 due to peripheral motor neuropathy, and 1 due to orthostatic hypotension.

Dr Forero-Torres emphasized that there were no grade 4 AEs, no AE-related deaths, and no deaths within 30 days of the last dose of medication.

Brentuximab plus dacarbazine

Fourteen of 18 patients in the combination arm were evaluable for efficacy and safety. Their median age was 72.5 (range, 62 to 87), 72% were male, 67% had an ECOG status of grade 0 or 1, and 56% had normal renal function with a creatinine clearance greater than 80 mL/min.

Forty-four percent exhibited B symptoms, 11% had bulky disease, and 50% had extra-nodal involvement.

They received brentuximab at 1.8 mg/kg plus dacarbazine at 375 mg/m² for cycles 1-12, followed by monotherapy for cycles 13-16.

At the time of the interim analysis, 83% of patients were still on treatment, “so this is very early preliminary data,” Dr Forero-Torres noted.

All of the patients achieved tumor reduction, and 4 patients achieved a CR.

They had a median treatment duration of 16.7 weeks (range, 3 to 36), received a median of 5.5 cycles (range, 1 to 12), and had a median follow-up time of 19.1 weeks (range, 6.1 to 36.1).

The most common grade 1 or 2 AEs were peripheral sensory neuropathy (33%), nausea (33%), diarrhea (28%), constipation (28%), fatigue (22%), alopecia (22%), arthralgia (22%), and headache (22%).

Grade 3 AEs or SAEs, with 1 patient each, were C difficile colitis (SAE), hypotension (SAE), and hyperglycemia.

Dr Forero-Torres noted that investigators observed “robust antitumor activity” among these older patients receiving front-line brentuximab.

The cohort combining brentuximab with bendamustine is currently enrolling patients.

The study is sponsored by Seattle Genetics, Inc., developer of brentuximab vedotin (Adcetris).

*Information in the abstract differs from that presented at the meeting.

Photo courtesy of ASH

SAN FRANCISCO—Two monoclonal antibodies that block the programmed death-1 (PD-1) pathway are showing promise in early phase trials in relapsed/refractory classic Hodgkin lymphoma (cHL).

Nivolumab prompted an 87% overall response rate (ORR) in heavily pretreated patients, and pembrolizumab elicited a 66% ORR in patients who had failed prior treatment with brentuximab vedotin.

These results were presented in 2 abstracts at the 2014 ASH Annual Meeting.

The rationale for using PD-1 blockade in cHL is that these patients frequently have an alteration in chromosome 9p24.1, which leads to increased expression of the PD-1 ligands, PD-L1 and PD-L2. The ligands engage the PD-1 receptors on activated T cells, inducing T-cell exhaustion. More than 85% of cHL tumors overexpress PD-L1.

Craig H. Moskowitz, MD, who presented the data on pembrolizumab at the meeting, sees nivolumab and pembrolizumab as being very similar.

“My gut feeling is that, at the end of the day, the response rates will be very similar,” he said. “The complete response rates will be similar. I think the toxicity profiles may be slightly dissimilar, and we’ll have to see what happens when these studies are both peer-reviewed.”

Nivolumab

Philippe Armand, MD, of Dana-Farber Cancer Institute in Boston, presented data on nivolumab in cHL (abstract 289), which was an independent expansion cohort of a phase 1b study in hematologic malignancies.

The 23 cHL patients received nivolumab at 3 mg/kg on weeks 1 and 4, then every 2 weeks.

Patients were a median age of 35 years (range, 20 to 54), and about two-thirds had received 4 or more prior systemic therapies. Seventy-eight percent had prior autologous stem cell transplant, and 78% had prior treatment with brentuximab.

“These were extensively pretreated patients” Dr Armand said, “with few options available.”

Twenty patients responded, for an ORR of 87%. Four patients (17%) achieved a complete response (CR), 16 (70%) had a partial response, and 3 (13%) had stable disease.

There were no progressions. And, at 24 weeks, the progression-free survival was 86%.

There were no life-threatening adverse events (AEs), no drug-related deaths, and no drug-related grade 4 AEs. Twenty-two patients (96%) experienced an AE, 18 (78%) had a drug-related AE, 5 (22%) had a grade 3 drug-related AE, and 2 (9%) patients discontinued treatment due to a drug-related AE.

The 2 events leading to discontinuation were myelodysplastic syndromes with grade 3 thrombocytopenia and grade 3 pancreatitis. The other grade 3 drug-related AEs were lymphopenia, increased lipase, GI inflammation, pneumonitis, colitis, and stomatitis.

“Overall, nivolumab has been used in thousands of patients already on clinical trials in solid tumors,” Dr Armand said. “And, overall, this safety profile mirrors that from what we expected in solid tumors.”

“But the interesting thing about that, from our standpoint, is that there was no apparent increase in the incidence of lung toxicity, which is something we worry about for those patients because many of them had had radiation or other drugs that can cause lung injury.”

This study was recently published in NEJM. It was funded by Bristol-Myers Squibb, the company developing nivolumab, and others.

Based on results of this study, the US Food and Drug Administration (FDA) granted nivolumab breakthrough therapy designation to treat HL. The drug recently gained FDA approval to treat advanced melanoma.

Pembrolizumab

Dr Moskowitz, of Memorial Sloan Kettering Cancer Center in New York, presented data on pembrolizumab as abstract 290.*

Investigators enrolled 31 patients onto the cHL cohort of the Keynote 013 trial. Patients were a median age of 32 years (range, 20 to 67).

All patients had failed therapy with brentuximab vedotin, 69% failed prior stem cell transplant, and 28% were transplant ineligible. Patients had to have an ECOG performance status of 0 or 1 and could not have autoimmune disease or interstitial lung disease.

Patients received 10 mg/kg of pembrolizumab intravenously every 2 weeks for up to 24 months or until progression.

Twenty-nine patients were evaluable for efficacy. The ORR was 66%, with a CR rate of 21% and a partial response rate of 45%. Twenty-one percent of patients had stable disease, and 14% had progressive disease. So the clinical benefit rate was 86%.

The median time to response was 12 weeks, and the median duration of response ranged from 1 to 185 days, but the median had not yet been reached.

Nine patients (31%) discontinued therapy, 1 (3%) due to an AE, 7 (24%) due to disease progression, and 1 (3%) after achieving a CR. Twenty patients (69%) were still on therapy at the time of the presentation, and 1 patient went on to transplant.

Sixteen patients (55%) experienced 1 or more treatment-related AE of any grade. Those occurring in 2 or more patients included hypothyroidism (10%), pneumonitis (10%), constipation (7%), diarrhea (7%), nausea (7%), hypercholesterolemia (7%), hypertriglyceridemia (7%), and hematuria (7%).

Treatment-related AEs of grade 3 or higher included axillary pain (3%), hypoxia (3%), joint swelling (3%), and pneumonitis (3%). Three patients experienced 4 grade 3 or higher AEs. There were no grade 4 treatment-related AEs or treatment-related deaths.

“In my opinion,” Dr Moskowitz concluded, “these results support continued development of pembrolizumab in Hodgkin lymphoma.”

“I think that these drugs are here to stay. Where we are going to put them in the armamentarium in Hodgkin lymphoma remains to be seen.”

This study was funded by Merck Sharp & Dohme Corp., the company developing pembrolizumab.

*Information in the abstract differs from that presented at the meeting.

Photo courtesy of ASH

SAN FRANCISCO—Two monoclonal antibodies that block the programmed death-1 (PD-1) pathway are showing promise in early phase trials in relapsed/refractory classic Hodgkin lymphoma (cHL).

Nivolumab prompted an 87% overall response rate (ORR) in heavily pretreated patients, and pembrolizumab elicited a 66% ORR in patients who had failed prior treatment with brentuximab vedotin.

These results were presented in 2 abstracts at the 2014 ASH Annual Meeting.

The rationale for using PD-1 blockade in cHL is that these patients frequently have an alteration in chromosome 9p24.1, which leads to increased expression of the PD-1 ligands, PD-L1 and PD-L2. The ligands engage the PD-1 receptors on activated T cells, inducing T-cell exhaustion. More than 85% of cHL tumors overexpress PD-L1.

Craig H. Moskowitz, MD, who presented the data on pembrolizumab at the meeting, sees nivolumab and pembrolizumab as being very similar.

“My gut feeling is that, at the end of the day, the response rates will be very similar,” he said. “The complete response rates will be similar. I think the toxicity profiles may be slightly dissimilar, and we’ll have to see what happens when these studies are both peer-reviewed.”

Nivolumab

Philippe Armand, MD, of Dana-Farber Cancer Institute in Boston, presented data on nivolumab in cHL (abstract 289), which was an independent expansion cohort of a phase 1b study in hematologic malignancies.

The 23 cHL patients received nivolumab at 3 mg/kg on weeks 1 and 4, then every 2 weeks.

Patients were a median age of 35 years (range, 20 to 54), and about two-thirds had received 4 or more prior systemic therapies. Seventy-eight percent had prior autologous stem cell transplant, and 78% had prior treatment with brentuximab.

“These were extensively pretreated patients” Dr Armand said, “with few options available.”

Twenty patients responded, for an ORR of 87%. Four patients (17%) achieved a complete response (CR), 16 (70%) had a partial response, and 3 (13%) had stable disease.

There were no progressions. And, at 24 weeks, the progression-free survival was 86%.

There were no life-threatening adverse events (AEs), no drug-related deaths, and no drug-related grade 4 AEs. Twenty-two patients (96%) experienced an AE, 18 (78%) had a drug-related AE, 5 (22%) had a grade 3 drug-related AE, and 2 (9%) patients discontinued treatment due to a drug-related AE.

The 2 events leading to discontinuation were myelodysplastic syndromes with grade 3 thrombocytopenia and grade 3 pancreatitis. The other grade 3 drug-related AEs were lymphopenia, increased lipase, GI inflammation, pneumonitis, colitis, and stomatitis.

“Overall, nivolumab has been used in thousands of patients already on clinical trials in solid tumors,” Dr Armand said. “And, overall, this safety profile mirrors that from what we expected in solid tumors.”

“But the interesting thing about that, from our standpoint, is that there was no apparent increase in the incidence of lung toxicity, which is something we worry about for those patients because many of them had had radiation or other drugs that can cause lung injury.”

This study was recently published in NEJM. It was funded by Bristol-Myers Squibb, the company developing nivolumab, and others.

Based on results of this study, the US Food and Drug Administration (FDA) granted nivolumab breakthrough therapy designation to treat HL. The drug recently gained FDA approval to treat advanced melanoma.

Pembrolizumab

Dr Moskowitz, of Memorial Sloan Kettering Cancer Center in New York, presented data on pembrolizumab as abstract 290.*

Investigators enrolled 31 patients onto the cHL cohort of the Keynote 013 trial. Patients were a median age of 32 years (range, 20 to 67).

All patients had failed therapy with brentuximab vedotin, 69% failed prior stem cell transplant, and 28% were transplant ineligible. Patients had to have an ECOG performance status of 0 or 1 and could not have autoimmune disease or interstitial lung disease.

Patients received 10 mg/kg of pembrolizumab intravenously every 2 weeks for up to 24 months or until progression.

Twenty-nine patients were evaluable for efficacy. The ORR was 66%, with a CR rate of 21% and a partial response rate of 45%. Twenty-one percent of patients had stable disease, and 14% had progressive disease. So the clinical benefit rate was 86%.

The median time to response was 12 weeks, and the median duration of response ranged from 1 to 185 days, but the median had not yet been reached.

Nine patients (31%) discontinued therapy, 1 (3%) due to an AE, 7 (24%) due to disease progression, and 1 (3%) after achieving a CR. Twenty patients (69%) were still on therapy at the time of the presentation, and 1 patient went on to transplant.

Sixteen patients (55%) experienced 1 or more treatment-related AE of any grade. Those occurring in 2 or more patients included hypothyroidism (10%), pneumonitis (10%), constipation (7%), diarrhea (7%), nausea (7%), hypercholesterolemia (7%), hypertriglyceridemia (7%), and hematuria (7%).

Treatment-related AEs of grade 3 or higher included axillary pain (3%), hypoxia (3%), joint swelling (3%), and pneumonitis (3%). Three patients experienced 4 grade 3 or higher AEs. There were no grade 4 treatment-related AEs or treatment-related deaths.

“In my opinion,” Dr Moskowitz concluded, “these results support continued development of pembrolizumab in Hodgkin lymphoma.”

“I think that these drugs are here to stay. Where we are going to put them in the armamentarium in Hodgkin lymphoma remains to be seen.”

This study was funded by Merck Sharp & Dohme Corp., the company developing pembrolizumab.

*Information in the abstract differs from that presented at the meeting.

Photo courtesy of ASH

SAN FRANCISCO—Two monoclonal antibodies that block the programmed death-1 (PD-1) pathway are showing promise in early phase trials in relapsed/refractory classic Hodgkin lymphoma (cHL).

Nivolumab prompted an 87% overall response rate (ORR) in heavily pretreated patients, and pembrolizumab elicited a 66% ORR in patients who had failed prior treatment with brentuximab vedotin.

These results were presented in 2 abstracts at the 2014 ASH Annual Meeting.

The rationale for using PD-1 blockade in cHL is that these patients frequently have an alteration in chromosome 9p24.1, which leads to increased expression of the PD-1 ligands, PD-L1 and PD-L2. The ligands engage the PD-1 receptors on activated T cells, inducing T-cell exhaustion. More than 85% of cHL tumors overexpress PD-L1.

Craig H. Moskowitz, MD, who presented the data on pembrolizumab at the meeting, sees nivolumab and pembrolizumab as being very similar.

“My gut feeling is that, at the end of the day, the response rates will be very similar,” he said. “The complete response rates will be similar. I think the toxicity profiles may be slightly dissimilar, and we’ll have to see what happens when these studies are both peer-reviewed.”

Nivolumab

Philippe Armand, MD, of Dana-Farber Cancer Institute in Boston, presented data on nivolumab in cHL (abstract 289), which was an independent expansion cohort of a phase 1b study in hematologic malignancies.

The 23 cHL patients received nivolumab at 3 mg/kg on weeks 1 and 4, then every 2 weeks.

Patients were a median age of 35 years (range, 20 to 54), and about two-thirds had received 4 or more prior systemic therapies. Seventy-eight percent had prior autologous stem cell transplant, and 78% had prior treatment with brentuximab.

“These were extensively pretreated patients” Dr Armand said, “with few options available.”

Twenty patients responded, for an ORR of 87%. Four patients (17%) achieved a complete response (CR), 16 (70%) had a partial response, and 3 (13%) had stable disease.

There were no progressions. And, at 24 weeks, the progression-free survival was 86%.

There were no life-threatening adverse events (AEs), no drug-related deaths, and no drug-related grade 4 AEs. Twenty-two patients (96%) experienced an AE, 18 (78%) had a drug-related AE, 5 (22%) had a grade 3 drug-related AE, and 2 (9%) patients discontinued treatment due to a drug-related AE.

The 2 events leading to discontinuation were myelodysplastic syndromes with grade 3 thrombocytopenia and grade 3 pancreatitis. The other grade 3 drug-related AEs were lymphopenia, increased lipase, GI inflammation, pneumonitis, colitis, and stomatitis.

“Overall, nivolumab has been used in thousands of patients already on clinical trials in solid tumors,” Dr Armand said. “And, overall, this safety profile mirrors that from what we expected in solid tumors.”

“But the interesting thing about that, from our standpoint, is that there was no apparent increase in the incidence of lung toxicity, which is something we worry about for those patients because many of them had had radiation or other drugs that can cause lung injury.”

This study was recently published in NEJM. It was funded by Bristol-Myers Squibb, the company developing nivolumab, and others.

Based on results of this study, the US Food and Drug Administration (FDA) granted nivolumab breakthrough therapy designation to treat HL. The drug recently gained FDA approval to treat advanced melanoma.

Pembrolizumab

Dr Moskowitz, of Memorial Sloan Kettering Cancer Center in New York, presented data on pembrolizumab as abstract 290.*

Investigators enrolled 31 patients onto the cHL cohort of the Keynote 013 trial. Patients were a median age of 32 years (range, 20 to 67).

All patients had failed therapy with brentuximab vedotin, 69% failed prior stem cell transplant, and 28% were transplant ineligible. Patients had to have an ECOG performance status of 0 or 1 and could not have autoimmune disease or interstitial lung disease.

Patients received 10 mg/kg of pembrolizumab intravenously every 2 weeks for up to 24 months or until progression.

Twenty-nine patients were evaluable for efficacy. The ORR was 66%, with a CR rate of 21% and a partial response rate of 45%. Twenty-one percent of patients had stable disease, and 14% had progressive disease. So the clinical benefit rate was 86%.

The median time to response was 12 weeks, and the median duration of response ranged from 1 to 185 days, but the median had not yet been reached.

Nine patients (31%) discontinued therapy, 1 (3%) due to an AE, 7 (24%) due to disease progression, and 1 (3%) after achieving a CR. Twenty patients (69%) were still on therapy at the time of the presentation, and 1 patient went on to transplant.

Sixteen patients (55%) experienced 1 or more treatment-related AE of any grade. Those occurring in 2 or more patients included hypothyroidism (10%), pneumonitis (10%), constipation (7%), diarrhea (7%), nausea (7%), hypercholesterolemia (7%), hypertriglyceridemia (7%), and hematuria (7%).

Treatment-related AEs of grade 3 or higher included axillary pain (3%), hypoxia (3%), joint swelling (3%), and pneumonitis (3%). Three patients experienced 4 grade 3 or higher AEs. There were no grade 4 treatment-related AEs or treatment-related deaths.

“In my opinion,” Dr Moskowitz concluded, “these results support continued development of pembrolizumab in Hodgkin lymphoma.”

“I think that these drugs are here to stay. Where we are going to put them in the armamentarium in Hodgkin lymphoma remains to be seen.”

This study was funded by Merck Sharp & Dohme Corp., the company developing pembrolizumab.

*Information in the abstract differs from that presented at the meeting.

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—Two recent studies have shown combination therapy with brentuximab vedotin to be highly active in newly diagnosed patients with Hodgkin lymphoma (HL) and in relapsed or refractory patients after frontline therapy.

The first study evaluated brentuximab with ABVD or AVD and the second with bendamustine.

Objective response rates were 95% with ABVD, 96% with AVD, and 96% with bendamustine.

Both studies were presented at the 2014 ASH Annual Meeting, and both were sponsored by Seattle Genetics, Inc., the company developing brentuximab vedotin.

Brentuximab with ABVD or AVD

Standard frontline therapy with ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) or AVD (the same regimen without bleomycin) fails to cure up to 30% of patients with HL.

So investigators decided to try a new approach to increase efficacy and reduce toxicity—combining brentuximab with standard therapy.

Joseph M. Connors, MD, of the BC Cancer Agency and University of British Columbia in Vancouver, Canada, presented long-term outcomes of the brentuximab-ABVD combination as abstract 292.*

Phase 1 dose-escalation study

The key initial study of the combination determined the maximum tolerated dose of brentuximab to be 1.2 mg/kg delivered on a 2-week schedule to match the other agents in the ABVD regimen. Brentuximab was delivered for up to 6 cycles.

Of the 50 patients treated, 75% were males with an ECOG status of 0 or 1. Their median age was 32.5 years (range, 18 to 59). Approximately 80% were stage III or IV.

“We learned several key lessons from that initial study,” Dr Connors said. “The first was that when one adds brentuximab vedotin to the full-dose combination ABVD, unacceptable levels of pulmonary toxicity occurred, with 44% of the patients eventually experiencing pulmonary toxicity, typically manifest between the third and sixth cycle of treatment.”

The toxicity resolved in 9 of the 11 patients, but was fatal in 2. The median time to resolution was 2.6 weeks.

Eight patients discontinued bleomycin but were able to complete treatment with AVD and brentuximab.

“When we dropped bleomycin from the combination and shifted to AVD without bleomycin, no patients experienced pulmonary toxicity,” Dr Connors added.

Ultimately, the combination produced a response rate of 95% with ABVD and 96% with AVD.

Long-term follow-up

Investigators then assessed the durability of the response and the time distribution of any relapses.

All but 1 patient was available for follow-up. Patients were followed for a median of 45 months in the ABVD arm and 36 months in the AVD arm.

In the ABVD arm, 22 of 24 patients are living, and all 26 patients in the AVD group are alive. Altogether, there have been 5 relapses—3 in the ABVD arm (occurring at 9, 22, and 23 months) and 2 in the AVD arm (occurring at 7 and 22 months).

The 3-year failure-free survival is 79% with ABVD and 92% with AVD.  And the 3-year overall survival is 92% in the ABVD arm and 100% in the AVD arm.

No deaths from HL have occurred, and all 5 relapsed patients have undergone autologous stem cell transplant. One of those has subsequently relapsed.

“So far,” Dr Connors said, “survival has been excellent.” And responses are durable.

“This has encouraged activation of the large, international trial,” Dr Connors said, comparing AVD plus brentuximab to standard ABVD in frontline treatment of HL.

Brentuximab with bendamustine

Brentuximab is also active as a single agent in relapsed/refractory HL, producing a 34% complete response (CR) rate. And the alkylating agent bendamustine produces a 33% CR rate in these patients. Furthermore, both agents have manageable safety profiles and different mechanisms of action.

Investigators therefore hypothesized that brentuximab in combination with bendamustine could induce more CRs in HL patients with relapsed or refractory disease after frontline therapy.

Ann LaCasce, MD, of Dana-Farber Cancer Institute in Boston, presented the data at ASH as abstract 293.*

Ten patients were enrolled in the phase 1 portion of the study to determine the optimal dose level of bendamustine and to assess safety and tolerability.

No dose-limiting toxicities were observed. So the investigators used bendamustine at 90 mg/m² and brentuximab at 1.8 mg/kg. Patients received a median of 2 cycles (range, 1 to 6) of combination therapy.

Patients had the option to proceed to an autologous stem cell transplant at any time after cycle 2 and could receive brentuximab monotherapy thereafter for up to 16 total doses.

The phase 2 expansion portion enrolled 44 patients and assessed the best response, duration of response, and progression-free survival.

Results

Patients were a median age of 37 years (range, 27 to 51), and 57% were male. Ninety-eight percent were ECOG status 0 or 1, and 54% had stage III or IV disease at diagnosis.

The majority of patients had received ABVD as frontline therapy, Dr LaCasce pointed out.

The most common treatment-emergent adverse event was infusion-related reactions, accounting for 96% of the events. Dyspnea (15%), chills (13%), and flushing (13%) were the most common symptoms, and hypotension requiring vasopressor support also occurred.

Most reactions occurred within 24 hours of the cycle 2 infusion and were considered related to both agents. However, delayed hypersensitivity reactions also occurred, Dr LaCasce said, the most common being rash in 14 patients up to 22 days after infusion.

“Based on the number of infusion-related reactions after 24 patients, the protocol was amended to require mandatory corticosteroids and anthistamine premedication,” Dr LaCasce explained. “[T]his resulted in a significant decrease in the severity of the infusion-related reactions.”

The best clinical response for the 48 evaluable patients was 83% CR and 13% partial remission, for an objective response rate of 96%.

The median progression-free survival has not yet been reached, and the combination has had no negative impact on stem cell mobilization or engraftment to date.

The response rate compares very favorably to historical data, Dr LaCasce said, and the combination represents a promising salvage regimen for HL patients.

*Data in the presentation differ from the abstract.

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—Two recent studies have shown combination therapy with brentuximab vedotin to be highly active in newly diagnosed patients with Hodgkin lymphoma (HL) and in relapsed or refractory patients after frontline therapy.

The first study evaluated brentuximab with ABVD or AVD and the second with bendamustine.

Objective response rates were 95% with ABVD, 96% with AVD, and 96% with bendamustine.

Both studies were presented at the 2014 ASH Annual Meeting, and both were sponsored by Seattle Genetics, Inc., the company developing brentuximab vedotin.

Brentuximab with ABVD or AVD

Standard frontline therapy with ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) or AVD (the same regimen without bleomycin) fails to cure up to 30% of patients with HL.

So investigators decided to try a new approach to increase efficacy and reduce toxicity—combining brentuximab with standard therapy.

Joseph M. Connors, MD, of the BC Cancer Agency and University of British Columbia in Vancouver, Canada, presented long-term outcomes of the brentuximab-ABVD combination as abstract 292.*

Phase 1 dose-escalation study

The key initial study of the combination determined the maximum tolerated dose of brentuximab to be 1.2 mg/kg delivered on a 2-week schedule to match the other agents in the ABVD regimen. Brentuximab was delivered for up to 6 cycles.

Of the 50 patients treated, 75% were males with an ECOG status of 0 or 1. Their median age was 32.5 years (range, 18 to 59). Approximately 80% were stage III or IV.

“We learned several key lessons from that initial study,” Dr Connors said. “The first was that when one adds brentuximab vedotin to the full-dose combination ABVD, unacceptable levels of pulmonary toxicity occurred, with 44% of the patients eventually experiencing pulmonary toxicity, typically manifest between the third and sixth cycle of treatment.”

The toxicity resolved in 9 of the 11 patients, but was fatal in 2. The median time to resolution was 2.6 weeks.

Eight patients discontinued bleomycin but were able to complete treatment with AVD and brentuximab.

“When we dropped bleomycin from the combination and shifted to AVD without bleomycin, no patients experienced pulmonary toxicity,” Dr Connors added.

Ultimately, the combination produced a response rate of 95% with ABVD and 96% with AVD.

Long-term follow-up

Investigators then assessed the durability of the response and the time distribution of any relapses.

All but 1 patient was available for follow-up. Patients were followed for a median of 45 months in the ABVD arm and 36 months in the AVD arm.

In the ABVD arm, 22 of 24 patients are living, and all 26 patients in the AVD group are alive. Altogether, there have been 5 relapses—3 in the ABVD arm (occurring at 9, 22, and 23 months) and 2 in the AVD arm (occurring at 7 and 22 months).

The 3-year failure-free survival is 79% with ABVD and 92% with AVD.  And the 3-year overall survival is 92% in the ABVD arm and 100% in the AVD arm.

No deaths from HL have occurred, and all 5 relapsed patients have undergone autologous stem cell transplant. One of those has subsequently relapsed.

“So far,” Dr Connors said, “survival has been excellent.” And responses are durable.

“This has encouraged activation of the large, international trial,” Dr Connors said, comparing AVD plus brentuximab to standard ABVD in frontline treatment of HL.

Brentuximab with bendamustine

Brentuximab is also active as a single agent in relapsed/refractory HL, producing a 34% complete response (CR) rate. And the alkylating agent bendamustine produces a 33% CR rate in these patients. Furthermore, both agents have manageable safety profiles and different mechanisms of action.

Investigators therefore hypothesized that brentuximab in combination with bendamustine could induce more CRs in HL patients with relapsed or refractory disease after frontline therapy.

Ann LaCasce, MD, of Dana-Farber Cancer Institute in Boston, presented the data at ASH as abstract 293.*

Ten patients were enrolled in the phase 1 portion of the study to determine the optimal dose level of bendamustine and to assess safety and tolerability.

No dose-limiting toxicities were observed. So the investigators used bendamustine at 90 mg/m² and brentuximab at 1.8 mg/kg. Patients received a median of 2 cycles (range, 1 to 6) of combination therapy.

Patients had the option to proceed to an autologous stem cell transplant at any time after cycle 2 and could receive brentuximab monotherapy thereafter for up to 16 total doses.

The phase 2 expansion portion enrolled 44 patients and assessed the best response, duration of response, and progression-free survival.

Results

Patients were a median age of 37 years (range, 27 to 51), and 57% were male. Ninety-eight percent were ECOG status 0 or 1, and 54% had stage III or IV disease at diagnosis.

The majority of patients had received ABVD as frontline therapy, Dr LaCasce pointed out.

The most common treatment-emergent adverse event was infusion-related reactions, accounting for 96% of the events. Dyspnea (15%), chills (13%), and flushing (13%) were the most common symptoms, and hypotension requiring vasopressor support also occurred.

Most reactions occurred within 24 hours of the cycle 2 infusion and were considered related to both agents. However, delayed hypersensitivity reactions also occurred, Dr LaCasce said, the most common being rash in 14 patients up to 22 days after infusion.

“Based on the number of infusion-related reactions after 24 patients, the protocol was amended to require mandatory corticosteroids and anthistamine premedication,” Dr LaCasce explained. “[T]his resulted in a significant decrease in the severity of the infusion-related reactions.”

The best clinical response for the 48 evaluable patients was 83% CR and 13% partial remission, for an objective response rate of 96%.

The median progression-free survival has not yet been reached, and the combination has had no negative impact on stem cell mobilization or engraftment to date.

The response rate compares very favorably to historical data, Dr LaCasce said, and the combination represents a promising salvage regimen for HL patients.

*Data in the presentation differ from the abstract.

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—Two recent studies have shown combination therapy with brentuximab vedotin to be highly active in newly diagnosed patients with Hodgkin lymphoma (HL) and in relapsed or refractory patients after frontline therapy.

The first study evaluated brentuximab with ABVD or AVD and the second with bendamustine.

Objective response rates were 95% with ABVD, 96% with AVD, and 96% with bendamustine.

Both studies were presented at the 2014 ASH Annual Meeting, and both were sponsored by Seattle Genetics, Inc., the company developing brentuximab vedotin.

Brentuximab with ABVD or AVD

Standard frontline therapy with ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) or AVD (the same regimen without bleomycin) fails to cure up to 30% of patients with HL.

So investigators decided to try a new approach to increase efficacy and reduce toxicity—combining brentuximab with standard therapy.

Joseph M. Connors, MD, of the BC Cancer Agency and University of British Columbia in Vancouver, Canada, presented long-term outcomes of the brentuximab-ABVD combination as abstract 292.*

Phase 1 dose-escalation study

The key initial study of the combination determined the maximum tolerated dose of brentuximab to be 1.2 mg/kg delivered on a 2-week schedule to match the other agents in the ABVD regimen. Brentuximab was delivered for up to 6 cycles.

Of the 50 patients treated, 75% were males with an ECOG status of 0 or 1. Their median age was 32.5 years (range, 18 to 59). Approximately 80% were stage III or IV.

“We learned several key lessons from that initial study,” Dr Connors said. “The first was that when one adds brentuximab vedotin to the full-dose combination ABVD, unacceptable levels of pulmonary toxicity occurred, with 44% of the patients eventually experiencing pulmonary toxicity, typically manifest between the third and sixth cycle of treatment.”

The toxicity resolved in 9 of the 11 patients, but was fatal in 2. The median time to resolution was 2.6 weeks.

Eight patients discontinued bleomycin but were able to complete treatment with AVD and brentuximab.

“When we dropped bleomycin from the combination and shifted to AVD without bleomycin, no patients experienced pulmonary toxicity,” Dr Connors added.

Ultimately, the combination produced a response rate of 95% with ABVD and 96% with AVD.

Long-term follow-up

Investigators then assessed the durability of the response and the time distribution of any relapses.

All but 1 patient was available for follow-up. Patients were followed for a median of 45 months in the ABVD arm and 36 months in the AVD arm.

In the ABVD arm, 22 of 24 patients are living, and all 26 patients in the AVD group are alive. Altogether, there have been 5 relapses—3 in the ABVD arm (occurring at 9, 22, and 23 months) and 2 in the AVD arm (occurring at 7 and 22 months).

The 3-year failure-free survival is 79% with ABVD and 92% with AVD.  And the 3-year overall survival is 92% in the ABVD arm and 100% in the AVD arm.

No deaths from HL have occurred, and all 5 relapsed patients have undergone autologous stem cell transplant. One of those has subsequently relapsed.

“So far,” Dr Connors said, “survival has been excellent.” And responses are durable.

“This has encouraged activation of the large, international trial,” Dr Connors said, comparing AVD plus brentuximab to standard ABVD in frontline treatment of HL.

Brentuximab with bendamustine

Brentuximab is also active as a single agent in relapsed/refractory HL, producing a 34% complete response (CR) rate. And the alkylating agent bendamustine produces a 33% CR rate in these patients. Furthermore, both agents have manageable safety profiles and different mechanisms of action.

Investigators therefore hypothesized that brentuximab in combination with bendamustine could induce more CRs in HL patients with relapsed or refractory disease after frontline therapy.

Ann LaCasce, MD, of Dana-Farber Cancer Institute in Boston, presented the data at ASH as abstract 293.*

Ten patients were enrolled in the phase 1 portion of the study to determine the optimal dose level of bendamustine and to assess safety and tolerability.

No dose-limiting toxicities were observed. So the investigators used bendamustine at 90 mg/m² and brentuximab at 1.8 mg/kg. Patients received a median of 2 cycles (range, 1 to 6) of combination therapy.

Patients had the option to proceed to an autologous stem cell transplant at any time after cycle 2 and could receive brentuximab monotherapy thereafter for up to 16 total doses.

The phase 2 expansion portion enrolled 44 patients and assessed the best response, duration of response, and progression-free survival.

Results

Patients were a median age of 37 years (range, 27 to 51), and 57% were male. Ninety-eight percent were ECOG status 0 or 1, and 54% had stage III or IV disease at diagnosis.

The majority of patients had received ABVD as frontline therapy, Dr LaCasce pointed out.

The most common treatment-emergent adverse event was infusion-related reactions, accounting for 96% of the events. Dyspnea (15%), chills (13%), and flushing (13%) were the most common symptoms, and hypotension requiring vasopressor support also occurred.

Most reactions occurred within 24 hours of the cycle 2 infusion and were considered related to both agents. However, delayed hypersensitivity reactions also occurred, Dr LaCasce said, the most common being rash in 14 patients up to 22 days after infusion.

“Based on the number of infusion-related reactions after 24 patients, the protocol was amended to require mandatory corticosteroids and anthistamine premedication,” Dr LaCasce explained. “[T]his resulted in a significant decrease in the severity of the infusion-related reactions.”

The best clinical response for the 48 evaluable patients was 83% CR and 13% partial remission, for an objective response rate of 96%.

The median progression-free survival has not yet been reached, and the combination has had no negative impact on stem cell mobilization or engraftment to date.

The response rate compares very favorably to historical data, Dr LaCasce said, and the combination represents a promising salvage regimen for HL patients.

*Data in the presentation differ from the abstract.

SAN FRANCISCO—Administering brentuximab vedotin immediately after autologous stem cell transplant can improve progression-free survival (PFS) in patients with Hodgkin lymphoma (HL), results of the phase 3 AETHERA trial suggest.

The overall survival (OS) data for this study are not yet mature, but the significant improvement in PFS will likely translate to improved OS in a few years’ time, according to Craig Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr Moskowitz presented results from the AETHERA trial at the 2014 ASH Annual Meeting as abstract 673. The trial was funded by Seattle Genetics, Inc., and Takeda Pharmaceutical Company Limited, the companies developing brentuximab.

The trial included HL patients with at least one risk factor for progression. Eligible patients must have had a history of refractory HL, relapsed within a year of receiving frontline chemotherapy, and/or had disease outside of the lymph nodes at the time of pre-transplant relapse.

Researchers enrolled 329 patients, and they were randomized to receive brentuximab or placebo every 3 weeks for up to about a year. Baseline characteristics were similar between the 2 arms.

Dr Moskowitz pointed out that 43% of patients in the brentuximab arm and 48% in the placebo arm had required 2 or more prior salvage therapies, and 60% and 59%, respectively, had primary refractory HL.

Patients in both arms received a median of 15 treatment cycles, with an average of 12 cycles on the brentuximab arm and 11 cycles on the placebo arm.

“Patients who progressed in the placebo arm could be unblinded and subsequently receive brentuximab on a companion study,” Dr Moskowitz noted. “So technically, this was a cross-over design, making overall survival at 24 months quite unlikely.”

Efficacy/survival results

About half of patients in each arm completed treatment—47% in the brentuximab arm and 49% in the placebo arm. The reasons for discontinuation included disease progression (15% and 42%, respectively), adverse events (33% and 6%, respectively), and patient decision (5% and 2%, respectively).

Still, the trial achieved its primary endpoint, demonstrating a significant increase in PFS, according to an independent review facility (IRF).

The median PFS per the IRF was 43 months for patients in the brentuximab arm and 24 months in the placebo arm (hazard ratio=0.57, P=0.001). The 2-year PFS rates per the IRF were 63% and 51%, respectively.

The 2-year PFS rate according to investigators was 65% in the brentuximab arm and 45% in the placebo arm. The median PFS per investigators has not yet been reached for brentuximab but was 16 months for placebo.

The PFS benefit was consistent across all pre-specified subgroups, Dr Moskowitz noted, including primary refractory patients, patients who relapsed within 12 months of frontline therapy, and patients who relapsed after 12 months with extranodal disease.

Patients who experienced disease progression received a variety of subsequent therapies.

In the brentuximab arm, 16% of patients receiving subsequent therapy were treated with brentuximab after relapse. In the placebo arm, 85% of patients receiving subsequent therapy were treated with single-agent brentuximab.

Twenty-eight percent of patients in the placebo arm and 25% in the brentuximab arm received stem cell transplant as subsequent therapy, the majority of which were allogeneic transplants. Dr Moskowitz said a second transplant could have improved survival in these patients, but whether it actually did is unclear.

He noted that the OS data are immature, but there is currently no significant difference in OS between the treatment arms (hazard ratio=1.15; P=0.62).

“The median follow-up right now is 24 months,” he said. “So one will have to wait for a survival advantage or disadvantage, but from my point of view, a PFS of 65% at 2 years will translate to an overall survival difference. We’re just going to have to wait a few more years.”

Dr Moskowitz said another analysis of OS is planned in 2016.

Safety data

The most common adverse events in the brentuximab arm were peripheral sensory neuropathy (56%), neutropenia (35%), upper respiratory tract infection (26%), fatigue (24%), and peripheral motor neuropathy (23%).

The most common adverse events in the placebo arm were upper respiratory tract infection (23%), fatigue (18%), peripheral sensory neuropathy (16%), cough (16%), and neutropenia (12%).

Eighty-five percent of patients with peripheral neuropathy in the brentuximab arm had a resolution or improvement in symptoms, with a median time to improvement of 23.4 weeks.

Grade 3 or higher adverse events in the brentuximab arm included neutropenia, peripheral sensory neuropathy, peripheral motor neuropathy, nausea, fatigue, and diarrhea.

Grade 3 or higher adverse events in the placebo arm included neutropenia, fatigue, peripheral motor neuropathy, diarrhea, and peripheral sensory neuropathy. No Grade 4 peripheral neuropathy events occurred.

One death occurred within 30 days of brentuximab treatment. The patient died from treatment-related acute respiratory distress syndrome (ARDS) associated with pneumonitis.

Another death occurred on the brentuximab arm at day 40 from ARDS following an episode of treatment-related acute pancreatitis, which had resolved at the time of death.

Nevertheless, Dr Moskowitz characterized brentuximab consolidation as “very well-tolerated” in this patient population.

He concluded, “For patients with a remission duration of less than a year, patients with primary refractory Hodgkin lymphoma, and patients with Hodgkin lymphoma with extranodal involvement, I do believe this will become standard treatment.”

SAN FRANCISCO—Administering brentuximab vedotin immediately after autologous stem cell transplant can improve progression-free survival (PFS) in patients with Hodgkin lymphoma (HL), results of the phase 3 AETHERA trial suggest.

The overall survival (OS) data for this study are not yet mature, but the significant improvement in PFS will likely translate to improved OS in a few years’ time, according to Craig Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr Moskowitz presented results from the AETHERA trial at the 2014 ASH Annual Meeting as abstract 673. The trial was funded by Seattle Genetics, Inc., and Takeda Pharmaceutical Company Limited, the companies developing brentuximab.

The trial included HL patients with at least one risk factor for progression. Eligible patients must have had a history of refractory HL, relapsed within a year of receiving frontline chemotherapy, and/or had disease outside of the lymph nodes at the time of pre-transplant relapse.

Researchers enrolled 329 patients, and they were randomized to receive brentuximab or placebo every 3 weeks for up to about a year. Baseline characteristics were similar between the 2 arms.

Dr Moskowitz pointed out that 43% of patients in the brentuximab arm and 48% in the placebo arm had required 2 or more prior salvage therapies, and 60% and 59%, respectively, had primary refractory HL.

Patients in both arms received a median of 15 treatment cycles, with an average of 12 cycles on the brentuximab arm and 11 cycles on the placebo arm.

“Patients who progressed in the placebo arm could be unblinded and subsequently receive brentuximab on a companion study,” Dr Moskowitz noted. “So technically, this was a cross-over design, making overall survival at 24 months quite unlikely.”

Efficacy/survival results

About half of patients in each arm completed treatment—47% in the brentuximab arm and 49% in the placebo arm. The reasons for discontinuation included disease progression (15% and 42%, respectively), adverse events (33% and 6%, respectively), and patient decision (5% and 2%, respectively).

Still, the trial achieved its primary endpoint, demonstrating a significant increase in PFS, according to an independent review facility (IRF).

The median PFS per the IRF was 43 months for patients in the brentuximab arm and 24 months in the placebo arm (hazard ratio=0.57, P=0.001). The 2-year PFS rates per the IRF were 63% and 51%, respectively.

The 2-year PFS rate according to investigators was 65% in the brentuximab arm and 45% in the placebo arm. The median PFS per investigators has not yet been reached for brentuximab but was 16 months for placebo.

The PFS benefit was consistent across all pre-specified subgroups, Dr Moskowitz noted, including primary refractory patients, patients who relapsed within 12 months of frontline therapy, and patients who relapsed after 12 months with extranodal disease.

Patients who experienced disease progression received a variety of subsequent therapies.

In the brentuximab arm, 16% of patients receiving subsequent therapy were treated with brentuximab after relapse. In the placebo arm, 85% of patients receiving subsequent therapy were treated with single-agent brentuximab.

Twenty-eight percent of patients in the placebo arm and 25% in the brentuximab arm received stem cell transplant as subsequent therapy, the majority of which were allogeneic transplants. Dr Moskowitz said a second transplant could have improved survival in these patients, but whether it actually did is unclear.

He noted that the OS data are immature, but there is currently no significant difference in OS between the treatment arms (hazard ratio=1.15; P=0.62).

“The median follow-up right now is 24 months,” he said. “So one will have to wait for a survival advantage or disadvantage, but from my point of view, a PFS of 65% at 2 years will translate to an overall survival difference. We’re just going to have to wait a few more years.”

Dr Moskowitz said another analysis of OS is planned in 2016.

Safety data

The most common adverse events in the brentuximab arm were peripheral sensory neuropathy (56%), neutropenia (35%), upper respiratory tract infection (26%), fatigue (24%), and peripheral motor neuropathy (23%).

The most common adverse events in the placebo arm were upper respiratory tract infection (23%), fatigue (18%), peripheral sensory neuropathy (16%), cough (16%), and neutropenia (12%).

Eighty-five percent of patients with peripheral neuropathy in the brentuximab arm had a resolution or improvement in symptoms, with a median time to improvement of 23.4 weeks.

Grade 3 or higher adverse events in the brentuximab arm included neutropenia, peripheral sensory neuropathy, peripheral motor neuropathy, nausea, fatigue, and diarrhea.

Grade 3 or higher adverse events in the placebo arm included neutropenia, fatigue, peripheral motor neuropathy, diarrhea, and peripheral sensory neuropathy. No Grade 4 peripheral neuropathy events occurred.

One death occurred within 30 days of brentuximab treatment. The patient died from treatment-related acute respiratory distress syndrome (ARDS) associated with pneumonitis.

Another death occurred on the brentuximab arm at day 40 from ARDS following an episode of treatment-related acute pancreatitis, which had resolved at the time of death.

Nevertheless, Dr Moskowitz characterized brentuximab consolidation as “very well-tolerated” in this patient population.

He concluded, “For patients with a remission duration of less than a year, patients with primary refractory Hodgkin lymphoma, and patients with Hodgkin lymphoma with extranodal involvement, I do believe this will become standard treatment.”

SAN FRANCISCO—Administering brentuximab vedotin immediately after autologous stem cell transplant can improve progression-free survival (PFS) in patients with Hodgkin lymphoma (HL), results of the phase 3 AETHERA trial suggest.

The overall survival (OS) data for this study are not yet mature, but the significant improvement in PFS will likely translate to improved OS in a few years’ time, according to Craig Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr Moskowitz presented results from the AETHERA trial at the 2014 ASH Annual Meeting as abstract 673. The trial was funded by Seattle Genetics, Inc., and Takeda Pharmaceutical Company Limited, the companies developing brentuximab.

The trial included HL patients with at least one risk factor for progression. Eligible patients must have had a history of refractory HL, relapsed within a year of receiving frontline chemotherapy, and/or had disease outside of the lymph nodes at the time of pre-transplant relapse.

Researchers enrolled 329 patients, and they were randomized to receive brentuximab or placebo every 3 weeks for up to about a year. Baseline characteristics were similar between the 2 arms.

Dr Moskowitz pointed out that 43% of patients in the brentuximab arm and 48% in the placebo arm had required 2 or more prior salvage therapies, and 60% and 59%, respectively, had primary refractory HL.

Patients in both arms received a median of 15 treatment cycles, with an average of 12 cycles on the brentuximab arm and 11 cycles on the placebo arm.

“Patients who progressed in the placebo arm could be unblinded and subsequently receive brentuximab on a companion study,” Dr Moskowitz noted. “So technically, this was a cross-over design, making overall survival at 24 months quite unlikely.”

Efficacy/survival results

About half of patients in each arm completed treatment—47% in the brentuximab arm and 49% in the placebo arm. The reasons for discontinuation included disease progression (15% and 42%, respectively), adverse events (33% and 6%, respectively), and patient decision (5% and 2%, respectively).

Still, the trial achieved its primary endpoint, demonstrating a significant increase in PFS, according to an independent review facility (IRF).

The median PFS per the IRF was 43 months for patients in the brentuximab arm and 24 months in the placebo arm (hazard ratio=0.57, P=0.001). The 2-year PFS rates per the IRF were 63% and 51%, respectively.

The 2-year PFS rate according to investigators was 65% in the brentuximab arm and 45% in the placebo arm. The median PFS per investigators has not yet been reached for brentuximab but was 16 months for placebo.

The PFS benefit was consistent across all pre-specified subgroups, Dr Moskowitz noted, including primary refractory patients, patients who relapsed within 12 months of frontline therapy, and patients who relapsed after 12 months with extranodal disease.

Patients who experienced disease progression received a variety of subsequent therapies.

In the brentuximab arm, 16% of patients receiving subsequent therapy were treated with brentuximab after relapse. In the placebo arm, 85% of patients receiving subsequent therapy were treated with single-agent brentuximab.

Twenty-eight percent of patients in the placebo arm and 25% in the brentuximab arm received stem cell transplant as subsequent therapy, the majority of which were allogeneic transplants. Dr Moskowitz said a second transplant could have improved survival in these patients, but whether it actually did is unclear.

He noted that the OS data are immature, but there is currently no significant difference in OS between the treatment arms (hazard ratio=1.15; P=0.62).

“The median follow-up right now is 24 months,” he said. “So one will have to wait for a survival advantage or disadvantage, but from my point of view, a PFS of 65% at 2 years will translate to an overall survival difference. We’re just going to have to wait a few more years.”

Dr Moskowitz said another analysis of OS is planned in 2016.

Safety data

The most common adverse events in the brentuximab arm were peripheral sensory neuropathy (56%), neutropenia (35%), upper respiratory tract infection (26%), fatigue (24%), and peripheral motor neuropathy (23%).

The most common adverse events in the placebo arm were upper respiratory tract infection (23%), fatigue (18%), peripheral sensory neuropathy (16%), cough (16%), and neutropenia (12%).

Eighty-five percent of patients with peripheral neuropathy in the brentuximab arm had a resolution or improvement in symptoms, with a median time to improvement of 23.4 weeks.

Grade 3 or higher adverse events in the brentuximab arm included neutropenia, peripheral sensory neuropathy, peripheral motor neuropathy, nausea, fatigue, and diarrhea.

Grade 3 or higher adverse events in the placebo arm included neutropenia, fatigue, peripheral motor neuropathy, diarrhea, and peripheral sensory neuropathy. No Grade 4 peripheral neuropathy events occurred.

One death occurred within 30 days of brentuximab treatment. The patient died from treatment-related acute respiratory distress syndrome (ARDS) associated with pneumonitis.

Another death occurred on the brentuximab arm at day 40 from ARDS following an episode of treatment-related acute pancreatitis, which had resolved at the time of death.

Nevertheless, Dr Moskowitz characterized brentuximab consolidation as “very well-tolerated” in this patient population.

He concluded, “For patients with a remission duration of less than a year, patients with primary refractory Hodgkin lymphoma, and patients with Hodgkin lymphoma with extranodal involvement, I do believe this will become standard treatment.”

SAN FRANCISCO – Early post-transplant brentuximab vedotin dramatically slows Hodgkin’s lymphoma progression in patients at high risk for relapse or progression, the phase III AETHERA study shows.

After a median follow-up of about 28 months, the primary end point of progression-free survival (PFS) per independent review increased from a median of 24 months with placebo and best supportive care (BSC) to 43 months with brentuximab and BSC (Hazard ratio, 0.57; P = .001).

Per investigator assessment, median PFS was 16 months with placebo and had not been reached with brentuximab (HR, 0.50),Dr. Craig Moskowitz reported at the annual meeting of the American Society of Hematology.

Patrice Wendling/Frontline Medical News

The benefit of brentuximab maintenance was consistent across every subgroup. Historically, roughly half of patients who undergo an autologous stem cell transplant will relapse.

“Once this study is published, in patients who met eligibility criteria to be on this study - and once again I’ll remind you that’s remission duration less than one year, disease outside the lymph node system, or primary refractory disease - in my opinion, this will be the standard of care,” Dr. Moskowitz said during a press briefing.

Brentuximab, an anti-CD30 antibody conjugate, is already approved in the U.S. for the management of Hodgkin’s lymphoma (HL) after failure of autologous stem cell transplantation (ASCT) or at least two prior lines of multi-agent chemotherapy in patients ineligible for ASCT.

Brentuximab is also indicated for systemic anaplastic large cell lymphoma after failure of at least one multi-agent chemotherapy regimen.

In September it was announced that AETHERA met its primary end point, but this was the first full look at the absolute survival rates and safety data.

The 2-year PFS rate for the brentuximab and placebo groups is now 63% vs. 51% per independent review and 65% vs. 45% per investigator.

“The bottom line is there’s a 20% difference in progression-free survival at 2 years upon investigator review. This has never been seen in patients with relapsed, refractory lymphoma, let alone Hodgkin lymphoma,” Dr. Moskowitz, clinical director of hematology oncology at Memorial Sloan-Kettering Cancer Center in New York City, said.

Overall survival data are immature, but was the same in both groups at 2 years (P = .62). The likelihood of showing a survival difference was not expected because 85% of patients who relapsed on the placebo arm crossed over to brentuximab, as allowed per protocol, and it’s known that brentuximab alone in auto-transplant failures improves outcomes by at least a year, he said. Also, twice as many patients who failed placebo received a second transplant.

Dr. Moskowitz stressed that nearly every patient in the trial had at least three risk factors that would place them at high risk of treatment failure and that studies have shown that for patients with this many risk factors, the chance of being cured by an auto-transplant is about 25%. The risk factors are: relapsed less than 12 months or refractory to frontline therapy, best response of partial remission or stable disease to most recent salvage therapy, extranodal disease at pre-ASCT relapse, B symptoms at pre-ASCT relapse, or two or more prior salvage therapies.

Press briefing moderator Dr. Brad Kahl of the University of Wisconsin-Madison, said Aethera is the first study to show a significant benefit for a post-transplant strategy.

“The biggest question in my mind is whether the application of maintenance brentuximab vedotin is just delaying the inevitable relapse, so the patients will still relapse, just later, or has the brentuximab taken patients who are destined to relapse and turned them into a cured patient,” Dr. Kahl said. “We don’t know the answer to that question. That will become apparent with more time.”

Dr. Moscowitz observed that relapses almost never happen after two year, adding, “So if you’re in remission at two years after stem cell transplantation for Hodgkin lymphoma, you are likely to be cured.”

AETHERA enrolled 329 patients with Hodgkin’s lymphoma and randomly assigned them after ASCT to brentuximab vedotin 1.8 mg/kg or placebo given every 3 weeks for up to 16 cycles, plus BSC. All patients were required to have achieved a complete response, partial remission, or stable disease to salvage therapy prior to ASCT. Their median age was 32 years and 53% were male.

Roughly 60% were refractory to upfront therapy, 43% in the brentuximab arm and 48% of controls had received 2 or more prior systemic therapies, and a third in each arm had extranodal involvement.

Consolidation therapy with brentuximab was generally well tolerated, Dr. Moskowitz said. Peripheral sensory neuropathy was the most common side effect, experienced at any grade in 67% on brentuximab vs. 19% of controls and at grade 3 in 13% vs. 1%. There were no grade 4 events and 85% of patients had resolution or improvement with dose reductions or stopping the drug.

Other adverse events in the brentuximab and control groups were neutropenia (35% vs. 12%), upper respiratory tract infections (26% vs. 23%), and fatigue (24% vs. 18%). Two patients died within 40 days of dosing with brentuximab, one from treatment-related acute respiratory distress syndrome associated with pneumonitis and one following an episode of treatment-related acute pancreatitis that had resolved at the time of death, he reported.

Based on the results, study sponsor Seattle Genetics is expected to seek approval for brentuximab in this consolidation setting in the first half of 2015, according to a statement from the company. The ongoing phase III ECHELON-1 and ECHELON 2 trials in HL and mature T-cell lymphomas are looking at the use of brentuximab in frontline disease.

[email protected]

SAN FRANCISCO – Early post-transplant brentuximab vedotin dramatically slows Hodgkin’s lymphoma progression in patients at high risk for relapse or progression, the phase III AETHERA study shows.

After a median follow-up of about 28 months, the primary end point of progression-free survival (PFS) per independent review increased from a median of 24 months with placebo and best supportive care (BSC) to 43 months with brentuximab and BSC (Hazard ratio, 0.57; P = .001).

Per investigator assessment, median PFS was 16 months with placebo and had not been reached with brentuximab (HR, 0.50),Dr. Craig Moskowitz reported at the annual meeting of the American Society of Hematology.

Patrice Wendling/Frontline Medical News

The benefit of brentuximab maintenance was consistent across every subgroup. Historically, roughly half of patients who undergo an autologous stem cell transplant will relapse.

“Once this study is published, in patients who met eligibility criteria to be on this study - and once again I’ll remind you that’s remission duration less than one year, disease outside the lymph node system, or primary refractory disease - in my opinion, this will be the standard of care,” Dr. Moskowitz said during a press briefing.

Brentuximab, an anti-CD30 antibody conjugate, is already approved in the U.S. for the management of Hodgkin’s lymphoma (HL) after failure of autologous stem cell transplantation (ASCT) or at least two prior lines of multi-agent chemotherapy in patients ineligible for ASCT.

Brentuximab is also indicated for systemic anaplastic large cell lymphoma after failure of at least one multi-agent chemotherapy regimen.

In September it was announced that AETHERA met its primary end point, but this was the first full look at the absolute survival rates and safety data.

The 2-year PFS rate for the brentuximab and placebo groups is now 63% vs. 51% per independent review and 65% vs. 45% per investigator.

“The bottom line is there’s a 20% difference in progression-free survival at 2 years upon investigator review. This has never been seen in patients with relapsed, refractory lymphoma, let alone Hodgkin lymphoma,” Dr. Moskowitz, clinical director of hematology oncology at Memorial Sloan-Kettering Cancer Center in New York City, said.

Overall survival data are immature, but was the same in both groups at 2 years (P = .62). The likelihood of showing a survival difference was not expected because 85% of patients who relapsed on the placebo arm crossed over to brentuximab, as allowed per protocol, and it’s known that brentuximab alone in auto-transplant failures improves outcomes by at least a year, he said. Also, twice as many patients who failed placebo received a second transplant.

Dr. Moskowitz stressed that nearly every patient in the trial had at least three risk factors that would place them at high risk of treatment failure and that studies have shown that for patients with this many risk factors, the chance of being cured by an auto-transplant is about 25%. The risk factors are: relapsed less than 12 months or refractory to frontline therapy, best response of partial remission or stable disease to most recent salvage therapy, extranodal disease at pre-ASCT relapse, B symptoms at pre-ASCT relapse, or two or more prior salvage therapies.

Press briefing moderator Dr. Brad Kahl of the University of Wisconsin-Madison, said Aethera is the first study to show a significant benefit for a post-transplant strategy.

“The biggest question in my mind is whether the application of maintenance brentuximab vedotin is just delaying the inevitable relapse, so the patients will still relapse, just later, or has the brentuximab taken patients who are destined to relapse and turned them into a cured patient,” Dr. Kahl said. “We don’t know the answer to that question. That will become apparent with more time.”

Dr. Moscowitz observed that relapses almost never happen after two year, adding, “So if you’re in remission at two years after stem cell transplantation for Hodgkin lymphoma, you are likely to be cured.”

AETHERA enrolled 329 patients with Hodgkin’s lymphoma and randomly assigned them after ASCT to brentuximab vedotin 1.8 mg/kg or placebo given every 3 weeks for up to 16 cycles, plus BSC. All patients were required to have achieved a complete response, partial remission, or stable disease to salvage therapy prior to ASCT. Their median age was 32 years and 53% were male.

Roughly 60% were refractory to upfront therapy, 43% in the brentuximab arm and 48% of controls had received 2 or more prior systemic therapies, and a third in each arm had extranodal involvement.

Consolidation therapy with brentuximab was generally well tolerated, Dr. Moskowitz said. Peripheral sensory neuropathy was the most common side effect, experienced at any grade in 67% on brentuximab vs. 19% of controls and at grade 3 in 13% vs. 1%. There were no grade 4 events and 85% of patients had resolution or improvement with dose reductions or stopping the drug.

Other adverse events in the brentuximab and control groups were neutropenia (35% vs. 12%), upper respiratory tract infections (26% vs. 23%), and fatigue (24% vs. 18%). Two patients died within 40 days of dosing with brentuximab, one from treatment-related acute respiratory distress syndrome associated with pneumonitis and one following an episode of treatment-related acute pancreatitis that had resolved at the time of death, he reported.

Based on the results, study sponsor Seattle Genetics is expected to seek approval for brentuximab in this consolidation setting in the first half of 2015, according to a statement from the company. The ongoing phase III ECHELON-1 and ECHELON 2 trials in HL and mature T-cell lymphomas are looking at the use of brentuximab in frontline disease.

[email protected]

SAN FRANCISCO – Early post-transplant brentuximab vedotin dramatically slows Hodgkin’s lymphoma progression in patients at high risk for relapse or progression, the phase III AETHERA study shows.

After a median follow-up of about 28 months, the primary end point of progression-free survival (PFS) per independent review increased from a median of 24 months with placebo and best supportive care (BSC) to 43 months with brentuximab and BSC (Hazard ratio, 0.57; P = .001).

Per investigator assessment, median PFS was 16 months with placebo and had not been reached with brentuximab (HR, 0.50),Dr. Craig Moskowitz reported at the annual meeting of the American Society of Hematology.

Patrice Wendling/Frontline Medical News

The benefit of brentuximab maintenance was consistent across every subgroup. Historically, roughly half of patients who undergo an autologous stem cell transplant will relapse.

“Once this study is published, in patients who met eligibility criteria to be on this study - and once again I’ll remind you that’s remission duration less than one year, disease outside the lymph node system, or primary refractory disease - in my opinion, this will be the standard of care,” Dr. Moskowitz said during a press briefing.

Brentuximab, an anti-CD30 antibody conjugate, is already approved in the U.S. for the management of Hodgkin’s lymphoma (HL) after failure of autologous stem cell transplantation (ASCT) or at least two prior lines of multi-agent chemotherapy in patients ineligible for ASCT.

Brentuximab is also indicated for systemic anaplastic large cell lymphoma after failure of at least one multi-agent chemotherapy regimen.

In September it was announced that AETHERA met its primary end point, but this was the first full look at the absolute survival rates and safety data.

The 2-year PFS rate for the brentuximab and placebo groups is now 63% vs. 51% per independent review and 65% vs. 45% per investigator.

“The bottom line is there’s a 20% difference in progression-free survival at 2 years upon investigator review. This has never been seen in patients with relapsed, refractory lymphoma, let alone Hodgkin lymphoma,” Dr. Moskowitz, clinical director of hematology oncology at Memorial Sloan-Kettering Cancer Center in New York City, said.

Overall survival data are immature, but was the same in both groups at 2 years (P = .62). The likelihood of showing a survival difference was not expected because 85% of patients who relapsed on the placebo arm crossed over to brentuximab, as allowed per protocol, and it’s known that brentuximab alone in auto-transplant failures improves outcomes by at least a year, he said. Also, twice as many patients who failed placebo received a second transplant.

Dr. Moskowitz stressed that nearly every patient in the trial had at least three risk factors that would place them at high risk of treatment failure and that studies have shown that for patients with this many risk factors, the chance of being cured by an auto-transplant is about 25%. The risk factors are: relapsed less than 12 months or refractory to frontline therapy, best response of partial remission or stable disease to most recent salvage therapy, extranodal disease at pre-ASCT relapse, B symptoms at pre-ASCT relapse, or two or more prior salvage therapies.

Press briefing moderator Dr. Brad Kahl of the University of Wisconsin-Madison, said Aethera is the first study to show a significant benefit for a post-transplant strategy.

“The biggest question in my mind is whether the application of maintenance brentuximab vedotin is just delaying the inevitable relapse, so the patients will still relapse, just later, or has the brentuximab taken patients who are destined to relapse and turned them into a cured patient,” Dr. Kahl said. “We don’t know the answer to that question. That will become apparent with more time.”

Dr. Moscowitz observed that relapses almost never happen after two year, adding, “So if you’re in remission at two years after stem cell transplantation for Hodgkin lymphoma, you are likely to be cured.”

AETHERA enrolled 329 patients with Hodgkin’s lymphoma and randomly assigned them after ASCT to brentuximab vedotin 1.8 mg/kg or placebo given every 3 weeks for up to 16 cycles, plus BSC. All patients were required to have achieved a complete response, partial remission, or stable disease to salvage therapy prior to ASCT. Their median age was 32 years and 53% were male.

Roughly 60% were refractory to upfront therapy, 43% in the brentuximab arm and 48% of controls had received 2 or more prior systemic therapies, and a third in each arm had extranodal involvement.

Consolidation therapy with brentuximab was generally well tolerated, Dr. Moskowitz said. Peripheral sensory neuropathy was the most common side effect, experienced at any grade in 67% on brentuximab vs. 19% of controls and at grade 3 in 13% vs. 1%. There were no grade 4 events and 85% of patients had resolution or improvement with dose reductions or stopping the drug.

Other adverse events in the brentuximab and control groups were neutropenia (35% vs. 12%), upper respiratory tract infections (26% vs. 23%), and fatigue (24% vs. 18%). Two patients died within 40 days of dosing with brentuximab, one from treatment-related acute respiratory distress syndrome associated with pneumonitis and one following an episode of treatment-related acute pancreatitis that had resolved at the time of death, he reported.

Based on the results, study sponsor Seattle Genetics is expected to seek approval for brentuximab in this consolidation setting in the first half of 2015, according to a statement from the company. The ongoing phase III ECHELON-1 and ECHELON 2 trials in HL and mature T-cell lymphomas are looking at the use of brentuximab in frontline disease.

[email protected]

SAN FRANCISCO– PD-1 checkpoint inhibitors, which have shown remarkable efficacy against advanced malignant melanoma, appear to hold similar promise in the treatment of relapsed or refractory Hodgkin’s lymphoma, results from two early studies suggest.

In a phase I study, the PD-1 blocking antibody nivolumab produced an 87% response rate in 23 heavily pre-treated patients with relapsed Hodgkin’s lymphoma (HL). In a separate phase Ib study, pembrolizumab, which blocks the PD-1 and PD-2 ligands, produced a 66% overall response rate, 21% complete remission rate, and 86% clinical benefit rate among 29 patients with HL for whom therapy with brentuximab vedotin (Adcetris) had failed.

The studies were presented at a media briefing prior to the presentation of data in oral sessions at the annual meeting of the American Society of Hematology.

“Classical Hodgkin lymphoma appears to be a tumor with genetically determined vulnerability to PD-1 blockade. We hope that PD-1 blockade in the future can become an important part of the treatment of patients with Hodgkin lymphoma,” said Dr. Phillipe Armand from the Dana-Farber Cancer Institute in Boston, an investigator for the nivolumab study.

Neil Osterweil/Frontline Medical News

Evidence from preclinical studies suggests that the Reed-Sternberg malignant cells characteristic of HL may use the PD-1 (programmed death 1) pathway to evade detection by immune cells, as suggested by pathologic studies showing the cells surrounded by an extensive but ineffective infiltrate of inflammatory cells.

“We’ve wondered for a long time how Hodgkin lymphoma could attract such a brisk immune response and yet have this immune response fail to kill the tumor,” he said.

Genetic Achilles heel

Genetic analyses had shown that HL frequently has a mutation that results in amplification of a region on chromosome 9 (9p24.1) which leads to increased expression of PD-1 ligands 1 and 2, and leads to a downregulation or weakening of the immune response. The mutation appears to work through the Janus kinase (JAK)-signal transducer and activator transcription (STAT) signalling. These findings suggested to researchers that classical HL has a genetically driven and, ideally, targetable dependence on the PD-1 pathway for survival, Dr. Armand explained.

To test this idea, he and colleagues studied 23 patients with relapsed or refractory HL that had been heavily pre-treated who were part of an independent expansion cohort of a study of nivolumab in hematologic malignancies. Of these patients, 78% were enrolled after a relapse following autologous stem cell transplantation, and 22% after treatment with brentuximab vedotin had failed.

The patients received nivolumab 3 mg/kg every 2 weeks until they had either a complete response, tumor progression, or excessive side effects. In all, 20 of the 23 patients (87%) had an objective response to the single-agent therapy, including 4 (17%) complete responses and 16 (70%) partial responses. The remaining three patients (13%) had stable disease.

The longest time on study at the data cutoff point was 72 weeks. Among all responders, 60% had a response by 8 weeks of therapy, 48% are ongoing, and 43% of patients are still on treatment.

Drug-related adverse events were reported in 18 patients, most commonly rash and decreased platelet count. Five patients had grade 3 events. There were no drug-related grade 4 events or deaths.

In an editorial accompanying the study, which was also published online in The New England Journal of Medicine, Dr. Mario Sznoll and Dr. Dan L. Longo from the Yale University School of Medicine in New Haven, Connecticut write that “with recent data showing impressive clinical activity of PD-1 or PD-L1 antagonists in subgroups of patients with a variety of different cancers, the critical and foundational role of immune interventions in cancer treatment is no longer deniable,” (NEJM, Dec. 6, 2014 [DOI: 10.1056/NEJMoa1411087]).

Pembrolizumab trial

Dr. Craig H. Moskowitz from Memorial Sloan-Kettering Cancer Center in New York City discussed results of the second study, dubbed KEYNOTE-013 (A Phase Ib Multi-Cohort Trial of MK-3475 in Subjects With Hematologic Malignancies).

In this study, patients with HL who were not transplant eligible or for whom transplant had failed and who either had a relapse or were refractory to therapy with brentuximab vedotin received 19 mg/kg IV infusion of pembrolizumab every 2 weeks until complete response, partial response/stable disease, or disease progression.

Of the 31 patients enrolled, 29 were available for the analysis. As of the data cutoff in November 2014, 6 patients (21%) had achieved a complete remission, and 13 (45%) had a partial response, for an overall response rate of 66%. The median time to response was 12 weeks, and as of the data cutoff 17 of 19 patients had ongoing responses. The median response duration has not yet been reached. An additional 6 patients (21%) had stable disease, leading to an overall clinical benefit rate (responses plus stable disease) of 86%.

The patients generally tolerated the drug well. There were 4 treatment-related adverse events in 3 patients, including axillary pain, hypoxia, joint swelling, and pneumonitis. There were no grade 4 treatment-related events or deaths.

Of the tumor samples evaluable, all expressed PD-L1, supporting the rationale for PD-1 blockade in this population, Dr. Moskowitz said.

The results of both his and Dr. Armand’s study support the continued development of PD-1 inhibitors in various subsets of patients with classical Hodgkin’s lymphoma, he said.

SAN FRANCISCO– PD-1 checkpoint inhibitors, which have shown remarkable efficacy against advanced malignant melanoma, appear to hold similar promise in the treatment of relapsed or refractory Hodgkin’s lymphoma, results from two early studies suggest.

In a phase I study, the PD-1 blocking antibody nivolumab produced an 87% response rate in 23 heavily pre-treated patients with relapsed Hodgkin’s lymphoma (HL). In a separate phase Ib study, pembrolizumab, which blocks the PD-1 and PD-2 ligands, produced a 66% overall response rate, 21% complete remission rate, and 86% clinical benefit rate among 29 patients with HL for whom therapy with brentuximab vedotin (Adcetris) had failed.

The studies were presented at a media briefing prior to the presentation of data in oral sessions at the annual meeting of the American Society of Hematology.

“Classical Hodgkin lymphoma appears to be a tumor with genetically determined vulnerability to PD-1 blockade. We hope that PD-1 blockade in the future can become an important part of the treatment of patients with Hodgkin lymphoma,” said Dr. Phillipe Armand from the Dana-Farber Cancer Institute in Boston, an investigator for the nivolumab study.

Neil Osterweil/Frontline Medical News

Evidence from preclinical studies suggests that the Reed-Sternberg malignant cells characteristic of HL may use the PD-1 (programmed death 1) pathway to evade detection by immune cells, as suggested by pathologic studies showing the cells surrounded by an extensive but ineffective infiltrate of inflammatory cells.

“We’ve wondered for a long time how Hodgkin lymphoma could attract such a brisk immune response and yet have this immune response fail to kill the tumor,” he said.

Genetic Achilles heel

Genetic analyses had shown that HL frequently has a mutation that results in amplification of a region on chromosome 9 (9p24.1) which leads to increased expression of PD-1 ligands 1 and 2, and leads to a downregulation or weakening of the immune response. The mutation appears to work through the Janus kinase (JAK)-signal transducer and activator transcription (STAT) signalling. These findings suggested to researchers that classical HL has a genetically driven and, ideally, targetable dependence on the PD-1 pathway for survival, Dr. Armand explained.

To test this idea, he and colleagues studied 23 patients with relapsed or refractory HL that had been heavily pre-treated who were part of an independent expansion cohort of a study of nivolumab in hematologic malignancies. Of these patients, 78% were enrolled after a relapse following autologous stem cell transplantation, and 22% after treatment with brentuximab vedotin had failed.

The patients received nivolumab 3 mg/kg every 2 weeks until they had either a complete response, tumor progression, or excessive side effects. In all, 20 of the 23 patients (87%) had an objective response to the single-agent therapy, including 4 (17%) complete responses and 16 (70%) partial responses. The remaining three patients (13%) had stable disease.

The longest time on study at the data cutoff point was 72 weeks. Among all responders, 60% had a response by 8 weeks of therapy, 48% are ongoing, and 43% of patients are still on treatment.

Drug-related adverse events were reported in 18 patients, most commonly rash and decreased platelet count. Five patients had grade 3 events. There were no drug-related grade 4 events or deaths.

In an editorial accompanying the study, which was also published online in The New England Journal of Medicine, Dr. Mario Sznoll and Dr. Dan L. Longo from the Yale University School of Medicine in New Haven, Connecticut write that “with recent data showing impressive clinical activity of PD-1 or PD-L1 antagonists in subgroups of patients with a variety of different cancers, the critical and foundational role of immune interventions in cancer treatment is no longer deniable,” (NEJM, Dec. 6, 2014 [DOI: 10.1056/NEJMoa1411087]).

Pembrolizumab trial

Dr. Craig H. Moskowitz from Memorial Sloan-Kettering Cancer Center in New York City discussed results of the second study, dubbed KEYNOTE-013 (A Phase Ib Multi-Cohort Trial of MK-3475 in Subjects With Hematologic Malignancies).

In this study, patients with HL who were not transplant eligible or for whom transplant had failed and who either had a relapse or were refractory to therapy with brentuximab vedotin received 19 mg/kg IV infusion of pembrolizumab every 2 weeks until complete response, partial response/stable disease, or disease progression.

Of the 31 patients enrolled, 29 were available for the analysis. As of the data cutoff in November 2014, 6 patients (21%) had achieved a complete remission, and 13 (45%) had a partial response, for an overall response rate of 66%. The median time to response was 12 weeks, and as of the data cutoff 17 of 19 patients had ongoing responses. The median response duration has not yet been reached. An additional 6 patients (21%) had stable disease, leading to an overall clinical benefit rate (responses plus stable disease) of 86%.

The patients generally tolerated the drug well. There were 4 treatment-related adverse events in 3 patients, including axillary pain, hypoxia, joint swelling, and pneumonitis. There were no grade 4 treatment-related events or deaths.

Of the tumor samples evaluable, all expressed PD-L1, supporting the rationale for PD-1 blockade in this population, Dr. Moskowitz said.

The results of both his and Dr. Armand’s study support the continued development of PD-1 inhibitors in various subsets of patients with classical Hodgkin’s lymphoma, he said.

SAN FRANCISCO– PD-1 checkpoint inhibitors, which have shown remarkable efficacy against advanced malignant melanoma, appear to hold similar promise in the treatment of relapsed or refractory Hodgkin’s lymphoma, results from two early studies suggest.

In a phase I study, the PD-1 blocking antibody nivolumab produced an 87% response rate in 23 heavily pre-treated patients with relapsed Hodgkin’s lymphoma (HL). In a separate phase Ib study, pembrolizumab, which blocks the PD-1 and PD-2 ligands, produced a 66% overall response rate, 21% complete remission rate, and 86% clinical benefit rate among 29 patients with HL for whom therapy with brentuximab vedotin (Adcetris) had failed.

The studies were presented at a media briefing prior to the presentation of data in oral sessions at the annual meeting of the American Society of Hematology.

“Classical Hodgkin lymphoma appears to be a tumor with genetically determined vulnerability to PD-1 blockade. We hope that PD-1 blockade in the future can become an important part of the treatment of patients with Hodgkin lymphoma,” said Dr. Phillipe Armand from the Dana-Farber Cancer Institute in Boston, an investigator for the nivolumab study.

Neil Osterweil/Frontline Medical News

Evidence from preclinical studies suggests that the Reed-Sternberg malignant cells characteristic of HL may use the PD-1 (programmed death 1) pathway to evade detection by immune cells, as suggested by pathologic studies showing the cells surrounded by an extensive but ineffective infiltrate of inflammatory cells.

“We’ve wondered for a long time how Hodgkin lymphoma could attract such a brisk immune response and yet have this immune response fail to kill the tumor,” he said.

Genetic Achilles heel

Genetic analyses had shown that HL frequently has a mutation that results in amplification of a region on chromosome 9 (9p24.1) which leads to increased expression of PD-1 ligands 1 and 2, and leads to a downregulation or weakening of the immune response. The mutation appears to work through the Janus kinase (JAK)-signal transducer and activator transcription (STAT) signalling. These findings suggested to researchers that classical HL has a genetically driven and, ideally, targetable dependence on the PD-1 pathway for survival, Dr. Armand explained.

To test this idea, he and colleagues studied 23 patients with relapsed or refractory HL that had been heavily pre-treated who were part of an independent expansion cohort of a study of nivolumab in hematologic malignancies. Of these patients, 78% were enrolled after a relapse following autologous stem cell transplantation, and 22% after treatment with brentuximab vedotin had failed.

The patients received nivolumab 3 mg/kg every 2 weeks until they had either a complete response, tumor progression, or excessive side effects. In all, 20 of the 23 patients (87%) had an objective response to the single-agent therapy, including 4 (17%) complete responses and 16 (70%) partial responses. The remaining three patients (13%) had stable disease.

The longest time on study at the data cutoff point was 72 weeks. Among all responders, 60% had a response by 8 weeks of therapy, 48% are ongoing, and 43% of patients are still on treatment.

Drug-related adverse events were reported in 18 patients, most commonly rash and decreased platelet count. Five patients had grade 3 events. There were no drug-related grade 4 events or deaths.

In an editorial accompanying the study, which was also published online in The New England Journal of Medicine, Dr. Mario Sznoll and Dr. Dan L. Longo from the Yale University School of Medicine in New Haven, Connecticut write that “with recent data showing impressive clinical activity of PD-1 or PD-L1 antagonists in subgroups of patients with a variety of different cancers, the critical and foundational role of immune interventions in cancer treatment is no longer deniable,” (NEJM, Dec. 6, 2014 [DOI: 10.1056/NEJMoa1411087]).

Pembrolizumab trial

Dr. Craig H. Moskowitz from Memorial Sloan-Kettering Cancer Center in New York City discussed results of the second study, dubbed KEYNOTE-013 (A Phase Ib Multi-Cohort Trial of MK-3475 in Subjects With Hematologic Malignancies).

In this study, patients with HL who were not transplant eligible or for whom transplant had failed and who either had a relapse or were refractory to therapy with brentuximab vedotin received 19 mg/kg IV infusion of pembrolizumab every 2 weeks until complete response, partial response/stable disease, or disease progression.

Of the 31 patients enrolled, 29 were available for the analysis. As of the data cutoff in November 2014, 6 patients (21%) had achieved a complete remission, and 13 (45%) had a partial response, for an overall response rate of 66%. The median time to response was 12 weeks, and as of the data cutoff 17 of 19 patients had ongoing responses. The median response duration has not yet been reached. An additional 6 patients (21%) had stable disease, leading to an overall clinical benefit rate (responses plus stable disease) of 86%.

The patients generally tolerated the drug well. There were 4 treatment-related adverse events in 3 patients, including axillary pain, hypoxia, joint swelling, and pneumonitis. There were no grade 4 treatment-related events or deaths.

Of the tumor samples evaluable, all expressed PD-L1, supporting the rationale for PD-1 blockade in this population, Dr. Moskowitz said.

The results of both his and Dr. Armand’s study support the continued development of PD-1 inhibitors in various subsets of patients with classical Hodgkin’s lymphoma, he said.

Vials of a drug

NEW YORK—Brentuximab vendotin—not conventional chemotherapy—is the second-line regimen of choice for recurrent Hodgkin lymphoma (HL) patients prior to stem cell transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.

Catherine Diefenbach, MD, of New York University’s Langone Medical Center in New York, argued that conventional chemotherapy, the existing paradigm for first salvage therapy, does not maximize a cure or minimize toxicity, is inconvenient, and is not cost-effective.

She noted that a quarter of HL patients relapse or have a primary refractory diagnosis.

“These are young patients,” Dr Diefenbach said. “Autologous stem cell transplant [ASCT] cures only half of them. There is no other established curative salvage therapy.”

She noted that the median time to progression with relapse after transplant is 3.8 months in patients treated with subsequent therapy, with a median survival of 26 months.

After ASCT, the median progression-free survival with relapse is 1.3 years. And about three-quarters of relapses occur within the first year.

“Achieving a complete response [CR] before ASCT is the most important factor in determining long-term disease-free survival and to maximizing transplant-related benefit,” Dr Diefenbach said. “High overall response rates [ORRs] do not equal high CR. Only one-third of patients achieve a CR [with chemotherapy].”

She said studies have shown that chemotherapy with ICE (ifosfamide, carboplatin, and etoposide) leads to a 3-year event-free survival rate of 22%. Post-ASCT, event-free survival increases to more than 52%.

The overall survival post-ASCT is 44%. The median survival of patients who do not get therapy is 3.7 months. Myelosuppression and deaths are common.

“Conventional chemotherapy fails,” Dr Diefenbach continued. “There is inadequate disease control, unacceptable toxicity, it’s not cost-effective, requires patients to be hospitalized, and there is no clear standard of care.”

On the other hand, brentuximab as first salvage is highly active with minimal adverse events in relapsed HL.

“Rash is the only grade 3-4 toxicity,” Dr Diefenbach said. “There are no significant cytopenias [and] no febrile neutropenia. Growth factor support is not required, and it’s administered outpatient.”

Using brentuximab as second-line therapy results in an ORR of 85.7% and a CR of 50%, she added. And ASCT after brentuximab shows similar successes and toxicities.

Brentuximab followed by ICE leads to high rates of PET normalization, allows successful transplantation of virtually all evaluable patients, and poses no issues with stem cell collection.

Furthermore, studies show a 92% disease-free survival, with minimal toxicity at 10 months of follow-up.

In conclusion, Dr Diefenbach said, “Maximizing disease control prior to ASCT will maximize cure from ASCT. Brentuximab vedotin is a novel agent that leads to a high ORR and high CR rate with low toxicity and outpatient administration. In contrast, conventional chemotherapy fails to provide a high CR rate, has unacceptable toxicity, and there is no single standard of care.”

For an opposing opinion on salvage in HL, see “Speaker adovcates chemo-based salvage in HL.”

Vials of a drug

NEW YORK—Brentuximab vendotin—not conventional chemotherapy—is the second-line regimen of choice for recurrent Hodgkin lymphoma (HL) patients prior to stem cell transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.

Catherine Diefenbach, MD, of New York University’s Langone Medical Center in New York, argued that conventional chemotherapy, the existing paradigm for first salvage therapy, does not maximize a cure or minimize toxicity, is inconvenient, and is not cost-effective.

She noted that a quarter of HL patients relapse or have a primary refractory diagnosis.

“These are young patients,” Dr Diefenbach said. “Autologous stem cell transplant [ASCT] cures only half of them. There is no other established curative salvage therapy.”

She noted that the median time to progression with relapse after transplant is 3.8 months in patients treated with subsequent therapy, with a median survival of 26 months.

After ASCT, the median progression-free survival with relapse is 1.3 years. And about three-quarters of relapses occur within the first year.

“Achieving a complete response [CR] before ASCT is the most important factor in determining long-term disease-free survival and to maximizing transplant-related benefit,” Dr Diefenbach said. “High overall response rates [ORRs] do not equal high CR. Only one-third of patients achieve a CR [with chemotherapy].”

She said studies have shown that chemotherapy with ICE (ifosfamide, carboplatin, and etoposide) leads to a 3-year event-free survival rate of 22%. Post-ASCT, event-free survival increases to more than 52%.

The overall survival post-ASCT is 44%. The median survival of patients who do not get therapy is 3.7 months. Myelosuppression and deaths are common.

“Conventional chemotherapy fails,” Dr Diefenbach continued. “There is inadequate disease control, unacceptable toxicity, it’s not cost-effective, requires patients to be hospitalized, and there is no clear standard of care.”

On the other hand, brentuximab as first salvage is highly active with minimal adverse events in relapsed HL.

“Rash is the only grade 3-4 toxicity,” Dr Diefenbach said. “There are no significant cytopenias [and] no febrile neutropenia. Growth factor support is not required, and it’s administered outpatient.”

Using brentuximab as second-line therapy results in an ORR of 85.7% and a CR of 50%, she added. And ASCT after brentuximab shows similar successes and toxicities.

Brentuximab followed by ICE leads to high rates of PET normalization, allows successful transplantation of virtually all evaluable patients, and poses no issues with stem cell collection.

Furthermore, studies show a 92% disease-free survival, with minimal toxicity at 10 months of follow-up.

In conclusion, Dr Diefenbach said, “Maximizing disease control prior to ASCT will maximize cure from ASCT. Brentuximab vedotin is a novel agent that leads to a high ORR and high CR rate with low toxicity and outpatient administration. In contrast, conventional chemotherapy fails to provide a high CR rate, has unacceptable toxicity, and there is no single standard of care.”

For an opposing opinion on salvage in HL, see “Speaker adovcates chemo-based salvage in HL.”

Vials of a drug

NEW YORK—Brentuximab vendotin—not conventional chemotherapy—is the second-line regimen of choice for recurrent Hodgkin lymphoma (HL) patients prior to stem cell transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.

Catherine Diefenbach, MD, of New York University’s Langone Medical Center in New York, argued that conventional chemotherapy, the existing paradigm for first salvage therapy, does not maximize a cure or minimize toxicity, is inconvenient, and is not cost-effective.

She noted that a quarter of HL patients relapse or have a primary refractory diagnosis.

“These are young patients,” Dr Diefenbach said. “Autologous stem cell transplant [ASCT] cures only half of them. There is no other established curative salvage therapy.”

She noted that the median time to progression with relapse after transplant is 3.8 months in patients treated with subsequent therapy, with a median survival of 26 months.

After ASCT, the median progression-free survival with relapse is 1.3 years. And about three-quarters of relapses occur within the first year.

“Achieving a complete response [CR] before ASCT is the most important factor in determining long-term disease-free survival and to maximizing transplant-related benefit,” Dr Diefenbach said. “High overall response rates [ORRs] do not equal high CR. Only one-third of patients achieve a CR [with chemotherapy].”

She said studies have shown that chemotherapy with ICE (ifosfamide, carboplatin, and etoposide) leads to a 3-year event-free survival rate of 22%. Post-ASCT, event-free survival increases to more than 52%.

The overall survival post-ASCT is 44%. The median survival of patients who do not get therapy is 3.7 months. Myelosuppression and deaths are common.

“Conventional chemotherapy fails,” Dr Diefenbach continued. “There is inadequate disease control, unacceptable toxicity, it’s not cost-effective, requires patients to be hospitalized, and there is no clear standard of care.”

On the other hand, brentuximab as first salvage is highly active with minimal adverse events in relapsed HL.

“Rash is the only grade 3-4 toxicity,” Dr Diefenbach said. “There are no significant cytopenias [and] no febrile neutropenia. Growth factor support is not required, and it’s administered outpatient.”

Using brentuximab as second-line therapy results in an ORR of 85.7% and a CR of 50%, she added. And ASCT after brentuximab shows similar successes and toxicities.

Brentuximab followed by ICE leads to high rates of PET normalization, allows successful transplantation of virtually all evaluable patients, and poses no issues with stem cell collection.

Furthermore, studies show a 92% disease-free survival, with minimal toxicity at 10 months of follow-up.

In conclusion, Dr Diefenbach said, “Maximizing disease control prior to ASCT will maximize cure from ASCT. Brentuximab vedotin is a novel agent that leads to a high ORR and high CR rate with low toxicity and outpatient administration. In contrast, conventional chemotherapy fails to provide a high CR rate, has unacceptable toxicity, and there is no single standard of care.”

For an opposing opinion on salvage in HL, see “Speaker adovcates chemo-based salvage in HL.”

Patient receiving chemotherapy

Credit: Rhoda Baer

NEW YORK—Physicians should use chemotherapy-based approaches—not brentuximab vedotin—as second-line therapy for recurrent

Hodgkin lymphoma (HL) prior to transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.

Nina Wagner-Johnston, MD, of Washington University in St Louis, Missouri, provided the meeting’s audience with a handful of arguments to support chemotherapy-based salvage regimens and a number of reasons why brentuximab is not ideal as salvage therapy in HL.

First, there is data supporting the use of chemotherapy-based salvage regimens in these patients, but the brentuximab data is lacking.

“Other issues include chemosensitivity, stem cell collection, unknown progressive multifocal leukoencephalopathy (PML) risk with brentuximab pre-ASCT [autologous stem cell transplant], cost, and alternative roles for brentuximab to enhance cure upfront post-ASCT maintenance,” Dr Wagner-Johnston said.

She also noted that chemotherapy-based salvage regimens yield high response rates with adequate stem cell collections.

“The vast majority of patients proceed to ASCT, 86% with ICE chemotherapy [ifosfamide, carboplatin, and etoposide],” she said. “Many are cured with a chemotherapy-based approach, with a 5-year PFS [progression-free survival] of 50% to 60%, with a low incidence of febrile neutropenia.”

Dr Wagner-Johnston also raised the possibility that giving patients brentuximab prior to ASCT might increase the risk of PML. The risk is already increased with lymphoma and ASCT. And in cases of PML in which patients are treated with brentuximab, the onset is rapid, with a median of about 2 months after initiation.

Furthermore, the cost of therapy clearly favors chemotherapy over brentuximab, she said. Three cycles of brentuximab at 1.8 mg/kg cost more than $58,000, and 2 cycles of brentuximab (3 weeks on, 1 week off) at 1.2 mg/kg cost more than $78,000.

In comparison, 3 cycles of ICE cost less than $38,000 and 3 cycles of ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin) cost $17,000. These costs do not account for the increased risk of febrile neutropenia.

Dr Wagner-Johnston expressed other concerns about brentuximab as well.

“Brentuximab is probably not effective to pursue as a single agent,” she said. “The addition of brentuximab to chemotherapy increases toxicity and cost. Continuous progressions years after ASCT call into question a 2-year benchmark and further highlight the importance of a maintenance approach.”

There are several unanswered pivotal questions about brentuximab, Dr Wagner-Johnston continued.

“Is brentuximab sensitivity equivalent to chemosensitivity?” she asked. “Does improved CR [complete response] rate with brentuximab-based treatment equate to better outcomes? Is the likelihood of cure higher with brentuximab-based approaches?”

She said brentuximab may be best in the upfront setting. There are more upfront cures in the highest-risk group with this novel agent, and it may allow a greater number of patients to avoid the toxicity of ASCT.

Brentuximab has demonstrated safety in phase 1/2 studies, Dr Wagner-Johnston said, adding “we await data from an ongoing phase 3 trial to determine a PFS benefit with brentuximab.”

Furthermore, post-ASCT maintenance with brentuximab may be a better alternative than salvage brentuximab pre-ASCT. In the relapsed setting, the median duration of response for brentuximab is short (6.7 months in a phase 2 study) after a median of 9 cycles.

In the phase 3 placebo-controlled trial of maintenance brentuximab following ASCT, “an interim analysis based on safety and utility recommends continuation,” Dr Wagner-Johnston said.

In conclusion, she said, “Before letting brentuximab take over, we need to confirm its safety, efficacy, and determine the best positioning of brentuximab to enhance outcomes. In the meantime, stick with what we know works.”

For the dissenting opinion on salvage in HL, see “Brentuximab tops chemo in HL, doc says.”

Patient receiving chemotherapy

Credit: Rhoda Baer

NEW YORK—Physicians should use chemotherapy-based approaches—not brentuximab vedotin—as second-line therapy for recurrent

Hodgkin lymphoma (HL) prior to transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.

Nina Wagner-Johnston, MD, of Washington University in St Louis, Missouri, provided the meeting’s audience with a handful of arguments to support chemotherapy-based salvage regimens and a number of reasons why brentuximab is not ideal as salvage therapy in HL.

First, there is data supporting the use of chemotherapy-based salvage regimens in these patients, but the brentuximab data is lacking.

“Other issues include chemosensitivity, stem cell collection, unknown progressive multifocal leukoencephalopathy (PML) risk with brentuximab pre-ASCT [autologous stem cell transplant], cost, and alternative roles for brentuximab to enhance cure upfront post-ASCT maintenance,” Dr Wagner-Johnston said.

She also noted that chemotherapy-based salvage regimens yield high response rates with adequate stem cell collections.

“The vast majority of patients proceed to ASCT, 86% with ICE chemotherapy [ifosfamide, carboplatin, and etoposide],” she said. “Many are cured with a chemotherapy-based approach, with a 5-year PFS [progression-free survival] of 50% to 60%, with a low incidence of febrile neutropenia.”

Dr Wagner-Johnston also raised the possibility that giving patients brentuximab prior to ASCT might increase the risk of PML. The risk is already increased with lymphoma and ASCT. And in cases of PML in which patients are treated with brentuximab, the onset is rapid, with a median of about 2 months after initiation.

Furthermore, the cost of therapy clearly favors chemotherapy over brentuximab, she said. Three cycles of brentuximab at 1.8 mg/kg cost more than $58,000, and 2 cycles of brentuximab (3 weeks on, 1 week off) at 1.2 mg/kg cost more than $78,000.

In comparison, 3 cycles of ICE cost less than $38,000 and 3 cycles of ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin) cost $17,000. These costs do not account for the increased risk of febrile neutropenia.

Dr Wagner-Johnston expressed other concerns about brentuximab as well.

“Brentuximab is probably not effective to pursue as a single agent,” she said. “The addition of brentuximab to chemotherapy increases toxicity and cost. Continuous progressions years after ASCT call into question a 2-year benchmark and further highlight the importance of a maintenance approach.”

There are several unanswered pivotal questions about brentuximab, Dr Wagner-Johnston continued.

“Is brentuximab sensitivity equivalent to chemosensitivity?” she asked. “Does improved CR [complete response] rate with brentuximab-based treatment equate to better outcomes? Is the likelihood of cure higher with brentuximab-based approaches?”

She said brentuximab may be best in the upfront setting. There are more upfront cures in the highest-risk group with this novel agent, and it may allow a greater number of patients to avoid the toxicity of ASCT.

Brentuximab has demonstrated safety in phase 1/2 studies, Dr Wagner-Johnston said, adding “we await data from an ongoing phase 3 trial to determine a PFS benefit with brentuximab.”

Furthermore, post-ASCT maintenance with brentuximab may be a better alternative than salvage brentuximab pre-ASCT. In the relapsed setting, the median duration of response for brentuximab is short (6.7 months in a phase 2 study) after a median of 9 cycles.

In the phase 3 placebo-controlled trial of maintenance brentuximab following ASCT, “an interim analysis based on safety and utility recommends continuation,” Dr Wagner-Johnston said.

In conclusion, she said, “Before letting brentuximab take over, we need to confirm its safety, efficacy, and determine the best positioning of brentuximab to enhance outcomes. In the meantime, stick with what we know works.”

For the dissenting opinion on salvage in HL, see “Brentuximab tops chemo in HL, doc says.”

Patient receiving chemotherapy

Credit: Rhoda Baer

NEW YORK—Physicians should use chemotherapy-based approaches—not brentuximab vedotin—as second-line therapy for recurrent

Hodgkin lymphoma (HL) prior to transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.

Nina Wagner-Johnston, MD, of Washington University in St Louis, Missouri, provided the meeting’s audience with a handful of arguments to support chemotherapy-based salvage regimens and a number of reasons why brentuximab is not ideal as salvage therapy in HL.

First, there is data supporting the use of chemotherapy-based salvage regimens in these patients, but the brentuximab data is lacking.

“Other issues include chemosensitivity, stem cell collection, unknown progressive multifocal leukoencephalopathy (PML) risk with brentuximab pre-ASCT [autologous stem cell transplant], cost, and alternative roles for brentuximab to enhance cure upfront post-ASCT maintenance,” Dr Wagner-Johnston said.

She also noted that chemotherapy-based salvage regimens yield high response rates with adequate stem cell collections.

“The vast majority of patients proceed to ASCT, 86% with ICE chemotherapy [ifosfamide, carboplatin, and etoposide],” she said. “Many are cured with a chemotherapy-based approach, with a 5-year PFS [progression-free survival] of 50% to 60%, with a low incidence of febrile neutropenia.”

Dr Wagner-Johnston also raised the possibility that giving patients brentuximab prior to ASCT might increase the risk of PML. The risk is already increased with lymphoma and ASCT. And in cases of PML in which patients are treated with brentuximab, the onset is rapid, with a median of about 2 months after initiation.

Furthermore, the cost of therapy clearly favors chemotherapy over brentuximab, she said. Three cycles of brentuximab at 1.8 mg/kg cost more than $58,000, and 2 cycles of brentuximab (3 weeks on, 1 week off) at 1.2 mg/kg cost more than $78,000.

In comparison, 3 cycles of ICE cost less than $38,000 and 3 cycles of ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin) cost $17,000. These costs do not account for the increased risk of febrile neutropenia.

Dr Wagner-Johnston expressed other concerns about brentuximab as well.

“Brentuximab is probably not effective to pursue as a single agent,” she said. “The addition of brentuximab to chemotherapy increases toxicity and cost. Continuous progressions years after ASCT call into question a 2-year benchmark and further highlight the importance of a maintenance approach.”

There are several unanswered pivotal questions about brentuximab, Dr Wagner-Johnston continued.

“Is brentuximab sensitivity equivalent to chemosensitivity?” she asked. “Does improved CR [complete response] rate with brentuximab-based treatment equate to better outcomes? Is the likelihood of cure higher with brentuximab-based approaches?”

She said brentuximab may be best in the upfront setting. There are more upfront cures in the highest-risk group with this novel agent, and it may allow a greater number of patients to avoid the toxicity of ASCT.

Brentuximab has demonstrated safety in phase 1/2 studies, Dr Wagner-Johnston said, adding “we await data from an ongoing phase 3 trial to determine a PFS benefit with brentuximab.”

Furthermore, post-ASCT maintenance with brentuximab may be a better alternative than salvage brentuximab pre-ASCT. In the relapsed setting, the median duration of response for brentuximab is short (6.7 months in a phase 2 study) after a median of 9 cycles.

In the phase 3 placebo-controlled trial of maintenance brentuximab following ASCT, “an interim analysis based on safety and utility recommends continuation,” Dr Wagner-Johnston said.

In conclusion, she said, “Before letting brentuximab take over, we need to confirm its safety, efficacy, and determine the best positioning of brentuximab to enhance outcomes. In the meantime, stick with what we know works.”

For the dissenting opinion on salvage in HL, see “Brentuximab tops chemo in HL, doc says.”