Hematology Times

SAN FRANCISCO—The anti-CD19 antibody M0R208 has demonstrated encouraging single-agent activity in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), according to a presenter at the 2014 ASH Annual Meeting.

“It is encouraging to see results in an NHL study that selects a different target than CD20,” said Kristie Blum, MD, of The Ohio State University in Columbus.

“In particular, it is good to see activity in elderly large-cell lymphoma patients.”

MOR208 is an Fc-engineered humanized monoclonal antibody that targets the CD19 antigen.

“It possesses significantly enhanced antibody-dependent cell-mediated cytotoxicity, a key mechanism for tumor cell killing,” Dr Blum explained. “We have seen previous responses in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL).”

In fact, MOR208 recently received fast-track designation from the US Food and Drug Administration to treat DLBCL.

At ASH, Dr Blum reported on a non-randomized, phase 2a study designed to assess the efficacy and safety of single-agent MOR208 in adults with relapsed or refractory NHL (abstract 3089). The trial was sponsored by MorphoSys AG, the company developing MOR208.

The study included 89 patients—35 with DLBCL, 31 with FL, 12 with mantle cell lymphoma (MCL), and 11 with other indolent NHLs (iNHLs). The patients had a median age of 67 years, were previously treated with rituximab, and were not candidates for high-dose therapy with stem cell support.

The patients were treated over 56 days. MOR208 was given intravenously at 12 mg/kg as 8 weekly doses on days 1, 8, 15, and 22 of each cycle. Patients with at least stable disease continued treatment for another cycle.

After completing 12 weekly doses of treatment, responding patients received maintenance MOR208 every 2 or 4 weeks, depending on the investigator’s decision, until progression.

The results showed overall response rates of 26% for DLBCL patients, 23% for FL patients, and 36% in iNHL patients. No MCL patients responded.

There were 2 complete responses in the DLBCL cohort and 1 complete response each in the FL and iNHL cohorts. Response duration reached 13.8 months.

The drug was well-tolerated with an acceptable toxicity profile, Dr Blum said. The most frequently reported treatment-emergent adverse events of any grade were thrombocytopenia, anemia, and neutropenia, all at 9%.

Infusion-related reactions were reported in 9% of patients and were typically grade 1 or 2. There have been no treatment-related deaths.

Protocols are being developed for trials that combine MOR208 with other anti-lymphoma therapies, with plans to open phase 1/2 trials by mid-2015.

“We plan to take the drug forward in combination with bendamustine or lenalidomide plus rituximab,” Dr Blum said. “By adding the drug into a bendamustine-rituximab combination, we will hit 2 different targets and may see synergistic cell killing.”

SAN FRANCISCO—The anti-CD19 antibody M0R208 has demonstrated encouraging single-agent activity in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), according to a presenter at the 2014 ASH Annual Meeting.

“It is encouraging to see results in an NHL study that selects a different target than CD20,” said Kristie Blum, MD, of The Ohio State University in Columbus.

“In particular, it is good to see activity in elderly large-cell lymphoma patients.”

MOR208 is an Fc-engineered humanized monoclonal antibody that targets the CD19 antigen.

“It possesses significantly enhanced antibody-dependent cell-mediated cytotoxicity, a key mechanism for tumor cell killing,” Dr Blum explained. “We have seen previous responses in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL).”

In fact, MOR208 recently received fast-track designation from the US Food and Drug Administration to treat DLBCL.

At ASH, Dr Blum reported on a non-randomized, phase 2a study designed to assess the efficacy and safety of single-agent MOR208 in adults with relapsed or refractory NHL (abstract 3089). The trial was sponsored by MorphoSys AG, the company developing MOR208.

The study included 89 patients—35 with DLBCL, 31 with FL, 12 with mantle cell lymphoma (MCL), and 11 with other indolent NHLs (iNHLs). The patients had a median age of 67 years, were previously treated with rituximab, and were not candidates for high-dose therapy with stem cell support.

The patients were treated over 56 days. MOR208 was given intravenously at 12 mg/kg as 8 weekly doses on days 1, 8, 15, and 22 of each cycle. Patients with at least stable disease continued treatment for another cycle.

After completing 12 weekly doses of treatment, responding patients received maintenance MOR208 every 2 or 4 weeks, depending on the investigator’s decision, until progression.

The results showed overall response rates of 26% for DLBCL patients, 23% for FL patients, and 36% in iNHL patients. No MCL patients responded.

There were 2 complete responses in the DLBCL cohort and 1 complete response each in the FL and iNHL cohorts. Response duration reached 13.8 months.

The drug was well-tolerated with an acceptable toxicity profile, Dr Blum said. The most frequently reported treatment-emergent adverse events of any grade were thrombocytopenia, anemia, and neutropenia, all at 9%.

Infusion-related reactions were reported in 9% of patients and were typically grade 1 or 2. There have been no treatment-related deaths.

Protocols are being developed for trials that combine MOR208 with other anti-lymphoma therapies, with plans to open phase 1/2 trials by mid-2015.

“We plan to take the drug forward in combination with bendamustine or lenalidomide plus rituximab,” Dr Blum said. “By adding the drug into a bendamustine-rituximab combination, we will hit 2 different targets and may see synergistic cell killing.”

SAN FRANCISCO—The anti-CD19 antibody M0R208 has demonstrated encouraging single-agent activity in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), according to a presenter at the 2014 ASH Annual Meeting.

“It is encouraging to see results in an NHL study that selects a different target than CD20,” said Kristie Blum, MD, of The Ohio State University in Columbus.

“In particular, it is good to see activity in elderly large-cell lymphoma patients.”

MOR208 is an Fc-engineered humanized monoclonal antibody that targets the CD19 antigen.

“It possesses significantly enhanced antibody-dependent cell-mediated cytotoxicity, a key mechanism for tumor cell killing,” Dr Blum explained. “We have seen previous responses in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL).”

In fact, MOR208 recently received fast-track designation from the US Food and Drug Administration to treat DLBCL.

At ASH, Dr Blum reported on a non-randomized, phase 2a study designed to assess the efficacy and safety of single-agent MOR208 in adults with relapsed or refractory NHL (abstract 3089). The trial was sponsored by MorphoSys AG, the company developing MOR208.

The study included 89 patients—35 with DLBCL, 31 with FL, 12 with mantle cell lymphoma (MCL), and 11 with other indolent NHLs (iNHLs). The patients had a median age of 67 years, were previously treated with rituximab, and were not candidates for high-dose therapy with stem cell support.

The patients were treated over 56 days. MOR208 was given intravenously at 12 mg/kg as 8 weekly doses on days 1, 8, 15, and 22 of each cycle. Patients with at least stable disease continued treatment for another cycle.

After completing 12 weekly doses of treatment, responding patients received maintenance MOR208 every 2 or 4 weeks, depending on the investigator’s decision, until progression.

The results showed overall response rates of 26% for DLBCL patients, 23% for FL patients, and 36% in iNHL patients. No MCL patients responded.

There were 2 complete responses in the DLBCL cohort and 1 complete response each in the FL and iNHL cohorts. Response duration reached 13.8 months.

The drug was well-tolerated with an acceptable toxicity profile, Dr Blum said. The most frequently reported treatment-emergent adverse events of any grade were thrombocytopenia, anemia, and neutropenia, all at 9%.

Infusion-related reactions were reported in 9% of patients and were typically grade 1 or 2. There have been no treatment-related deaths.

Protocols are being developed for trials that combine MOR208 with other anti-lymphoma therapies, with plans to open phase 1/2 trials by mid-2015.

“We plan to take the drug forward in combination with bendamustine or lenalidomide plus rituximab,” Dr Blum said. “By adding the drug into a bendamustine-rituximab combination, we will hit 2 different targets and may see synergistic cell killing.”

The US Food and Drug Administration (FDA) has approved denosumab (XGEVA) to treat hypercalcemia of malignancy (HCM) that is refractory to bisphosphonate therapy.

HCM results from cancer-driven increases in bone resorption. If left untreated, the condition can lead to renal failure, progressive mental impairment, coma, and death.

Denosumab works by binding to RANK ligand, a protein essential for the formation, function, and survival of osteoclasts.

The drug prevents RANK ligand from activating its receptor, RANK, on the surface of osteoclasts, thereby decreasing bone destruction and calcium release.

Denosumab previously received FDA approval to treat giant cell tumor of the bone and for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

The FDA’s approval of denosumab for HCM is based on positive results from an open-label, single-arm study, which enrolled 33 patients with advanced cancer and persistent hypercalcemia after recent bisphosphonate treatment.

The primary endpoint was the proportion of patients with a response, defined as albumin-corrected serum calcium (CSC) < 11.5 mg/dL (2.9 mmol/L; adverse events grade < 1) within 10 days of the first dose of denosumab.

Secondary endpoints included the proportion of patients who experienced a complete response (defined as CSC < 10.8 mg/dL [2.7 mmol/L]) by day 10, time to response, and response duration (defined as the number of days from the first occurrence of CSC < 11.5 mg/dL).

The primary endpoint was met. At day 10, the response rate was 63.6%. Likewise, the overall complete response rate was 63.6%. The estimated median time to response was 9 days, and the median duration of response was 104 days.

The most common adverse events were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea.

Potential safety risks

Patients with HCM should receive 120 mg of denosumab as a subcutaneous injection every 4 weeks with additional doses of 120 mg on days 8 and 15 of the first month of therapy.

Pre-existing hypocalcemia must be corrected prior to initiating denosumab therapy. The drug can cause severe, symptomatic hypocalcemia, and fatal cases have been reported.

Physicians should monitor patients’ calcium levels and administer calcium, magnesium, and vitamin D as necessary. Levels should be monitored more frequently when denosumab is given with other drugs that can lower calcium levels. Patients should be advised to contact a healthcare professional if they experience symptoms of hypocalcemia.

Osteonecrosis of the jaw can occur in patients receiving denosumab. Patients who are suspected of having or who develop osteonecrosis of the jaw while on treatment should receive care by a dentist or an oral surgeon.

Atypical femoral fracture has been reported with denosumab, so patients should be advised to report new or unusual thigh, hip, or groin pain. Patients presenting with an atypical femur fracture should be assessed for signs of fracture in the contralateral limb. Physicians should consider interrupting denosumab pending a risk/benefit assessment.

Denosumab can cause fetal harm when administered to a pregnant woman. Physicians should advise females of reproductive potential to use highly effective contraception during therapy and for at least 5 months after the last dose of denosumab.

Amgen, the company developing denosumab, markets the drug as both XGEVA and Prolia (for different indications). Patients receiving XGEVA should not take Prolia.

For more information on denosumab (XGEVA), visit www.xgeva.com.

The US Food and Drug Administration (FDA) has approved denosumab (XGEVA) to treat hypercalcemia of malignancy (HCM) that is refractory to bisphosphonate therapy.

HCM results from cancer-driven increases in bone resorption. If left untreated, the condition can lead to renal failure, progressive mental impairment, coma, and death.

Denosumab works by binding to RANK ligand, a protein essential for the formation, function, and survival of osteoclasts.

The drug prevents RANK ligand from activating its receptor, RANK, on the surface of osteoclasts, thereby decreasing bone destruction and calcium release.

Denosumab previously received FDA approval to treat giant cell tumor of the bone and for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

The FDA’s approval of denosumab for HCM is based on positive results from an open-label, single-arm study, which enrolled 33 patients with advanced cancer and persistent hypercalcemia after recent bisphosphonate treatment.

The primary endpoint was the proportion of patients with a response, defined as albumin-corrected serum calcium (CSC) < 11.5 mg/dL (2.9 mmol/L; adverse events grade < 1) within 10 days of the first dose of denosumab.

Secondary endpoints included the proportion of patients who experienced a complete response (defined as CSC < 10.8 mg/dL [2.7 mmol/L]) by day 10, time to response, and response duration (defined as the number of days from the first occurrence of CSC < 11.5 mg/dL).

The primary endpoint was met. At day 10, the response rate was 63.6%. Likewise, the overall complete response rate was 63.6%. The estimated median time to response was 9 days, and the median duration of response was 104 days.

The most common adverse events were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea.

Potential safety risks

Patients with HCM should receive 120 mg of denosumab as a subcutaneous injection every 4 weeks with additional doses of 120 mg on days 8 and 15 of the first month of therapy.

Pre-existing hypocalcemia must be corrected prior to initiating denosumab therapy. The drug can cause severe, symptomatic hypocalcemia, and fatal cases have been reported.

Physicians should monitor patients’ calcium levels and administer calcium, magnesium, and vitamin D as necessary. Levels should be monitored more frequently when denosumab is given with other drugs that can lower calcium levels. Patients should be advised to contact a healthcare professional if they experience symptoms of hypocalcemia.

Osteonecrosis of the jaw can occur in patients receiving denosumab. Patients who are suspected of having or who develop osteonecrosis of the jaw while on treatment should receive care by a dentist or an oral surgeon.

Atypical femoral fracture has been reported with denosumab, so patients should be advised to report new or unusual thigh, hip, or groin pain. Patients presenting with an atypical femur fracture should be assessed for signs of fracture in the contralateral limb. Physicians should consider interrupting denosumab pending a risk/benefit assessment.

Denosumab can cause fetal harm when administered to a pregnant woman. Physicians should advise females of reproductive potential to use highly effective contraception during therapy and for at least 5 months after the last dose of denosumab.

Amgen, the company developing denosumab, markets the drug as both XGEVA and Prolia (for different indications). Patients receiving XGEVA should not take Prolia.

For more information on denosumab (XGEVA), visit www.xgeva.com.

The US Food and Drug Administration (FDA) has approved denosumab (XGEVA) to treat hypercalcemia of malignancy (HCM) that is refractory to bisphosphonate therapy.

HCM results from cancer-driven increases in bone resorption. If left untreated, the condition can lead to renal failure, progressive mental impairment, coma, and death.

Denosumab works by binding to RANK ligand, a protein essential for the formation, function, and survival of osteoclasts.

The drug prevents RANK ligand from activating its receptor, RANK, on the surface of osteoclasts, thereby decreasing bone destruction and calcium release.

Denosumab previously received FDA approval to treat giant cell tumor of the bone and for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

The FDA’s approval of denosumab for HCM is based on positive results from an open-label, single-arm study, which enrolled 33 patients with advanced cancer and persistent hypercalcemia after recent bisphosphonate treatment.

The primary endpoint was the proportion of patients with a response, defined as albumin-corrected serum calcium (CSC) < 11.5 mg/dL (2.9 mmol/L; adverse events grade < 1) within 10 days of the first dose of denosumab.

Secondary endpoints included the proportion of patients who experienced a complete response (defined as CSC < 10.8 mg/dL [2.7 mmol/L]) by day 10, time to response, and response duration (defined as the number of days from the first occurrence of CSC < 11.5 mg/dL).

The primary endpoint was met. At day 10, the response rate was 63.6%. Likewise, the overall complete response rate was 63.6%. The estimated median time to response was 9 days, and the median duration of response was 104 days.

The most common adverse events were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea.

Potential safety risks

Patients with HCM should receive 120 mg of denosumab as a subcutaneous injection every 4 weeks with additional doses of 120 mg on days 8 and 15 of the first month of therapy.

Pre-existing hypocalcemia must be corrected prior to initiating denosumab therapy. The drug can cause severe, symptomatic hypocalcemia, and fatal cases have been reported.

Physicians should monitor patients’ calcium levels and administer calcium, magnesium, and vitamin D as necessary. Levels should be monitored more frequently when denosumab is given with other drugs that can lower calcium levels. Patients should be advised to contact a healthcare professional if they experience symptoms of hypocalcemia.

Osteonecrosis of the jaw can occur in patients receiving denosumab. Patients who are suspected of having or who develop osteonecrosis of the jaw while on treatment should receive care by a dentist or an oral surgeon.

Atypical femoral fracture has been reported with denosumab, so patients should be advised to report new or unusual thigh, hip, or groin pain. Patients presenting with an atypical femur fracture should be assessed for signs of fracture in the contralateral limb. Physicians should consider interrupting denosumab pending a risk/benefit assessment.

Denosumab can cause fetal harm when administered to a pregnant woman. Physicians should advise females of reproductive potential to use highly effective contraception during therapy and for at least 5 months after the last dose of denosumab.

Amgen, the company developing denosumab, markets the drug as both XGEVA and Prolia (for different indications). Patients receiving XGEVA should not take Prolia.

For more information on denosumab (XGEVA), visit www.xgeva.com.

Attendees stop to talk at

the 2014 ASH Annual Meeting

SAN FRANCISCO—Combination therapy with ruxolitinib and panobinostat shows signs of efficacy in myelofibrosis (MF), according to research

presented at the 2014 ASH Annual Meeting.

“Targeting multiple components of the JAK/STAT pathway, as well as parallel signaling pathways that may also be involved in the pathogenesis of myelofibrosis, has the potential to have a synergistic therapeutic effect on the underlying disease,” said Jean-Jacques Kiladjian MD, PhD, of the Hôpital Saint-Louis and Université Paris Diderot in Paris, France.

Ruxolitinib, a potent JAK1/JAK2 inhibitor, demonstrated rapid and durable reductions in splenomegaly and MF-related symptoms, improved quality of life, and provided a survival advantage in the phase 3 COMFORT studies.

Panobinostat, a potent oral pan-deacetylase inhibitor, reduced spleen size, symptoms, and JAK2^V617F allele burden in patients with MF in phase 1 and phase 2 studies.

The combination of ruxolitinib and panobinostat demonstrated synergistic anti-MF activity in a phase 1b study.

At ASH, Dr Kiladjian presented updated results from the expansion phase of this trial (abstract 711). This study was sponsored by Novartis, the company developing ruxolitinib.

The treatment schedule was ruxolitinib at 5 mg to 15 mg twice daily and panobinostat at 10 mg to 25 mg once daily 3 times per week on days 2, 4, and 6 every other week in a 28-day cycle.

A dose-escalation phase included 38 patients with a median age of 63 years, and an expansion phase included 23 patients with a median age of 67 years.

The recommended phase 2 dose was 15 mg of ruxolitinib twice daily and 25 mg of panobinostat twice weekly, every other week.

“Changes in spleen size were seen in the escalation phase, even at low doses,” Dr Kiladjian said. “Some patients completely eliminated splenomegaly.”

The expansion phase showed similar results. At 24 weeks, more than 85% of patients had a 50% or greater reduction in splenomegaly. Some 59% of patients achieved a 50% or greater reduction in palpable spleen length.

“We saw some JAK2 inhibition and reduction in bone marrow fibrosis, as well as significant reduction in several cytokines related to inflammation,” Dr Kiladjian said.

The most common hematologic adverse events were anemia and thrombocytopenia. There were few neutropenias.

“We saw quite remarkably stable levels of hemoglobin and platelets,” Dr Kiladjian said.

Non-hematologic adverse events were primarily gastrointestinal toxicity associated with panobinostat, including grade 3 or 4 diarrhea and asthenia.

“The rates of adverse events observed in this trial are in line with the expected and known adverse events of these 2 agents when used as monotherapies,” Dr Kiladjian said.

“The combination of ruxolitinib and panobinostat was well-tolerated and resulted in substantial reductions in splenomegaly. Most patients treated at the [recommended phase 2 dose] of combination therapy achieved a spleen response.”

Dr Kiladjian therefore encouraged further exploration of this “favorable” combination.

Attendees stop to talk at

the 2014 ASH Annual Meeting

SAN FRANCISCO—Combination therapy with ruxolitinib and panobinostat shows signs of efficacy in myelofibrosis (MF), according to research

presented at the 2014 ASH Annual Meeting.

“Targeting multiple components of the JAK/STAT pathway, as well as parallel signaling pathways that may also be involved in the pathogenesis of myelofibrosis, has the potential to have a synergistic therapeutic effect on the underlying disease,” said Jean-Jacques Kiladjian MD, PhD, of the Hôpital Saint-Louis and Université Paris Diderot in Paris, France.

Ruxolitinib, a potent JAK1/JAK2 inhibitor, demonstrated rapid and durable reductions in splenomegaly and MF-related symptoms, improved quality of life, and provided a survival advantage in the phase 3 COMFORT studies.

Panobinostat, a potent oral pan-deacetylase inhibitor, reduced spleen size, symptoms, and JAK2^V617F allele burden in patients with MF in phase 1 and phase 2 studies.

The combination of ruxolitinib and panobinostat demonstrated synergistic anti-MF activity in a phase 1b study.

At ASH, Dr Kiladjian presented updated results from the expansion phase of this trial (abstract 711). This study was sponsored by Novartis, the company developing ruxolitinib.

The treatment schedule was ruxolitinib at 5 mg to 15 mg twice daily and panobinostat at 10 mg to 25 mg once daily 3 times per week on days 2, 4, and 6 every other week in a 28-day cycle.

A dose-escalation phase included 38 patients with a median age of 63 years, and an expansion phase included 23 patients with a median age of 67 years.

The recommended phase 2 dose was 15 mg of ruxolitinib twice daily and 25 mg of panobinostat twice weekly, every other week.

“Changes in spleen size were seen in the escalation phase, even at low doses,” Dr Kiladjian said. “Some patients completely eliminated splenomegaly.”

The expansion phase showed similar results. At 24 weeks, more than 85% of patients had a 50% or greater reduction in splenomegaly. Some 59% of patients achieved a 50% or greater reduction in palpable spleen length.

“We saw some JAK2 inhibition and reduction in bone marrow fibrosis, as well as significant reduction in several cytokines related to inflammation,” Dr Kiladjian said.

The most common hematologic adverse events were anemia and thrombocytopenia. There were few neutropenias.

“We saw quite remarkably stable levels of hemoglobin and platelets,” Dr Kiladjian said.

Non-hematologic adverse events were primarily gastrointestinal toxicity associated with panobinostat, including grade 3 or 4 diarrhea and asthenia.

“The rates of adverse events observed in this trial are in line with the expected and known adverse events of these 2 agents when used as monotherapies,” Dr Kiladjian said.

“The combination of ruxolitinib and panobinostat was well-tolerated and resulted in substantial reductions in splenomegaly. Most patients treated at the [recommended phase 2 dose] of combination therapy achieved a spleen response.”

Dr Kiladjian therefore encouraged further exploration of this “favorable” combination.

Attendees stop to talk at

the 2014 ASH Annual Meeting

SAN FRANCISCO—Combination therapy with ruxolitinib and panobinostat shows signs of efficacy in myelofibrosis (MF), according to research

presented at the 2014 ASH Annual Meeting.

“Targeting multiple components of the JAK/STAT pathway, as well as parallel signaling pathways that may also be involved in the pathogenesis of myelofibrosis, has the potential to have a synergistic therapeutic effect on the underlying disease,” said Jean-Jacques Kiladjian MD, PhD, of the Hôpital Saint-Louis and Université Paris Diderot in Paris, France.

Ruxolitinib, a potent JAK1/JAK2 inhibitor, demonstrated rapid and durable reductions in splenomegaly and MF-related symptoms, improved quality of life, and provided a survival advantage in the phase 3 COMFORT studies.

Panobinostat, a potent oral pan-deacetylase inhibitor, reduced spleen size, symptoms, and JAK2^V617F allele burden in patients with MF in phase 1 and phase 2 studies.

The combination of ruxolitinib and panobinostat demonstrated synergistic anti-MF activity in a phase 1b study.

At ASH, Dr Kiladjian presented updated results from the expansion phase of this trial (abstract 711). This study was sponsored by Novartis, the company developing ruxolitinib.

The treatment schedule was ruxolitinib at 5 mg to 15 mg twice daily and panobinostat at 10 mg to 25 mg once daily 3 times per week on days 2, 4, and 6 every other week in a 28-day cycle.

A dose-escalation phase included 38 patients with a median age of 63 years, and an expansion phase included 23 patients with a median age of 67 years.

The recommended phase 2 dose was 15 mg of ruxolitinib twice daily and 25 mg of panobinostat twice weekly, every other week.

“Changes in spleen size were seen in the escalation phase, even at low doses,” Dr Kiladjian said. “Some patients completely eliminated splenomegaly.”

The expansion phase showed similar results. At 24 weeks, more than 85% of patients had a 50% or greater reduction in splenomegaly. Some 59% of patients achieved a 50% or greater reduction in palpable spleen length.

“We saw some JAK2 inhibition and reduction in bone marrow fibrosis, as well as significant reduction in several cytokines related to inflammation,” Dr Kiladjian said.

The most common hematologic adverse events were anemia and thrombocytopenia. There were few neutropenias.

“We saw quite remarkably stable levels of hemoglobin and platelets,” Dr Kiladjian said.

Non-hematologic adverse events were primarily gastrointestinal toxicity associated with panobinostat, including grade 3 or 4 diarrhea and asthenia.

“The rates of adverse events observed in this trial are in line with the expected and known adverse events of these 2 agents when used as monotherapies,” Dr Kiladjian said.

“The combination of ruxolitinib and panobinostat was well-tolerated and resulted in substantial reductions in splenomegaly. Most patients treated at the [recommended phase 2 dose] of combination therapy achieved a spleen response.”

Dr Kiladjian therefore encouraged further exploration of this “favorable” combination.

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—Results regarding daunorubicin escalation in induction for patients with acute myeloid leukemia (AML) have varied among different studies.

And a 90 mg/m² dose has been shown to be more effective than 45. Now, results of the UK NCRI AML17 trial have added yet another dimension to the discussion—the use of 60 mg/m² compared to 90.

Alan K. Burnett, MD, of Cardiff University in the UK, presented the data as abstract 7 at the 2014 ASH Annual Meeting.

He explained that ECOG E1900 had demonstrated superior remission and overall survival for a 90-mg dose of daunorubicin compared to a 45-mg dose in adults younger than 60.

The HOVON trial showed superior remission but no difference in overall survival for the higher dose of daunorubicin in patients older than 60.

The Korean trial demonstrated superior remission and survival rates for the 90-mg dose in patients younger than 60.

And in the GOELAMS trial, investigators found no difference between a 90-mg and a 60-mg dose level.

So the UK AML Study Group undertook to clarify the issue by comparing 90 mg to 60 mg in induction.

The investigators randomized 1206 patients younger than 60 with de novo or secondary AML or high-risk myelodysplastic syndromes (MDS) to receive 90 or 60 mg of daunorubicin on days 1, 3, and 5 of their first induction course, followed by 50 mg/m² on days 1, 3, and 5 in course 2.

All patients received ara-C during courses 1 and 2. Patients had to have LVEF of 45% or greater to be included in the trial.

The median follow-up was 29 months. Patient characteristics were comparable between the 2 groups.

The median age was 53 in both groups (range, 16-72 years), and slightly more than half of patients were male. Eighty-five percent and 84% had de novo AML in the 60-mg and 90-mg arms, respectively. Ten percent in each group had secondary AML. And 5% and 6%, respectively, had high-risk MDS.

Eleven percent in the 60-mg arm had favorable cytogenetics, compared with 9% in the 90-mg arm. Eighteen percent in each arm had mutant FLT3-ITD, and 40% in each arm were poor risk.

The investigators found no significant difference in response between the two arms—84% in the 60-mg arm and 81% in the 90-mg arm.

However, they observed a trend for increased 30-day mortality in the 90-mg arm and a significant difference in the 60-day mortality rate, which was 5% in the 60-mg arm and 10% in the 90-mg arm (P=0.001).

Twenty-nine people died by day 60 in the 60-mg arm compared with 58 in the 90-mg arm.

The main reasons for 60-day mortality in the 60-mg and 90-mg dose groups, respectively, included infection (11 vs 25 deaths), hemorrhage (3 vs 5 deaths), infection plus hemorrhage (3 vs 1 death), and resistant disease (2 vs 14 deaths), among other causes.

At 24 months, overall survival between the 2 groups was comparable, at 60% in the 60-mg arm and 59% in the 90-mg arm.

The cumulative incidence of relapse at 24 months from complete response was 41% in the 60-mg arm and 37% in the 90-mg arm.

One hundred ninety-seven patients in the 60-mg arm and 169 patients in the 90-mg arm went on to receive a stem cell transplant.

When survival was censored at transplant, there was also no difference between the arms, at 60% for the 90-mg group and 61% for the 60-mg group.

The investigators conducted subgroup analyses and found no significant benefit for 90 mg/m² in any subgroup. Dr Burnett noted, however, that there could be a potential late benefit for FLT3-ITD mutated patients who receive a 90-mg dose.

FLT3 mutated patients had a non-significant survival benefit (HR 0.74 [0.47-1.17] P=0.2) with a 90-mg dose.  However, survival was significantly worse for FLT3 wild type patients receiving 90 mg (HR 1.31 [1.03-1.67] P=0.03).

Otherwise, the group found that there is no evidence to suggest that 90 mg is superior to 60 mg.

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—Results regarding daunorubicin escalation in induction for patients with acute myeloid leukemia (AML) have varied among different studies.

And a 90 mg/m² dose has been shown to be more effective than 45. Now, results of the UK NCRI AML17 trial have added yet another dimension to the discussion—the use of 60 mg/m² compared to 90.

Alan K. Burnett, MD, of Cardiff University in the UK, presented the data as abstract 7 at the 2014 ASH Annual Meeting.

He explained that ECOG E1900 had demonstrated superior remission and overall survival for a 90-mg dose of daunorubicin compared to a 45-mg dose in adults younger than 60.

The HOVON trial showed superior remission but no difference in overall survival for the higher dose of daunorubicin in patients older than 60.

The Korean trial demonstrated superior remission and survival rates for the 90-mg dose in patients younger than 60.

And in the GOELAMS trial, investigators found no difference between a 90-mg and a 60-mg dose level.

So the UK AML Study Group undertook to clarify the issue by comparing 90 mg to 60 mg in induction.

The investigators randomized 1206 patients younger than 60 with de novo or secondary AML or high-risk myelodysplastic syndromes (MDS) to receive 90 or 60 mg of daunorubicin on days 1, 3, and 5 of their first induction course, followed by 50 mg/m² on days 1, 3, and 5 in course 2.

All patients received ara-C during courses 1 and 2. Patients had to have LVEF of 45% or greater to be included in the trial.

The median follow-up was 29 months. Patient characteristics were comparable between the 2 groups.

The median age was 53 in both groups (range, 16-72 years), and slightly more than half of patients were male. Eighty-five percent and 84% had de novo AML in the 60-mg and 90-mg arms, respectively. Ten percent in each group had secondary AML. And 5% and 6%, respectively, had high-risk MDS.

Eleven percent in the 60-mg arm had favorable cytogenetics, compared with 9% in the 90-mg arm. Eighteen percent in each arm had mutant FLT3-ITD, and 40% in each arm were poor risk.

The investigators found no significant difference in response between the two arms—84% in the 60-mg arm and 81% in the 90-mg arm.

However, they observed a trend for increased 30-day mortality in the 90-mg arm and a significant difference in the 60-day mortality rate, which was 5% in the 60-mg arm and 10% in the 90-mg arm (P=0.001).

Twenty-nine people died by day 60 in the 60-mg arm compared with 58 in the 90-mg arm.

The main reasons for 60-day mortality in the 60-mg and 90-mg dose groups, respectively, included infection (11 vs 25 deaths), hemorrhage (3 vs 5 deaths), infection plus hemorrhage (3 vs 1 death), and resistant disease (2 vs 14 deaths), among other causes.

At 24 months, overall survival between the 2 groups was comparable, at 60% in the 60-mg arm and 59% in the 90-mg arm.

The cumulative incidence of relapse at 24 months from complete response was 41% in the 60-mg arm and 37% in the 90-mg arm.

One hundred ninety-seven patients in the 60-mg arm and 169 patients in the 90-mg arm went on to receive a stem cell transplant.

When survival was censored at transplant, there was also no difference between the arms, at 60% for the 90-mg group and 61% for the 60-mg group.

The investigators conducted subgroup analyses and found no significant benefit for 90 mg/m² in any subgroup. Dr Burnett noted, however, that there could be a potential late benefit for FLT3-ITD mutated patients who receive a 90-mg dose.

FLT3 mutated patients had a non-significant survival benefit (HR 0.74 [0.47-1.17] P=0.2) with a 90-mg dose.  However, survival was significantly worse for FLT3 wild type patients receiving 90 mg (HR 1.31 [1.03-1.67] P=0.03).

Otherwise, the group found that there is no evidence to suggest that 90 mg is superior to 60 mg.

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—Results regarding daunorubicin escalation in induction for patients with acute myeloid leukemia (AML) have varied among different studies.

And a 90 mg/m² dose has been shown to be more effective than 45. Now, results of the UK NCRI AML17 trial have added yet another dimension to the discussion—the use of 60 mg/m² compared to 90.

Alan K. Burnett, MD, of Cardiff University in the UK, presented the data as abstract 7 at the 2014 ASH Annual Meeting.

He explained that ECOG E1900 had demonstrated superior remission and overall survival for a 90-mg dose of daunorubicin compared to a 45-mg dose in adults younger than 60.

The HOVON trial showed superior remission but no difference in overall survival for the higher dose of daunorubicin in patients older than 60.

The Korean trial demonstrated superior remission and survival rates for the 90-mg dose in patients younger than 60.

And in the GOELAMS trial, investigators found no difference between a 90-mg and a 60-mg dose level.

So the UK AML Study Group undertook to clarify the issue by comparing 90 mg to 60 mg in induction.

The investigators randomized 1206 patients younger than 60 with de novo or secondary AML or high-risk myelodysplastic syndromes (MDS) to receive 90 or 60 mg of daunorubicin on days 1, 3, and 5 of their first induction course, followed by 50 mg/m² on days 1, 3, and 5 in course 2.

All patients received ara-C during courses 1 and 2. Patients had to have LVEF of 45% or greater to be included in the trial.

The median follow-up was 29 months. Patient characteristics were comparable between the 2 groups.

The median age was 53 in both groups (range, 16-72 years), and slightly more than half of patients were male. Eighty-five percent and 84% had de novo AML in the 60-mg and 90-mg arms, respectively. Ten percent in each group had secondary AML. And 5% and 6%, respectively, had high-risk MDS.

Eleven percent in the 60-mg arm had favorable cytogenetics, compared with 9% in the 90-mg arm. Eighteen percent in each arm had mutant FLT3-ITD, and 40% in each arm were poor risk.

The investigators found no significant difference in response between the two arms—84% in the 60-mg arm and 81% in the 90-mg arm.

However, they observed a trend for increased 30-day mortality in the 90-mg arm and a significant difference in the 60-day mortality rate, which was 5% in the 60-mg arm and 10% in the 90-mg arm (P=0.001).

Twenty-nine people died by day 60 in the 60-mg arm compared with 58 in the 90-mg arm.

The main reasons for 60-day mortality in the 60-mg and 90-mg dose groups, respectively, included infection (11 vs 25 deaths), hemorrhage (3 vs 5 deaths), infection plus hemorrhage (3 vs 1 death), and resistant disease (2 vs 14 deaths), among other causes.

At 24 months, overall survival between the 2 groups was comparable, at 60% in the 60-mg arm and 59% in the 90-mg arm.

The cumulative incidence of relapse at 24 months from complete response was 41% in the 60-mg arm and 37% in the 90-mg arm.

One hundred ninety-seven patients in the 60-mg arm and 169 patients in the 90-mg arm went on to receive a stem cell transplant.

When survival was censored at transplant, there was also no difference between the arms, at 60% for the 90-mg group and 61% for the 60-mg group.

The investigators conducted subgroup analyses and found no significant benefit for 90 mg/m² in any subgroup. Dr Burnett noted, however, that there could be a potential late benefit for FLT3-ITD mutated patients who receive a 90-mg dose.

FLT3 mutated patients had a non-significant survival benefit (HR 0.74 [0.47-1.17] P=0.2) with a 90-mg dose.  However, survival was significantly worse for FLT3 wild type patients receiving 90 mg (HR 1.31 [1.03-1.67] P=0.03).

Otherwise, the group found that there is no evidence to suggest that 90 mg is superior to 60 mg.

Piglet

Credit: USDA

VIENNA—Encapsulating the anthracycline doxorubicin in a liposome can reduce the risk of developing heart damage, according to a study presented at EuroEcho-Imaging 2014.

Researchers administered doxorubicin encased in a liposome to a small group of pigs and compared cardiac outcomes to those in pigs that received unmanipulated doxorubicin or epirubicin.

Pigs that received encapsulated doxorubicin still developed cardiotoxicity, but at lower rates than pigs that received traditional doxorubicin.

Pigs that received epirubicin were excluded due to low survival rates.

“[M]any chemotherapies—in particular, anthracyclines—cause cardiac side effects that can lead to cardiomyopathy and severe heart failure,” said study investigator Jutta Bergler-Klein, MD, of the Medical University of Vienna in Austria. “Cardiotoxicity can occur acutely or up to 30 years after chemotherapy and is the second most common cause of death in cancer patients, after secondary malignancy in childhood cancer survivors.”

“Liposomal encapsulation is a new technique which wraps the chemotherapy drug in a fatty cover called a liposome. More of the drug reaches the cancer cells because there is less degradation, and there are fewer side effects on healthy cells because the fat cover acts as a barrier.”

“The drug stays in the bloodstream longer, allowing higher cumulative doses to be given. We tested whether non-pegylated liposome encapsulation of the anthracycline doxorubicin (called Myocet) could decrease its cardiotoxicity compared to conventional doxorubicin or epirubicin, another anthracycline.”

The study included 24 pigs that were randomized to receive the human dose-equivalent of Myocet, conventional doxorubicin, or epirubicin in 3 cycles. The epirubicin group was excluded from the final analyses because of low survival levels.

The researchers assessed cardiac function by echocardiography and MRI at baseline and follow-up (after about 3 months). Laboratory follow-up included hematology, renal function, and measurement of the cardiac enzymes troponin and BNP.

“The dose, imaging methodology, and blood parameters simulate the monitoring that patients on this treatment would receive and produces valuable translational data,” Dr Bergler-Klein said.

The researchers found that the group receiving Myocet had better diastolic and systolic function in the left and right ventricles, compared to conventional doxorubicin. The Myocet group also had less fibrosis in the myocardium, as shown by MRI and histology staining.

“Our study shows that doxorubicin encapsulated in a liposome had fewer cardiac side effects than doxorubicin given in the conventional way,” Dr Bergler-Klein said.

“We did find cardiac toxicity in the Myocet group as well, despite the fact that the pigs were young, healthy, and received anthracyclines for only a short period. This emphasizes how important it is for all cancer patients taking anthracyclines to receive cardiac monitoring using echocardiography and biomarkers, and MRI where indicated.”

“Many patients who recover after chemotherapy have asymptomatic heart damage, which can become symptomatic as they get older. When heart problems are picked up early, patients can be given preventive treatment, including ACE inhibitors, angiotensin receptor blockers, or beta-blockers, to prevent the progression to overt heart failure.”

The researchers are now conducting gene-expression profiling on the histology samples, hoping to explain the better outcome and cardiac function after Myocet therapy. They have found differences in the expression of genes that control energy use and the metabolic state, with better regulation in the Myocet group.

Piglet

Credit: USDA

VIENNA—Encapsulating the anthracycline doxorubicin in a liposome can reduce the risk of developing heart damage, according to a study presented at EuroEcho-Imaging 2014.

Researchers administered doxorubicin encased in a liposome to a small group of pigs and compared cardiac outcomes to those in pigs that received unmanipulated doxorubicin or epirubicin.

Pigs that received encapsulated doxorubicin still developed cardiotoxicity, but at lower rates than pigs that received traditional doxorubicin.

Pigs that received epirubicin were excluded due to low survival rates.

“[M]any chemotherapies—in particular, anthracyclines—cause cardiac side effects that can lead to cardiomyopathy and severe heart failure,” said study investigator Jutta Bergler-Klein, MD, of the Medical University of Vienna in Austria. “Cardiotoxicity can occur acutely or up to 30 years after chemotherapy and is the second most common cause of death in cancer patients, after secondary malignancy in childhood cancer survivors.”

“Liposomal encapsulation is a new technique which wraps the chemotherapy drug in a fatty cover called a liposome. More of the drug reaches the cancer cells because there is less degradation, and there are fewer side effects on healthy cells because the fat cover acts as a barrier.”

“The drug stays in the bloodstream longer, allowing higher cumulative doses to be given. We tested whether non-pegylated liposome encapsulation of the anthracycline doxorubicin (called Myocet) could decrease its cardiotoxicity compared to conventional doxorubicin or epirubicin, another anthracycline.”

The study included 24 pigs that were randomized to receive the human dose-equivalent of Myocet, conventional doxorubicin, or epirubicin in 3 cycles. The epirubicin group was excluded from the final analyses because of low survival levels.

The researchers assessed cardiac function by echocardiography and MRI at baseline and follow-up (after about 3 months). Laboratory follow-up included hematology, renal function, and measurement of the cardiac enzymes troponin and BNP.

“The dose, imaging methodology, and blood parameters simulate the monitoring that patients on this treatment would receive and produces valuable translational data,” Dr Bergler-Klein said.

The researchers found that the group receiving Myocet had better diastolic and systolic function in the left and right ventricles, compared to conventional doxorubicin. The Myocet group also had less fibrosis in the myocardium, as shown by MRI and histology staining.

“Our study shows that doxorubicin encapsulated in a liposome had fewer cardiac side effects than doxorubicin given in the conventional way,” Dr Bergler-Klein said.

“We did find cardiac toxicity in the Myocet group as well, despite the fact that the pigs were young, healthy, and received anthracyclines for only a short period. This emphasizes how important it is for all cancer patients taking anthracyclines to receive cardiac monitoring using echocardiography and biomarkers, and MRI where indicated.”

“Many patients who recover after chemotherapy have asymptomatic heart damage, which can become symptomatic as they get older. When heart problems are picked up early, patients can be given preventive treatment, including ACE inhibitors, angiotensin receptor blockers, or beta-blockers, to prevent the progression to overt heart failure.”

The researchers are now conducting gene-expression profiling on the histology samples, hoping to explain the better outcome and cardiac function after Myocet therapy. They have found differences in the expression of genes that control energy use and the metabolic state, with better regulation in the Myocet group.

Piglet

Credit: USDA

VIENNA—Encapsulating the anthracycline doxorubicin in a liposome can reduce the risk of developing heart damage, according to a study presented at EuroEcho-Imaging 2014.

Researchers administered doxorubicin encased in a liposome to a small group of pigs and compared cardiac outcomes to those in pigs that received unmanipulated doxorubicin or epirubicin.

Pigs that received encapsulated doxorubicin still developed cardiotoxicity, but at lower rates than pigs that received traditional doxorubicin.

Pigs that received epirubicin were excluded due to low survival rates.

“[M]any chemotherapies—in particular, anthracyclines—cause cardiac side effects that can lead to cardiomyopathy and severe heart failure,” said study investigator Jutta Bergler-Klein, MD, of the Medical University of Vienna in Austria. “Cardiotoxicity can occur acutely or up to 30 years after chemotherapy and is the second most common cause of death in cancer patients, after secondary malignancy in childhood cancer survivors.”

“Liposomal encapsulation is a new technique which wraps the chemotherapy drug in a fatty cover called a liposome. More of the drug reaches the cancer cells because there is less degradation, and there are fewer side effects on healthy cells because the fat cover acts as a barrier.”

“The drug stays in the bloodstream longer, allowing higher cumulative doses to be given. We tested whether non-pegylated liposome encapsulation of the anthracycline doxorubicin (called Myocet) could decrease its cardiotoxicity compared to conventional doxorubicin or epirubicin, another anthracycline.”

The study included 24 pigs that were randomized to receive the human dose-equivalent of Myocet, conventional doxorubicin, or epirubicin in 3 cycles. The epirubicin group was excluded from the final analyses because of low survival levels.

The researchers assessed cardiac function by echocardiography and MRI at baseline and follow-up (after about 3 months). Laboratory follow-up included hematology, renal function, and measurement of the cardiac enzymes troponin and BNP.

“The dose, imaging methodology, and blood parameters simulate the monitoring that patients on this treatment would receive and produces valuable translational data,” Dr Bergler-Klein said.

The researchers found that the group receiving Myocet had better diastolic and systolic function in the left and right ventricles, compared to conventional doxorubicin. The Myocet group also had less fibrosis in the myocardium, as shown by MRI and histology staining.

“Our study shows that doxorubicin encapsulated in a liposome had fewer cardiac side effects than doxorubicin given in the conventional way,” Dr Bergler-Klein said.

“We did find cardiac toxicity in the Myocet group as well, despite the fact that the pigs were young, healthy, and received anthracyclines for only a short period. This emphasizes how important it is for all cancer patients taking anthracyclines to receive cardiac monitoring using echocardiography and biomarkers, and MRI where indicated.”

“Many patients who recover after chemotherapy have asymptomatic heart damage, which can become symptomatic as they get older. When heart problems are picked up early, patients can be given preventive treatment, including ACE inhibitors, angiotensin receptor blockers, or beta-blockers, to prevent the progression to overt heart failure.”

The researchers are now conducting gene-expression profiling on the histology samples, hoping to explain the better outcome and cardiac function after Myocet therapy. They have found differences in the expression of genes that control energy use and the metabolic state, with better regulation in the Myocet group.

DNA methylation

Credit: Christoph Bock

New research suggests disordered methylation is one of the defining characteristics of cancer and helps tumors adapt to changing circumstances.

The study, published in Cancer Cell, showed that disordered methylation has a direct bearing on the effectiveness of cancer therapy.

In patients with chronic lymphocytic leukemia (CLL), researchers found that treatment produced shorter remissions if the tumor tissue showed signs of highly disordered methylation.

The findings indicate that such disorganization can actually benefit tumors and render them less vulnerable to anticancer drugs.

“The behavior of a cancer cell is dictated not only by genetics . . . but also by epigenetics,” said study author Catherine Wu, MD, of the Dana-Farber Cancer Institute in Boston.

“We know that tumors are composed of many subgroups of cells, each with its own array of gene mutations. In this study, we wanted to see if that type of genetic diversity coincides with epigenetic diversity. In other words, does the range of methylation patterns mirror the genetic variety we find in tumors?”

To find out, the researchers used bisulfite sequencing, which allows scientists to track the presence or absence of methyl groups at specific rungs on the DNA ladder.

They also devised a simple measure called PDR—percent discordant reads—for quantifying the extent of irregular methylation within a tissue sample. The higher the PDR, the more variability in how the methyl groups are arranged.

They measured the PDR and the amount of genetic diversity in 104 CLL samples and 27 samples of normal B cells.

“We thought the epigenetic structure would map right onto the genetic structure,” said study author Alexander Meissner, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Massachusetts.

“That is, the degree of genetic diversity in each sample would match the variation in methylation marks in an organized fashion.”

To the researchers’ surprise, the methylation patterns showed a tremendous degree of random disarray.

“We know that individual tumors are checkered with genetically distinct groups of cells,” Dr Meissner explained. “Bisulfite sequencing enabled us to see that the placement of methyl groups across tumor cell DNA also varies substantially among cells in the same tumor. In fact, disorderly methylation pervades the entire tumor.”

The results revealed that the diversity within individual tumors apparently proceeds along two independent, yet interrelated tracks: one resulting in a genetic hodgepodge of cell groups, the other resulting in haphazard methylation.

The methylation irregularities, technically known as “local methylation disorder,” were highly evident in CLL and other types of cancer.

Because methyl groups control the expression of genes, disorderly methylation might be expected to cause wildly inconsistent gene activity even within a single tumor. This, in fact, is what the researchers found.

The disruption of methylation machinery might seem hazardous to tumor survival, but the researchers theorize that tumors can turn the disorderliness to their own advantage.

“Just as in the case of genetic heterogeneity within tumors, increased random variation of the epigenetic profile may augment the diversity of malignant cells,” said study author Dan Landau, MD, PhD, of Dana-Farber and the Broad Institute.

“The ability of cancers to maintain high levels of diversity is an effective hedging strategy, enabling them to better adapt to therapy, as well as enhancing the ‘trial and error’ process in search of better evolutionary trajectories.”

“Cancer survives through some wildly inventive ways,” Dr Wu added. “Methylation disorder is one of the ways it creates the conditions that enable it to adapt.”

DNA methylation

Credit: Christoph Bock

New research suggests disordered methylation is one of the defining characteristics of cancer and helps tumors adapt to changing circumstances.

The study, published in Cancer Cell, showed that disordered methylation has a direct bearing on the effectiveness of cancer therapy.

In patients with chronic lymphocytic leukemia (CLL), researchers found that treatment produced shorter remissions if the tumor tissue showed signs of highly disordered methylation.

The findings indicate that such disorganization can actually benefit tumors and render them less vulnerable to anticancer drugs.

“The behavior of a cancer cell is dictated not only by genetics . . . but also by epigenetics,” said study author Catherine Wu, MD, of the Dana-Farber Cancer Institute in Boston.

“We know that tumors are composed of many subgroups of cells, each with its own array of gene mutations. In this study, we wanted to see if that type of genetic diversity coincides with epigenetic diversity. In other words, does the range of methylation patterns mirror the genetic variety we find in tumors?”

To find out, the researchers used bisulfite sequencing, which allows scientists to track the presence or absence of methyl groups at specific rungs on the DNA ladder.

They also devised a simple measure called PDR—percent discordant reads—for quantifying the extent of irregular methylation within a tissue sample. The higher the PDR, the more variability in how the methyl groups are arranged.

They measured the PDR and the amount of genetic diversity in 104 CLL samples and 27 samples of normal B cells.

“We thought the epigenetic structure would map right onto the genetic structure,” said study author Alexander Meissner, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Massachusetts.

“That is, the degree of genetic diversity in each sample would match the variation in methylation marks in an organized fashion.”

To the researchers’ surprise, the methylation patterns showed a tremendous degree of random disarray.

“We know that individual tumors are checkered with genetically distinct groups of cells,” Dr Meissner explained. “Bisulfite sequencing enabled us to see that the placement of methyl groups across tumor cell DNA also varies substantially among cells in the same tumor. In fact, disorderly methylation pervades the entire tumor.”

The results revealed that the diversity within individual tumors apparently proceeds along two independent, yet interrelated tracks: one resulting in a genetic hodgepodge of cell groups, the other resulting in haphazard methylation.

The methylation irregularities, technically known as “local methylation disorder,” were highly evident in CLL and other types of cancer.

Because methyl groups control the expression of genes, disorderly methylation might be expected to cause wildly inconsistent gene activity even within a single tumor. This, in fact, is what the researchers found.

The disruption of methylation machinery might seem hazardous to tumor survival, but the researchers theorize that tumors can turn the disorderliness to their own advantage.

“Just as in the case of genetic heterogeneity within tumors, increased random variation of the epigenetic profile may augment the diversity of malignant cells,” said study author Dan Landau, MD, PhD, of Dana-Farber and the Broad Institute.

“The ability of cancers to maintain high levels of diversity is an effective hedging strategy, enabling them to better adapt to therapy, as well as enhancing the ‘trial and error’ process in search of better evolutionary trajectories.”

“Cancer survives through some wildly inventive ways,” Dr Wu added. “Methylation disorder is one of the ways it creates the conditions that enable it to adapt.”

DNA methylation

Credit: Christoph Bock

New research suggests disordered methylation is one of the defining characteristics of cancer and helps tumors adapt to changing circumstances.

The study, published in Cancer Cell, showed that disordered methylation has a direct bearing on the effectiveness of cancer therapy.

In patients with chronic lymphocytic leukemia (CLL), researchers found that treatment produced shorter remissions if the tumor tissue showed signs of highly disordered methylation.

The findings indicate that such disorganization can actually benefit tumors and render them less vulnerable to anticancer drugs.

“The behavior of a cancer cell is dictated not only by genetics . . . but also by epigenetics,” said study author Catherine Wu, MD, of the Dana-Farber Cancer Institute in Boston.

“We know that tumors are composed of many subgroups of cells, each with its own array of gene mutations. In this study, we wanted to see if that type of genetic diversity coincides with epigenetic diversity. In other words, does the range of methylation patterns mirror the genetic variety we find in tumors?”

To find out, the researchers used bisulfite sequencing, which allows scientists to track the presence or absence of methyl groups at specific rungs on the DNA ladder.

They also devised a simple measure called PDR—percent discordant reads—for quantifying the extent of irregular methylation within a tissue sample. The higher the PDR, the more variability in how the methyl groups are arranged.

They measured the PDR and the amount of genetic diversity in 104 CLL samples and 27 samples of normal B cells.

“We thought the epigenetic structure would map right onto the genetic structure,” said study author Alexander Meissner, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Massachusetts.

“That is, the degree of genetic diversity in each sample would match the variation in methylation marks in an organized fashion.”

To the researchers’ surprise, the methylation patterns showed a tremendous degree of random disarray.

“We know that individual tumors are checkered with genetically distinct groups of cells,” Dr Meissner explained. “Bisulfite sequencing enabled us to see that the placement of methyl groups across tumor cell DNA also varies substantially among cells in the same tumor. In fact, disorderly methylation pervades the entire tumor.”

The results revealed that the diversity within individual tumors apparently proceeds along two independent, yet interrelated tracks: one resulting in a genetic hodgepodge of cell groups, the other resulting in haphazard methylation.

The methylation irregularities, technically known as “local methylation disorder,” were highly evident in CLL and other types of cancer.

Because methyl groups control the expression of genes, disorderly methylation might be expected to cause wildly inconsistent gene activity even within a single tumor. This, in fact, is what the researchers found.

The disruption of methylation machinery might seem hazardous to tumor survival, but the researchers theorize that tumors can turn the disorderliness to their own advantage.

“Just as in the case of genetic heterogeneity within tumors, increased random variation of the epigenetic profile may augment the diversity of malignant cells,” said study author Dan Landau, MD, PhD, of Dana-Farber and the Broad Institute.

“The ability of cancers to maintain high levels of diversity is an effective hedging strategy, enabling them to better adapt to therapy, as well as enhancing the ‘trial and error’ process in search of better evolutionary trajectories.”

“Cancer survives through some wildly inventive ways,” Dr Wu added. “Methylation disorder is one of the ways it creates the conditions that enable it to adapt.”

Pills

Credit: FDA

SAN FRANCISCO—A BCL2 inhibitor that previously proved active against chronic lymphocytic leukemia has shown activity in certain patients with acute myelogenous leukemia (AML) as well.

This phase 2 trial was the first use of the inhibitor, ABT-199 (or venetoclax), in patients with relapsed or refractory AML.

Five of 32 patients treated with ABT-199 achieved a complete response (CR) or CR with incomplete blood count recovery (CRi), and several more had stable disease.

The drug appeared to be particularly active in patients with IDH mutations.

Marina Konopleva, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2014 ASH Annual Meeting (abstract 118). The research was funded by AbbVie, Inc., the company developing ABT-199.

The trial was launched on the basis of preclinical studies showing that ABT-199 could kill AML cell lines, patients’ AML cells, and patient-derived AML cells implanted in mice.

The researchers enrolled 32 AML patients, 30 of whom had relapsed or refractory disease. Patients had a median age of 71 (range, 19 to 84), and half were male.

The overall response rate was 15.5%, with 1 patient achieving a CR and 4 patients achieving a CRi. The researchers noted that 3 of the patients who had a CR/CRi had IDH mutations. Two of these patients also achieved minimal residual disease negativity.

The team said these results suggest single-agent ABT-199 can have considerable clinical activity in patients with relapsed or refractory AML, and patients with mutations in IDH genes may be particularly sensitive to the drug.

The researchers also found the median bone marrow blast count in evaluable patients decreased 36% after treatment with ABT-199. And 6 patients (19%) had at least a 50% reduction in bone marrow blasts.

Common adverse events following treatment (occurring in at least 25% of patients) included nausea, diarrhea, fatigue, neutropenia, and vomiting. Grade 3 and 4 adverse events (occurring in 3 or more patients) included febrile neutropenia, anemia, and pneumonia.

No patients died as a result of treatment-related adverse events.

Furthermore, the maximum-tolerated dose was not reached, leaving open the possibility of higher doses in further trials. The next step is to carry out trials combining ABT-199 with other agents. These trials are currently opening at several sites.

AbbVie said ABT-199 will be studied in combination with common AML treatments, and the company is developing ABT-199 for, and evaluating the drug in, several hematologic malignancies.

Pills

Credit: FDA

SAN FRANCISCO—A BCL2 inhibitor that previously proved active against chronic lymphocytic leukemia has shown activity in certain patients with acute myelogenous leukemia (AML) as well.

This phase 2 trial was the first use of the inhibitor, ABT-199 (or venetoclax), in patients with relapsed or refractory AML.

Five of 32 patients treated with ABT-199 achieved a complete response (CR) or CR with incomplete blood count recovery (CRi), and several more had stable disease.

The drug appeared to be particularly active in patients with IDH mutations.

Marina Konopleva, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2014 ASH Annual Meeting (abstract 118). The research was funded by AbbVie, Inc., the company developing ABT-199.

The trial was launched on the basis of preclinical studies showing that ABT-199 could kill AML cell lines, patients’ AML cells, and patient-derived AML cells implanted in mice.

The researchers enrolled 32 AML patients, 30 of whom had relapsed or refractory disease. Patients had a median age of 71 (range, 19 to 84), and half were male.

The overall response rate was 15.5%, with 1 patient achieving a CR and 4 patients achieving a CRi. The researchers noted that 3 of the patients who had a CR/CRi had IDH mutations. Two of these patients also achieved minimal residual disease negativity.

The team said these results suggest single-agent ABT-199 can have considerable clinical activity in patients with relapsed or refractory AML, and patients with mutations in IDH genes may be particularly sensitive to the drug.

The researchers also found the median bone marrow blast count in evaluable patients decreased 36% after treatment with ABT-199. And 6 patients (19%) had at least a 50% reduction in bone marrow blasts.

Common adverse events following treatment (occurring in at least 25% of patients) included nausea, diarrhea, fatigue, neutropenia, and vomiting. Grade 3 and 4 adverse events (occurring in 3 or more patients) included febrile neutropenia, anemia, and pneumonia.

No patients died as a result of treatment-related adverse events.

Furthermore, the maximum-tolerated dose was not reached, leaving open the possibility of higher doses in further trials. The next step is to carry out trials combining ABT-199 with other agents. These trials are currently opening at several sites.

AbbVie said ABT-199 will be studied in combination with common AML treatments, and the company is developing ABT-199 for, and evaluating the drug in, several hematologic malignancies.

Pills

Credit: FDA

SAN FRANCISCO—A BCL2 inhibitor that previously proved active against chronic lymphocytic leukemia has shown activity in certain patients with acute myelogenous leukemia (AML) as well.

This phase 2 trial was the first use of the inhibitor, ABT-199 (or venetoclax), in patients with relapsed or refractory AML.

Five of 32 patients treated with ABT-199 achieved a complete response (CR) or CR with incomplete blood count recovery (CRi), and several more had stable disease.

The drug appeared to be particularly active in patients with IDH mutations.

Marina Konopleva, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2014 ASH Annual Meeting (abstract 118). The research was funded by AbbVie, Inc., the company developing ABT-199.

The trial was launched on the basis of preclinical studies showing that ABT-199 could kill AML cell lines, patients’ AML cells, and patient-derived AML cells implanted in mice.

The researchers enrolled 32 AML patients, 30 of whom had relapsed or refractory disease. Patients had a median age of 71 (range, 19 to 84), and half were male.

The overall response rate was 15.5%, with 1 patient achieving a CR and 4 patients achieving a CRi. The researchers noted that 3 of the patients who had a CR/CRi had IDH mutations. Two of these patients also achieved minimal residual disease negativity.

The team said these results suggest single-agent ABT-199 can have considerable clinical activity in patients with relapsed or refractory AML, and patients with mutations in IDH genes may be particularly sensitive to the drug.

The researchers also found the median bone marrow blast count in evaluable patients decreased 36% after treatment with ABT-199. And 6 patients (19%) had at least a 50% reduction in bone marrow blasts.

Common adverse events following treatment (occurring in at least 25% of patients) included nausea, diarrhea, fatigue, neutropenia, and vomiting. Grade 3 and 4 adverse events (occurring in 3 or more patients) included febrile neutropenia, anemia, and pneumonia.

No patients died as a result of treatment-related adverse events.

Furthermore, the maximum-tolerated dose was not reached, leaving open the possibility of higher doses in further trials. The next step is to carry out trials combining ABT-199 with other agents. These trials are currently opening at several sites.

AbbVie said ABT-199 will be studied in combination with common AML treatments, and the company is developing ABT-199 for, and evaluating the drug in, several hematologic malignancies.

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.”

Scientist at a computer

Credit: Darren Baker

Researchers say that computer modeling of next-generation DNA sequencing data can help us understand the variable outcomes of stem cell transplant and provide a theoretical framework to make transplant a possibility for more patients who don’t have a related donor.

The team analyzed data obtained from whole-exome sequencing of 9 donor-recipient pairs (DRPs) and found it’s possible to predict the risk of graft-vs-host disease (GVHD).

This finding could one day help physicians tailor immunosuppressive therapies to possibly improve transplant outcomes.

The investigators say their data provide evidence that the way a patient’s immune system rebuilds itself following transplant is representative of a dynamical system, a system in which the current state determines what future state will follow.

“The immune system seems chaotic, but that is because there are so many variables involved,” said Amir Toor, MD, of the Virginia Commonwealth University in Richmond.

“We have found evidence of an underlying order. Using next-generation DNA sequencing technology, it may be possible to account for many of the molecular variables that eventually determine how well a donor’s immune system will graft to a patient.”

Dr Toor and his colleagues describe this work in two articles in Frontiers in Immunology.

In the first paper, the researchers recount how they used whole-exome sequencing to examine variation in minor histocompatibility antigens (mHAs) of transplant DRPs.

Using advanced computer-based analysis, the investigators examined potential interactions between mHAs and HLAs and discovered a high level of mHA variation in HLA-matched DRPs that could potentially contribute to GVHD.

These findings may help explain why many HLA-matched recipients experience GVHD, but why some HLA-mismatched recipients do not develop GVHD remains a mystery.

The researchers offer an explanation for this seeming paradox in a companion article. In this paper, they suggest that by inhibiting peptide generation through immunosuppressive therapies in the earliest weeks following stem cell transplant, antigen presentation to donor T cells could be diminished, which reduces the risk of GVHD as the recipients reconstitute their T-cell repertoire.

In previous research, Dr Toor and his colleagues discovered a fractal pattern in the DNA of recipients’ T-cell repertoires. (Fractals are self-similar patterns that repeat themselves at every scale.)

Based on their data, the researchers believe that the presentation of mHAs following transplant helps shape the development of T-cell clonal families.

Thus, inhibiting this antigen presentation through immunosuppressive therapies in patients who have high mHA variation can potentially reduce the risk of GVHD by influencing the development of their T-cell repertoire. This is supported by data from clinical studies showing immune suppression soon after transplant improves outcomes in unrelated DRPs.

The investigators suggest that an equation such as the logistic model of growth, a mathematical formula used to explain population growth, could be employed to predict the evolution of T-cell clones and determine a patient’s future risk of GVHD.

“Currently, we rely on population-based outcomes derived from probabilistic studies to determine the best way to perform stem cell transplants,” Dr Toor said. “The development of accurate mathematical models that account for the key variables influencing transplant outcomes may allow us to treat patients using a systematic and personalized approach.”

“We plan to keep exploring this concept in hopes that we can tailor the transplantation process to each individual in order to improve outcomes and make transplantation an option for more patients.”

Scientist at a computer

Credit: Darren Baker

Researchers say that computer modeling of next-generation DNA sequencing data can help us understand the variable outcomes of stem cell transplant and provide a theoretical framework to make transplant a possibility for more patients who don’t have a related donor.

The team analyzed data obtained from whole-exome sequencing of 9 donor-recipient pairs (DRPs) and found it’s possible to predict the risk of graft-vs-host disease (GVHD).

This finding could one day help physicians tailor immunosuppressive therapies to possibly improve transplant outcomes.

The investigators say their data provide evidence that the way a patient’s immune system rebuilds itself following transplant is representative of a dynamical system, a system in which the current state determines what future state will follow.

“The immune system seems chaotic, but that is because there are so many variables involved,” said Amir Toor, MD, of the Virginia Commonwealth University in Richmond.

“We have found evidence of an underlying order. Using next-generation DNA sequencing technology, it may be possible to account for many of the molecular variables that eventually determine how well a donor’s immune system will graft to a patient.”

Dr Toor and his colleagues describe this work in two articles in Frontiers in Immunology.

In the first paper, the researchers recount how they used whole-exome sequencing to examine variation in minor histocompatibility antigens (mHAs) of transplant DRPs.

Using advanced computer-based analysis, the investigators examined potential interactions between mHAs and HLAs and discovered a high level of mHA variation in HLA-matched DRPs that could potentially contribute to GVHD.

These findings may help explain why many HLA-matched recipients experience GVHD, but why some HLA-mismatched recipients do not develop GVHD remains a mystery.

The researchers offer an explanation for this seeming paradox in a companion article. In this paper, they suggest that by inhibiting peptide generation through immunosuppressive therapies in the earliest weeks following stem cell transplant, antigen presentation to donor T cells could be diminished, which reduces the risk of GVHD as the recipients reconstitute their T-cell repertoire.

In previous research, Dr Toor and his colleagues discovered a fractal pattern in the DNA of recipients’ T-cell repertoires. (Fractals are self-similar patterns that repeat themselves at every scale.)

Based on their data, the researchers believe that the presentation of mHAs following transplant helps shape the development of T-cell clonal families.

Thus, inhibiting this antigen presentation through immunosuppressive therapies in patients who have high mHA variation can potentially reduce the risk of GVHD by influencing the development of their T-cell repertoire. This is supported by data from clinical studies showing immune suppression soon after transplant improves outcomes in unrelated DRPs.

The investigators suggest that an equation such as the logistic model of growth, a mathematical formula used to explain population growth, could be employed to predict the evolution of T-cell clones and determine a patient’s future risk of GVHD.

“Currently, we rely on population-based outcomes derived from probabilistic studies to determine the best way to perform stem cell transplants,” Dr Toor said. “The development of accurate mathematical models that account for the key variables influencing transplant outcomes may allow us to treat patients using a systematic and personalized approach.”

“We plan to keep exploring this concept in hopes that we can tailor the transplantation process to each individual in order to improve outcomes and make transplantation an option for more patients.”

Scientist at a computer

Credit: Darren Baker

Researchers say that computer modeling of next-generation DNA sequencing data can help us understand the variable outcomes of stem cell transplant and provide a theoretical framework to make transplant a possibility for more patients who don’t have a related donor.

The team analyzed data obtained from whole-exome sequencing of 9 donor-recipient pairs (DRPs) and found it’s possible to predict the risk of graft-vs-host disease (GVHD).

This finding could one day help physicians tailor immunosuppressive therapies to possibly improve transplant outcomes.

The investigators say their data provide evidence that the way a patient’s immune system rebuilds itself following transplant is representative of a dynamical system, a system in which the current state determines what future state will follow.

“The immune system seems chaotic, but that is because there are so many variables involved,” said Amir Toor, MD, of the Virginia Commonwealth University in Richmond.

“We have found evidence of an underlying order. Using next-generation DNA sequencing technology, it may be possible to account for many of the molecular variables that eventually determine how well a donor’s immune system will graft to a patient.”

Dr Toor and his colleagues describe this work in two articles in Frontiers in Immunology.

In the first paper, the researchers recount how they used whole-exome sequencing to examine variation in minor histocompatibility antigens (mHAs) of transplant DRPs.

Using advanced computer-based analysis, the investigators examined potential interactions between mHAs and HLAs and discovered a high level of mHA variation in HLA-matched DRPs that could potentially contribute to GVHD.

These findings may help explain why many HLA-matched recipients experience GVHD, but why some HLA-mismatched recipients do not develop GVHD remains a mystery.

The researchers offer an explanation for this seeming paradox in a companion article. In this paper, they suggest that by inhibiting peptide generation through immunosuppressive therapies in the earliest weeks following stem cell transplant, antigen presentation to donor T cells could be diminished, which reduces the risk of GVHD as the recipients reconstitute their T-cell repertoire.

In previous research, Dr Toor and his colleagues discovered a fractal pattern in the DNA of recipients’ T-cell repertoires. (Fractals are self-similar patterns that repeat themselves at every scale.)

Based on their data, the researchers believe that the presentation of mHAs following transplant helps shape the development of T-cell clonal families.

Thus, inhibiting this antigen presentation through immunosuppressive therapies in patients who have high mHA variation can potentially reduce the risk of GVHD by influencing the development of their T-cell repertoire. This is supported by data from clinical studies showing immune suppression soon after transplant improves outcomes in unrelated DRPs.

The investigators suggest that an equation such as the logistic model of growth, a mathematical formula used to explain population growth, could be employed to predict the evolution of T-cell clones and determine a patient’s future risk of GVHD.

“Currently, we rely on population-based outcomes derived from probabilistic studies to determine the best way to perform stem cell transplants,” Dr Toor said. “The development of accurate mathematical models that account for the key variables influencing transplant outcomes may allow us to treat patients using a systematic and personalized approach.”

“We plan to keep exploring this concept in hopes that we can tailor the transplantation process to each individual in order to improve outcomes and make transplantation an option for more patients.”

Attendees at ASH 2014

SAN FRANCISCO—Multiple myeloma (MM) is driven to spread by only a subset of the myeloma cells within a patient’s body, according to research presented at the 2014 ASH Annual Meeting.

Attacking those cells with targeted drugs may degrade MM’s ability to spread throughout the bone marrow, study investigators said.

The team had used a mouse model of MM to track which of 15 subclones of myeloma cells spread beyond their initial site in the animals’ hind legs.

By labeling the different subgroups with fluorescent dyes, the researchers determined that just one of the subclones was responsible for disease metastasis.

They then compared the pattern of gene abnormalities in the initial myeloma tissue and the metastatic tumors. And they found that 238 genes were significantly less active in the latter group, comprising a gene signature of metastatic myeloma.

“Out of all the genes that were differently expressed in the 2 groups, we found 11 that played a functional role in metastasis and therefore may be drivers of the disease,” said study investigator Irene Ghobrial, MD, of the Dana-Farber Cancer Institute in Boston.

If future studies confirm that role, the genes may become targets for therapies that inhibit MM metastasis, she added.

Dr Ghobrial and her colleagues presented this research in a poster session at ASH (abstract 3370).

Attendees at ASH 2014

SAN FRANCISCO—Multiple myeloma (MM) is driven to spread by only a subset of the myeloma cells within a patient’s body, according to research presented at the 2014 ASH Annual Meeting.

Attacking those cells with targeted drugs may degrade MM’s ability to spread throughout the bone marrow, study investigators said.

The team had used a mouse model of MM to track which of 15 subclones of myeloma cells spread beyond their initial site in the animals’ hind legs.

By labeling the different subgroups with fluorescent dyes, the researchers determined that just one of the subclones was responsible for disease metastasis.

They then compared the pattern of gene abnormalities in the initial myeloma tissue and the metastatic tumors. And they found that 238 genes were significantly less active in the latter group, comprising a gene signature of metastatic myeloma.

“Out of all the genes that were differently expressed in the 2 groups, we found 11 that played a functional role in metastasis and therefore may be drivers of the disease,” said study investigator Irene Ghobrial, MD, of the Dana-Farber Cancer Institute in Boston.

If future studies confirm that role, the genes may become targets for therapies that inhibit MM metastasis, she added.

Dr Ghobrial and her colleagues presented this research in a poster session at ASH (abstract 3370).

Attendees at ASH 2014

SAN FRANCISCO—Multiple myeloma (MM) is driven to spread by only a subset of the myeloma cells within a patient’s body, according to research presented at the 2014 ASH Annual Meeting.

Attacking those cells with targeted drugs may degrade MM’s ability to spread throughout the bone marrow, study investigators said.

The team had used a mouse model of MM to track which of 15 subclones of myeloma cells spread beyond their initial site in the animals’ hind legs.

By labeling the different subgroups with fluorescent dyes, the researchers determined that just one of the subclones was responsible for disease metastasis.

They then compared the pattern of gene abnormalities in the initial myeloma tissue and the metastatic tumors. And they found that 238 genes were significantly less active in the latter group, comprising a gene signature of metastatic myeloma.

“Out of all the genes that were differently expressed in the 2 groups, we found 11 that played a functional role in metastasis and therefore may be drivers of the disease,” said study investigator Irene Ghobrial, MD, of the Dana-Farber Cancer Institute in Boston.

If future studies confirm that role, the genes may become targets for therapies that inhibit MM metastasis, she added.

Dr Ghobrial and her colleagues presented this research in a poster session at ASH (abstract 3370).