Leukemia, Myelodysplasia, Transplantation

Vials of a drug

The US Food and Drug Administration (FDA) has approved the intravenous administration of asparaginase Erwinia chrysanthemi (Erwinaze).

The product is indicated as a component of a multi-agent chemotherapy regimen to treat patients with acute lymphoblastic leukemia (ALL) who have developed hypersensitivity to E coli-derived asparaginase.

Previously, the only FDA-approved route of administration for asparaginase Erwinia chrysanthemi was through intramuscular injection.

The FDA’s decision to expand the drug’s use was based on a pharmacokinetic study (published in Blood in 2013) of intravenous asparaginase Erwinia chrysanthemi.

The trial included 30 patients with ALL or lymphoblastic lymphoma who developed hypersensitivity (grade ≥ 2) to E coli–derived asparaginase. The patients’ median age was 6.5 years (range, 1-17), 63% were male, and 83% were Caucasian.

Patients received intravenous asparaginase Erwinia chrysanthemi at 25,000 IU/m²/dose, on a Monday/Wednesday/Friday schedule for 2 consecutive weeks (6 doses=1 cycle) for each dose of pegaspargase remaining in their original treatment plan. All other chemotherapy was continued per the original treatment plan.

Before the first dose of intravenous asparaginase Erwinia chrysanthemi, nadir serum asparaginase activity (NSAA) levels were below the limit of quantification (defined as 0.0129 IU/mL) for 91% of patients.

The study’s primary endpoint was the proportion of patients who achieved NSAA ≥ 0.1 IU/mL, which has been associated with complete asparagine depletion, at 48 hours after dose 5 in cycle 1. Nineteen of the 23 evaluable patients (83%) achieved this endpoint.

A secondary objective of the study was to determine the proportion of patients who achieved NSAA ≥ 0.1 IU/mL at 72 hours after dose 6 in cycle 1. Nine patients (45%) achieved this endpoint.

In all 30 patients, the most common asparaginase-related toxicities reported during cycle 1 were hypersensitivity (23%), vomiting (20%), nausea (20%), and hyperglycemia (13%). Pancreatitis and thrombosis each occurred in 3% of patients. One patient experienced a transient ischemic attack.

The most common grade 3 or 4 adverse event was febrile neutropenia (7%). Four patients discontinued treatment before completing cycle 1—3 of them due to hypersensitivity and 1 due to pancreatitis. There were no deaths.

This study was funded by Jazz Pharmaceuticals, the company developing asparaginase Erwinia chrysanthemi.

Vials of a drug

The US Food and Drug Administration (FDA) has approved the intravenous administration of asparaginase Erwinia chrysanthemi (Erwinaze).

The product is indicated as a component of a multi-agent chemotherapy regimen to treat patients with acute lymphoblastic leukemia (ALL) who have developed hypersensitivity to E coli-derived asparaginase.

Previously, the only FDA-approved route of administration for asparaginase Erwinia chrysanthemi was through intramuscular injection.

The FDA’s decision to expand the drug’s use was based on a pharmacokinetic study (published in Blood in 2013) of intravenous asparaginase Erwinia chrysanthemi.

The trial included 30 patients with ALL or lymphoblastic lymphoma who developed hypersensitivity (grade ≥ 2) to E coli–derived asparaginase. The patients’ median age was 6.5 years (range, 1-17), 63% were male, and 83% were Caucasian.

Patients received intravenous asparaginase Erwinia chrysanthemi at 25,000 IU/m²/dose, on a Monday/Wednesday/Friday schedule for 2 consecutive weeks (6 doses=1 cycle) for each dose of pegaspargase remaining in their original treatment plan. All other chemotherapy was continued per the original treatment plan.

Before the first dose of intravenous asparaginase Erwinia chrysanthemi, nadir serum asparaginase activity (NSAA) levels were below the limit of quantification (defined as 0.0129 IU/mL) for 91% of patients.

The study’s primary endpoint was the proportion of patients who achieved NSAA ≥ 0.1 IU/mL, which has been associated with complete asparagine depletion, at 48 hours after dose 5 in cycle 1. Nineteen of the 23 evaluable patients (83%) achieved this endpoint.

A secondary objective of the study was to determine the proportion of patients who achieved NSAA ≥ 0.1 IU/mL at 72 hours after dose 6 in cycle 1. Nine patients (45%) achieved this endpoint.

In all 30 patients, the most common asparaginase-related toxicities reported during cycle 1 were hypersensitivity (23%), vomiting (20%), nausea (20%), and hyperglycemia (13%). Pancreatitis and thrombosis each occurred in 3% of patients. One patient experienced a transient ischemic attack.

The most common grade 3 or 4 adverse event was febrile neutropenia (7%). Four patients discontinued treatment before completing cycle 1—3 of them due to hypersensitivity and 1 due to pancreatitis. There were no deaths.

This study was funded by Jazz Pharmaceuticals, the company developing asparaginase Erwinia chrysanthemi.

Vials of a drug

The US Food and Drug Administration (FDA) has approved the intravenous administration of asparaginase Erwinia chrysanthemi (Erwinaze).

The product is indicated as a component of a multi-agent chemotherapy regimen to treat patients with acute lymphoblastic leukemia (ALL) who have developed hypersensitivity to E coli-derived asparaginase.

Previously, the only FDA-approved route of administration for asparaginase Erwinia chrysanthemi was through intramuscular injection.

The FDA’s decision to expand the drug’s use was based on a pharmacokinetic study (published in Blood in 2013) of intravenous asparaginase Erwinia chrysanthemi.

The trial included 30 patients with ALL or lymphoblastic lymphoma who developed hypersensitivity (grade ≥ 2) to E coli–derived asparaginase. The patients’ median age was 6.5 years (range, 1-17), 63% were male, and 83% were Caucasian.

Patients received intravenous asparaginase Erwinia chrysanthemi at 25,000 IU/m²/dose, on a Monday/Wednesday/Friday schedule for 2 consecutive weeks (6 doses=1 cycle) for each dose of pegaspargase remaining in their original treatment plan. All other chemotherapy was continued per the original treatment plan.

Before the first dose of intravenous asparaginase Erwinia chrysanthemi, nadir serum asparaginase activity (NSAA) levels were below the limit of quantification (defined as 0.0129 IU/mL) for 91% of patients.

The study’s primary endpoint was the proportion of patients who achieved NSAA ≥ 0.1 IU/mL, which has been associated with complete asparagine depletion, at 48 hours after dose 5 in cycle 1. Nineteen of the 23 evaluable patients (83%) achieved this endpoint.

A secondary objective of the study was to determine the proportion of patients who achieved NSAA ≥ 0.1 IU/mL at 72 hours after dose 6 in cycle 1. Nine patients (45%) achieved this endpoint.

In all 30 patients, the most common asparaginase-related toxicities reported during cycle 1 were hypersensitivity (23%), vomiting (20%), nausea (20%), and hyperglycemia (13%). Pancreatitis and thrombosis each occurred in 3% of patients. One patient experienced a transient ischemic attack.

The most common grade 3 or 4 adverse event was febrile neutropenia (7%). Four patients discontinued treatment before completing cycle 1—3 of them due to hypersensitivity and 1 due to pancreatitis. There were no deaths.

This study was funded by Jazz Pharmaceuticals, the company developing asparaginase Erwinia chrysanthemi.

SAN FRANCISCO—New research suggests complex metaphase karyotype (CKT) is a stronger predictor of inferior outcome than 17p deletion in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who are treated with the BTK inhibitor ibrutinib.

The study showed that CKT, defined as 3 or more distinct chromosomal abnormalities, was independently associated with inferior event-free survival (EFS) and overall survival (OS), but del(17p) was not.

According to investigators, this suggests that del(17p) patients without CKT could be managed with long-term ibrutinib and close monitoring, as these patients have similar outcomes as patients without del(17p).

However, patients with CKT will likely require treatment-intensification strategies after ibrutinib-based therapy.

“We believe that patients with a complex karyotype represent an ideal group in whom to study novel treatment approaches, including ibrutinib-based combination regimens and/or consolidated approaches after initial ibrutinib response,” said investigator Philip A. Thompson, MBBS, of the University of Texas MD Anderson Cancer Center in Houston.

Dr Thompson presented his group’s findings at the 2014 ASH Annual Meeting as abstract 22.* Investigators involved in this study received research funding or consultancy fees from Pharmacyclics, Inc., makers of ibrutinib.

Patient characteristics

Dr Thompson and his colleagues analyzed 100 patients with relapsed/refractory CLL who received treatment with ibrutinib-based regimens—50 with ibrutinib alone, 36 with ibrutinib and rituximab, and 14 with ibrutinib, rituximab, and bendamustine.

The median age was 65 (range, 35-83), patients received a median of 2 prior therapies (range, 1-12), and 19% were fludarabine-refractory. Sixty percent of patients had Rai stage III-IV disease, 52% had bulky adenopathy, 81% had unmutated IGHV, and 56% had β2-microglobulin ≥ 4.0 mg/L.

FISH was available for 94 patients, and metaphase analysis was available for 65 patients. Forty-two percent (27/65) of patients had CKT, 28% (26/94) had del(11q), and 48% (45/94) had del(17p).

Of the 45 patients who had del(17p), 23 also had CKT. And of the 49 patients who did not have del(17p), 4 had CKT.

Event-free survival

The median follow-up in surviving patients was 27 months (range, 11-48). Eight patients had planned allogeneic stem cell transplant and were censored for the EFS analysis.

“As has been shown previously, patients with 17p deletion by FISH did have inferior event-free survival,” Dr Thompson said. “And when we looked at those patients with complex metaphase karyotype, there was a highly significant inferior event-free survival in these patients, compared to those with complex karyotype.”

EFS was 78% in patients with neither del(17p) nor del(11q), 69% in patients with del(11q), and 60% in patients with del(17p) (P=0.014).

EFS was 82% in patients without CKT and 44% in those with CKT (P<0.0001). In patients with del(17p), EFS was 78% in those without CKT and 48% in those with CKT (P=0.047).

In patients without CKT, EFS was 79% in those without del(17p) or del(11q), 90% in those with del(11q), and 78% in those with del(17p) (P=0.516).

“Interestingly, when we looked at the events that occurred in those patients without complex karyotype, none were due to CLL progression or Richter’s transformation,” Dr Thompson said.

In multivariable analysis, CKT was significantly associated with EFS (P=0.011), but del(17p) was not (P=0.887).

Overall survival

There was no significant difference in OS according to the presence of del(17p) or del(11q). OS was 87% in patients with neither del(17p) nor del(11q), 81% in patients with del(11q), and 67% in patients with del(17p) (P=0.054).

However, there was a significant difference in OS for patients with and without CKT. OS was 82% in patients without CKT and 56% in patients with CKT (P=0.006).

Among patients without CKT, OS was 84% in those with neither del(17p) nor del(11q), 80% in those with del(11q), and 78% in those with del(17p) (P=0.52).

In multivariable analysis, OS was significantly associated with CKT (P=0.011) and fludarabine-refractory disease (P=0.004) but not del(17p) (P=0.981).

“So, in summary, complex karyotype appears to be a more important predictor of outcomes in patients with relapsed or refractory CLL treated with ibrutinib-based regimens than the presence of del(17p) by FISH,” Dr Thompson said.

“Patients without complex karyotype have a low rate of disease progression, including those who have del(17p). Most progressions during ibrutinib therapy occur late, beyond the 12-month time point, but survival is short after disease progression.”

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

SAN FRANCISCO—New research suggests complex metaphase karyotype (CKT) is a stronger predictor of inferior outcome than 17p deletion in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who are treated with the BTK inhibitor ibrutinib.

The study showed that CKT, defined as 3 or more distinct chromosomal abnormalities, was independently associated with inferior event-free survival (EFS) and overall survival (OS), but del(17p) was not.

According to investigators, this suggests that del(17p) patients without CKT could be managed with long-term ibrutinib and close monitoring, as these patients have similar outcomes as patients without del(17p).

However, patients with CKT will likely require treatment-intensification strategies after ibrutinib-based therapy.

“We believe that patients with a complex karyotype represent an ideal group in whom to study novel treatment approaches, including ibrutinib-based combination regimens and/or consolidated approaches after initial ibrutinib response,” said investigator Philip A. Thompson, MBBS, of the University of Texas MD Anderson Cancer Center in Houston.

Dr Thompson presented his group’s findings at the 2014 ASH Annual Meeting as abstract 22.* Investigators involved in this study received research funding or consultancy fees from Pharmacyclics, Inc., makers of ibrutinib.

Patient characteristics

Dr Thompson and his colleagues analyzed 100 patients with relapsed/refractory CLL who received treatment with ibrutinib-based regimens—50 with ibrutinib alone, 36 with ibrutinib and rituximab, and 14 with ibrutinib, rituximab, and bendamustine.

The median age was 65 (range, 35-83), patients received a median of 2 prior therapies (range, 1-12), and 19% were fludarabine-refractory. Sixty percent of patients had Rai stage III-IV disease, 52% had bulky adenopathy, 81% had unmutated IGHV, and 56% had β2-microglobulin ≥ 4.0 mg/L.

FISH was available for 94 patients, and metaphase analysis was available for 65 patients. Forty-two percent (27/65) of patients had CKT, 28% (26/94) had del(11q), and 48% (45/94) had del(17p).

Of the 45 patients who had del(17p), 23 also had CKT. And of the 49 patients who did not have del(17p), 4 had CKT.

Event-free survival

The median follow-up in surviving patients was 27 months (range, 11-48). Eight patients had planned allogeneic stem cell transplant and were censored for the EFS analysis.

“As has been shown previously, patients with 17p deletion by FISH did have inferior event-free survival,” Dr Thompson said. “And when we looked at those patients with complex metaphase karyotype, there was a highly significant inferior event-free survival in these patients, compared to those with complex karyotype.”

EFS was 78% in patients with neither del(17p) nor del(11q), 69% in patients with del(11q), and 60% in patients with del(17p) (P=0.014).

EFS was 82% in patients without CKT and 44% in those with CKT (P<0.0001). In patients with del(17p), EFS was 78% in those without CKT and 48% in those with CKT (P=0.047).

In patients without CKT, EFS was 79% in those without del(17p) or del(11q), 90% in those with del(11q), and 78% in those with del(17p) (P=0.516).

“Interestingly, when we looked at the events that occurred in those patients without complex karyotype, none were due to CLL progression or Richter’s transformation,” Dr Thompson said.

In multivariable analysis, CKT was significantly associated with EFS (P=0.011), but del(17p) was not (P=0.887).

Overall survival

There was no significant difference in OS according to the presence of del(17p) or del(11q). OS was 87% in patients with neither del(17p) nor del(11q), 81% in patients with del(11q), and 67% in patients with del(17p) (P=0.054).

However, there was a significant difference in OS for patients with and without CKT. OS was 82% in patients without CKT and 56% in patients with CKT (P=0.006).

Among patients without CKT, OS was 84% in those with neither del(17p) nor del(11q), 80% in those with del(11q), and 78% in those with del(17p) (P=0.52).

In multivariable analysis, OS was significantly associated with CKT (P=0.011) and fludarabine-refractory disease (P=0.004) but not del(17p) (P=0.981).

“So, in summary, complex karyotype appears to be a more important predictor of outcomes in patients with relapsed or refractory CLL treated with ibrutinib-based regimens than the presence of del(17p) by FISH,” Dr Thompson said.

“Patients without complex karyotype have a low rate of disease progression, including those who have del(17p). Most progressions during ibrutinib therapy occur late, beyond the 12-month time point, but survival is short after disease progression.”

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

SAN FRANCISCO—New research suggests complex metaphase karyotype (CKT) is a stronger predictor of inferior outcome than 17p deletion in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who are treated with the BTK inhibitor ibrutinib.

The study showed that CKT, defined as 3 or more distinct chromosomal abnormalities, was independently associated with inferior event-free survival (EFS) and overall survival (OS), but del(17p) was not.

According to investigators, this suggests that del(17p) patients without CKT could be managed with long-term ibrutinib and close monitoring, as these patients have similar outcomes as patients without del(17p).

However, patients with CKT will likely require treatment-intensification strategies after ibrutinib-based therapy.

“We believe that patients with a complex karyotype represent an ideal group in whom to study novel treatment approaches, including ibrutinib-based combination regimens and/or consolidated approaches after initial ibrutinib response,” said investigator Philip A. Thompson, MBBS, of the University of Texas MD Anderson Cancer Center in Houston.

Dr Thompson presented his group’s findings at the 2014 ASH Annual Meeting as abstract 22.* Investigators involved in this study received research funding or consultancy fees from Pharmacyclics, Inc., makers of ibrutinib.

Patient characteristics

Dr Thompson and his colleagues analyzed 100 patients with relapsed/refractory CLL who received treatment with ibrutinib-based regimens—50 with ibrutinib alone, 36 with ibrutinib and rituximab, and 14 with ibrutinib, rituximab, and bendamustine.

The median age was 65 (range, 35-83), patients received a median of 2 prior therapies (range, 1-12), and 19% were fludarabine-refractory. Sixty percent of patients had Rai stage III-IV disease, 52% had bulky adenopathy, 81% had unmutated IGHV, and 56% had β2-microglobulin ≥ 4.0 mg/L.

FISH was available for 94 patients, and metaphase analysis was available for 65 patients. Forty-two percent (27/65) of patients had CKT, 28% (26/94) had del(11q), and 48% (45/94) had del(17p).

Of the 45 patients who had del(17p), 23 also had CKT. And of the 49 patients who did not have del(17p), 4 had CKT.

Event-free survival

The median follow-up in surviving patients was 27 months (range, 11-48). Eight patients had planned allogeneic stem cell transplant and were censored for the EFS analysis.

“As has been shown previously, patients with 17p deletion by FISH did have inferior event-free survival,” Dr Thompson said. “And when we looked at those patients with complex metaphase karyotype, there was a highly significant inferior event-free survival in these patients, compared to those with complex karyotype.”

EFS was 78% in patients with neither del(17p) nor del(11q), 69% in patients with del(11q), and 60% in patients with del(17p) (P=0.014).

EFS was 82% in patients without CKT and 44% in those with CKT (P<0.0001). In patients with del(17p), EFS was 78% in those without CKT and 48% in those with CKT (P=0.047).

In patients without CKT, EFS was 79% in those without del(17p) or del(11q), 90% in those with del(11q), and 78% in those with del(17p) (P=0.516).

“Interestingly, when we looked at the events that occurred in those patients without complex karyotype, none were due to CLL progression or Richter’s transformation,” Dr Thompson said.

In multivariable analysis, CKT was significantly associated with EFS (P=0.011), but del(17p) was not (P=0.887).

Overall survival

There was no significant difference in OS according to the presence of del(17p) or del(11q). OS was 87% in patients with neither del(17p) nor del(11q), 81% in patients with del(11q), and 67% in patients with del(17p) (P=0.054).

However, there was a significant difference in OS for patients with and without CKT. OS was 82% in patients without CKT and 56% in patients with CKT (P=0.006).

Among patients without CKT, OS was 84% in those with neither del(17p) nor del(11q), 80% in those with del(11q), and 78% in those with del(17p) (P=0.52).

In multivariable analysis, OS was significantly associated with CKT (P=0.011) and fludarabine-refractory disease (P=0.004) but not del(17p) (P=0.981).

“So, in summary, complex karyotype appears to be a more important predictor of outcomes in patients with relapsed or refractory CLL treated with ibrutinib-based regimens than the presence of del(17p) by FISH,” Dr Thompson said.

“Patients without complex karyotype have a low rate of disease progression, including those who have del(17p). Most progressions during ibrutinib therapy occur late, beyond the 12-month time point, but survival is short after disease progression.”

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

ASH attendees gather

in the Moscone Center

SAN FRANCISCO—The first-in-human study of AG-221 has confirmed IDH2 as a therapeutic target in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to investigators.

From the first dose of therapy, the high plasma level observed in patients “translates into a drastic decrease in 2-HG,” said Eytan M. Stein, MD, of Memorial Sloan Kettering Cancer Center in New York.

Mutations in IDH1 and IDH2 result in the accumulation of the oncometabolite 2-HG. And high levels of 2-HG prompt epigenetic changes to the cell, resulting in impaired cellular differentiation.

“By cycle 1, day 15, at all dose levels, there was fantastic inhibition of 2-HG,” Dr Stein said. “Indeed, this drastic inhibition of 2-HG led to profound clinical benefit.”

He presented interim results of the phase 1 study of AG-221 at the 2014 ASH Annual Meeting (abstract 115).*

The investigators have treated 73 patients with advanced IDH2-mutation-positive hematologic malignancies since the study began in September 2013.

Patients were a median age of 67 years (range, 33-90), and 74% had IDH2 R140 mutations. Most had relapsed/refractory AML (n=55), and the rest had MDS (n=6), untreated AML (n=5), chronic myelomonocytic leukemia (n=5), and myeloid sarcoma (n=1).

Patients received AG-221 as a single agent orally, once or twice a day, continuously, in 28-day cycles. Four dose-expansion cohorts at 100 mg each day were added last October.

To date, the maximum tolerated dose has not been reached, with the highest cumulative daily dose being 300 mg. Investigators observed a single dose-limiting toxicity in 1 patient: grade 5 hypoxia with fungal pneumonia and septic shock.

As of the data cutoff on October 1, 2014, 38 patients were still on therapy, and 35 had discontinued. Five patients withdrew after achieving complete remission (CR) in order to pursue allogeneic transplant.

Dr Stein pointed out that although the median number of prior chemotherapy regimens for the entire cohort was 2, “all of the patients who went on study were predicted to have dismal outcomes with conventional therapy.”

Safety

The therapy was well tolerated, with the most common adverse events (AEs) overall being typical for patients with advanced AML: nausea (23%), pyrexia (19%), and diarrhea (17%).

The majority of serious AEs were disease-related and unrelated to the study drug, Dr Stein said. Thirteen patients experienced 21 serious AEs that were possibly or probably related to treatment.

Investigators observed treatment-related leukocytosis in 3 patients, “but we think that is a differentiating effect of the study drug,” Dr Stein said.

He also pointed out that there was no increase in AEs with increased dose of the drug.

Of the 11 deaths reported, 9 were unrelated to the drug, and 2—sepsis/hypoxia and atrial flutter—were possibly related. The 30-day and 60-day all-cause mortality rates were 4.1% and 13.7%, respectively.

Efficacy

Of the 45 patients who were treated for at least 1 cycle and were evaluable for efficacy, 15 achieved a CR (n=6) or a CR with incomplete blood count recovery. The overall response rate is 56% (25/45).

“Responses appear durable,” Dr Stein commented, “and 90% of responders have had a response duration of at least 3 months, with the earliest patients on study having had durable responses for over 6 months.”

Many of the durable responses are partial remissions, he noted.

Seventeen patients have stable disease, and many of these patients remain on study. Two patients had progressive disease.

“Patients with stable disease have remained on study for a similar amount of time as the responders,” Dr Stein said, “suggesting that, despite the lack of a formal partial remission, many patients are deriving clinical benefit from study treatment.”

This study was sponsored by Agios Pharmaceuticals Inc., the company developing AG-221 in collaboration with Celgene.

Previous results from this study were presented at the 2014 EHA Annual Congress. Based on those results, AG-221 received fast track designation from the US Food and Drug Administration.

*Data in the presentation were updated from the abstract.

ASH attendees gather

in the Moscone Center

SAN FRANCISCO—The first-in-human study of AG-221 has confirmed IDH2 as a therapeutic target in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to investigators.

From the first dose of therapy, the high plasma level observed in patients “translates into a drastic decrease in 2-HG,” said Eytan M. Stein, MD, of Memorial Sloan Kettering Cancer Center in New York.

Mutations in IDH1 and IDH2 result in the accumulation of the oncometabolite 2-HG. And high levels of 2-HG prompt epigenetic changes to the cell, resulting in impaired cellular differentiation.

“By cycle 1, day 15, at all dose levels, there was fantastic inhibition of 2-HG,” Dr Stein said. “Indeed, this drastic inhibition of 2-HG led to profound clinical benefit.”

He presented interim results of the phase 1 study of AG-221 at the 2014 ASH Annual Meeting (abstract 115).*

The investigators have treated 73 patients with advanced IDH2-mutation-positive hematologic malignancies since the study began in September 2013.

Patients were a median age of 67 years (range, 33-90), and 74% had IDH2 R140 mutations. Most had relapsed/refractory AML (n=55), and the rest had MDS (n=6), untreated AML (n=5), chronic myelomonocytic leukemia (n=5), and myeloid sarcoma (n=1).

Patients received AG-221 as a single agent orally, once or twice a day, continuously, in 28-day cycles. Four dose-expansion cohorts at 100 mg each day were added last October.

To date, the maximum tolerated dose has not been reached, with the highest cumulative daily dose being 300 mg. Investigators observed a single dose-limiting toxicity in 1 patient: grade 5 hypoxia with fungal pneumonia and septic shock.

As of the data cutoff on October 1, 2014, 38 patients were still on therapy, and 35 had discontinued. Five patients withdrew after achieving complete remission (CR) in order to pursue allogeneic transplant.

Dr Stein pointed out that although the median number of prior chemotherapy regimens for the entire cohort was 2, “all of the patients who went on study were predicted to have dismal outcomes with conventional therapy.”

Safety

The therapy was well tolerated, with the most common adverse events (AEs) overall being typical for patients with advanced AML: nausea (23%), pyrexia (19%), and diarrhea (17%).

The majority of serious AEs were disease-related and unrelated to the study drug, Dr Stein said. Thirteen patients experienced 21 serious AEs that were possibly or probably related to treatment.

Investigators observed treatment-related leukocytosis in 3 patients, “but we think that is a differentiating effect of the study drug,” Dr Stein said.

He also pointed out that there was no increase in AEs with increased dose of the drug.

Of the 11 deaths reported, 9 were unrelated to the drug, and 2—sepsis/hypoxia and atrial flutter—were possibly related. The 30-day and 60-day all-cause mortality rates were 4.1% and 13.7%, respectively.

Efficacy

Of the 45 patients who were treated for at least 1 cycle and were evaluable for efficacy, 15 achieved a CR (n=6) or a CR with incomplete blood count recovery. The overall response rate is 56% (25/45).

“Responses appear durable,” Dr Stein commented, “and 90% of responders have had a response duration of at least 3 months, with the earliest patients on study having had durable responses for over 6 months.”

Many of the durable responses are partial remissions, he noted.

Seventeen patients have stable disease, and many of these patients remain on study. Two patients had progressive disease.

“Patients with stable disease have remained on study for a similar amount of time as the responders,” Dr Stein said, “suggesting that, despite the lack of a formal partial remission, many patients are deriving clinical benefit from study treatment.”

This study was sponsored by Agios Pharmaceuticals Inc., the company developing AG-221 in collaboration with Celgene.

Previous results from this study were presented at the 2014 EHA Annual Congress. Based on those results, AG-221 received fast track designation from the US Food and Drug Administration.

*Data in the presentation were updated from the abstract.

ASH attendees gather

in the Moscone Center

SAN FRANCISCO—The first-in-human study of AG-221 has confirmed IDH2 as a therapeutic target in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to investigators.

From the first dose of therapy, the high plasma level observed in patients “translates into a drastic decrease in 2-HG,” said Eytan M. Stein, MD, of Memorial Sloan Kettering Cancer Center in New York.

Mutations in IDH1 and IDH2 result in the accumulation of the oncometabolite 2-HG. And high levels of 2-HG prompt epigenetic changes to the cell, resulting in impaired cellular differentiation.

“By cycle 1, day 15, at all dose levels, there was fantastic inhibition of 2-HG,” Dr Stein said. “Indeed, this drastic inhibition of 2-HG led to profound clinical benefit.”

He presented interim results of the phase 1 study of AG-221 at the 2014 ASH Annual Meeting (abstract 115).*

The investigators have treated 73 patients with advanced IDH2-mutation-positive hematologic malignancies since the study began in September 2013.

Patients were a median age of 67 years (range, 33-90), and 74% had IDH2 R140 mutations. Most had relapsed/refractory AML (n=55), and the rest had MDS (n=6), untreated AML (n=5), chronic myelomonocytic leukemia (n=5), and myeloid sarcoma (n=1).

Patients received AG-221 as a single agent orally, once or twice a day, continuously, in 28-day cycles. Four dose-expansion cohorts at 100 mg each day were added last October.

To date, the maximum tolerated dose has not been reached, with the highest cumulative daily dose being 300 mg. Investigators observed a single dose-limiting toxicity in 1 patient: grade 5 hypoxia with fungal pneumonia and septic shock.

As of the data cutoff on October 1, 2014, 38 patients were still on therapy, and 35 had discontinued. Five patients withdrew after achieving complete remission (CR) in order to pursue allogeneic transplant.

Dr Stein pointed out that although the median number of prior chemotherapy regimens for the entire cohort was 2, “all of the patients who went on study were predicted to have dismal outcomes with conventional therapy.”

Safety

The therapy was well tolerated, with the most common adverse events (AEs) overall being typical for patients with advanced AML: nausea (23%), pyrexia (19%), and diarrhea (17%).

The majority of serious AEs were disease-related and unrelated to the study drug, Dr Stein said. Thirteen patients experienced 21 serious AEs that were possibly or probably related to treatment.

Investigators observed treatment-related leukocytosis in 3 patients, “but we think that is a differentiating effect of the study drug,” Dr Stein said.

He also pointed out that there was no increase in AEs with increased dose of the drug.

Of the 11 deaths reported, 9 were unrelated to the drug, and 2—sepsis/hypoxia and atrial flutter—were possibly related. The 30-day and 60-day all-cause mortality rates were 4.1% and 13.7%, respectively.

Efficacy

Of the 45 patients who were treated for at least 1 cycle and were evaluable for efficacy, 15 achieved a CR (n=6) or a CR with incomplete blood count recovery. The overall response rate is 56% (25/45).

“Responses appear durable,” Dr Stein commented, “and 90% of responders have had a response duration of at least 3 months, with the earliest patients on study having had durable responses for over 6 months.”

Many of the durable responses are partial remissions, he noted.

Seventeen patients have stable disease, and many of these patients remain on study. Two patients had progressive disease.

“Patients with stable disease have remained on study for a similar amount of time as the responders,” Dr Stein said, “suggesting that, despite the lack of a formal partial remission, many patients are deriving clinical benefit from study treatment.”

This study was sponsored by Agios Pharmaceuticals Inc., the company developing AG-221 in collaboration with Celgene.

Previous results from this study were presented at the 2014 EHA Annual Congress. Based on those results, AG-221 received fast track designation from the US Food and Drug Administration.

*Data in the presentation were updated from the abstract.

AML in the bone marrow

Researchers say they’ve identified novel prognostic markers for older patients with cytogenetically normal acute myeloid leukemia (CN-AML).

The team examined the expression of long noncoding RNAs (lncRNAs) in patients with CN-AML who were at least 60 years of age.

This revealed a pattern of 48 lncRNAs that predicted both response to standard chemotherapy and overall survival.

The researchers described this discovery in PNAS.

“[Our findings] strongly suggest that lncRNA expression profiles can predict which patients will respond to standard therapy,” said principal investigator Clara D. Bloomfield, MD, of The Ohio State University Comprehensive Cancer Center in Columbus.

“That’s important because it would spare these patients from the toxic side effects of experimental therapies. Patients who are classified in the unfavorable group would receive different therapy: stem cell transplant or a clinical trial using new therapeutic approaches. Thus, this research will help to tailor leukemia therapy to each individual.”

In addition, she said, the study revealed novel targets for the development of new therapies.

Dr Bloomfield and her colleagues began this research by analyzing bone marrow samples from 148 older patients with CN-AML who were treated on Cancer and Leukemia Group B clinical trials. All had received similar chemotherapy regimens.

The researchers first identified the 48 lncRNAs that were most associated with survival. Using these 48 lncRNAs, the team divided patients into two groups: those with a favorable prognostic score and those with an unfavorable score.

The researchers then validated the scores in an independent matched set of 71 similarly treated CN-AML patients and compared patients with an unfavorable score to those with a favorable score.

Results showed that patients with an unfavorable score had a lower complete response (CR) rate—54%, compared to 89% for patients with a favorable score.

Three years after CR, only 7% of patients with an unfavorable score were disease-free, compared with 39% of patients with a favorable score.

Overall survival at 3 years for those with an unfavorable score was 10%, compared to 43% for patients with a favorable score.

Distinct lncRNA profiles were associated with mutations in 6 genes—FLT3, NPM1, CEBPA, IDH2, ASXL1, and RUNX1.

The researchers concluded that lncRNA expression profiles are associated with recurrent mutations, clinical features, and outcome in AML. A fraction of these lncRNAs may have a functional role in leukemogenesis. Furthermore, lncRNAs could be used as biomarkers for outcome in AML.

AML in the bone marrow

Researchers say they’ve identified novel prognostic markers for older patients with cytogenetically normal acute myeloid leukemia (CN-AML).

The team examined the expression of long noncoding RNAs (lncRNAs) in patients with CN-AML who were at least 60 years of age.

This revealed a pattern of 48 lncRNAs that predicted both response to standard chemotherapy and overall survival.

The researchers described this discovery in PNAS.

“[Our findings] strongly suggest that lncRNA expression profiles can predict which patients will respond to standard therapy,” said principal investigator Clara D. Bloomfield, MD, of The Ohio State University Comprehensive Cancer Center in Columbus.

“That’s important because it would spare these patients from the toxic side effects of experimental therapies. Patients who are classified in the unfavorable group would receive different therapy: stem cell transplant or a clinical trial using new therapeutic approaches. Thus, this research will help to tailor leukemia therapy to each individual.”

In addition, she said, the study revealed novel targets for the development of new therapies.

Dr Bloomfield and her colleagues began this research by analyzing bone marrow samples from 148 older patients with CN-AML who were treated on Cancer and Leukemia Group B clinical trials. All had received similar chemotherapy regimens.

The researchers first identified the 48 lncRNAs that were most associated with survival. Using these 48 lncRNAs, the team divided patients into two groups: those with a favorable prognostic score and those with an unfavorable score.

The researchers then validated the scores in an independent matched set of 71 similarly treated CN-AML patients and compared patients with an unfavorable score to those with a favorable score.

Results showed that patients with an unfavorable score had a lower complete response (CR) rate—54%, compared to 89% for patients with a favorable score.

Three years after CR, only 7% of patients with an unfavorable score were disease-free, compared with 39% of patients with a favorable score.

Overall survival at 3 years for those with an unfavorable score was 10%, compared to 43% for patients with a favorable score.

Distinct lncRNA profiles were associated with mutations in 6 genes—FLT3, NPM1, CEBPA, IDH2, ASXL1, and RUNX1.

The researchers concluded that lncRNA expression profiles are associated with recurrent mutations, clinical features, and outcome in AML. A fraction of these lncRNAs may have a functional role in leukemogenesis. Furthermore, lncRNAs could be used as biomarkers for outcome in AML.

AML in the bone marrow

Researchers say they’ve identified novel prognostic markers for older patients with cytogenetically normal acute myeloid leukemia (CN-AML).

The team examined the expression of long noncoding RNAs (lncRNAs) in patients with CN-AML who were at least 60 years of age.

This revealed a pattern of 48 lncRNAs that predicted both response to standard chemotherapy and overall survival.

The researchers described this discovery in PNAS.

“[Our findings] strongly suggest that lncRNA expression profiles can predict which patients will respond to standard therapy,” said principal investigator Clara D. Bloomfield, MD, of The Ohio State University Comprehensive Cancer Center in Columbus.

“That’s important because it would spare these patients from the toxic side effects of experimental therapies. Patients who are classified in the unfavorable group would receive different therapy: stem cell transplant or a clinical trial using new therapeutic approaches. Thus, this research will help to tailor leukemia therapy to each individual.”

In addition, she said, the study revealed novel targets for the development of new therapies.

Dr Bloomfield and her colleagues began this research by analyzing bone marrow samples from 148 older patients with CN-AML who were treated on Cancer and Leukemia Group B clinical trials. All had received similar chemotherapy regimens.

The researchers first identified the 48 lncRNAs that were most associated with survival. Using these 48 lncRNAs, the team divided patients into two groups: those with a favorable prognostic score and those with an unfavorable score.

The researchers then validated the scores in an independent matched set of 71 similarly treated CN-AML patients and compared patients with an unfavorable score to those with a favorable score.

Results showed that patients with an unfavorable score had a lower complete response (CR) rate—54%, compared to 89% for patients with a favorable score.

Three years after CR, only 7% of patients with an unfavorable score were disease-free, compared with 39% of patients with a favorable score.

Overall survival at 3 years for those with an unfavorable score was 10%, compared to 43% for patients with a favorable score.

Distinct lncRNA profiles were associated with mutations in 6 genes—FLT3, NPM1, CEBPA, IDH2, ASXL1, and RUNX1.

The researchers concluded that lncRNA expression profiles are associated with recurrent mutations, clinical features, and outcome in AML. A fraction of these lncRNAs may have a functional role in leukemogenesis. Furthermore, lncRNAs could be used as biomarkers for outcome in AML.

Nicola Gökbuget, MD, PhD

SAN FRANCISCO—The first international, multicenter trial in acute lymphoblastic leukemia (ALL) using minimal residual disease (MRD) as a criterion for inclusion has confirmed clinical benefit for patients using a non-chemotherapeutic approach.

In the BLAST trial, blinatumomab, a bispecific T-cell engager antibody that directs cytotoxic T cells to CD19-positive cells, produced a complete MRD response in 80% of patients who were in complete hematologic remission but had quantifiable MRD at the time of treatment.

This echoes results of an earlier phase 2 study, in which blinatumomab produced an 80% MRD response rate in 20 patients with B-precursor ALL and persistent or relapsed MRD.

Nearly all patients with persistent or recurrent MRD relapse despite continued chemotherapy, according to Nicola Gökbuget, MD, PhD, of Goethe University Hospital in Frankfurt, Germany.

“The question,” she said, “is how to treat these patients.”

She presented one effective method, as shown by the BLAST trial, at the 2014 ASH Annual Meeting (abstract 379).

The trial enrolled 116 patients aged 18 or older with B-precursor ALL in complete hematologic remission but with MRD ≥ 10^-3.

Patients could be in second or later remission, but they were excluded if they had a prior allogeneic stem cell transplant, circulating blasts or extra medullary ALL involvement, CNS pathology, prior chemotherapy within 2 weeks, or radiotherapy within 4 weeks.

Enrolled patients were a median age of 45 years (range, 18-76), and 34% were 65 or older. Most patients had high baseline MRD levels: 39% were ≥ 10^-2 to < 10^-1, and 45% were ≥ 10^-3 to < 10^-2.

Investigators evaluated MRD levels after each cycle. Analysis was performed in a central lab in Kiel, Germany, and was based on amplification of immunoglobulin and/or T-cell receptor gene rearrangements by PCR.

The primary endpoint was the proportion of patients achieving a complete MRD response after 1 cycle of blinatumomab.

Patients received 15 μg/m² of blinatumomab per day by continuous intravenous infusion for 4 weeks, followed by a treatment-free period of 2 weeks. Responders could receive up to 4 cycles of therapy or receive a transplant any time after the first cycle.

Results

In the efficacy-evaluable population, 80% of 103 patients achieved a complete MRD response after 1 cycle, defined as MRD negative with no amplification in PCR with a minimum sensitivity of 10^-4. And 85% achieved an incomplete MRD response of <10^-4 with a minimum sensitivity of 10^-4.

Results were similar in the full analysis set of 113 patients: 78% achieved complete MRD response after 1 cycle, and 85% achieved an incomplete MRD response.

Dr Gökbuget noted that 2 patients who initially achieved an incomplete response achieved a complete response during continued treatment in cycle 2.

The investigators analyzed the clinical characteristics of the patients and found that no factor—age, treatment interruptions, neurologic events, relapse history, nor gender—correlated with MRD response.

“I think that the good news is that it means that the compound was active in all of the patients,” Dr Gökbuget commented.

Adverse events

All patients experienced at least one adverse event (AE), and 2 were fatal—subdural hemorrhage and treatment-related pneumonitis. Serious treatment-related AEs that occurred in 3% or more of the

patients included tremor (7%), aphasia (5%), and encephalopathy (5%).

Thirty-one percent of patients interrupted their treatment because of AEs, which were primarily due to cytokine-related symptoms like pyrexia and neurologic events, including tremor, aphasia, and dizziness. Seventeen percent of patients permanently discontinued treatment due to an AE.

However, Dr Gökbuget pointed out that most AEs were grade 1 or 2, and the treatment interruption did not correlate with response.

She said the next step for this trial is to investigate whether high MRD response translates into long-term clinical benefit such as continued molecular remission and long-term survival.

“For me personally, this trial is very important because it is an up-to-date trial where we used PCR-based methods to identify patients with a high risk of relapse and treat them before the relapse occurs,” Dr Gökbuget said. “[W]e used a new endpoint, which is also MRD based, and . . . we used a new, non-chemotherapy treatment to eradicate this highly resistant, persistent ALL subclone.”

Blinatumomab received US Food and Drug Administration approval a few days before the start of the ASH Annual Meeting.

The BLAST trial was funded by Amgen Inc., the company developing blinatumomab.

Nicola Gökbuget, MD, PhD

SAN FRANCISCO—The first international, multicenter trial in acute lymphoblastic leukemia (ALL) using minimal residual disease (MRD) as a criterion for inclusion has confirmed clinical benefit for patients using a non-chemotherapeutic approach.

In the BLAST trial, blinatumomab, a bispecific T-cell engager antibody that directs cytotoxic T cells to CD19-positive cells, produced a complete MRD response in 80% of patients who were in complete hematologic remission but had quantifiable MRD at the time of treatment.

This echoes results of an earlier phase 2 study, in which blinatumomab produced an 80% MRD response rate in 20 patients with B-precursor ALL and persistent or relapsed MRD.

Nearly all patients with persistent or recurrent MRD relapse despite continued chemotherapy, according to Nicola Gökbuget, MD, PhD, of Goethe University Hospital in Frankfurt, Germany.

“The question,” she said, “is how to treat these patients.”

She presented one effective method, as shown by the BLAST trial, at the 2014 ASH Annual Meeting (abstract 379).

The trial enrolled 116 patients aged 18 or older with B-precursor ALL in complete hematologic remission but with MRD ≥ 10^-3.

Patients could be in second or later remission, but they were excluded if they had a prior allogeneic stem cell transplant, circulating blasts or extra medullary ALL involvement, CNS pathology, prior chemotherapy within 2 weeks, or radiotherapy within 4 weeks.

Enrolled patients were a median age of 45 years (range, 18-76), and 34% were 65 or older. Most patients had high baseline MRD levels: 39% were ≥ 10^-2 to < 10^-1, and 45% were ≥ 10^-3 to < 10^-2.

Investigators evaluated MRD levels after each cycle. Analysis was performed in a central lab in Kiel, Germany, and was based on amplification of immunoglobulin and/or T-cell receptor gene rearrangements by PCR.

The primary endpoint was the proportion of patients achieving a complete MRD response after 1 cycle of blinatumomab.

Patients received 15 μg/m² of blinatumomab per day by continuous intravenous infusion for 4 weeks, followed by a treatment-free period of 2 weeks. Responders could receive up to 4 cycles of therapy or receive a transplant any time after the first cycle.

Results

In the efficacy-evaluable population, 80% of 103 patients achieved a complete MRD response after 1 cycle, defined as MRD negative with no amplification in PCR with a minimum sensitivity of 10^-4. And 85% achieved an incomplete MRD response of <10^-4 with a minimum sensitivity of 10^-4.

Results were similar in the full analysis set of 113 patients: 78% achieved complete MRD response after 1 cycle, and 85% achieved an incomplete MRD response.

Dr Gökbuget noted that 2 patients who initially achieved an incomplete response achieved a complete response during continued treatment in cycle 2.

The investigators analyzed the clinical characteristics of the patients and found that no factor—age, treatment interruptions, neurologic events, relapse history, nor gender—correlated with MRD response.

“I think that the good news is that it means that the compound was active in all of the patients,” Dr Gökbuget commented.

Adverse events

All patients experienced at least one adverse event (AE), and 2 were fatal—subdural hemorrhage and treatment-related pneumonitis. Serious treatment-related AEs that occurred in 3% or more of the

patients included tremor (7%), aphasia (5%), and encephalopathy (5%).

Thirty-one percent of patients interrupted their treatment because of AEs, which were primarily due to cytokine-related symptoms like pyrexia and neurologic events, including tremor, aphasia, and dizziness. Seventeen percent of patients permanently discontinued treatment due to an AE.

However, Dr Gökbuget pointed out that most AEs were grade 1 or 2, and the treatment interruption did not correlate with response.

She said the next step for this trial is to investigate whether high MRD response translates into long-term clinical benefit such as continued molecular remission and long-term survival.

“For me personally, this trial is very important because it is an up-to-date trial where we used PCR-based methods to identify patients with a high risk of relapse and treat them before the relapse occurs,” Dr Gökbuget said. “[W]e used a new endpoint, which is also MRD based, and . . . we used a new, non-chemotherapy treatment to eradicate this highly resistant, persistent ALL subclone.”

Blinatumomab received US Food and Drug Administration approval a few days before the start of the ASH Annual Meeting.

The BLAST trial was funded by Amgen Inc., the company developing blinatumomab.

Nicola Gökbuget, MD, PhD

SAN FRANCISCO—The first international, multicenter trial in acute lymphoblastic leukemia (ALL) using minimal residual disease (MRD) as a criterion for inclusion has confirmed clinical benefit for patients using a non-chemotherapeutic approach.

In the BLAST trial, blinatumomab, a bispecific T-cell engager antibody that directs cytotoxic T cells to CD19-positive cells, produced a complete MRD response in 80% of patients who were in complete hematologic remission but had quantifiable MRD at the time of treatment.

This echoes results of an earlier phase 2 study, in which blinatumomab produced an 80% MRD response rate in 20 patients with B-precursor ALL and persistent or relapsed MRD.

Nearly all patients with persistent or recurrent MRD relapse despite continued chemotherapy, according to Nicola Gökbuget, MD, PhD, of Goethe University Hospital in Frankfurt, Germany.

“The question,” she said, “is how to treat these patients.”

She presented one effective method, as shown by the BLAST trial, at the 2014 ASH Annual Meeting (abstract 379).

The trial enrolled 116 patients aged 18 or older with B-precursor ALL in complete hematologic remission but with MRD ≥ 10^-3.

Patients could be in second or later remission, but they were excluded if they had a prior allogeneic stem cell transplant, circulating blasts or extra medullary ALL involvement, CNS pathology, prior chemotherapy within 2 weeks, or radiotherapy within 4 weeks.

Enrolled patients were a median age of 45 years (range, 18-76), and 34% were 65 or older. Most patients had high baseline MRD levels: 39% were ≥ 10^-2 to < 10^-1, and 45% were ≥ 10^-3 to < 10^-2.

Investigators evaluated MRD levels after each cycle. Analysis was performed in a central lab in Kiel, Germany, and was based on amplification of immunoglobulin and/or T-cell receptor gene rearrangements by PCR.

The primary endpoint was the proportion of patients achieving a complete MRD response after 1 cycle of blinatumomab.

Patients received 15 μg/m² of blinatumomab per day by continuous intravenous infusion for 4 weeks, followed by a treatment-free period of 2 weeks. Responders could receive up to 4 cycles of therapy or receive a transplant any time after the first cycle.

Results

In the efficacy-evaluable population, 80% of 103 patients achieved a complete MRD response after 1 cycle, defined as MRD negative with no amplification in PCR with a minimum sensitivity of 10^-4. And 85% achieved an incomplete MRD response of <10^-4 with a minimum sensitivity of 10^-4.

Results were similar in the full analysis set of 113 patients: 78% achieved complete MRD response after 1 cycle, and 85% achieved an incomplete MRD response.

Dr Gökbuget noted that 2 patients who initially achieved an incomplete response achieved a complete response during continued treatment in cycle 2.

The investigators analyzed the clinical characteristics of the patients and found that no factor—age, treatment interruptions, neurologic events, relapse history, nor gender—correlated with MRD response.

“I think that the good news is that it means that the compound was active in all of the patients,” Dr Gökbuget commented.

Adverse events

All patients experienced at least one adverse event (AE), and 2 were fatal—subdural hemorrhage and treatment-related pneumonitis. Serious treatment-related AEs that occurred in 3% or more of the

patients included tremor (7%), aphasia (5%), and encephalopathy (5%).

Thirty-one percent of patients interrupted their treatment because of AEs, which were primarily due to cytokine-related symptoms like pyrexia and neurologic events, including tremor, aphasia, and dizziness. Seventeen percent of patients permanently discontinued treatment due to an AE.

However, Dr Gökbuget pointed out that most AEs were grade 1 or 2, and the treatment interruption did not correlate with response.

She said the next step for this trial is to investigate whether high MRD response translates into long-term clinical benefit such as continued molecular remission and long-term survival.

“For me personally, this trial is very important because it is an up-to-date trial where we used PCR-based methods to identify patients with a high risk of relapse and treat them before the relapse occurs,” Dr Gökbuget said. “[W]e used a new endpoint, which is also MRD based, and . . . we used a new, non-chemotherapy treatment to eradicate this highly resistant, persistent ALL subclone.”

Blinatumomab received US Food and Drug Administration approval a few days before the start of the ASH Annual Meeting.

The BLAST trial was funded by Amgen Inc., the company developing blinatumomab.

SAN FRANCISCO—Two goals for cell therapy with chimeric antigen receptor (CAR) T cells are significant levels of in vivo proliferation and persistence after the cells are infused.

Researchers at the University of Pennsylvania, working with CTL019 cells, are beginning to see both of these phenomena in children with relapsed, refractory acute lymphoblastic leukemia (ALL).

Stephan Grupp, MD, PhD, described these results at the 2014 ASH Annual Meeting (abstract 380).*

CTL019 is a second-generation chimeric protein engineered using a single-chain variable fragment of an antibody that targets CD19 on B cells. It is combined with the intracellular signaling domains 4-1BB and CD3 zeta and expanded ex vivo with anti-CD3/anti-CD28.

“We take T cells from the patient—this is an individualized or personalized product,” Dr Grupp explained. “We transfect the T cells with a virus, and, in our case, we are using a lentiviral vector. This permanently modifies the T cells.”

“And this allows the expression of the CAR protein in the T cells, which then drives the interaction between the T cell and the cancer cell, hopefully killing the cancer cell but also, and I think this is extraordinarily important, allowing for T-cell activation and significant proliferation.”

More than 130 patients have been treated with CTL019, including patients with CLL whose results were reported at the 2014 ASCO Annual Meeting.

Updated results

At ASH, Dr Grupp provided an update on the 39 children with relapsed, refractory ALL treated with CTL019.  He and his colleagues previously reported results in children and adults with ALL in NEJM.

Thirty-six patients (92%) achieved complete remission within a month after infusion. Ten patients relapsed, of whom 5 were CD19⁺ and 5 were CD19^-.

Dr Grupp explained that CD19⁺ relapses represent waning T cells, and CD19^- relapses represent true antigen escape. The latter patients still have CTL019 cells.

Patients were followed for a median of 6 months, ranging from 6 weeks to 31 months. And 15 patients have been followed for more than 1 year.

The patient followed for 31 months “represents the first patient treated who remains in remission with no further therapy,” Dr Grupp said.

Three patients went on to have a stem cell transplant, and 2 had other treatments. One patient had a donor-lymphocyte infusion, and 1 patient who developed myelodysplastic syndrome received treatment for that condition.

“And I think this is a key point,” Dr Grupp noted. “[I]t was a possibility to consider not continuing with a second, third, or, in one case, a fourth transplant.”

Another important point is disease burden, he said. Patients with more than 50% bone marrow blasts at the time of their T-cell infusion had a similar response rate (82%) to those patients who had a lower disease burden of 5% blasts or more (88%). Relapse occurred in all levels of disease burden in a small number of patients.

To date, there has been no graft-vs-host disease.

In terms of efficacy, there appeared to be no significant difference if the patient had received a transplant before CAR therapy or not. Eighty-nine percent of patients who had received an allogeneic transplant responded, compared to 100% who had not had a transplant.

Persistence and proliferation

“Q-PCR detection of CAR cells shows enormous proliferation,” Dr Grupp said. “We have an extraordinary amount of expansion of these cells that’s nearly universal.”

Specifically, the researchers saw 100,000- to 110,000-fold expansions of CAR-positive cells.

Two-thirds of patients have circulating CAR cells 6 months out from their CTL019 infusion. And a group of patients have kept their CAR cells for longer than 12 months. In the group that loses their cells more quickly, CD19⁺ recurrence is overrepresented, Dr Grupp noted.

Event-free survival is 70% at 6 months, and 76% of patients had a 6-month duration of response.

Toxicity

Cytokine release syndrome (CRS) is a “significant toxicity,” Dr Grupp said, but investigators are beginning to understand some correlates that impact treatment.

Patients with extraordinary levels of the cytokine interleukin-6 (IL-6)—those who require blood pressure or respiratory support—have significantly more severe CRS than those with lower IL-6 levels (P<0.001). Responding patients have high IL-6 levels as well, but patients with severe CRS have very high levels.

The effector cytokine IFNγ, which may be required for the T-cell response, is also elevated in patients with severe CRS compared to those without CRS (P<0.001).

“The thing that I think we’ve really learned from these patients is the impact of disease burden,” Dr Grupp said.

Patients with high disease burden—those with more than 50% bone marrow blasts—have a high likelihood of developing severe CRS. Patients with less burden—fewer than 50% blasts—have a low likelihood.

Dr Grupp pointed out that only 2 patients with more than 50% blasts did not have severe CRS, and they did not respond to therapy.

“This is highly significant and quite predictive for our patients,” he said, adding that CRS is quite controllable via IL-6 blockade with tocilizumab.

B-cell aplasia is “inevitable” as long as these patients have their CAR T cells, Dr Grupp noted. Patients require IVIg replacement therapy for the entire period.

Macrophage activation syndrome, the flip side of CRS, is also a concern, and neurotoxicity, consisting of confusion and aphasia, occurred in a small number of patients and required no therapy.

Given these results, the investigators believe that CTL019 cells may be able to provide long-term response without subsequent therapy.

CTL019 recently received breakthrough therapy designation from the US Food and Drug Administration.

CTL019 was invented at The University of Pennsylvania but has been licensed to Novartis. Several researchers involved in this study reported research funding and/or consultancy payments from Novartis, and 2 researchers are employed by the company.

*Data in the presentation differ from the abstract.

SAN FRANCISCO—Two goals for cell therapy with chimeric antigen receptor (CAR) T cells are significant levels of in vivo proliferation and persistence after the cells are infused.

Researchers at the University of Pennsylvania, working with CTL019 cells, are beginning to see both of these phenomena in children with relapsed, refractory acute lymphoblastic leukemia (ALL).

Stephan Grupp, MD, PhD, described these results at the 2014 ASH Annual Meeting (abstract 380).*

CTL019 is a second-generation chimeric protein engineered using a single-chain variable fragment of an antibody that targets CD19 on B cells. It is combined with the intracellular signaling domains 4-1BB and CD3 zeta and expanded ex vivo with anti-CD3/anti-CD28.

“We take T cells from the patient—this is an individualized or personalized product,” Dr Grupp explained. “We transfect the T cells with a virus, and, in our case, we are using a lentiviral vector. This permanently modifies the T cells.”

“And this allows the expression of the CAR protein in the T cells, which then drives the interaction between the T cell and the cancer cell, hopefully killing the cancer cell but also, and I think this is extraordinarily important, allowing for T-cell activation and significant proliferation.”

More than 130 patients have been treated with CTL019, including patients with CLL whose results were reported at the 2014 ASCO Annual Meeting.

Updated results

At ASH, Dr Grupp provided an update on the 39 children with relapsed, refractory ALL treated with CTL019.  He and his colleagues previously reported results in children and adults with ALL in NEJM.

Thirty-six patients (92%) achieved complete remission within a month after infusion. Ten patients relapsed, of whom 5 were CD19⁺ and 5 were CD19^-.

Dr Grupp explained that CD19⁺ relapses represent waning T cells, and CD19^- relapses represent true antigen escape. The latter patients still have CTL019 cells.

Patients were followed for a median of 6 months, ranging from 6 weeks to 31 months. And 15 patients have been followed for more than 1 year.

The patient followed for 31 months “represents the first patient treated who remains in remission with no further therapy,” Dr Grupp said.

Three patients went on to have a stem cell transplant, and 2 had other treatments. One patient had a donor-lymphocyte infusion, and 1 patient who developed myelodysplastic syndrome received treatment for that condition.

“And I think this is a key point,” Dr Grupp noted. “[I]t was a possibility to consider not continuing with a second, third, or, in one case, a fourth transplant.”

Another important point is disease burden, he said. Patients with more than 50% bone marrow blasts at the time of their T-cell infusion had a similar response rate (82%) to those patients who had a lower disease burden of 5% blasts or more (88%). Relapse occurred in all levels of disease burden in a small number of patients.

To date, there has been no graft-vs-host disease.

In terms of efficacy, there appeared to be no significant difference if the patient had received a transplant before CAR therapy or not. Eighty-nine percent of patients who had received an allogeneic transplant responded, compared to 100% who had not had a transplant.

Persistence and proliferation

“Q-PCR detection of CAR cells shows enormous proliferation,” Dr Grupp said. “We have an extraordinary amount of expansion of these cells that’s nearly universal.”

Specifically, the researchers saw 100,000- to 110,000-fold expansions of CAR-positive cells.

Two-thirds of patients have circulating CAR cells 6 months out from their CTL019 infusion. And a group of patients have kept their CAR cells for longer than 12 months. In the group that loses their cells more quickly, CD19⁺ recurrence is overrepresented, Dr Grupp noted.

Event-free survival is 70% at 6 months, and 76% of patients had a 6-month duration of response.

Toxicity

Cytokine release syndrome (CRS) is a “significant toxicity,” Dr Grupp said, but investigators are beginning to understand some correlates that impact treatment.

Patients with extraordinary levels of the cytokine interleukin-6 (IL-6)—those who require blood pressure or respiratory support—have significantly more severe CRS than those with lower IL-6 levels (P<0.001). Responding patients have high IL-6 levels as well, but patients with severe CRS have very high levels.

The effector cytokine IFNγ, which may be required for the T-cell response, is also elevated in patients with severe CRS compared to those without CRS (P<0.001).

“The thing that I think we’ve really learned from these patients is the impact of disease burden,” Dr Grupp said.

Patients with high disease burden—those with more than 50% bone marrow blasts—have a high likelihood of developing severe CRS. Patients with less burden—fewer than 50% blasts—have a low likelihood.

Dr Grupp pointed out that only 2 patients with more than 50% blasts did not have severe CRS, and they did not respond to therapy.

“This is highly significant and quite predictive for our patients,” he said, adding that CRS is quite controllable via IL-6 blockade with tocilizumab.

B-cell aplasia is “inevitable” as long as these patients have their CAR T cells, Dr Grupp noted. Patients require IVIg replacement therapy for the entire period.

Macrophage activation syndrome, the flip side of CRS, is also a concern, and neurotoxicity, consisting of confusion and aphasia, occurred in a small number of patients and required no therapy.

Given these results, the investigators believe that CTL019 cells may be able to provide long-term response without subsequent therapy.

CTL019 recently received breakthrough therapy designation from the US Food and Drug Administration.

CTL019 was invented at The University of Pennsylvania but has been licensed to Novartis. Several researchers involved in this study reported research funding and/or consultancy payments from Novartis, and 2 researchers are employed by the company.

*Data in the presentation differ from the abstract.

SAN FRANCISCO—Two goals for cell therapy with chimeric antigen receptor (CAR) T cells are significant levels of in vivo proliferation and persistence after the cells are infused.

Researchers at the University of Pennsylvania, working with CTL019 cells, are beginning to see both of these phenomena in children with relapsed, refractory acute lymphoblastic leukemia (ALL).

Stephan Grupp, MD, PhD, described these results at the 2014 ASH Annual Meeting (abstract 380).*

CTL019 is a second-generation chimeric protein engineered using a single-chain variable fragment of an antibody that targets CD19 on B cells. It is combined with the intracellular signaling domains 4-1BB and CD3 zeta and expanded ex vivo with anti-CD3/anti-CD28.

“We take T cells from the patient—this is an individualized or personalized product,” Dr Grupp explained. “We transfect the T cells with a virus, and, in our case, we are using a lentiviral vector. This permanently modifies the T cells.”

“And this allows the expression of the CAR protein in the T cells, which then drives the interaction between the T cell and the cancer cell, hopefully killing the cancer cell but also, and I think this is extraordinarily important, allowing for T-cell activation and significant proliferation.”

More than 130 patients have been treated with CTL019, including patients with CLL whose results were reported at the 2014 ASCO Annual Meeting.

Updated results

At ASH, Dr Grupp provided an update on the 39 children with relapsed, refractory ALL treated with CTL019.  He and his colleagues previously reported results in children and adults with ALL in NEJM.

Thirty-six patients (92%) achieved complete remission within a month after infusion. Ten patients relapsed, of whom 5 were CD19⁺ and 5 were CD19^-.

Dr Grupp explained that CD19⁺ relapses represent waning T cells, and CD19^- relapses represent true antigen escape. The latter patients still have CTL019 cells.

Patients were followed for a median of 6 months, ranging from 6 weeks to 31 months. And 15 patients have been followed for more than 1 year.

The patient followed for 31 months “represents the first patient treated who remains in remission with no further therapy,” Dr Grupp said.

Three patients went on to have a stem cell transplant, and 2 had other treatments. One patient had a donor-lymphocyte infusion, and 1 patient who developed myelodysplastic syndrome received treatment for that condition.

“And I think this is a key point,” Dr Grupp noted. “[I]t was a possibility to consider not continuing with a second, third, or, in one case, a fourth transplant.”

Another important point is disease burden, he said. Patients with more than 50% bone marrow blasts at the time of their T-cell infusion had a similar response rate (82%) to those patients who had a lower disease burden of 5% blasts or more (88%). Relapse occurred in all levels of disease burden in a small number of patients.

To date, there has been no graft-vs-host disease.

In terms of efficacy, there appeared to be no significant difference if the patient had received a transplant before CAR therapy or not. Eighty-nine percent of patients who had received an allogeneic transplant responded, compared to 100% who had not had a transplant.

Persistence and proliferation

“Q-PCR detection of CAR cells shows enormous proliferation,” Dr Grupp said. “We have an extraordinary amount of expansion of these cells that’s nearly universal.”

Specifically, the researchers saw 100,000- to 110,000-fold expansions of CAR-positive cells.

Two-thirds of patients have circulating CAR cells 6 months out from their CTL019 infusion. And a group of patients have kept their CAR cells for longer than 12 months. In the group that loses their cells more quickly, CD19⁺ recurrence is overrepresented, Dr Grupp noted.

Event-free survival is 70% at 6 months, and 76% of patients had a 6-month duration of response.

Toxicity

Cytokine release syndrome (CRS) is a “significant toxicity,” Dr Grupp said, but investigators are beginning to understand some correlates that impact treatment.

Patients with extraordinary levels of the cytokine interleukin-6 (IL-6)—those who require blood pressure or respiratory support—have significantly more severe CRS than those with lower IL-6 levels (P<0.001). Responding patients have high IL-6 levels as well, but patients with severe CRS have very high levels.

The effector cytokine IFNγ, which may be required for the T-cell response, is also elevated in patients with severe CRS compared to those without CRS (P<0.001).

“The thing that I think we’ve really learned from these patients is the impact of disease burden,” Dr Grupp said.

Patients with high disease burden—those with more than 50% bone marrow blasts—have a high likelihood of developing severe CRS. Patients with less burden—fewer than 50% blasts—have a low likelihood.

Dr Grupp pointed out that only 2 patients with more than 50% blasts did not have severe CRS, and they did not respond to therapy.

“This is highly significant and quite predictive for our patients,” he said, adding that CRS is quite controllable via IL-6 blockade with tocilizumab.

B-cell aplasia is “inevitable” as long as these patients have their CAR T cells, Dr Grupp noted. Patients require IVIg replacement therapy for the entire period.

Macrophage activation syndrome, the flip side of CRS, is also a concern, and neurotoxicity, consisting of confusion and aphasia, occurred in a small number of patients and required no therapy.

Given these results, the investigators believe that CTL019 cells may be able to provide long-term response without subsequent therapy.

CTL019 recently received breakthrough therapy designation from the US Food and Drug Administration.

CTL019 was invented at The University of Pennsylvania but has been licensed to Novartis. Several researchers involved in this study reported research funding and/or consultancy payments from Novartis, and 2 researchers are employed by the company.

*Data in the presentation differ from the abstract.

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—Iron chelation therapy significantly improves survival for patients with lower-risk myelodysplastic syndrome (MDS) and delays the progression to acute myeloid leukemia (AML), a new study suggests.

“There is a signal for survival with an impressive difference with chelation therapy,” said study investigator Roger Lyons, MD, of Cancer Care Centers of South Texas in San Antonio.

“If this is real, then everyone with lower-risk MDS will go on chelation therapy upfront.”

Dr Lyons presented the results of this research at the 2014 ASH Annual Meeting (abstract 1350).

He and his colleagues initiated a US registry to collect prospective data on clinical outcomes of patients with lower-risk MDS who received chelation or non-chelation therapy.

The registry enrolled 599 adult patients, with a median age of 76 years, from 107 US centers. The patients had transfusional iron overload with serum ferritin ≥ 1000 µg/L and/or ≥ 20 packed red blood cell units and/or ≥ 6 units every 12 weeks.

Patients were divided into 2 groups: those who had never been chelated and those who had used iron chelation. The researchers also looked at a subgroup of patients: those who received chelation therapy for 6 months or more.

The team evaluated patients every 5 months for 5 years or until death, assessing patient characteristics, survival, disease status, comorbidities, cause of death, and MDS therapy.

At enrollment, the 271 chelated patients had a greater median number of lifetime units transfused compared to the 328 non-chelated patients. Additionally, fewer patients receiving chelation therapy had cardiac, vascular, or endocrine concomitant conditions.

Of the chelated patients, 187 (69%) were chelated with deferasirox, 40 (14.8%) with deferasirox and deferoxamine, and 32 (11.8%) with deferoxamine. For 12 patients (4.5%), the researchers did not know which chelator was used.

The cumulative duration of chelation was 18.9 months in patients who had ever used iron chelation and 27 months in patients with at least 6 months of iron chelation.

Patient outcomes

“From the date of diagnosis, the overall survival for patients receiving chelation therapy was significantly longer than for patients receiving non-chelation therapy, including those with cardiovascular or endocrine concomitant conditions,” Dr Lyons noted.

However, there was a potential clinical bias in patient selection, since patients with longer predicted survival may have been chosen for chelation therapy.

At 5 years of follow-up, the mortality rate was 72.9% for non-chelated patients and 59.4% for patients who received chelation therapy (P=0.0005).

Among patients chelated for 6 months or more, the mortality rate was 56.9% (P=0.0002, compared to non-chelated patients). The most common causes of death were MDS/AML and cardiac conditions.

The time from MDS diagnosis to AML progression was significantly longer for chelated patients than for non-chelated patients—72.1 months and 46.4 months, respectively (P<0.0001).

Among patients chelated for 6 months or more, the time to AML transformation was 78.8 months (P<0.0001, compared to non-chelated patients).

Twice as many patients developed AML in the non-chelation group (n=34, 10.4%) than in the chelation group (n=17, 6.3%). However, this difference was not statistically significant.

Taken together, these results suggest chelation can benefit patients with lower-risk MDS, according to Dr Lyons and his colleagues.

“If you think a lower-risk MDS patient will live 1 or 2 years or is a candidate for transplant, get the patient’s iron levels down by chelation, if possible,” Dr Lyons advised.

Three researchers involved in this study are employed by Novartis, and 1 reported research funding from the company, which manufactures deferasirox (Exjade).

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—Iron chelation therapy significantly improves survival for patients with lower-risk myelodysplastic syndrome (MDS) and delays the progression to acute myeloid leukemia (AML), a new study suggests.

“There is a signal for survival with an impressive difference with chelation therapy,” said study investigator Roger Lyons, MD, of Cancer Care Centers of South Texas in San Antonio.

“If this is real, then everyone with lower-risk MDS will go on chelation therapy upfront.”

Dr Lyons presented the results of this research at the 2014 ASH Annual Meeting (abstract 1350).

He and his colleagues initiated a US registry to collect prospective data on clinical outcomes of patients with lower-risk MDS who received chelation or non-chelation therapy.

The registry enrolled 599 adult patients, with a median age of 76 years, from 107 US centers. The patients had transfusional iron overload with serum ferritin ≥ 1000 µg/L and/or ≥ 20 packed red blood cell units and/or ≥ 6 units every 12 weeks.

Patients were divided into 2 groups: those who had never been chelated and those who had used iron chelation. The researchers also looked at a subgroup of patients: those who received chelation therapy for 6 months or more.

The team evaluated patients every 5 months for 5 years or until death, assessing patient characteristics, survival, disease status, comorbidities, cause of death, and MDS therapy.

At enrollment, the 271 chelated patients had a greater median number of lifetime units transfused compared to the 328 non-chelated patients. Additionally, fewer patients receiving chelation therapy had cardiac, vascular, or endocrine concomitant conditions.

Of the chelated patients, 187 (69%) were chelated with deferasirox, 40 (14.8%) with deferasirox and deferoxamine, and 32 (11.8%) with deferoxamine. For 12 patients (4.5%), the researchers did not know which chelator was used.

The cumulative duration of chelation was 18.9 months in patients who had ever used iron chelation and 27 months in patients with at least 6 months of iron chelation.

Patient outcomes

“From the date of diagnosis, the overall survival for patients receiving chelation therapy was significantly longer than for patients receiving non-chelation therapy, including those with cardiovascular or endocrine concomitant conditions,” Dr Lyons noted.

However, there was a potential clinical bias in patient selection, since patients with longer predicted survival may have been chosen for chelation therapy.

At 5 years of follow-up, the mortality rate was 72.9% for non-chelated patients and 59.4% for patients who received chelation therapy (P=0.0005).

Among patients chelated for 6 months or more, the mortality rate was 56.9% (P=0.0002, compared to non-chelated patients). The most common causes of death were MDS/AML and cardiac conditions.

The time from MDS diagnosis to AML progression was significantly longer for chelated patients than for non-chelated patients—72.1 months and 46.4 months, respectively (P<0.0001).

Among patients chelated for 6 months or more, the time to AML transformation was 78.8 months (P<0.0001, compared to non-chelated patients).

Twice as many patients developed AML in the non-chelation group (n=34, 10.4%) than in the chelation group (n=17, 6.3%). However, this difference was not statistically significant.

Taken together, these results suggest chelation can benefit patients with lower-risk MDS, according to Dr Lyons and his colleagues.

“If you think a lower-risk MDS patient will live 1 or 2 years or is a candidate for transplant, get the patient’s iron levels down by chelation, if possible,” Dr Lyons advised.

Three researchers involved in this study are employed by Novartis, and 1 reported research funding from the company, which manufactures deferasirox (Exjade).

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—Iron chelation therapy significantly improves survival for patients with lower-risk myelodysplastic syndrome (MDS) and delays the progression to acute myeloid leukemia (AML), a new study suggests.

“There is a signal for survival with an impressive difference with chelation therapy,” said study investigator Roger Lyons, MD, of Cancer Care Centers of South Texas in San Antonio.

“If this is real, then everyone with lower-risk MDS will go on chelation therapy upfront.”

Dr Lyons presented the results of this research at the 2014 ASH Annual Meeting (abstract 1350).

He and his colleagues initiated a US registry to collect prospective data on clinical outcomes of patients with lower-risk MDS who received chelation or non-chelation therapy.

The registry enrolled 599 adult patients, with a median age of 76 years, from 107 US centers. The patients had transfusional iron overload with serum ferritin ≥ 1000 µg/L and/or ≥ 20 packed red blood cell units and/or ≥ 6 units every 12 weeks.

Patients were divided into 2 groups: those who had never been chelated and those who had used iron chelation. The researchers also looked at a subgroup of patients: those who received chelation therapy for 6 months or more.

The team evaluated patients every 5 months for 5 years or until death, assessing patient characteristics, survival, disease status, comorbidities, cause of death, and MDS therapy.

At enrollment, the 271 chelated patients had a greater median number of lifetime units transfused compared to the 328 non-chelated patients. Additionally, fewer patients receiving chelation therapy had cardiac, vascular, or endocrine concomitant conditions.

Of the chelated patients, 187 (69%) were chelated with deferasirox, 40 (14.8%) with deferasirox and deferoxamine, and 32 (11.8%) with deferoxamine. For 12 patients (4.5%), the researchers did not know which chelator was used.

The cumulative duration of chelation was 18.9 months in patients who had ever used iron chelation and 27 months in patients with at least 6 months of iron chelation.

Patient outcomes

“From the date of diagnosis, the overall survival for patients receiving chelation therapy was significantly longer than for patients receiving non-chelation therapy, including those with cardiovascular or endocrine concomitant conditions,” Dr Lyons noted.

However, there was a potential clinical bias in patient selection, since patients with longer predicted survival may have been chosen for chelation therapy.

At 5 years of follow-up, the mortality rate was 72.9% for non-chelated patients and 59.4% for patients who received chelation therapy (P=0.0005).

Among patients chelated for 6 months or more, the mortality rate was 56.9% (P=0.0002, compared to non-chelated patients). The most common causes of death were MDS/AML and cardiac conditions.

The time from MDS diagnosis to AML progression was significantly longer for chelated patients than for non-chelated patients—72.1 months and 46.4 months, respectively (P<0.0001).

Among patients chelated for 6 months or more, the time to AML transformation was 78.8 months (P<0.0001, compared to non-chelated patients).

Twice as many patients developed AML in the non-chelation group (n=34, 10.4%) than in the chelation group (n=17, 6.3%). However, this difference was not statistically significant.

Taken together, these results suggest chelation can benefit patients with lower-risk MDS, according to Dr Lyons and his colleagues.

“If you think a lower-risk MDS patient will live 1 or 2 years or is a candidate for transplant, get the patient’s iron levels down by chelation, if possible,” Dr Lyons advised.

Three researchers involved in this study are employed by Novartis, and 1 reported research funding from the company, which manufactures deferasirox (Exjade).

Donald Metcalf, MD

Photo courtesy of The Walter

and Eliza Hall Institute

of Medical Research

Donald Metcalf, MD, an Australian researcher who has been called “the father of hematopoietic cytokines,” has died at the age of 85.

Dr Metcalf’s studies of blood production led to his speculation that there must be a biological mechanism—one or more hormones—that control white blood cell production.

These substances, which he termed colony-stimulating factors (CSFs), were the focus of more than 50 years of research.

Over this time, Dr Metcalf led researchers to characterize and purify 4 separate CSFs—granulocyte CSF (G-CSF), granulocyte-macrophage CSF (GM-CSF), macrophage CSF (M-CSF), and multi-CSF (now called interleukin-3).

Dr Metcalf recognized that CSFs had a potential role in clinical medicine, and his team was among the first in the world to discover the genes for CSFs.

Dr Metcalf was a central figure in the international clinical trials of CSFs in the 1980s, assessing whether CSFs could boost immune cell numbers in cancer patients whose immune system was weakened as a side effect of chemotherapy. On the basis of these studies, G-CSF (Neupogen) was approved for clinical use in 1991.

Now, an estimated 20 million people have been treated with CSFs. As well as boosting the immune system in patients who receive chemotherapy or have other immune deficiencies, CSFs are thought to have revolutionized hematopoietic stem cell transplantation.

A man with many achievements

Dr Metcalf was born in 1929 and started school at the age of 3, by which time he was already reading. He entered university at the age of 16, ultimately obtaining bachelor’s and medical degrees from the University of Sydney.

After an internship at the Royal Prince Alfred Hospital in Sydney, Dr Metcalf joined the staff of the Walter and Eliza Hall Institute of Medical Research (WEHI) in Melbourne in 1954. He was supported by Cancer Council Victoria’s Carden Fellowship, an award he held until his retirement in 2014. (Dr Metcalf officially retired in 1996 but continued to do research until 2014.)

Dr Metcalf spent his early years at WEHI studying vaccinia virus. In 1965, he began studying blood cell formation and, by association, leukemia. In 1966, he became deputy director of WEHI and the head of its Cancer Research Unit.

Dr Metcalf took several sabbaticals from WEHI, serving as a visiting scientist at Harvard Medical School in Boston, Massachusetts; the Roswell Park Memorial Institute in Buffalo, New York; the Swiss Institute for Experimental Cancer Research in Lausanne, Switzerland; the Radiobiological Institute in Rijswijk, The Netherlands; and the University of Cambridge in the UK.

Among Dr Metcalf’s many honors and awards are the Companion of the Order of Australia (1993), the Albert Lasker Award for Clinical Medical Research (1993), the Gairdner Foundation International Award (1994), the Royal Medal of the Royal Society (1995), the Victoria Prize (2000), and the Prime Minister’s Prize for Science (2001).

Dr Metcalf is survived by his wife Jo; daughters Kate, Johanna, Penelope, and Mary-Ann; grandchildren James, Martin, Patrick, Elizabeth, Rose, and Robert; and their extended families.

Donald Metcalf, MD

Photo courtesy of The Walter

and Eliza Hall Institute

of Medical Research

Donald Metcalf, MD, an Australian researcher who has been called “the father of hematopoietic cytokines,” has died at the age of 85.

Dr Metcalf’s studies of blood production led to his speculation that there must be a biological mechanism—one or more hormones—that control white blood cell production.

These substances, which he termed colony-stimulating factors (CSFs), were the focus of more than 50 years of research.

Over this time, Dr Metcalf led researchers to characterize and purify 4 separate CSFs—granulocyte CSF (G-CSF), granulocyte-macrophage CSF (GM-CSF), macrophage CSF (M-CSF), and multi-CSF (now called interleukin-3).

Dr Metcalf recognized that CSFs had a potential role in clinical medicine, and his team was among the first in the world to discover the genes for CSFs.

Dr Metcalf was a central figure in the international clinical trials of CSFs in the 1980s, assessing whether CSFs could boost immune cell numbers in cancer patients whose immune system was weakened as a side effect of chemotherapy. On the basis of these studies, G-CSF (Neupogen) was approved for clinical use in 1991.

Now, an estimated 20 million people have been treated with CSFs. As well as boosting the immune system in patients who receive chemotherapy or have other immune deficiencies, CSFs are thought to have revolutionized hematopoietic stem cell transplantation.

A man with many achievements

Dr Metcalf was born in 1929 and started school at the age of 3, by which time he was already reading. He entered university at the age of 16, ultimately obtaining bachelor’s and medical degrees from the University of Sydney.

After an internship at the Royal Prince Alfred Hospital in Sydney, Dr Metcalf joined the staff of the Walter and Eliza Hall Institute of Medical Research (WEHI) in Melbourne in 1954. He was supported by Cancer Council Victoria’s Carden Fellowship, an award he held until his retirement in 2014. (Dr Metcalf officially retired in 1996 but continued to do research until 2014.)

Dr Metcalf spent his early years at WEHI studying vaccinia virus. In 1965, he began studying blood cell formation and, by association, leukemia. In 1966, he became deputy director of WEHI and the head of its Cancer Research Unit.

Dr Metcalf took several sabbaticals from WEHI, serving as a visiting scientist at Harvard Medical School in Boston, Massachusetts; the Roswell Park Memorial Institute in Buffalo, New York; the Swiss Institute for Experimental Cancer Research in Lausanne, Switzerland; the Radiobiological Institute in Rijswijk, The Netherlands; and the University of Cambridge in the UK.

Among Dr Metcalf’s many honors and awards are the Companion of the Order of Australia (1993), the Albert Lasker Award for Clinical Medical Research (1993), the Gairdner Foundation International Award (1994), the Royal Medal of the Royal Society (1995), the Victoria Prize (2000), and the Prime Minister’s Prize for Science (2001).

Dr Metcalf is survived by his wife Jo; daughters Kate, Johanna, Penelope, and Mary-Ann; grandchildren James, Martin, Patrick, Elizabeth, Rose, and Robert; and their extended families.

Donald Metcalf, MD

Photo courtesy of The Walter

and Eliza Hall Institute

of Medical Research

Donald Metcalf, MD, an Australian researcher who has been called “the father of hematopoietic cytokines,” has died at the age of 85.

Dr Metcalf’s studies of blood production led to his speculation that there must be a biological mechanism—one or more hormones—that control white blood cell production.

These substances, which he termed colony-stimulating factors (CSFs), were the focus of more than 50 years of research.

Over this time, Dr Metcalf led researchers to characterize and purify 4 separate CSFs—granulocyte CSF (G-CSF), granulocyte-macrophage CSF (GM-CSF), macrophage CSF (M-CSF), and multi-CSF (now called interleukin-3).

Dr Metcalf recognized that CSFs had a potential role in clinical medicine, and his team was among the first in the world to discover the genes for CSFs.

Dr Metcalf was a central figure in the international clinical trials of CSFs in the 1980s, assessing whether CSFs could boost immune cell numbers in cancer patients whose immune system was weakened as a side effect of chemotherapy. On the basis of these studies, G-CSF (Neupogen) was approved for clinical use in 1991.

Now, an estimated 20 million people have been treated with CSFs. As well as boosting the immune system in patients who receive chemotherapy or have other immune deficiencies, CSFs are thought to have revolutionized hematopoietic stem cell transplantation.

A man with many achievements

Dr Metcalf was born in 1929 and started school at the age of 3, by which time he was already reading. He entered university at the age of 16, ultimately obtaining bachelor’s and medical degrees from the University of Sydney.

After an internship at the Royal Prince Alfred Hospital in Sydney, Dr Metcalf joined the staff of the Walter and Eliza Hall Institute of Medical Research (WEHI) in Melbourne in 1954. He was supported by Cancer Council Victoria’s Carden Fellowship, an award he held until his retirement in 2014. (Dr Metcalf officially retired in 1996 but continued to do research until 2014.)

Dr Metcalf spent his early years at WEHI studying vaccinia virus. In 1965, he began studying blood cell formation and, by association, leukemia. In 1966, he became deputy director of WEHI and the head of its Cancer Research Unit.

Dr Metcalf took several sabbaticals from WEHI, serving as a visiting scientist at Harvard Medical School in Boston, Massachusetts; the Roswell Park Memorial Institute in Buffalo, New York; the Swiss Institute for Experimental Cancer Research in Lausanne, Switzerland; the Radiobiological Institute in Rijswijk, The Netherlands; and the University of Cambridge in the UK.

Among Dr Metcalf’s many honors and awards are the Companion of the Order of Australia (1993), the Albert Lasker Award for Clinical Medical Research (1993), the Gairdner Foundation International Award (1994), the Royal Medal of the Royal Society (1995), the Victoria Prize (2000), and the Prime Minister’s Prize for Science (2001).

Dr Metcalf is survived by his wife Jo; daughters Kate, Johanna, Penelope, and Mary-Ann; grandchildren James, Martin, Patrick, Elizabeth, Rose, and Robert; and their extended families.

Genetically modified zebrafish

Investigators have identified compounds that appear to prevent the cardiac damage caused by the chemotherapy drug doxorubicin.

The compounds target MDH2, an enzyme key to the generation of cellular energy in mitochondria.

And preclinical experiments showed that inhibiting MDH2 could prevent doxorubicin-induced damage to cardiac cells without reducing the drug’s antitumor effects.

The investigators detailed these experiments in Science Translational Medicine.

“Doxorubicin-induced cardiomyopathy limits the amount of the drug a patient can receive—which limits the ability to treat cancer—and even low, safer doses can lead to heart failure in up to 8% of patients,” explained study author Randall Peterson, PhD, of Massachusetts General Hospital in Charlestown.

“Finding an effective cardioprotective drug—essentially separating the good and bad effects of this form of chemotherapy—could increase the beneficial effects of doxorubicin against cancer while reducing the rate of heart failure in treated patients.”

To conduct a broad search for potential protective compounds, Dr Peterson and his colleagues developed a zebrafish model of doxorubicin-induced heart failure. They used this model to screen 3000 molecules from 2 chemical libraries for the ability to prevent the kind of cardiac damage caused by the drug.

Eight of the tested chemicals reduced damage to the hearts of zebrafish embryos, and two compounds—visnagin and diphenylurea—were the most potent in preventing both structural and functional damage.

Further in vitro and in vivo experiments revealed that either compound almost completely prevented the death of cardiac cells caused by doxorubicin. In mouse models of both high- and low-dose doxorubicin treatment, visnagin—a natural compound synthesized by the toothpick weed—was able to maintain cardiac function.

Investigation into the possible mechanism behind visnagin’s protective ability showed that the compound binds to and inhibits the action of MDH2, an enzyme essential to the generation of cellular energy by mitochondria.

Other agents that block MDH2 activity also protected zebrafish against doxorubicin-induced cardiac damage. And tests in both cellular and animal models of several types of cancer showed that neither visnagin nor diphenylurea reduced the antitumor action of doxorubicin.

“We are still trying to determine exactly how inhibition of MDH2 protects the heart, but one intriguing idea is that doxorubicin may kill cardiac and tumor cells in different ways,” Dr Peterson said. “Given the intense energy requirements of the beating heart, we speculate that cardiac cells may be especially susceptible to metabolic disturbance caused by doxorubicin and that inhibiting MDH2 may correct the metabolic imbalance and prevent the cells from dying.”

“It remains to be seen if visnagin’s protective effects are restricted to doxorubicin or if it can protect the heart from other kinds of damage. We are pursuing this question by testing its ability to protect heart muscle from oxygen deprivation during heart attacks and from the effects of other heart-damaging chemotherapy drugs.”

Genetically modified zebrafish

Investigators have identified compounds that appear to prevent the cardiac damage caused by the chemotherapy drug doxorubicin.

The compounds target MDH2, an enzyme key to the generation of cellular energy in mitochondria.

And preclinical experiments showed that inhibiting MDH2 could prevent doxorubicin-induced damage to cardiac cells without reducing the drug’s antitumor effects.

The investigators detailed these experiments in Science Translational Medicine.

“Doxorubicin-induced cardiomyopathy limits the amount of the drug a patient can receive—which limits the ability to treat cancer—and even low, safer doses can lead to heart failure in up to 8% of patients,” explained study author Randall Peterson, PhD, of Massachusetts General Hospital in Charlestown.

“Finding an effective cardioprotective drug—essentially separating the good and bad effects of this form of chemotherapy—could increase the beneficial effects of doxorubicin against cancer while reducing the rate of heart failure in treated patients.”

To conduct a broad search for potential protective compounds, Dr Peterson and his colleagues developed a zebrafish model of doxorubicin-induced heart failure. They used this model to screen 3000 molecules from 2 chemical libraries for the ability to prevent the kind of cardiac damage caused by the drug.

Eight of the tested chemicals reduced damage to the hearts of zebrafish embryos, and two compounds—visnagin and diphenylurea—were the most potent in preventing both structural and functional damage.

Further in vitro and in vivo experiments revealed that either compound almost completely prevented the death of cardiac cells caused by doxorubicin. In mouse models of both high- and low-dose doxorubicin treatment, visnagin—a natural compound synthesized by the toothpick weed—was able to maintain cardiac function.

Investigation into the possible mechanism behind visnagin’s protective ability showed that the compound binds to and inhibits the action of MDH2, an enzyme essential to the generation of cellular energy by mitochondria.

Other agents that block MDH2 activity also protected zebrafish against doxorubicin-induced cardiac damage. And tests in both cellular and animal models of several types of cancer showed that neither visnagin nor diphenylurea reduced the antitumor action of doxorubicin.

“We are still trying to determine exactly how inhibition of MDH2 protects the heart, but one intriguing idea is that doxorubicin may kill cardiac and tumor cells in different ways,” Dr Peterson said. “Given the intense energy requirements of the beating heart, we speculate that cardiac cells may be especially susceptible to metabolic disturbance caused by doxorubicin and that inhibiting MDH2 may correct the metabolic imbalance and prevent the cells from dying.”

“It remains to be seen if visnagin’s protective effects are restricted to doxorubicin or if it can protect the heart from other kinds of damage. We are pursuing this question by testing its ability to protect heart muscle from oxygen deprivation during heart attacks and from the effects of other heart-damaging chemotherapy drugs.”

Genetically modified zebrafish

Investigators have identified compounds that appear to prevent the cardiac damage caused by the chemotherapy drug doxorubicin.

The compounds target MDH2, an enzyme key to the generation of cellular energy in mitochondria.

And preclinical experiments showed that inhibiting MDH2 could prevent doxorubicin-induced damage to cardiac cells without reducing the drug’s antitumor effects.

The investigators detailed these experiments in Science Translational Medicine.

“Doxorubicin-induced cardiomyopathy limits the amount of the drug a patient can receive—which limits the ability to treat cancer—and even low, safer doses can lead to heart failure in up to 8% of patients,” explained study author Randall Peterson, PhD, of Massachusetts General Hospital in Charlestown.

“Finding an effective cardioprotective drug—essentially separating the good and bad effects of this form of chemotherapy—could increase the beneficial effects of doxorubicin against cancer while reducing the rate of heart failure in treated patients.”

To conduct a broad search for potential protective compounds, Dr Peterson and his colleagues developed a zebrafish model of doxorubicin-induced heart failure. They used this model to screen 3000 molecules from 2 chemical libraries for the ability to prevent the kind of cardiac damage caused by the drug.

Eight of the tested chemicals reduced damage to the hearts of zebrafish embryos, and two compounds—visnagin and diphenylurea—were the most potent in preventing both structural and functional damage.

Further in vitro and in vivo experiments revealed that either compound almost completely prevented the death of cardiac cells caused by doxorubicin. In mouse models of both high- and low-dose doxorubicin treatment, visnagin—a natural compound synthesized by the toothpick weed—was able to maintain cardiac function.

Investigation into the possible mechanism behind visnagin’s protective ability showed that the compound binds to and inhibits the action of MDH2, an enzyme essential to the generation of cellular energy by mitochondria.

Other agents that block MDH2 activity also protected zebrafish against doxorubicin-induced cardiac damage. And tests in both cellular and animal models of several types of cancer showed that neither visnagin nor diphenylurea reduced the antitumor action of doxorubicin.

“We are still trying to determine exactly how inhibition of MDH2 protects the heart, but one intriguing idea is that doxorubicin may kill cardiac and tumor cells in different ways,” Dr Peterson said. “Given the intense energy requirements of the beating heart, we speculate that cardiac cells may be especially susceptible to metabolic disturbance caused by doxorubicin and that inhibiting MDH2 may correct the metabolic imbalance and prevent the cells from dying.”

“It remains to be seen if visnagin’s protective effects are restricted to doxorubicin or if it can protect the heart from other kinds of damage. We are pursuing this question by testing its ability to protect heart muscle from oxygen deprivation during heart attacks and from the effects of other heart-damaging chemotherapy drugs.”

Power lines

Research first carried out in the 1970s revealed an association between living near overhead power lines and an increased risk of childhood leukemia.

Although some later studies failed to find such a link, the International Agency for Research on Cancer has categorized low-frequency magnetic fields as “possibly carcinogenic.”

However, a mechanism for this association has never been found, and, now, researchers have ruled out one of the prime candidates.

The team studied the effects of weak magnetic fields (WMFs) on key human proteins, including those

crucial for health, and found they have no detectable impact.

The researchers detailed this discovery in the Journal of the Royal Society Interface.

Alex Jones, PhD, of The University of Manchester in the UK, and his colleagues looked at how WMFs affect flavoproteins, which are key to processes vital for healthy human function, such as the nervous system, DNA repair, and the biological clock.

If these proteins malfunction, there are serious knock-on effects for human health. But after subjecting flavoproteins to WMFs in the lab, the researchers found that WMFs have no detectable impact on these proteins.

“There is still some concern among the public about this potential link, which has been found in some studies into cases of childhood leukemia, but without any clear mechanism for why,” Dr Jones said.

“Flavoproteins transfer electrons from one place to another. Along the path the electrons take, very short-lived chemical species known as radical pairs are often created. Biochemical reactions involving radical pairs are considered the most plausible candidates for sensitivity to WMFs, but for them to be so, the reaction conditions have to be right. This research suggests that the correct conditions for biochemical effects of WMFs are likely to be rare in human biology.”

“More work on other possible links will need to be done,” noted study author Nigel Scrutton, PhD, also of the University of Manchester.

“But this study definitely takes us nearer to the point where we can say that power lines, mobile phones, and other similar devices are likely to be safe for humans.”

Power lines

Research first carried out in the 1970s revealed an association between living near overhead power lines and an increased risk of childhood leukemia.

Although some later studies failed to find such a link, the International Agency for Research on Cancer has categorized low-frequency magnetic fields as “possibly carcinogenic.”

However, a mechanism for this association has never been found, and, now, researchers have ruled out one of the prime candidates.

The team studied the effects of weak magnetic fields (WMFs) on key human proteins, including those

crucial for health, and found they have no detectable impact.

The researchers detailed this discovery in the Journal of the Royal Society Interface.

Alex Jones, PhD, of The University of Manchester in the UK, and his colleagues looked at how WMFs affect flavoproteins, which are key to processes vital for healthy human function, such as the nervous system, DNA repair, and the biological clock.

If these proteins malfunction, there are serious knock-on effects for human health. But after subjecting flavoproteins to WMFs in the lab, the researchers found that WMFs have no detectable impact on these proteins.

“There is still some concern among the public about this potential link, which has been found in some studies into cases of childhood leukemia, but without any clear mechanism for why,” Dr Jones said.

“Flavoproteins transfer electrons from one place to another. Along the path the electrons take, very short-lived chemical species known as radical pairs are often created. Biochemical reactions involving radical pairs are considered the most plausible candidates for sensitivity to WMFs, but for them to be so, the reaction conditions have to be right. This research suggests that the correct conditions for biochemical effects of WMFs are likely to be rare in human biology.”

“More work on other possible links will need to be done,” noted study author Nigel Scrutton, PhD, also of the University of Manchester.

“But this study definitely takes us nearer to the point where we can say that power lines, mobile phones, and other similar devices are likely to be safe for humans.”

Power lines

Research first carried out in the 1970s revealed an association between living near overhead power lines and an increased risk of childhood leukemia.

Although some later studies failed to find such a link, the International Agency for Research on Cancer has categorized low-frequency magnetic fields as “possibly carcinogenic.”

However, a mechanism for this association has never been found, and, now, researchers have ruled out one of the prime candidates.

The team studied the effects of weak magnetic fields (WMFs) on key human proteins, including those

crucial for health, and found they have no detectable impact.

The researchers detailed this discovery in the Journal of the Royal Society Interface.

Alex Jones, PhD, of The University of Manchester in the UK, and his colleagues looked at how WMFs affect flavoproteins, which are key to processes vital for healthy human function, such as the nervous system, DNA repair, and the biological clock.

If these proteins malfunction, there are serious knock-on effects for human health. But after subjecting flavoproteins to WMFs in the lab, the researchers found that WMFs have no detectable impact on these proteins.

“There is still some concern among the public about this potential link, which has been found in some studies into cases of childhood leukemia, but without any clear mechanism for why,” Dr Jones said.

“Flavoproteins transfer electrons from one place to another. Along the path the electrons take, very short-lived chemical species known as radical pairs are often created. Biochemical reactions involving radical pairs are considered the most plausible candidates for sensitivity to WMFs, but for them to be so, the reaction conditions have to be right. This research suggests that the correct conditions for biochemical effects of WMFs are likely to be rare in human biology.”

“More work on other possible links will need to be done,” noted study author Nigel Scrutton, PhD, also of the University of Manchester.

“But this study definitely takes us nearer to the point where we can say that power lines, mobile phones, and other similar devices are likely to be safe for humans.”