Erilyn Riley

AML cells in bone marrow

NEW YORK—We are “finally” making progress in the treatment of acute myeloid leukemia (AML), according to a speaker at the NCCN 11th Annual Congress: Hematologic Malignancies.

Jessica K. Altman, MD, said a number of developments have resulted in improved AML treatment, including a better understanding of biology and prognostic assessment, continued advances in transplant, and updating standard treatments and incorporating novel agents in both relapsed/refractory and newly diagnosed patients.

“There are a couple of practice-changing treatments in acute myeloid leukemia, 2 of which happened over the last decade: daunorubicin intensification and the use of FLT3 inhibitors,” said Dr Altman, an associate professor at Northwestern University Feinberg School of Medicine in Chicago, Illinois.

Dr Altman went on to explain that novel therapies for AML can be divided into 2 basic categories. There are agents that don’t depend on mutation status (like daunorubicin) and those that are mutation-specific (like FLT3 inhibitors).

Therapies not dependent on mutational complexity

The therapies that are not dependent on mutational complexity include anti-CD33 antibodies, BCL‐2 inhibitors, a dose-intensified anthracycline regimen, and different formulations of 7+3, including CPX‐351.

Escalated daunorubicin

Randomized trials of escalated daunorubicin (90 vs 45 mg/m²) have demonstrated benefit in complete responses (CRs) and overall survival (OS) in intermediate-risk patients and patients with core-binding factor mutation. They have demonstrated benefit in OS in FLT3 ITD+ patients.

In patients up to 65 years of age, 60–90 mg/m² of daunorubicin is now standard.

“It’s still not clear to me—and I don’t know if it ever will be—if 90 is equivalent to 60,” Dr Altman said.

CPX-351

CPX-351 is a liposomal formulation of cytarabine and daunorubicin. In a randomized, phase 3 study of older adults with secondary AML, the median OS was 9.56 months for patients treated with CPX-351 and 5.95 months for patients on the 7+3 regimen (P=0.005).

The median event-free survival was significantly better with CPX-351 (P=0.021), as was the rate of CR + CR with incomplete blood count recovery (CRi). The rate of CR + CRi was 47.7% with CPX-351 and 33.3% for 7+3 (P=0.016).

A similar number of patients went on to transplant in each arm. Grade 3-5 adverse events were similar in frequency and severity in both arms—92% with CPX-351 vs 91% with 7+3.

SGN-CD33A

CD33 is not a new target in myeloid leukemia, Dr Altman pointed out. Gemtuzumab ozogamicin has been studied, approved by the US Food and Drug Administration, and then withdrawn.

However, an increasing number of studies with gemtuzumab are underway, she said, and the agent may once again have a place in the AML armamentarium.

The newest CD33 construct is SGN-CD33A, a stable dipeptide linker that enables uniform drug loading of a pyrrolobenzodiazepine dimer that crosslinks DNA and leads to cell death.

“Single-agent data was quite promising,” Dr Altman noted, with a CR + CRi rate of 41% in previously treated patients and 58% in 12 treatment-naïve patients.

These results prompted a combination study of SGN-CD33A with hypomethylating agents.

“Results were higher than expected with a hypomethylating agent,” Dr Altman pointed out.

The CR + CRi + CR with incomplete platelet recovery was 58%. And the median relapse-free survival was 7.7 months.

A phase 3 randomized trial of SGN-CD33A is planned.

Venetoclax

BCL-2 inhibitors are the fourth type of agent not dependent on mutation complexity. Venetoclax (ABT‐199) is a small‐molecule BCL-2 inhibitor that leads to the initiation of apoptosis.

In a phase 1b trial of venetoclax in combination with a hypomethylating agent, the overall CR rate was 35%, and the CRi rate was 35%.

“Again, higher than what would be expected with a hypomethylating agent alone,” Dr Altman said.

In a phase 1b/2 trial of venetoclax in combination with low‐dose cytarabine, the CR + CRi rate was 54%. Patients responded even if they had prior exposure to hypomethylating agents.

Mutation-specific novel agents

The FLT3 inhibitor midostaurin and the IDH inhibitors AG-120 and AG-221 are among the most exciting mutation-specific agents and the ones most progressed, according to Dr Altman.

FLT3-ITD is mutated in about 30% of AML patients and carries an unfavorable prognosis, and the IDH mutation occurs in about 10% and confers a favorable prognosis.

Midostaurin

A phase 3, randomized, double-blind study of daunorubicin/cytarabine induction and high-dose cytarabine consolidation with midostaurin (PKC412) or placebo had a 59% CR rate by day 60 in the midostaurin arm, compared with 53% in the placebo arm.

“The CR rate was slightly higher in the midostaurin arm,” Dr Altman said, “but what’s the most remarkable about this study is the difference in overall survival.”

The median OS in the midostaurin arm was 74.7 months, compared with 25.6 months in the placebo arm (P=0.0074).

“The major take-home message from this clinical trial,” Dr Altman said, “is that midostaurin improved the overall survival when added to standard therapy and represents a new standard of care.”

AG-120 and AG-221

Two IDH inhibitors that have substantial data available are the IDH1 inhibitor AG-120 and the IDH2 inhibitor AG-221.

As of October 2015, 78 patients had been treated with AG-120 in a phase 1 trial, yielding an overall response rate of 35% and a CR rate of 15%.

As of September 2015, 209 patients had been treated with AG-221 in a phase 1/2 trial, and 66 are still on study. The overall response rate was 37% in 159 adults with relapsed/refractory AML, with a median duration of response of 6.9 months. The CR rate was 18%.

Investigators have initiated a phase 3 study of AG-221 compared to conventional care regimens.

AML cells in bone marrow

NEW YORK—We are “finally” making progress in the treatment of acute myeloid leukemia (AML), according to a speaker at the NCCN 11th Annual Congress: Hematologic Malignancies.

Jessica K. Altman, MD, said a number of developments have resulted in improved AML treatment, including a better understanding of biology and prognostic assessment, continued advances in transplant, and updating standard treatments and incorporating novel agents in both relapsed/refractory and newly diagnosed patients.

“There are a couple of practice-changing treatments in acute myeloid leukemia, 2 of which happened over the last decade: daunorubicin intensification and the use of FLT3 inhibitors,” said Dr Altman, an associate professor at Northwestern University Feinberg School of Medicine in Chicago, Illinois.

Dr Altman went on to explain that novel therapies for AML can be divided into 2 basic categories. There are agents that don’t depend on mutation status (like daunorubicin) and those that are mutation-specific (like FLT3 inhibitors).

Therapies not dependent on mutational complexity

The therapies that are not dependent on mutational complexity include anti-CD33 antibodies, BCL‐2 inhibitors, a dose-intensified anthracycline regimen, and different formulations of 7+3, including CPX‐351.

Escalated daunorubicin

Randomized trials of escalated daunorubicin (90 vs 45 mg/m²) have demonstrated benefit in complete responses (CRs) and overall survival (OS) in intermediate-risk patients and patients with core-binding factor mutation. They have demonstrated benefit in OS in FLT3 ITD+ patients.

In patients up to 65 years of age, 60–90 mg/m² of daunorubicin is now standard.

“It’s still not clear to me—and I don’t know if it ever will be—if 90 is equivalent to 60,” Dr Altman said.

CPX-351

CPX-351 is a liposomal formulation of cytarabine and daunorubicin. In a randomized, phase 3 study of older adults with secondary AML, the median OS was 9.56 months for patients treated with CPX-351 and 5.95 months for patients on the 7+3 regimen (P=0.005).

The median event-free survival was significantly better with CPX-351 (P=0.021), as was the rate of CR + CR with incomplete blood count recovery (CRi). The rate of CR + CRi was 47.7% with CPX-351 and 33.3% for 7+3 (P=0.016).

A similar number of patients went on to transplant in each arm. Grade 3-5 adverse events were similar in frequency and severity in both arms—92% with CPX-351 vs 91% with 7+3.

SGN-CD33A

CD33 is not a new target in myeloid leukemia, Dr Altman pointed out. Gemtuzumab ozogamicin has been studied, approved by the US Food and Drug Administration, and then withdrawn.

However, an increasing number of studies with gemtuzumab are underway, she said, and the agent may once again have a place in the AML armamentarium.

The newest CD33 construct is SGN-CD33A, a stable dipeptide linker that enables uniform drug loading of a pyrrolobenzodiazepine dimer that crosslinks DNA and leads to cell death.

“Single-agent data was quite promising,” Dr Altman noted, with a CR + CRi rate of 41% in previously treated patients and 58% in 12 treatment-naïve patients.

These results prompted a combination study of SGN-CD33A with hypomethylating agents.

“Results were higher than expected with a hypomethylating agent,” Dr Altman pointed out.

The CR + CRi + CR with incomplete platelet recovery was 58%. And the median relapse-free survival was 7.7 months.

A phase 3 randomized trial of SGN-CD33A is planned.

Venetoclax

BCL-2 inhibitors are the fourth type of agent not dependent on mutation complexity. Venetoclax (ABT‐199) is a small‐molecule BCL-2 inhibitor that leads to the initiation of apoptosis.

In a phase 1b trial of venetoclax in combination with a hypomethylating agent, the overall CR rate was 35%, and the CRi rate was 35%.

“Again, higher than what would be expected with a hypomethylating agent alone,” Dr Altman said.

In a phase 1b/2 trial of venetoclax in combination with low‐dose cytarabine, the CR + CRi rate was 54%. Patients responded even if they had prior exposure to hypomethylating agents.

Mutation-specific novel agents

The FLT3 inhibitor midostaurin and the IDH inhibitors AG-120 and AG-221 are among the most exciting mutation-specific agents and the ones most progressed, according to Dr Altman.

FLT3-ITD is mutated in about 30% of AML patients and carries an unfavorable prognosis, and the IDH mutation occurs in about 10% and confers a favorable prognosis.

Midostaurin

A phase 3, randomized, double-blind study of daunorubicin/cytarabine induction and high-dose cytarabine consolidation with midostaurin (PKC412) or placebo had a 59% CR rate by day 60 in the midostaurin arm, compared with 53% in the placebo arm.

“The CR rate was slightly higher in the midostaurin arm,” Dr Altman said, “but what’s the most remarkable about this study is the difference in overall survival.”

The median OS in the midostaurin arm was 74.7 months, compared with 25.6 months in the placebo arm (P=0.0074).

“The major take-home message from this clinical trial,” Dr Altman said, “is that midostaurin improved the overall survival when added to standard therapy and represents a new standard of care.”

AG-120 and AG-221

Two IDH inhibitors that have substantial data available are the IDH1 inhibitor AG-120 and the IDH2 inhibitor AG-221.

As of October 2015, 78 patients had been treated with AG-120 in a phase 1 trial, yielding an overall response rate of 35% and a CR rate of 15%.

As of September 2015, 209 patients had been treated with AG-221 in a phase 1/2 trial, and 66 are still on study. The overall response rate was 37% in 159 adults with relapsed/refractory AML, with a median duration of response of 6.9 months. The CR rate was 18%.

Investigators have initiated a phase 3 study of AG-221 compared to conventional care regimens.

AML cells in bone marrow

NEW YORK—We are “finally” making progress in the treatment of acute myeloid leukemia (AML), according to a speaker at the NCCN 11th Annual Congress: Hematologic Malignancies.

Jessica K. Altman, MD, said a number of developments have resulted in improved AML treatment, including a better understanding of biology and prognostic assessment, continued advances in transplant, and updating standard treatments and incorporating novel agents in both relapsed/refractory and newly diagnosed patients.

“There are a couple of practice-changing treatments in acute myeloid leukemia, 2 of which happened over the last decade: daunorubicin intensification and the use of FLT3 inhibitors,” said Dr Altman, an associate professor at Northwestern University Feinberg School of Medicine in Chicago, Illinois.

Dr Altman went on to explain that novel therapies for AML can be divided into 2 basic categories. There are agents that don’t depend on mutation status (like daunorubicin) and those that are mutation-specific (like FLT3 inhibitors).

Therapies not dependent on mutational complexity

The therapies that are not dependent on mutational complexity include anti-CD33 antibodies, BCL‐2 inhibitors, a dose-intensified anthracycline regimen, and different formulations of 7+3, including CPX‐351.

Escalated daunorubicin

Randomized trials of escalated daunorubicin (90 vs 45 mg/m²) have demonstrated benefit in complete responses (CRs) and overall survival (OS) in intermediate-risk patients and patients with core-binding factor mutation. They have demonstrated benefit in OS in FLT3 ITD+ patients.

In patients up to 65 years of age, 60–90 mg/m² of daunorubicin is now standard.

“It’s still not clear to me—and I don’t know if it ever will be—if 90 is equivalent to 60,” Dr Altman said.

CPX-351

CPX-351 is a liposomal formulation of cytarabine and daunorubicin. In a randomized, phase 3 study of older adults with secondary AML, the median OS was 9.56 months for patients treated with CPX-351 and 5.95 months for patients on the 7+3 regimen (P=0.005).

The median event-free survival was significantly better with CPX-351 (P=0.021), as was the rate of CR + CR with incomplete blood count recovery (CRi). The rate of CR + CRi was 47.7% with CPX-351 and 33.3% for 7+3 (P=0.016).

A similar number of patients went on to transplant in each arm. Grade 3-5 adverse events were similar in frequency and severity in both arms—92% with CPX-351 vs 91% with 7+3.

SGN-CD33A

CD33 is not a new target in myeloid leukemia, Dr Altman pointed out. Gemtuzumab ozogamicin has been studied, approved by the US Food and Drug Administration, and then withdrawn.

However, an increasing number of studies with gemtuzumab are underway, she said, and the agent may once again have a place in the AML armamentarium.

The newest CD33 construct is SGN-CD33A, a stable dipeptide linker that enables uniform drug loading of a pyrrolobenzodiazepine dimer that crosslinks DNA and leads to cell death.

“Single-agent data was quite promising,” Dr Altman noted, with a CR + CRi rate of 41% in previously treated patients and 58% in 12 treatment-naïve patients.

These results prompted a combination study of SGN-CD33A with hypomethylating agents.

“Results were higher than expected with a hypomethylating agent,” Dr Altman pointed out.

The CR + CRi + CR with incomplete platelet recovery was 58%. And the median relapse-free survival was 7.7 months.

A phase 3 randomized trial of SGN-CD33A is planned.

Venetoclax

BCL-2 inhibitors are the fourth type of agent not dependent on mutation complexity. Venetoclax (ABT‐199) is a small‐molecule BCL-2 inhibitor that leads to the initiation of apoptosis.

In a phase 1b trial of venetoclax in combination with a hypomethylating agent, the overall CR rate was 35%, and the CRi rate was 35%.

“Again, higher than what would be expected with a hypomethylating agent alone,” Dr Altman said.

In a phase 1b/2 trial of venetoclax in combination with low‐dose cytarabine, the CR + CRi rate was 54%. Patients responded even if they had prior exposure to hypomethylating agents.

Mutation-specific novel agents

The FLT3 inhibitor midostaurin and the IDH inhibitors AG-120 and AG-221 are among the most exciting mutation-specific agents and the ones most progressed, according to Dr Altman.

FLT3-ITD is mutated in about 30% of AML patients and carries an unfavorable prognosis, and the IDH mutation occurs in about 10% and confers a favorable prognosis.

Midostaurin

A phase 3, randomized, double-blind study of daunorubicin/cytarabine induction and high-dose cytarabine consolidation with midostaurin (PKC412) or placebo had a 59% CR rate by day 60 in the midostaurin arm, compared with 53% in the placebo arm.

“The CR rate was slightly higher in the midostaurin arm,” Dr Altman said, “but what’s the most remarkable about this study is the difference in overall survival.”

The median OS in the midostaurin arm was 74.7 months, compared with 25.6 months in the placebo arm (P=0.0074).

“The major take-home message from this clinical trial,” Dr Altman said, “is that midostaurin improved the overall survival when added to standard therapy and represents a new standard of care.”

AG-120 and AG-221

Two IDH inhibitors that have substantial data available are the IDH1 inhibitor AG-120 and the IDH2 inhibitor AG-221.

As of October 2015, 78 patients had been treated with AG-120 in a phase 1 trial, yielding an overall response rate of 35% and a CR rate of 15%.

As of September 2015, 209 patients had been treated with AG-221 in a phase 1/2 trial, and 66 are still on study. The overall response rate was 37% in 159 adults with relapsed/refractory AML, with a median duration of response of 6.9 months. The CR rate was 18%.

Investigators have initiated a phase 3 study of AG-221 compared to conventional care regimens.

Imatinib (Gleevec) tablet

Photo by D. Meyer

NEW YORK—Evaluating treatment goals is essential when choosing which tyrosine kinase inhibitor (TKI) to prescribe for a patient with newly diagnosed chronic myeloid leukemia (CML), according to a speaker at the NCCN 11th Annual Congress: Hematologic Malignancies.

“Deciding what TKI to start people on really depends on what your goals are for that patient,” said the speaker, Jerald Radich, MD, of the Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance in Seattle, Washington.

Because the 3 TKIs approved for frontline treatment of CML—imatinib, dasatinib, and nilotinib—produce “amazingly similar” responses, treatment compliance becomes an important factor in patient outcomes, he noted.

“If you take 90% of your imatinib, your MMR [major molecular response] is 90%,” he said. “Your CMR [complete molecular response] is 40%. So taking drug obviously trumps the decision of what drug to take.”

Dr Radich added that the major goal of treatment is to keep patients out of accelerated-phase blast crisis. Once people progress to blast crisis on a TKI, the median survival is less than 1 year.

“So that’s why you treat people aggressively, that’s why you monitor them molecularly, to prevent that from happening,” he said.

Treatment goals

Aside from preventing patients from progressing to blast crisis, treatment goals vary.

Achieving early molecular response (MR) impacts progression and survival, as does achieving a complete cytogenetic response (CCyR).

A major molecular response (MMR) is considered a “safe haven,” Dr Radich said, because once people achieve it, they almost never progress if they stay on drug.

And with a deep/complete molecular response (CMR), patients may potentially discontinue the drug.

So how your response goals line up determines how you use the agents for your treatment course, Dr Radich said.

In all response categories—patients with CCyR, MMR, MR, CMR—survival is virtually within 95% of survival for the general population.

“This is absolutely astonishing,” Dr Radich said.

He emphasized the importance of molecular testing at 3 months and achieving a BCR-ABL level of less than 10%.

Patients who have more than 10% blasts at 3 months have an 88% chance of achieving MMR at 4 years, while those who still have more than 10% blasts at 6 months have a 3.3% chance of achieving MMR at 4 years.

Toxicity

Side effects common to the 3 frontline TKIs are myelosuppression, transaminase elevation, and change in electrolytes. Dr Radich noted that imatinib doesn’t cause much myelosuppression.

“You can give imatinib on day 28 after allogeneic transplant, and it doesn’t affect the counts, which I think is pretty darn good proof that it doesn’t have any primary hematopoietic toxicity,” he said. “You can’t try that trick with the others.”

Venous and arterial cardiovascular events with TKIs are more recently coming to light.

Cardiovascular events with imatinib are about the same as the general population, Dr Radich said.

“[In] fact, some people think it might be protective,” he noted.

Discontinuation

“When we first started treating people with these drugs, we figured that they would be on them for life . . . ,” Dr Radich said. “[Y]ou’d always have a reservoir of CML cells because you can’t extinguish all the stem cells.”

A mathematical model predicted it would take 30 to 40 years to wipe out all CML cells with a TKI. The cumulative cure rate after 15 years of treatment would be 14%. After 30 years, it would be 31%.

Conducting a discontinuation trial would have been out of the question based on these predictions.

“Fortunately, some of the people who did the next trials hadn’t read that literature,” Dr Radich said.

One discontinuation trial (EURO-SKI) included patients who had been on drug for at least 3 years and had CMR for at least 1 year. About half stayed in PCR negativity, now up to 4 years.

A number of trials are now underway evaluating the possibility of TKI discontinuation, and they are showing that between 40% and 50% of patients can remain off drug for years.

Using generic imatinib

While generic imatinib is good for cost-effective, long-term use, second-generation TKIs are better at preventing accelerated-phase blast crisis, Dr Radich said.

The second generation is also better at producing deep remissions, and discontinuation could bring with it a cost savings.

Dr Radich calculated that it cost about $2.5 million for every patient who achieves treatment-free remission using a TKI, while transplant cost $1.31 million per patient who achieves treatment-free remission.

So generic imatinib is good for low- and intermediate-risk patients, as well as for older, sicker patients.

Second-generation TKIs are appropriate for higher-risk patients until they achieve a CCyR or MMR, then they can switch to generic imatinib.

And second-generation TKIs should be used for younger patients in whom drug discontinuation is important.

Frontline treatment observations

In summary, Dr Radich made the following observations about frontline treatment in CML.

• For overall survival, imatinib is equivalent to second-generation TKIs.
• To achieve a deep MR, a second-generation TKI is better than imatinib.
• Discontinuation is equally successful with all TKIs.
• For lower-risk CML, imatinib is equivalent to second-generation TKIs.
• When it comes to progression and possibly high-risk CML, second-generation TKIs are better than imatinib.
• Second-generation TKIs produce more long-term toxicities than imatinib.
• There is substantial cost savings with generics.
  

Imatinib (Gleevec) tablet

Photo by D. Meyer

NEW YORK—Evaluating treatment goals is essential when choosing which tyrosine kinase inhibitor (TKI) to prescribe for a patient with newly diagnosed chronic myeloid leukemia (CML), according to a speaker at the NCCN 11th Annual Congress: Hematologic Malignancies.

“Deciding what TKI to start people on really depends on what your goals are for that patient,” said the speaker, Jerald Radich, MD, of the Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance in Seattle, Washington.

Because the 3 TKIs approved for frontline treatment of CML—imatinib, dasatinib, and nilotinib—produce “amazingly similar” responses, treatment compliance becomes an important factor in patient outcomes, he noted.

“If you take 90% of your imatinib, your MMR [major molecular response] is 90%,” he said. “Your CMR [complete molecular response] is 40%. So taking drug obviously trumps the decision of what drug to take.”

Dr Radich added that the major goal of treatment is to keep patients out of accelerated-phase blast crisis. Once people progress to blast crisis on a TKI, the median survival is less than 1 year.

“So that’s why you treat people aggressively, that’s why you monitor them molecularly, to prevent that from happening,” he said.

Treatment goals

Aside from preventing patients from progressing to blast crisis, treatment goals vary.

Achieving early molecular response (MR) impacts progression and survival, as does achieving a complete cytogenetic response (CCyR).

A major molecular response (MMR) is considered a “safe haven,” Dr Radich said, because once people achieve it, they almost never progress if they stay on drug.

And with a deep/complete molecular response (CMR), patients may potentially discontinue the drug.

So how your response goals line up determines how you use the agents for your treatment course, Dr Radich said.

In all response categories—patients with CCyR, MMR, MR, CMR—survival is virtually within 95% of survival for the general population.

“This is absolutely astonishing,” Dr Radich said.

He emphasized the importance of molecular testing at 3 months and achieving a BCR-ABL level of less than 10%.

Patients who have more than 10% blasts at 3 months have an 88% chance of achieving MMR at 4 years, while those who still have more than 10% blasts at 6 months have a 3.3% chance of achieving MMR at 4 years.

Toxicity

Side effects common to the 3 frontline TKIs are myelosuppression, transaminase elevation, and change in electrolytes. Dr Radich noted that imatinib doesn’t cause much myelosuppression.

“You can give imatinib on day 28 after allogeneic transplant, and it doesn’t affect the counts, which I think is pretty darn good proof that it doesn’t have any primary hematopoietic toxicity,” he said. “You can’t try that trick with the others.”

Venous and arterial cardiovascular events with TKIs are more recently coming to light.

Cardiovascular events with imatinib are about the same as the general population, Dr Radich said.

“[In] fact, some people think it might be protective,” he noted.

Discontinuation

“When we first started treating people with these drugs, we figured that they would be on them for life . . . ,” Dr Radich said. “[Y]ou’d always have a reservoir of CML cells because you can’t extinguish all the stem cells.”

A mathematical model predicted it would take 30 to 40 years to wipe out all CML cells with a TKI. The cumulative cure rate after 15 years of treatment would be 14%. After 30 years, it would be 31%.

Conducting a discontinuation trial would have been out of the question based on these predictions.

“Fortunately, some of the people who did the next trials hadn’t read that literature,” Dr Radich said.

One discontinuation trial (EURO-SKI) included patients who had been on drug for at least 3 years and had CMR for at least 1 year. About half stayed in PCR negativity, now up to 4 years.

A number of trials are now underway evaluating the possibility of TKI discontinuation, and they are showing that between 40% and 50% of patients can remain off drug for years.

Using generic imatinib

While generic imatinib is good for cost-effective, long-term use, second-generation TKIs are better at preventing accelerated-phase blast crisis, Dr Radich said.

The second generation is also better at producing deep remissions, and discontinuation could bring with it a cost savings.

Dr Radich calculated that it cost about $2.5 million for every patient who achieves treatment-free remission using a TKI, while transplant cost $1.31 million per patient who achieves treatment-free remission.

So generic imatinib is good for low- and intermediate-risk patients, as well as for older, sicker patients.

Second-generation TKIs are appropriate for higher-risk patients until they achieve a CCyR or MMR, then they can switch to generic imatinib.

And second-generation TKIs should be used for younger patients in whom drug discontinuation is important.

Frontline treatment observations

In summary, Dr Radich made the following observations about frontline treatment in CML.

• For overall survival, imatinib is equivalent to second-generation TKIs.
• To achieve a deep MR, a second-generation TKI is better than imatinib.
• Discontinuation is equally successful with all TKIs.
• For lower-risk CML, imatinib is equivalent to second-generation TKIs.
• When it comes to progression and possibly high-risk CML, second-generation TKIs are better than imatinib.
• Second-generation TKIs produce more long-term toxicities than imatinib.
• There is substantial cost savings with generics.
  

Imatinib (Gleevec) tablet

Photo by D. Meyer

NEW YORK—Evaluating treatment goals is essential when choosing which tyrosine kinase inhibitor (TKI) to prescribe for a patient with newly diagnosed chronic myeloid leukemia (CML), according to a speaker at the NCCN 11th Annual Congress: Hematologic Malignancies.

“Deciding what TKI to start people on really depends on what your goals are for that patient,” said the speaker, Jerald Radich, MD, of the Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance in Seattle, Washington.

Because the 3 TKIs approved for frontline treatment of CML—imatinib, dasatinib, and nilotinib—produce “amazingly similar” responses, treatment compliance becomes an important factor in patient outcomes, he noted.

“If you take 90% of your imatinib, your MMR [major molecular response] is 90%,” he said. “Your CMR [complete molecular response] is 40%. So taking drug obviously trumps the decision of what drug to take.”

Dr Radich added that the major goal of treatment is to keep patients out of accelerated-phase blast crisis. Once people progress to blast crisis on a TKI, the median survival is less than 1 year.

“So that’s why you treat people aggressively, that’s why you monitor them molecularly, to prevent that from happening,” he said.

Treatment goals

Aside from preventing patients from progressing to blast crisis, treatment goals vary.

Achieving early molecular response (MR) impacts progression and survival, as does achieving a complete cytogenetic response (CCyR).

A major molecular response (MMR) is considered a “safe haven,” Dr Radich said, because once people achieve it, they almost never progress if they stay on drug.

And with a deep/complete molecular response (CMR), patients may potentially discontinue the drug.

So how your response goals line up determines how you use the agents for your treatment course, Dr Radich said.

In all response categories—patients with CCyR, MMR, MR, CMR—survival is virtually within 95% of survival for the general population.

“This is absolutely astonishing,” Dr Radich said.

He emphasized the importance of molecular testing at 3 months and achieving a BCR-ABL level of less than 10%.

Patients who have more than 10% blasts at 3 months have an 88% chance of achieving MMR at 4 years, while those who still have more than 10% blasts at 6 months have a 3.3% chance of achieving MMR at 4 years.

Toxicity

Side effects common to the 3 frontline TKIs are myelosuppression, transaminase elevation, and change in electrolytes. Dr Radich noted that imatinib doesn’t cause much myelosuppression.

“You can give imatinib on day 28 after allogeneic transplant, and it doesn’t affect the counts, which I think is pretty darn good proof that it doesn’t have any primary hematopoietic toxicity,” he said. “You can’t try that trick with the others.”

Venous and arterial cardiovascular events with TKIs are more recently coming to light.

Cardiovascular events with imatinib are about the same as the general population, Dr Radich said.

“[In] fact, some people think it might be protective,” he noted.

Discontinuation

“When we first started treating people with these drugs, we figured that they would be on them for life . . . ,” Dr Radich said. “[Y]ou’d always have a reservoir of CML cells because you can’t extinguish all the stem cells.”

A mathematical model predicted it would take 30 to 40 years to wipe out all CML cells with a TKI. The cumulative cure rate after 15 years of treatment would be 14%. After 30 years, it would be 31%.

Conducting a discontinuation trial would have been out of the question based on these predictions.

“Fortunately, some of the people who did the next trials hadn’t read that literature,” Dr Radich said.

One discontinuation trial (EURO-SKI) included patients who had been on drug for at least 3 years and had CMR for at least 1 year. About half stayed in PCR negativity, now up to 4 years.

A number of trials are now underway evaluating the possibility of TKI discontinuation, and they are showing that between 40% and 50% of patients can remain off drug for years.

Using generic imatinib

While generic imatinib is good for cost-effective, long-term use, second-generation TKIs are better at preventing accelerated-phase blast crisis, Dr Radich said.

The second generation is also better at producing deep remissions, and discontinuation could bring with it a cost savings.

Dr Radich calculated that it cost about $2.5 million for every patient who achieves treatment-free remission using a TKI, while transplant cost $1.31 million per patient who achieves treatment-free remission.

So generic imatinib is good for low- and intermediate-risk patients, as well as for older, sicker patients.

Second-generation TKIs are appropriate for higher-risk patients until they achieve a CCyR or MMR, then they can switch to generic imatinib.

And second-generation TKIs should be used for younger patients in whom drug discontinuation is important.

Frontline treatment observations

In summary, Dr Radich made the following observations about frontline treatment in CML.

• For overall survival, imatinib is equivalent to second-generation TKIs.
• To achieve a deep MR, a second-generation TKI is better than imatinib.
• Discontinuation is equally successful with all TKIs.
• For lower-risk CML, imatinib is equivalent to second-generation TKIs.
• When it comes to progression and possibly high-risk CML, second-generation TKIs are better than imatinib.
• Second-generation TKIs produce more long-term toxicities than imatinib.
• There is substantial cost savings with generics.
  

Stem cells for transplant
Photo by Chad McNeeley

CHICAGO—A phase 3 study of tandem autologous stem cell transplant (ASCT) for children with high-risk neuroblastoma has shown that tandem transplant as consolidation significantly improved event-free survival (EFS). 

Nevertheless, the improvement comes “with an important caveat,” according to Julie R. Park, MD, “that this is in children who survive induction without disease progression after induction or severe induction-related toxicity.” 

Of note, the tandem transplant did not increase toxicity or regimen-related mortality.

Dr Park, of the Seattle Children’s Hospital and University of Washington, presented the study data on behalf of the Children’s Oncology Group and the COG ANBL0532 Study Committee during the plenary session at the 2016 ASCO Annual Meeting (LBA3*).

Neuroblastoma, Dr Park explained, is a disease that occurs in young children and is the most common extracranial tumor of childhood. Patients with high-risk neuroblastoma account for 50% of all children diagnosed with the disease, and neuroblastoma accounts for more than 10% of all childhood cancer mortality. 

The outcome for high-risk neuroblastoma patients is dismal: fewer than 50% survive following current multi-agent, aggressive therapy, she said. 

Randomized clinical trials performed over the last 25 years “have taught us that dose intensification of therapy is important,” Dr Park said, “and the treatment of minimal residual disease with non-cross resistant therapies is equally important.” 

Pilot studies of tandem ASCT demonstrated tolerable toxicity and suggested efficacy, and clinical trials demonstrated that collecting peripheral blood stem cells in small children with neuroblastoma was feasible. 

So the investigators undertook the current study to improve 3-year EFS of high-risk neuroblastoma patients using a strategy of tandem transplant consolidation.

Eligibility

Patients with newly diagnosed high-risk neuroblastoma were eligible. They had to have metastatic disease (INSS stage 4) and be older than 18 months to be eligible for the trial.

They could be any age if they had INSS stage 2, 3, or 4 with MYCN amplification.

“Our prior studies had identified that the group with regional disease and toddlers with MYCN non-amplified metastatic disease had a better outcome compared to other children with high-risk neuroblastoma,” Dr Park commented. 

“Therefore, these children were non-randomly assigned to single transplant and are not included in the randomization results provided today,” she explained.

All children had to have normal cardiac, liver, and renal function.

Trial design: Induction

Induction therapy consisted of 6 cycles of chemotherapy—2 cycles of cyclophosphamide/topotecan, followed by 4 alternating cycles of cisplatin/etoposide and cyclophosphamide/vincristine/doxorubicin. 

Peripheral blood stem cells (PBSCs) were harvested after the first 2 cycles of dose intensive cyclophosphamide and topotecan.  

Patients had surgery on the primary tumor after 5 cycles of induction.

Trial design: Consolidation

Following completion of induction therapy, patients were assessed for eligibility for consolidation. These criteria included sufficient PBSC harvest, adequate organ function, no evidence of disease progression, and consent for post induction therapy.

Children eligible for consolidation were randomized to either the standard transplant with carboplatin, etoposide, melphalan or tandem transplant with cyclophosphamide and thiotepa followed 6 – 8 weeks later by the second transplant with carboplatin, etoposide, and melphalan.

Patients in both arms received radiotherapy to their primary tumor site. 

Trial Design: Post-consolidation

Patients then went on for post consolidation chemotherapy with isotretinoin.

“During the conduct of ANBL0532,” Dr Park pointed out, “there was an additional trial running within the Children’s Oncology Group for which patients were eligible to enroll.”

So from 2007 – 2009, the additional trial (ANBL0032) randomized patients to their then standard of isotretinoin or isotretinoin plus the anti-GD2 antibody dinutuximab and cytokines.

“In 2009, results of that study were released and the dinutuximab arm was superior,” she noted, so patients were no longer randomized to isotretinoin only.

Prior studies indicated that 40% of patients went off trial at the end of induction therapy, so the investigators enrolled 665 patients to ensure a randomization of at least 332 patients. 

Data cut-off for the presentation was March 31, 2016.

Patient demographics

Of the 665 patients accrued, 13 were ineligible. Twenty-seven patients with favorable prognosis were non-randomly assigned to single ASCT.

Forty percent (229 patients) went off protocol therapy prior to randomization. The main reasons for this were death (8 patients), progressive disease (48 patients), and physician and patient discretion (206 patients).

Investigators randomized 355 patients, 179 to single ASCT and 176 to tandem ASCT.

Patients were a median age of 37.2 months, 38.2% had MYCN amplification, and 88% were INSS stage 4.

The randomized cohorts of patients were similar to the overall patient cohort in terms of age, MYCN amplification, and stage 4 disease.

The randomizations were also well balanced in terms of MYCN amplifications, stage 4 disease, and response to induction chemotherapy.

The investigators retrospectively reviewed the patient characteristics, including age at diagnosis, early response to induction, and assignment to receive immunotherapy, “and there was no statistically significant difference between the randomized cohorts for these characteristics,” Dr Park said.

Safety

The most commonly observed grade 3 or greater non-hematologic toxicities in the single and tandem arms included infection (18.3% and 17.9%, respectively), mucosal toxicities (17.2% and 13.6%, respectively), and hepatic toxicities, including sinusoidal obstructive disorder (6.5% and 6.2%, respectively). 

The investigators observed no significant differences between the arms in regard to the rate of these toxicities. In addition, they observed no difference between the arms in the rate of regimen-related mortality, 4.1% in the single arm, and 1.2% in the tandem arm.

Efficacy

For all patients (n=652) from time of enrollment, the 3-year EFS was 51.0% and the 3-year OS was 68.3%.

In randomized patients (n=355), from the time of randomization, the 3-year EFS was 54.8% and the 3-year OS, 71.5%, with a median survival time of 4.6 years.

There was a statistically significant improvement in EFS for those patients assigned to tandem transplant, with a 3-year EFS of 61.4% as compared to those assigned to single transplant, who had a 3-year EFS of 48.4% (P=0.0081).

There was not a statistically significant difference in OS. However, Dr Park pointed out that the trial was not powered to detect a difference in overall survival. 

When looking at the cohort of stage 4 patients who were older than 18 months, investigators again saw a statistically significant improvement in EFS. The 3-year EFS was 59%.1 for tandem transplants vs 45.5% for single transplants, P=0.0083.

Again, there was no difference in OS in the INSS stage 4 patients older than 18 months.

“And finally, when we analyzed the outcome for children who were assigned to receive immunotherapy,” Dr Park pointed out, “from the time of start of immunotherapy, there was a statistically significant improvement in both event-free survival and overall survival for those children who received tandem transplants.”

The 3-year EFS for patients who received a tandem transplant and immunotherapy was 73.7% compared to the 3-year EFS of 56.0% for patients who received a single transplant and immunotherapy (P=0.0033). 

The 3-year overall survival was also significantly improved for patients who received tandem transplants and immunotherapy (83.7%) compared to those who received a single transplant and immunotherapy (74.4%) (P=0.0322).

Conclusions

“Tandem transplant consolidation improves outcome in patients with high-risk neuroblastoma,” Dr Park said, with the important caveat mentioned earlier.

The tandem transplant does not increase toxicity or regimen-related mortality, and the benefit of tandem ASCT remains following anti-GD2-directed immunotherapy.

*Data in the presentation differ slightly from the abstract

Stem cells for transplant
Photo by Chad McNeeley

CHICAGO—A phase 3 study of tandem autologous stem cell transplant (ASCT) for children with high-risk neuroblastoma has shown that tandem transplant as consolidation significantly improved event-free survival (EFS). 

Nevertheless, the improvement comes “with an important caveat,” according to Julie R. Park, MD, “that this is in children who survive induction without disease progression after induction or severe induction-related toxicity.” 

Of note, the tandem transplant did not increase toxicity or regimen-related mortality.

Dr Park, of the Seattle Children’s Hospital and University of Washington, presented the study data on behalf of the Children’s Oncology Group and the COG ANBL0532 Study Committee during the plenary session at the 2016 ASCO Annual Meeting (LBA3*).

Neuroblastoma, Dr Park explained, is a disease that occurs in young children and is the most common extracranial tumor of childhood. Patients with high-risk neuroblastoma account for 50% of all children diagnosed with the disease, and neuroblastoma accounts for more than 10% of all childhood cancer mortality. 

The outcome for high-risk neuroblastoma patients is dismal: fewer than 50% survive following current multi-agent, aggressive therapy, she said. 

Randomized clinical trials performed over the last 25 years “have taught us that dose intensification of therapy is important,” Dr Park said, “and the treatment of minimal residual disease with non-cross resistant therapies is equally important.” 

Pilot studies of tandem ASCT demonstrated tolerable toxicity and suggested efficacy, and clinical trials demonstrated that collecting peripheral blood stem cells in small children with neuroblastoma was feasible. 

So the investigators undertook the current study to improve 3-year EFS of high-risk neuroblastoma patients using a strategy of tandem transplant consolidation.

Eligibility

Patients with newly diagnosed high-risk neuroblastoma were eligible. They had to have metastatic disease (INSS stage 4) and be older than 18 months to be eligible for the trial.

They could be any age if they had INSS stage 2, 3, or 4 with MYCN amplification.

“Our prior studies had identified that the group with regional disease and toddlers with MYCN non-amplified metastatic disease had a better outcome compared to other children with high-risk neuroblastoma,” Dr Park commented. 

“Therefore, these children were non-randomly assigned to single transplant and are not included in the randomization results provided today,” she explained.

All children had to have normal cardiac, liver, and renal function.

Trial design: Induction

Induction therapy consisted of 6 cycles of chemotherapy—2 cycles of cyclophosphamide/topotecan, followed by 4 alternating cycles of cisplatin/etoposide and cyclophosphamide/vincristine/doxorubicin. 

Peripheral blood stem cells (PBSCs) were harvested after the first 2 cycles of dose intensive cyclophosphamide and topotecan.  

Patients had surgery on the primary tumor after 5 cycles of induction.

Trial design: Consolidation

Following completion of induction therapy, patients were assessed for eligibility for consolidation. These criteria included sufficient PBSC harvest, adequate organ function, no evidence of disease progression, and consent for post induction therapy.

Children eligible for consolidation were randomized to either the standard transplant with carboplatin, etoposide, melphalan or tandem transplant with cyclophosphamide and thiotepa followed 6 – 8 weeks later by the second transplant with carboplatin, etoposide, and melphalan.

Patients in both arms received radiotherapy to their primary tumor site. 

Trial Design: Post-consolidation

Patients then went on for post consolidation chemotherapy with isotretinoin.

“During the conduct of ANBL0532,” Dr Park pointed out, “there was an additional trial running within the Children’s Oncology Group for which patients were eligible to enroll.”

So from 2007 – 2009, the additional trial (ANBL0032) randomized patients to their then standard of isotretinoin or isotretinoin plus the anti-GD2 antibody dinutuximab and cytokines.

“In 2009, results of that study were released and the dinutuximab arm was superior,” she noted, so patients were no longer randomized to isotretinoin only.

Prior studies indicated that 40% of patients went off trial at the end of induction therapy, so the investigators enrolled 665 patients to ensure a randomization of at least 332 patients. 

Data cut-off for the presentation was March 31, 2016.

Patient demographics

Of the 665 patients accrued, 13 were ineligible. Twenty-seven patients with favorable prognosis were non-randomly assigned to single ASCT.

Forty percent (229 patients) went off protocol therapy prior to randomization. The main reasons for this were death (8 patients), progressive disease (48 patients), and physician and patient discretion (206 patients).

Investigators randomized 355 patients, 179 to single ASCT and 176 to tandem ASCT.

Patients were a median age of 37.2 months, 38.2% had MYCN amplification, and 88% were INSS stage 4.

The randomized cohorts of patients were similar to the overall patient cohort in terms of age, MYCN amplification, and stage 4 disease.

The randomizations were also well balanced in terms of MYCN amplifications, stage 4 disease, and response to induction chemotherapy.

The investigators retrospectively reviewed the patient characteristics, including age at diagnosis, early response to induction, and assignment to receive immunotherapy, “and there was no statistically significant difference between the randomized cohorts for these characteristics,” Dr Park said.

Safety

The most commonly observed grade 3 or greater non-hematologic toxicities in the single and tandem arms included infection (18.3% and 17.9%, respectively), mucosal toxicities (17.2% and 13.6%, respectively), and hepatic toxicities, including sinusoidal obstructive disorder (6.5% and 6.2%, respectively). 

The investigators observed no significant differences between the arms in regard to the rate of these toxicities. In addition, they observed no difference between the arms in the rate of regimen-related mortality, 4.1% in the single arm, and 1.2% in the tandem arm.

Efficacy

For all patients (n=652) from time of enrollment, the 3-year EFS was 51.0% and the 3-year OS was 68.3%.

In randomized patients (n=355), from the time of randomization, the 3-year EFS was 54.8% and the 3-year OS, 71.5%, with a median survival time of 4.6 years.

There was a statistically significant improvement in EFS for those patients assigned to tandem transplant, with a 3-year EFS of 61.4% as compared to those assigned to single transplant, who had a 3-year EFS of 48.4% (P=0.0081).

There was not a statistically significant difference in OS. However, Dr Park pointed out that the trial was not powered to detect a difference in overall survival. 

When looking at the cohort of stage 4 patients who were older than 18 months, investigators again saw a statistically significant improvement in EFS. The 3-year EFS was 59%.1 for tandem transplants vs 45.5% for single transplants, P=0.0083.

Again, there was no difference in OS in the INSS stage 4 patients older than 18 months.

“And finally, when we analyzed the outcome for children who were assigned to receive immunotherapy,” Dr Park pointed out, “from the time of start of immunotherapy, there was a statistically significant improvement in both event-free survival and overall survival for those children who received tandem transplants.”

The 3-year EFS for patients who received a tandem transplant and immunotherapy was 73.7% compared to the 3-year EFS of 56.0% for patients who received a single transplant and immunotherapy (P=0.0033). 

The 3-year overall survival was also significantly improved for patients who received tandem transplants and immunotherapy (83.7%) compared to those who received a single transplant and immunotherapy (74.4%) (P=0.0322).

Conclusions

“Tandem transplant consolidation improves outcome in patients with high-risk neuroblastoma,” Dr Park said, with the important caveat mentioned earlier.

The tandem transplant does not increase toxicity or regimen-related mortality, and the benefit of tandem ASCT remains following anti-GD2-directed immunotherapy.

*Data in the presentation differ slightly from the abstract

Stem cells for transplant
Photo by Chad McNeeley

CHICAGO—A phase 3 study of tandem autologous stem cell transplant (ASCT) for children with high-risk neuroblastoma has shown that tandem transplant as consolidation significantly improved event-free survival (EFS). 

Nevertheless, the improvement comes “with an important caveat,” according to Julie R. Park, MD, “that this is in children who survive induction without disease progression after induction or severe induction-related toxicity.” 

Of note, the tandem transplant did not increase toxicity or regimen-related mortality.

Dr Park, of the Seattle Children’s Hospital and University of Washington, presented the study data on behalf of the Children’s Oncology Group and the COG ANBL0532 Study Committee during the plenary session at the 2016 ASCO Annual Meeting (LBA3*).

Neuroblastoma, Dr Park explained, is a disease that occurs in young children and is the most common extracranial tumor of childhood. Patients with high-risk neuroblastoma account for 50% of all children diagnosed with the disease, and neuroblastoma accounts for more than 10% of all childhood cancer mortality. 

The outcome for high-risk neuroblastoma patients is dismal: fewer than 50% survive following current multi-agent, aggressive therapy, she said. 

Randomized clinical trials performed over the last 25 years “have taught us that dose intensification of therapy is important,” Dr Park said, “and the treatment of minimal residual disease with non-cross resistant therapies is equally important.” 

Pilot studies of tandem ASCT demonstrated tolerable toxicity and suggested efficacy, and clinical trials demonstrated that collecting peripheral blood stem cells in small children with neuroblastoma was feasible. 

So the investigators undertook the current study to improve 3-year EFS of high-risk neuroblastoma patients using a strategy of tandem transplant consolidation.

Eligibility

Patients with newly diagnosed high-risk neuroblastoma were eligible. They had to have metastatic disease (INSS stage 4) and be older than 18 months to be eligible for the trial.

They could be any age if they had INSS stage 2, 3, or 4 with MYCN amplification.

“Our prior studies had identified that the group with regional disease and toddlers with MYCN non-amplified metastatic disease had a better outcome compared to other children with high-risk neuroblastoma,” Dr Park commented. 

“Therefore, these children were non-randomly assigned to single transplant and are not included in the randomization results provided today,” she explained.

All children had to have normal cardiac, liver, and renal function.

Trial design: Induction

Induction therapy consisted of 6 cycles of chemotherapy—2 cycles of cyclophosphamide/topotecan, followed by 4 alternating cycles of cisplatin/etoposide and cyclophosphamide/vincristine/doxorubicin. 

Peripheral blood stem cells (PBSCs) were harvested after the first 2 cycles of dose intensive cyclophosphamide and topotecan.  

Patients had surgery on the primary tumor after 5 cycles of induction.

Trial design: Consolidation

Following completion of induction therapy, patients were assessed for eligibility for consolidation. These criteria included sufficient PBSC harvest, adequate organ function, no evidence of disease progression, and consent for post induction therapy.

Children eligible for consolidation were randomized to either the standard transplant with carboplatin, etoposide, melphalan or tandem transplant with cyclophosphamide and thiotepa followed 6 – 8 weeks later by the second transplant with carboplatin, etoposide, and melphalan.

Patients in both arms received radiotherapy to their primary tumor site. 

Trial Design: Post-consolidation

Patients then went on for post consolidation chemotherapy with isotretinoin.

“During the conduct of ANBL0532,” Dr Park pointed out, “there was an additional trial running within the Children’s Oncology Group for which patients were eligible to enroll.”

So from 2007 – 2009, the additional trial (ANBL0032) randomized patients to their then standard of isotretinoin or isotretinoin plus the anti-GD2 antibody dinutuximab and cytokines.

“In 2009, results of that study were released and the dinutuximab arm was superior,” she noted, so patients were no longer randomized to isotretinoin only.

Prior studies indicated that 40% of patients went off trial at the end of induction therapy, so the investigators enrolled 665 patients to ensure a randomization of at least 332 patients. 

Data cut-off for the presentation was March 31, 2016.

Patient demographics

Of the 665 patients accrued, 13 were ineligible. Twenty-seven patients with favorable prognosis were non-randomly assigned to single ASCT.

Forty percent (229 patients) went off protocol therapy prior to randomization. The main reasons for this were death (8 patients), progressive disease (48 patients), and physician and patient discretion (206 patients).

Investigators randomized 355 patients, 179 to single ASCT and 176 to tandem ASCT.

Patients were a median age of 37.2 months, 38.2% had MYCN amplification, and 88% were INSS stage 4.

The randomized cohorts of patients were similar to the overall patient cohort in terms of age, MYCN amplification, and stage 4 disease.

The randomizations were also well balanced in terms of MYCN amplifications, stage 4 disease, and response to induction chemotherapy.

The investigators retrospectively reviewed the patient characteristics, including age at diagnosis, early response to induction, and assignment to receive immunotherapy, “and there was no statistically significant difference between the randomized cohorts for these characteristics,” Dr Park said.

Safety

The most commonly observed grade 3 or greater non-hematologic toxicities in the single and tandem arms included infection (18.3% and 17.9%, respectively), mucosal toxicities (17.2% and 13.6%, respectively), and hepatic toxicities, including sinusoidal obstructive disorder (6.5% and 6.2%, respectively). 

The investigators observed no significant differences between the arms in regard to the rate of these toxicities. In addition, they observed no difference between the arms in the rate of regimen-related mortality, 4.1% in the single arm, and 1.2% in the tandem arm.

Efficacy

For all patients (n=652) from time of enrollment, the 3-year EFS was 51.0% and the 3-year OS was 68.3%.

In randomized patients (n=355), from the time of randomization, the 3-year EFS was 54.8% and the 3-year OS, 71.5%, with a median survival time of 4.6 years.

There was a statistically significant improvement in EFS for those patients assigned to tandem transplant, with a 3-year EFS of 61.4% as compared to those assigned to single transplant, who had a 3-year EFS of 48.4% (P=0.0081).

There was not a statistically significant difference in OS. However, Dr Park pointed out that the trial was not powered to detect a difference in overall survival. 

When looking at the cohort of stage 4 patients who were older than 18 months, investigators again saw a statistically significant improvement in EFS. The 3-year EFS was 59%.1 for tandem transplants vs 45.5% for single transplants, P=0.0083.

Again, there was no difference in OS in the INSS stage 4 patients older than 18 months.

“And finally, when we analyzed the outcome for children who were assigned to receive immunotherapy,” Dr Park pointed out, “from the time of start of immunotherapy, there was a statistically significant improvement in both event-free survival and overall survival for those children who received tandem transplants.”

The 3-year EFS for patients who received a tandem transplant and immunotherapy was 73.7% compared to the 3-year EFS of 56.0% for patients who received a single transplant and immunotherapy (P=0.0033). 

The 3-year overall survival was also significantly improved for patients who received tandem transplants and immunotherapy (83.7%) compared to those who received a single transplant and immunotherapy (74.4%) (P=0.0322).

Conclusions

“Tandem transplant consolidation improves outcome in patients with high-risk neuroblastoma,” Dr Park said, with the important caveat mentioned earlier.

The tandem transplant does not increase toxicity or regimen-related mortality, and the benefit of tandem ASCT remains following anti-GD2-directed immunotherapy.

*Data in the presentation differ slightly from the abstract

Stairway at McCormick Place,
site of ASCO Annual Meeting
© ASCO/Todd Buchanan

CHICAGO—Investigators are pursuing the combination of the selective BCL-2 inhibitor venetoclax plus low-dose cytarabine (LDAC) in older, treatment-naïve patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy.

These patients have few treatment options, and to date, the combination is achieving significant reduction in bone marrow and peripheral blast counts.

The combination has also achieved some complete responses, including those with incomplete marrow recovery, for a complete response (CR) rate of 54%. By comparison, expected CR rates with LDAC are about 10%.

Tara L. Lin, MD, of the University of Kansas Medical Center in Kansas City, reported the results of the non-randomized, open-label phase 1/2 dose-escalation/expansion study as abstract 7007* at the 2016 ASCO Annual Meeting.

Dr Lin reported on the 18 patients enrolled in the phase 1 portion and on an additional 8 patients treated in the phase 2 portion.

Objectives of the study were safety, efficacy, and exploratory for biomarkers predictive of outcome.

Dr Lin noted that the entire study had almost reached full enrollment early in May, and an additional 50 patients had been treated on the phase 2 portion to date.

Eligibility criteria

Patients 65 years or older with untreated AML were eligible to enroll. They could not be eligible for standard induction therapy, and they had to have ECOG performance status of 0 – 2.

Patients were excluded if they had received cytarabine previously for a pre-existing myeloid disorder, acute promyelocytic leukemia, or active central nervous system involvement with AML.

Dosing schedule

In the phase 1 portion, patients received venetoclax orally once daily on days 2 – 28 of cycle 1 and days 1 – 28 of subsequent cycles, which were 28 days.

They received LDAC at 20 mg/m² subcutaneously on days 1 – 10 of all cycles.

The venetoclax dose escalated from 50 mg to 600 mg in 6 days for dose level 1, and from 100 mg to 800 mg in 6 days for dose level 2.

Every patient was hospitalized prior to the initiation of therapy and aggressive tumor lysis prophylaxis begun at least 48 hours prior to venetoclax administration during cycle 1 and 24 hours prior to start of LDAC.

Once the patients had received prophylaxis and had a white blood cell count <25,000/μL, they were able to begin therapy starting with LDAC on day 1 and continuing through day 10.

No patient received venetoclax on day 1, Dr Lin emphasized.

Instead venetoclax began 24 hours after the LDAC, starting on day 2, and dose escalated each day until patients reached the maximum dose that was designed for their cohort level, which was then continued on days 6 – 28.

“A dose-limiting toxicity of thrombocytopenia was identified in the phase 1 portion,” Dr Lin said, “which led to the phase 2 dose recommendation of 600 mg daily of venetoclax.”

Demographics

Twenty-six patients were evaluable at the time of the presentation, 16 in the venetoclax 600-mg dose group and 10 in the 800-mg dose group.

The patients were a median of 75 years (range 66 – 87).

Sixty-five percent were males, 62% were ECOG status 1, and 19% (5 patients) had received prior hypomethylating treatment for pre-existing myelodysplastic syndromes.

Thirty-eight percent had bone marrow blast counts of 51% or greater.

Safety

Treatment-emergent adverse events (TEAEs), excluding cytopenias, occurring in 30% or more of patients included nausea (77%), fatigue (42%), febrile neutropenia (38%), diarrhea (35%), and vomiting (31%).

Grade 3/4 TEAEs, excluding cytopenias, occurring in 10% or more of patients included febrile neutropenia (38%), hypertension (12%), hyponatremia (12%), and hypophosphatemia (12%).

“In general,” Dr Lin said, “the drug was very well tolerated and patients were not discontinuing therapy because of side effects.”

Pharmacokinetics

At day 10, which coincided with the end day of the co-administration of the 2 drugs, and again, at day 18, when patients were receiving venetoclax alone, no differences were seen in either the C_max per dose or AUC per dose between day 10 and day 18.

So the co-administration of LDAC did not markedly affect venetoclax exposures.

Efficacy

The overall response rate, consisting of CR plus CRi plus partial responses (PR), totaled 58% (15/26) of all patients.

Nine patients (35%) had resistant or progressive disease; 2 had incomplete data due to discontinuation.

Most patients (79%)—19 of 24—had a decrease in bone marrow blast count of over 50%, and 88% (15/17) had a decrease in peripheral blast count of over 50%.

Responses of patients who had received hypomethylating agents did not differ from those who had not.

The investigators also evaluated the impact of a prior myeloproliferative neoplasm (MPN) (n=4) on outcome and found that none of these patients had a response to therapy. 

However, patients who did not have a previous MPN had a response rate of 68%.

Survival

At 12 months, overall survival (OS) in all patients was 57.6%. If MPN patients were not included in the analysis, the OS increased to 70.5%.

The 11 non-responders had a median OS of 4 months, while for the 15 responders (CR, Cri, PR) the median OS has not yet been reached.

“This data, in terms of taking into account the safety data, how well it appears to have been tolerated by the patients, and these overall response data,” Dr Lin said, “certainly suggest that venetoclax plus low-dose araC appears to have significant activity in this older patient population and . . .  is worth further study for this patient group.”

Venetoclax has demonstrated single-agent activity in heavily pretreated patients with relapsed/refractory AML. It received accelerated approval from the US Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia (CLL), and has 3 breakthrough therapy designations from the FDA—one in combination with hypomethylating agents for treatment-naïve AML, one in relapsed or refractory CLL, and one in combination with rituximab for relapsed/refractory CLL.

The European Commission also granted venetoclax orphan designation for AML.

Venetoclax is being developed by AbbVie in collaboration with Genentech. AbbVie and Genentech provided financial support for the study and participated in the design, study conduct, analysis, and interpretation of data.

*Data in the abstract differ from the presentation.

Stairway at McCormick Place,
site of ASCO Annual Meeting
© ASCO/Todd Buchanan

CHICAGO—Investigators are pursuing the combination of the selective BCL-2 inhibitor venetoclax plus low-dose cytarabine (LDAC) in older, treatment-naïve patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy.

These patients have few treatment options, and to date, the combination is achieving significant reduction in bone marrow and peripheral blast counts.

The combination has also achieved some complete responses, including those with incomplete marrow recovery, for a complete response (CR) rate of 54%. By comparison, expected CR rates with LDAC are about 10%.

Tara L. Lin, MD, of the University of Kansas Medical Center in Kansas City, reported the results of the non-randomized, open-label phase 1/2 dose-escalation/expansion study as abstract 7007* at the 2016 ASCO Annual Meeting.

Dr Lin reported on the 18 patients enrolled in the phase 1 portion and on an additional 8 patients treated in the phase 2 portion.

Objectives of the study were safety, efficacy, and exploratory for biomarkers predictive of outcome.

Dr Lin noted that the entire study had almost reached full enrollment early in May, and an additional 50 patients had been treated on the phase 2 portion to date.

Eligibility criteria

Patients 65 years or older with untreated AML were eligible to enroll. They could not be eligible for standard induction therapy, and they had to have ECOG performance status of 0 – 2.

Patients were excluded if they had received cytarabine previously for a pre-existing myeloid disorder, acute promyelocytic leukemia, or active central nervous system involvement with AML.

Dosing schedule

In the phase 1 portion, patients received venetoclax orally once daily on days 2 – 28 of cycle 1 and days 1 – 28 of subsequent cycles, which were 28 days.

They received LDAC at 20 mg/m² subcutaneously on days 1 – 10 of all cycles.

The venetoclax dose escalated from 50 mg to 600 mg in 6 days for dose level 1, and from 100 mg to 800 mg in 6 days for dose level 2.

Every patient was hospitalized prior to the initiation of therapy and aggressive tumor lysis prophylaxis begun at least 48 hours prior to venetoclax administration during cycle 1 and 24 hours prior to start of LDAC.

Once the patients had received prophylaxis and had a white blood cell count <25,000/μL, they were able to begin therapy starting with LDAC on day 1 and continuing through day 10.

No patient received venetoclax on day 1, Dr Lin emphasized.

Instead venetoclax began 24 hours after the LDAC, starting on day 2, and dose escalated each day until patients reached the maximum dose that was designed for their cohort level, which was then continued on days 6 – 28.

“A dose-limiting toxicity of thrombocytopenia was identified in the phase 1 portion,” Dr Lin said, “which led to the phase 2 dose recommendation of 600 mg daily of venetoclax.”

Demographics

Twenty-six patients were evaluable at the time of the presentation, 16 in the venetoclax 600-mg dose group and 10 in the 800-mg dose group.

The patients were a median of 75 years (range 66 – 87).

Sixty-five percent were males, 62% were ECOG status 1, and 19% (5 patients) had received prior hypomethylating treatment for pre-existing myelodysplastic syndromes.

Thirty-eight percent had bone marrow blast counts of 51% or greater.

Safety

Treatment-emergent adverse events (TEAEs), excluding cytopenias, occurring in 30% or more of patients included nausea (77%), fatigue (42%), febrile neutropenia (38%), diarrhea (35%), and vomiting (31%).

Grade 3/4 TEAEs, excluding cytopenias, occurring in 10% or more of patients included febrile neutropenia (38%), hypertension (12%), hyponatremia (12%), and hypophosphatemia (12%).

“In general,” Dr Lin said, “the drug was very well tolerated and patients were not discontinuing therapy because of side effects.”

Pharmacokinetics

At day 10, which coincided with the end day of the co-administration of the 2 drugs, and again, at day 18, when patients were receiving venetoclax alone, no differences were seen in either the C_max per dose or AUC per dose between day 10 and day 18.

So the co-administration of LDAC did not markedly affect venetoclax exposures.

Efficacy

The overall response rate, consisting of CR plus CRi plus partial responses (PR), totaled 58% (15/26) of all patients.

Nine patients (35%) had resistant or progressive disease; 2 had incomplete data due to discontinuation.

Most patients (79%)—19 of 24—had a decrease in bone marrow blast count of over 50%, and 88% (15/17) had a decrease in peripheral blast count of over 50%.

Responses of patients who had received hypomethylating agents did not differ from those who had not.

The investigators also evaluated the impact of a prior myeloproliferative neoplasm (MPN) (n=4) on outcome and found that none of these patients had a response to therapy. 

However, patients who did not have a previous MPN had a response rate of 68%.

Survival

At 12 months, overall survival (OS) in all patients was 57.6%. If MPN patients were not included in the analysis, the OS increased to 70.5%.

The 11 non-responders had a median OS of 4 months, while for the 15 responders (CR, Cri, PR) the median OS has not yet been reached.

“This data, in terms of taking into account the safety data, how well it appears to have been tolerated by the patients, and these overall response data,” Dr Lin said, “certainly suggest that venetoclax plus low-dose araC appears to have significant activity in this older patient population and . . .  is worth further study for this patient group.”

Venetoclax has demonstrated single-agent activity in heavily pretreated patients with relapsed/refractory AML. It received accelerated approval from the US Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia (CLL), and has 3 breakthrough therapy designations from the FDA—one in combination with hypomethylating agents for treatment-naïve AML, one in relapsed or refractory CLL, and one in combination with rituximab for relapsed/refractory CLL.

The European Commission also granted venetoclax orphan designation for AML.

Venetoclax is being developed by AbbVie in collaboration with Genentech. AbbVie and Genentech provided financial support for the study and participated in the design, study conduct, analysis, and interpretation of data.

*Data in the abstract differ from the presentation.

Stairway at McCormick Place,
site of ASCO Annual Meeting
© ASCO/Todd Buchanan

CHICAGO—Investigators are pursuing the combination of the selective BCL-2 inhibitor venetoclax plus low-dose cytarabine (LDAC) in older, treatment-naïve patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy.

These patients have few treatment options, and to date, the combination is achieving significant reduction in bone marrow and peripheral blast counts.

The combination has also achieved some complete responses, including those with incomplete marrow recovery, for a complete response (CR) rate of 54%. By comparison, expected CR rates with LDAC are about 10%.

Tara L. Lin, MD, of the University of Kansas Medical Center in Kansas City, reported the results of the non-randomized, open-label phase 1/2 dose-escalation/expansion study as abstract 7007* at the 2016 ASCO Annual Meeting.

Dr Lin reported on the 18 patients enrolled in the phase 1 portion and on an additional 8 patients treated in the phase 2 portion.

Objectives of the study were safety, efficacy, and exploratory for biomarkers predictive of outcome.

Dr Lin noted that the entire study had almost reached full enrollment early in May, and an additional 50 patients had been treated on the phase 2 portion to date.

Eligibility criteria

Patients 65 years or older with untreated AML were eligible to enroll. They could not be eligible for standard induction therapy, and they had to have ECOG performance status of 0 – 2.

Patients were excluded if they had received cytarabine previously for a pre-existing myeloid disorder, acute promyelocytic leukemia, or active central nervous system involvement with AML.

Dosing schedule

In the phase 1 portion, patients received venetoclax orally once daily on days 2 – 28 of cycle 1 and days 1 – 28 of subsequent cycles, which were 28 days.

They received LDAC at 20 mg/m² subcutaneously on days 1 – 10 of all cycles.

The venetoclax dose escalated from 50 mg to 600 mg in 6 days for dose level 1, and from 100 mg to 800 mg in 6 days for dose level 2.

Every patient was hospitalized prior to the initiation of therapy and aggressive tumor lysis prophylaxis begun at least 48 hours prior to venetoclax administration during cycle 1 and 24 hours prior to start of LDAC.

Once the patients had received prophylaxis and had a white blood cell count <25,000/μL, they were able to begin therapy starting with LDAC on day 1 and continuing through day 10.

No patient received venetoclax on day 1, Dr Lin emphasized.

Instead venetoclax began 24 hours after the LDAC, starting on day 2, and dose escalated each day until patients reached the maximum dose that was designed for their cohort level, which was then continued on days 6 – 28.

“A dose-limiting toxicity of thrombocytopenia was identified in the phase 1 portion,” Dr Lin said, “which led to the phase 2 dose recommendation of 600 mg daily of venetoclax.”

Demographics

Twenty-six patients were evaluable at the time of the presentation, 16 in the venetoclax 600-mg dose group and 10 in the 800-mg dose group.

The patients were a median of 75 years (range 66 – 87).

Sixty-five percent were males, 62% were ECOG status 1, and 19% (5 patients) had received prior hypomethylating treatment for pre-existing myelodysplastic syndromes.

Thirty-eight percent had bone marrow blast counts of 51% or greater.

Safety

Treatment-emergent adverse events (TEAEs), excluding cytopenias, occurring in 30% or more of patients included nausea (77%), fatigue (42%), febrile neutropenia (38%), diarrhea (35%), and vomiting (31%).

Grade 3/4 TEAEs, excluding cytopenias, occurring in 10% or more of patients included febrile neutropenia (38%), hypertension (12%), hyponatremia (12%), and hypophosphatemia (12%).

“In general,” Dr Lin said, “the drug was very well tolerated and patients were not discontinuing therapy because of side effects.”

Pharmacokinetics

At day 10, which coincided with the end day of the co-administration of the 2 drugs, and again, at day 18, when patients were receiving venetoclax alone, no differences were seen in either the C_max per dose or AUC per dose between day 10 and day 18.

So the co-administration of LDAC did not markedly affect venetoclax exposures.

Efficacy

The overall response rate, consisting of CR plus CRi plus partial responses (PR), totaled 58% (15/26) of all patients.

Nine patients (35%) had resistant or progressive disease; 2 had incomplete data due to discontinuation.

Most patients (79%)—19 of 24—had a decrease in bone marrow blast count of over 50%, and 88% (15/17) had a decrease in peripheral blast count of over 50%.

Responses of patients who had received hypomethylating agents did not differ from those who had not.

The investigators also evaluated the impact of a prior myeloproliferative neoplasm (MPN) (n=4) on outcome and found that none of these patients had a response to therapy. 

However, patients who did not have a previous MPN had a response rate of 68%.

Survival

At 12 months, overall survival (OS) in all patients was 57.6%. If MPN patients were not included in the analysis, the OS increased to 70.5%.

The 11 non-responders had a median OS of 4 months, while for the 15 responders (CR, Cri, PR) the median OS has not yet been reached.

“This data, in terms of taking into account the safety data, how well it appears to have been tolerated by the patients, and these overall response data,” Dr Lin said, “certainly suggest that venetoclax plus low-dose araC appears to have significant activity in this older patient population and . . .  is worth further study for this patient group.”

Venetoclax has demonstrated single-agent activity in heavily pretreated patients with relapsed/refractory AML. It received accelerated approval from the US Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia (CLL), and has 3 breakthrough therapy designations from the FDA—one in combination with hypomethylating agents for treatment-naïve AML, one in relapsed or refractory CLL, and one in combination with rituximab for relapsed/refractory CLL.

The European Commission also granted venetoclax orphan designation for AML.

Venetoclax is being developed by AbbVie in collaboration with Genentech. AbbVie and Genentech provided financial support for the study and participated in the design, study conduct, analysis, and interpretation of data.

*Data in the abstract differ from the presentation.

ASCO Annual Meeting 2016

© ASCO/Matt Herp

CHICAGO—The first interim analysis of rituximab plus chemotherapy in children and adolescents with high-risk B-cell non-Hodgkin lymphoma (B-NHL) and acute leukemia has yielded results that “will change our clinical practice,” according to Veronique Minard-Colin, MD, PhD, one of the study investigators.

Patients who received rituximab had 13% better event-free survival (EFS) than those who did not. “The new standard of care will be rituximab plus chemotherapy,” she said, for these high-risk patients.

“And it is very unlikely that this outcome will change if the study continues,” she added.

Dr Minard-Colin, of Institut Gustave Roussy in Villejuif, France, presented the interim analysis of the phase 3 Intergroup trial Inter-B-NHL Ritux 2010 at the 2016 ASCO Annual Meeting as abstract 10507.

She explained that when the study was started in 2010, there was a clear need to demonstrate the effectiveness of rituximab in childhood B-NHL.

So the investigators conducted the trial, which took place in 292 sites in 12 countries.

The investigators enrolled 310 patients under the age of 18 years who had mature B-NHL, including Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), high-grade B-NHL not otherwise specified, and B-cell acute leukemia (B-AL). The investigators excluded patients with primary mediastinal B-cell lymphoma.

They defined advanced stages as stage III with LDH levels more than twice normal, any stage IV disease, or B-AL.

They randomized patients to receive the French LMB chemotherapy regimen either with or without rituximab—6 doses at 375 mg/m2.

The randomization was stratified based on national group, histology, and therapeutic group. Group B patients were in stage III or IV, with no central nervous system symptoms; group C1 patients were stage IV/B-AL with cerebrospinal fluid (CSF) negative; and group C3 patients were CSF positive.

One hundred fifty-five patients were randomized to receive rituximab, and 155 were randomized to the control arm.

The primary endpoint was improvement in EFS. Secondary endpoints included complete remission (CR) rate, overall survival (OS), safety, immunity status, and long-term risks.

Investigators performed the first interim analysis after 27 events occurred.

Patient characteristics

Patients were a median age of 8.2 years, 45% were stage III with high LDH, and 85% had Burkitt lymphoma.

About half (51%) the patients were in group B, 39% in C1, and 10% in C3.

Toxicity

There were 6 deaths due to toxicity, 3 in each arm.

Dr Minard-Colin indicated that this number reflects the high toxicity of the LMB regimen and is “similar” to the previous rate of toxic deaths observed in the international LMB 96 study.

She added, “Importantly, 5 out of 6 toxic deaths occurred in group C. The only patient who died in group B died of surgical complications after extensive inappropriate surgery at diagnosis.”

Toxicity was similar between the 2 arms except for the high rate of febrile neutropenia after the third course of cytarabine and etoposide in the rituximab arm (50% vs 34%, P=0.012).

Of the 27 events, 20 occurred in the control arm and 7 in the rituximab arm.

The control arm had 17 lymphoma events, while the rituximab arm had 3.

Only 1 patient relapsed in the rituximab arm compared to 12 who relapsed in the control arm.  And no patient died of lymphoma in the rituximab arm, while 2 died of lymphoma in the control arm.

One second malignancy, melanoma, occurred in the rituximab arm.

Dr Minard-Colin noted that all events occurred in the first year after randomization

Efficacy

Event-free survival at 1 year was 94.2% in the rituximab arm and 81.5% in the control arm.

However, the investigators could not definitely conclude superiority for the rituximab arm because the P value was higher than the significance level of 0.0014 required for this first interim analysis. The hazard ratio was 0.33 (90%CI: 0.16-0.69), P = 0.006.

The investigators performed additional analyses and found the probability of getting a positive study at final analysis was very high, from 99% – 100%.

This past November, following the recommendation of the independent monitoring committee, sponsors decided to halt the randomization and continue follow-up of all patients so as to have mature data.

And in March of this year, they reopened the study with single-arm rituximab for 120 additional patients to answer the secondary objectives.

Dr Minard-Colin emphasized that the results are consistent with the recently performed LMBA02 trial in adult Burkitt lymphoma, with a gain of 13% in EFS for the rituximab arm. The 3-year EFS was 62% in the control arm compared with 75% in the rituximab arm (HR 0.59).

So while rituximab in high-risk patients appears to be practice changing, “in the standard- risk patients,” she added, “the use of rituximab is questionable.”

Sponsors of the trial are Gustave Roussy Cancer, Children’s Oncology Group, and Roche.

Data analyses will be conducted annually hereafter.

ASCO Annual Meeting 2016

© ASCO/Matt Herp

CHICAGO—The first interim analysis of rituximab plus chemotherapy in children and adolescents with high-risk B-cell non-Hodgkin lymphoma (B-NHL) and acute leukemia has yielded results that “will change our clinical practice,” according to Veronique Minard-Colin, MD, PhD, one of the study investigators.

Patients who received rituximab had 13% better event-free survival (EFS) than those who did not. “The new standard of care will be rituximab plus chemotherapy,” she said, for these high-risk patients.

“And it is very unlikely that this outcome will change if the study continues,” she added.

Dr Minard-Colin, of Institut Gustave Roussy in Villejuif, France, presented the interim analysis of the phase 3 Intergroup trial Inter-B-NHL Ritux 2010 at the 2016 ASCO Annual Meeting as abstract 10507.

She explained that when the study was started in 2010, there was a clear need to demonstrate the effectiveness of rituximab in childhood B-NHL.

So the investigators conducted the trial, which took place in 292 sites in 12 countries.

The investigators enrolled 310 patients under the age of 18 years who had mature B-NHL, including Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), high-grade B-NHL not otherwise specified, and B-cell acute leukemia (B-AL). The investigators excluded patients with primary mediastinal B-cell lymphoma.

They defined advanced stages as stage III with LDH levels more than twice normal, any stage IV disease, or B-AL.

They randomized patients to receive the French LMB chemotherapy regimen either with or without rituximab—6 doses at 375 mg/m2.

The randomization was stratified based on national group, histology, and therapeutic group. Group B patients were in stage III or IV, with no central nervous system symptoms; group C1 patients were stage IV/B-AL with cerebrospinal fluid (CSF) negative; and group C3 patients were CSF positive.

One hundred fifty-five patients were randomized to receive rituximab, and 155 were randomized to the control arm.

The primary endpoint was improvement in EFS. Secondary endpoints included complete remission (CR) rate, overall survival (OS), safety, immunity status, and long-term risks.

Investigators performed the first interim analysis after 27 events occurred.

Patient characteristics

Patients were a median age of 8.2 years, 45% were stage III with high LDH, and 85% had Burkitt lymphoma.

About half (51%) the patients were in group B, 39% in C1, and 10% in C3.

Toxicity

There were 6 deaths due to toxicity, 3 in each arm.

Dr Minard-Colin indicated that this number reflects the high toxicity of the LMB regimen and is “similar” to the previous rate of toxic deaths observed in the international LMB 96 study.

She added, “Importantly, 5 out of 6 toxic deaths occurred in group C. The only patient who died in group B died of surgical complications after extensive inappropriate surgery at diagnosis.”

Toxicity was similar between the 2 arms except for the high rate of febrile neutropenia after the third course of cytarabine and etoposide in the rituximab arm (50% vs 34%, P=0.012).

Of the 27 events, 20 occurred in the control arm and 7 in the rituximab arm.

The control arm had 17 lymphoma events, while the rituximab arm had 3.

Only 1 patient relapsed in the rituximab arm compared to 12 who relapsed in the control arm.  And no patient died of lymphoma in the rituximab arm, while 2 died of lymphoma in the control arm.

One second malignancy, melanoma, occurred in the rituximab arm.

Dr Minard-Colin noted that all events occurred in the first year after randomization

Efficacy

Event-free survival at 1 year was 94.2% in the rituximab arm and 81.5% in the control arm.

However, the investigators could not definitely conclude superiority for the rituximab arm because the P value was higher than the significance level of 0.0014 required for this first interim analysis. The hazard ratio was 0.33 (90%CI: 0.16-0.69), P = 0.006.

The investigators performed additional analyses and found the probability of getting a positive study at final analysis was very high, from 99% – 100%.

This past November, following the recommendation of the independent monitoring committee, sponsors decided to halt the randomization and continue follow-up of all patients so as to have mature data.

And in March of this year, they reopened the study with single-arm rituximab for 120 additional patients to answer the secondary objectives.

Dr Minard-Colin emphasized that the results are consistent with the recently performed LMBA02 trial in adult Burkitt lymphoma, with a gain of 13% in EFS for the rituximab arm. The 3-year EFS was 62% in the control arm compared with 75% in the rituximab arm (HR 0.59).

So while rituximab in high-risk patients appears to be practice changing, “in the standard- risk patients,” she added, “the use of rituximab is questionable.”

Sponsors of the trial are Gustave Roussy Cancer, Children’s Oncology Group, and Roche.

Data analyses will be conducted annually hereafter.

ASCO Annual Meeting 2016

© ASCO/Matt Herp

CHICAGO—The first interim analysis of rituximab plus chemotherapy in children and adolescents with high-risk B-cell non-Hodgkin lymphoma (B-NHL) and acute leukemia has yielded results that “will change our clinical practice,” according to Veronique Minard-Colin, MD, PhD, one of the study investigators.

Patients who received rituximab had 13% better event-free survival (EFS) than those who did not. “The new standard of care will be rituximab plus chemotherapy,” she said, for these high-risk patients.

“And it is very unlikely that this outcome will change if the study continues,” she added.

Dr Minard-Colin, of Institut Gustave Roussy in Villejuif, France, presented the interim analysis of the phase 3 Intergroup trial Inter-B-NHL Ritux 2010 at the 2016 ASCO Annual Meeting as abstract 10507.

She explained that when the study was started in 2010, there was a clear need to demonstrate the effectiveness of rituximab in childhood B-NHL.

So the investigators conducted the trial, which took place in 292 sites in 12 countries.

The investigators enrolled 310 patients under the age of 18 years who had mature B-NHL, including Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), high-grade B-NHL not otherwise specified, and B-cell acute leukemia (B-AL). The investigators excluded patients with primary mediastinal B-cell lymphoma.

They defined advanced stages as stage III with LDH levels more than twice normal, any stage IV disease, or B-AL.

They randomized patients to receive the French LMB chemotherapy regimen either with or without rituximab—6 doses at 375 mg/m2.

The randomization was stratified based on national group, histology, and therapeutic group. Group B patients were in stage III or IV, with no central nervous system symptoms; group C1 patients were stage IV/B-AL with cerebrospinal fluid (CSF) negative; and group C3 patients were CSF positive.

One hundred fifty-five patients were randomized to receive rituximab, and 155 were randomized to the control arm.

The primary endpoint was improvement in EFS. Secondary endpoints included complete remission (CR) rate, overall survival (OS), safety, immunity status, and long-term risks.

Investigators performed the first interim analysis after 27 events occurred.

Patient characteristics

Patients were a median age of 8.2 years, 45% were stage III with high LDH, and 85% had Burkitt lymphoma.

About half (51%) the patients were in group B, 39% in C1, and 10% in C3.

Toxicity

There were 6 deaths due to toxicity, 3 in each arm.

Dr Minard-Colin indicated that this number reflects the high toxicity of the LMB regimen and is “similar” to the previous rate of toxic deaths observed in the international LMB 96 study.

She added, “Importantly, 5 out of 6 toxic deaths occurred in group C. The only patient who died in group B died of surgical complications after extensive inappropriate surgery at diagnosis.”

Toxicity was similar between the 2 arms except for the high rate of febrile neutropenia after the third course of cytarabine and etoposide in the rituximab arm (50% vs 34%, P=0.012).

Of the 27 events, 20 occurred in the control arm and 7 in the rituximab arm.

The control arm had 17 lymphoma events, while the rituximab arm had 3.

Only 1 patient relapsed in the rituximab arm compared to 12 who relapsed in the control arm.  And no patient died of lymphoma in the rituximab arm, while 2 died of lymphoma in the control arm.

One second malignancy, melanoma, occurred in the rituximab arm.

Dr Minard-Colin noted that all events occurred in the first year after randomization

Efficacy

Event-free survival at 1 year was 94.2% in the rituximab arm and 81.5% in the control arm.

However, the investigators could not definitely conclude superiority for the rituximab arm because the P value was higher than the significance level of 0.0014 required for this first interim analysis. The hazard ratio was 0.33 (90%CI: 0.16-0.69), P = 0.006.

The investigators performed additional analyses and found the probability of getting a positive study at final analysis was very high, from 99% – 100%.

This past November, following the recommendation of the independent monitoring committee, sponsors decided to halt the randomization and continue follow-up of all patients so as to have mature data.

And in March of this year, they reopened the study with single-arm rituximab for 120 additional patients to answer the secondary objectives.

Dr Minard-Colin emphasized that the results are consistent with the recently performed LMBA02 trial in adult Burkitt lymphoma, with a gain of 13% in EFS for the rituximab arm. The 3-year EFS was 62% in the control arm compared with 75% in the rituximab arm (HR 0.59).

So while rituximab in high-risk patients appears to be practice changing, “in the standard- risk patients,” she added, “the use of rituximab is questionable.”

Sponsors of the trial are Gustave Roussy Cancer, Children’s Oncology Group, and Roche.

Data analyses will be conducted annually hereafter.

Antonio Palumbo, MD

CHICAGO—The addition of the monoclonal antibody daratumumab to bortezomib and dexamethasone, the current standard of care for relapsed/refractory multiple myeloma (MM), has achieved progression-free survival that is “unprecedented in randomized studies that compared novel treatment” for this disease, according to Antonio Palumbo, MD, lead author of the phase 3 CASTOR study.

Dr Palumbo, of the University of Torino in Torino, Italy, presented the results on behalf of the CASTOR investigators during the plenary session of the 2016 ASCO Annual Meeting (abstract LBA4).

Daratumumab (Darzalex) is a human CD38 monoclonal antibody, which means it is targeted very specifically to the most relevant tumor antigen for plasma cells.

It also has direct major cytotoxic activity through the complement, which translates into major tumor reduction and a profound cytoreduction, Dr Palumbo said.

Even more important, he added, is that this is an immunomodulatory agent able to both increase the T-cell activity in the immune system, which controls the tumor, and also reduce the immunosuppressive regulatory cells that are suppressing the activity of the immune system.

Daratumumab is already approved by the US Food and Drug Administration and conditionally approved by the European Commission as a single agent for the treatment of relapsed/refractory multiple myeloma.

Study design

The CASTOR study was a multicenter, randomized, open-label, active-controlled phase 3 study.

Patients were eligible to enroll if they had relapsed or refractory MM with at least 1 prior line of therapy, which could include prior treatment with bortezomib, but they were not eligible if they were refractory to it.

Investigators randomized 251 patients to the experimental arm of daratumumab, bortezomib (Velcade), and dexamethasone (DVd) and 247 to the control arm of bortezomib and dexamethasone (Vd).

The dosing schedule was the same in both arms for bortezomib and dexamethasone. Patients in the experimental arm received daratumumab (16 mg/kg IV) every week for the first 3 cycles, on day 1 of cycles 4 – 8, and then every 4 weeks until progression.

The primary endpoint of the study was progression-free survival (PFS). Secondary endpoints included time to progression (TTP), overall survival (OS), overall response rate (ORR), very good partial response (VGPR), complete response (CR), minimal residual disease (MRD), time to response, and duration of response.

Patient demographics

Overall, patients had advanced stage disease with a long history of prior treatment.

They were a median age of 64 in both groups, and the time from diagnosis was a median 3.87 years in the experimental arm and 3.72 years in the control arm.

About 60% in both groups had had prior autologous stem cell transplant. Seventy-one percent in the experimental arm and 80% in the control arm had received a prior immunomodulatory drug, and 30% in the experimental arm and 34% in the control arm were refractory to their last line of therapy.

Dr Palumbo pointed out that accrual for the trial was rapid; 500 patients enrolled in 1 year, from September 2014 to September 2015.

“After 3 months, we already saw a difference in terms of efficacy,” he added, and the trial was stopped early. “So the median follow-up is short for this reason,” he explained, “and is around 7 months.”

The discontinuation rate was “as expected,” he said, “higher in the control arm,” with 44% discontinuing compared with 31% in the experimental arm.

Discontinuation for progressive disease was 25% in the control arm and 19% in the experimental arm, “showing already an advantage for the novel combination.”

Adverse events as reasons for discontinuation were 8% in the experimental arm and 10% in the control arm, “showing that the new agent is not adding any extra toxicity to the combination of bortezomib and dexamethasone.”

Efficacy

The “unprecedented” PFS, with a hazard ratio (HR) of 0.39 (95% CI, 0.28-0.53; P<0.0001), translated into a 61% reduction in the risk of disease progression or death for the experimental arm compared with the control arm.

The median PFS was not yet reached in the experimental arm, while the median PFS was 7.2 months in the control arm.

At 1 year, the PFS was 26.9% in the control arm and 60.7% in the experimental arm, “and this translates into a doubling in terms of remission duration for those patients,” Dr Palumbo stated.

“Even better was the outcome for the time to progression,” he said, with an HR of 0.30, “which means a 70% reduction in the risk of disease progression for DVd versus Vd, a more than doubling of time to disease progression.”

PFS by subgroup analysis showed that early intervention with daratumumab maximizes the efficacy of the combination.

For those patients who had received only 1 line of prior treatment, the HR was 0.31 (95% CI, 0.18 – 0.52; P<0.0001), which translated to a 69% reduction in the risk of progression or death for DVd compared with Vd.

The overall response rate revealed the profound cytoreduction achieved by the addition of daratumumab.

The CR rate increased from 9% in the control group to 19% in the experimental arm (P=0.0012), and the VGPR increased from 29% to 59%, in the control and experimental arms, respectively.

“So there is a doubling in the rate of CR and VGPR,” Dr Palumbo pointed out, “and this is quite relevant because more patients do achieve a profound cytoreduction.”

The rate of MRD negativity was 5 times higher for daratumumab-treated patients. Three percent of patients in the control arm were MRD negative (10^-4) compared with 14% in the experimental arm.

Time to response, “in my opinion, is an important issue because . . .  you can reach PR in around 1 month [with DVd] and this is clinically relevant because those patients are symptomatic,” he explained. “Reaching PR in 1 month means getting rid of pain in a quick way.”

“On the other hand, the achieving of CR requires a prolonged treatment,” he added. “CR is being achieved after 12 months of therapy, and MRD negativity might need even longer treatment.”

Safety

Daratumumab-treated patients experienced more thrombocytopenia and peripheral neuropathy (PN) of any grade than the control arm, 47% compared with 38%, respectively.

“But this is not due to the addition of the third agent,” Dr Palumbo clarified. “This is mainly the consequence, in the experimental arm, that treatment with bortezomib was longer in comparison to the control arm, and therefore, the typical toxicity of bortezomib—thrombocytopenia and PN—were slightly higher.”

There was also an increase in upper respiratory tract infections and cough in daratumumab-treated patients.

Grade 3-4 treatment-emergent adverse events occurring in more than 5% of patients included thrombocytopenia, anemia, neutropenia, lymphopenia, pneumonia, hypertension, and sensory PN.

However, grade 4 thrombocyotpenia, Dr Palumbo noted, did not translate into an increase in bleeding.

The major increase in toxicity due to daratumumab was in infusion-related reactions (IRRs), which occurred in 45% of patients. IRRs were consistent with the infusion of other monoclonal antibodies in cancer patients, he said, and 98% of patients with IRRs experienced them on the first infusion.

Conclusions

Dr Palumbo stressed that daratumumab did not increase the cumulative toxicity or the toxicity of the bortezomib-dexamethasone combination.

Daratumumab significantly improved PFS and the response rate; the experimental combination was associated with a 61% reduction in the risk of progression or death.

The benefit was maintained across different subgroups—whether younger, older, good prognosis, bad prognosis, previously exposed to bortezomib or not exposed to bortezomib.

And DVd doubled both VGPR rates and CR rates.

In a press briefing, Dr Palumbo said that in the myeloma field, “we hope to have our R-CHOP, that has been a major treatment for lymphoma now also available with a different antibody for multiple myeloma.”

So the final conclusion, he added, is that “daratumumab-Vd might be considered today a new standard of care for relapsed and refractory multiple myeloma.”

The study was funded by Janssen Research & Development.

Antonio Palumbo, MD

CHICAGO—The addition of the monoclonal antibody daratumumab to bortezomib and dexamethasone, the current standard of care for relapsed/refractory multiple myeloma (MM), has achieved progression-free survival that is “unprecedented in randomized studies that compared novel treatment” for this disease, according to Antonio Palumbo, MD, lead author of the phase 3 CASTOR study.

Dr Palumbo, of the University of Torino in Torino, Italy, presented the results on behalf of the CASTOR investigators during the plenary session of the 2016 ASCO Annual Meeting (abstract LBA4).

Daratumumab (Darzalex) is a human CD38 monoclonal antibody, which means it is targeted very specifically to the most relevant tumor antigen for plasma cells.

It also has direct major cytotoxic activity through the complement, which translates into major tumor reduction and a profound cytoreduction, Dr Palumbo said.

Even more important, he added, is that this is an immunomodulatory agent able to both increase the T-cell activity in the immune system, which controls the tumor, and also reduce the immunosuppressive regulatory cells that are suppressing the activity of the immune system.

Daratumumab is already approved by the US Food and Drug Administration and conditionally approved by the European Commission as a single agent for the treatment of relapsed/refractory multiple myeloma.

Study design

The CASTOR study was a multicenter, randomized, open-label, active-controlled phase 3 study.

Patients were eligible to enroll if they had relapsed or refractory MM with at least 1 prior line of therapy, which could include prior treatment with bortezomib, but they were not eligible if they were refractory to it.

Investigators randomized 251 patients to the experimental arm of daratumumab, bortezomib (Velcade), and dexamethasone (DVd) and 247 to the control arm of bortezomib and dexamethasone (Vd).

The dosing schedule was the same in both arms for bortezomib and dexamethasone. Patients in the experimental arm received daratumumab (16 mg/kg IV) every week for the first 3 cycles, on day 1 of cycles 4 – 8, and then every 4 weeks until progression.

The primary endpoint of the study was progression-free survival (PFS). Secondary endpoints included time to progression (TTP), overall survival (OS), overall response rate (ORR), very good partial response (VGPR), complete response (CR), minimal residual disease (MRD), time to response, and duration of response.

Patient demographics

Overall, patients had advanced stage disease with a long history of prior treatment.

They were a median age of 64 in both groups, and the time from diagnosis was a median 3.87 years in the experimental arm and 3.72 years in the control arm.

About 60% in both groups had had prior autologous stem cell transplant. Seventy-one percent in the experimental arm and 80% in the control arm had received a prior immunomodulatory drug, and 30% in the experimental arm and 34% in the control arm were refractory to their last line of therapy.

Dr Palumbo pointed out that accrual for the trial was rapid; 500 patients enrolled in 1 year, from September 2014 to September 2015.

“After 3 months, we already saw a difference in terms of efficacy,” he added, and the trial was stopped early. “So the median follow-up is short for this reason,” he explained, “and is around 7 months.”

The discontinuation rate was “as expected,” he said, “higher in the control arm,” with 44% discontinuing compared with 31% in the experimental arm.

Discontinuation for progressive disease was 25% in the control arm and 19% in the experimental arm, “showing already an advantage for the novel combination.”

Adverse events as reasons for discontinuation were 8% in the experimental arm and 10% in the control arm, “showing that the new agent is not adding any extra toxicity to the combination of bortezomib and dexamethasone.”

Efficacy

The “unprecedented” PFS, with a hazard ratio (HR) of 0.39 (95% CI, 0.28-0.53; P<0.0001), translated into a 61% reduction in the risk of disease progression or death for the experimental arm compared with the control arm.

The median PFS was not yet reached in the experimental arm, while the median PFS was 7.2 months in the control arm.

At 1 year, the PFS was 26.9% in the control arm and 60.7% in the experimental arm, “and this translates into a doubling in terms of remission duration for those patients,” Dr Palumbo stated.

“Even better was the outcome for the time to progression,” he said, with an HR of 0.30, “which means a 70% reduction in the risk of disease progression for DVd versus Vd, a more than doubling of time to disease progression.”

PFS by subgroup analysis showed that early intervention with daratumumab maximizes the efficacy of the combination.

For those patients who had received only 1 line of prior treatment, the HR was 0.31 (95% CI, 0.18 – 0.52; P<0.0001), which translated to a 69% reduction in the risk of progression or death for DVd compared with Vd.

The overall response rate revealed the profound cytoreduction achieved by the addition of daratumumab.

The CR rate increased from 9% in the control group to 19% in the experimental arm (P=0.0012), and the VGPR increased from 29% to 59%, in the control and experimental arms, respectively.

“So there is a doubling in the rate of CR and VGPR,” Dr Palumbo pointed out, “and this is quite relevant because more patients do achieve a profound cytoreduction.”

The rate of MRD negativity was 5 times higher for daratumumab-treated patients. Three percent of patients in the control arm were MRD negative (10^-4) compared with 14% in the experimental arm.

Time to response, “in my opinion, is an important issue because . . .  you can reach PR in around 1 month [with DVd] and this is clinically relevant because those patients are symptomatic,” he explained. “Reaching PR in 1 month means getting rid of pain in a quick way.”

“On the other hand, the achieving of CR requires a prolonged treatment,” he added. “CR is being achieved after 12 months of therapy, and MRD negativity might need even longer treatment.”

Safety

Daratumumab-treated patients experienced more thrombocytopenia and peripheral neuropathy (PN) of any grade than the control arm, 47% compared with 38%, respectively.

“But this is not due to the addition of the third agent,” Dr Palumbo clarified. “This is mainly the consequence, in the experimental arm, that treatment with bortezomib was longer in comparison to the control arm, and therefore, the typical toxicity of bortezomib—thrombocytopenia and PN—were slightly higher.”

There was also an increase in upper respiratory tract infections and cough in daratumumab-treated patients.

Grade 3-4 treatment-emergent adverse events occurring in more than 5% of patients included thrombocytopenia, anemia, neutropenia, lymphopenia, pneumonia, hypertension, and sensory PN.

However, grade 4 thrombocyotpenia, Dr Palumbo noted, did not translate into an increase in bleeding.

The major increase in toxicity due to daratumumab was in infusion-related reactions (IRRs), which occurred in 45% of patients. IRRs were consistent with the infusion of other monoclonal antibodies in cancer patients, he said, and 98% of patients with IRRs experienced them on the first infusion.

Conclusions

Dr Palumbo stressed that daratumumab did not increase the cumulative toxicity or the toxicity of the bortezomib-dexamethasone combination.

Daratumumab significantly improved PFS and the response rate; the experimental combination was associated with a 61% reduction in the risk of progression or death.

The benefit was maintained across different subgroups—whether younger, older, good prognosis, bad prognosis, previously exposed to bortezomib or not exposed to bortezomib.

And DVd doubled both VGPR rates and CR rates.

In a press briefing, Dr Palumbo said that in the myeloma field, “we hope to have our R-CHOP, that has been a major treatment for lymphoma now also available with a different antibody for multiple myeloma.”

So the final conclusion, he added, is that “daratumumab-Vd might be considered today a new standard of care for relapsed and refractory multiple myeloma.”

The study was funded by Janssen Research & Development.

Antonio Palumbo, MD

CHICAGO—The addition of the monoclonal antibody daratumumab to bortezomib and dexamethasone, the current standard of care for relapsed/refractory multiple myeloma (MM), has achieved progression-free survival that is “unprecedented in randomized studies that compared novel treatment” for this disease, according to Antonio Palumbo, MD, lead author of the phase 3 CASTOR study.

Dr Palumbo, of the University of Torino in Torino, Italy, presented the results on behalf of the CASTOR investigators during the plenary session of the 2016 ASCO Annual Meeting (abstract LBA4).

Daratumumab (Darzalex) is a human CD38 monoclonal antibody, which means it is targeted very specifically to the most relevant tumor antigen for plasma cells.

It also has direct major cytotoxic activity through the complement, which translates into major tumor reduction and a profound cytoreduction, Dr Palumbo said.

Even more important, he added, is that this is an immunomodulatory agent able to both increase the T-cell activity in the immune system, which controls the tumor, and also reduce the immunosuppressive regulatory cells that are suppressing the activity of the immune system.

Daratumumab is already approved by the US Food and Drug Administration and conditionally approved by the European Commission as a single agent for the treatment of relapsed/refractory multiple myeloma.

Study design

The CASTOR study was a multicenter, randomized, open-label, active-controlled phase 3 study.

Patients were eligible to enroll if they had relapsed or refractory MM with at least 1 prior line of therapy, which could include prior treatment with bortezomib, but they were not eligible if they were refractory to it.

Investigators randomized 251 patients to the experimental arm of daratumumab, bortezomib (Velcade), and dexamethasone (DVd) and 247 to the control arm of bortezomib and dexamethasone (Vd).

The dosing schedule was the same in both arms for bortezomib and dexamethasone. Patients in the experimental arm received daratumumab (16 mg/kg IV) every week for the first 3 cycles, on day 1 of cycles 4 – 8, and then every 4 weeks until progression.

The primary endpoint of the study was progression-free survival (PFS). Secondary endpoints included time to progression (TTP), overall survival (OS), overall response rate (ORR), very good partial response (VGPR), complete response (CR), minimal residual disease (MRD), time to response, and duration of response.

Patient demographics

Overall, patients had advanced stage disease with a long history of prior treatment.

They were a median age of 64 in both groups, and the time from diagnosis was a median 3.87 years in the experimental arm and 3.72 years in the control arm.

About 60% in both groups had had prior autologous stem cell transplant. Seventy-one percent in the experimental arm and 80% in the control arm had received a prior immunomodulatory drug, and 30% in the experimental arm and 34% in the control arm were refractory to their last line of therapy.

Dr Palumbo pointed out that accrual for the trial was rapid; 500 patients enrolled in 1 year, from September 2014 to September 2015.

“After 3 months, we already saw a difference in terms of efficacy,” he added, and the trial was stopped early. “So the median follow-up is short for this reason,” he explained, “and is around 7 months.”

The discontinuation rate was “as expected,” he said, “higher in the control arm,” with 44% discontinuing compared with 31% in the experimental arm.

Discontinuation for progressive disease was 25% in the control arm and 19% in the experimental arm, “showing already an advantage for the novel combination.”

Adverse events as reasons for discontinuation were 8% in the experimental arm and 10% in the control arm, “showing that the new agent is not adding any extra toxicity to the combination of bortezomib and dexamethasone.”

Efficacy

The “unprecedented” PFS, with a hazard ratio (HR) of 0.39 (95% CI, 0.28-0.53; P<0.0001), translated into a 61% reduction in the risk of disease progression or death for the experimental arm compared with the control arm.

The median PFS was not yet reached in the experimental arm, while the median PFS was 7.2 months in the control arm.

At 1 year, the PFS was 26.9% in the control arm and 60.7% in the experimental arm, “and this translates into a doubling in terms of remission duration for those patients,” Dr Palumbo stated.

“Even better was the outcome for the time to progression,” he said, with an HR of 0.30, “which means a 70% reduction in the risk of disease progression for DVd versus Vd, a more than doubling of time to disease progression.”

PFS by subgroup analysis showed that early intervention with daratumumab maximizes the efficacy of the combination.

For those patients who had received only 1 line of prior treatment, the HR was 0.31 (95% CI, 0.18 – 0.52; P<0.0001), which translated to a 69% reduction in the risk of progression or death for DVd compared with Vd.

The overall response rate revealed the profound cytoreduction achieved by the addition of daratumumab.

The CR rate increased from 9% in the control group to 19% in the experimental arm (P=0.0012), and the VGPR increased from 29% to 59%, in the control and experimental arms, respectively.

“So there is a doubling in the rate of CR and VGPR,” Dr Palumbo pointed out, “and this is quite relevant because more patients do achieve a profound cytoreduction.”

The rate of MRD negativity was 5 times higher for daratumumab-treated patients. Three percent of patients in the control arm were MRD negative (10^-4) compared with 14% in the experimental arm.

Time to response, “in my opinion, is an important issue because . . .  you can reach PR in around 1 month [with DVd] and this is clinically relevant because those patients are symptomatic,” he explained. “Reaching PR in 1 month means getting rid of pain in a quick way.”

“On the other hand, the achieving of CR requires a prolonged treatment,” he added. “CR is being achieved after 12 months of therapy, and MRD negativity might need even longer treatment.”

Safety

Daratumumab-treated patients experienced more thrombocytopenia and peripheral neuropathy (PN) of any grade than the control arm, 47% compared with 38%, respectively.

“But this is not due to the addition of the third agent,” Dr Palumbo clarified. “This is mainly the consequence, in the experimental arm, that treatment with bortezomib was longer in comparison to the control arm, and therefore, the typical toxicity of bortezomib—thrombocytopenia and PN—were slightly higher.”

There was also an increase in upper respiratory tract infections and cough in daratumumab-treated patients.

Grade 3-4 treatment-emergent adverse events occurring in more than 5% of patients included thrombocytopenia, anemia, neutropenia, lymphopenia, pneumonia, hypertension, and sensory PN.

However, grade 4 thrombocyotpenia, Dr Palumbo noted, did not translate into an increase in bleeding.

The major increase in toxicity due to daratumumab was in infusion-related reactions (IRRs), which occurred in 45% of patients. IRRs were consistent with the infusion of other monoclonal antibodies in cancer patients, he said, and 98% of patients with IRRs experienced them on the first infusion.

Conclusions

Dr Palumbo stressed that daratumumab did not increase the cumulative toxicity or the toxicity of the bortezomib-dexamethasone combination.

Daratumumab significantly improved PFS and the response rate; the experimental combination was associated with a 61% reduction in the risk of progression or death.

The benefit was maintained across different subgroups—whether younger, older, good prognosis, bad prognosis, previously exposed to bortezomib or not exposed to bortezomib.

And DVd doubled both VGPR rates and CR rates.

In a press briefing, Dr Palumbo said that in the myeloma field, “we hope to have our R-CHOP, that has been a major treatment for lymphoma now also available with a different antibody for multiple myeloma.”

So the final conclusion, he added, is that “daratumumab-Vd might be considered today a new standard of care for relapsed and refractory multiple myeloma.”

The study was funded by Janssen Research & Development.

Transplant preparation

Photo by Chad McNeeley

CHICAGO—An interim analysis of a large, phase 3 study has confirmed that upfront autologous stem cell transplantation (ASCT) is still the preferred

treatment for newly diagnosed, young multiple myeloma (MM) patients, even in the age of novel agents such as bortezomib.

Investigators compared 4 cycles of bortezomib-melphalan-prednisone (VMP) with high-dose melphalan (HDM) and single or double ASCT, depending upon the policy of the treating institution.

At a median follow-up of 24 months, the 3-year progression-free survival (PFS) was significantly better for patients who had received ASCT.

Michele Cavo, MD, of Seràgnoli Institute of Hematology in Bologna, Italy, reported the results of this first interim analysis of the European Myeloma Network trial (EMN/HO95 MM) at a press briefing preceding the 2016 ASCO Annual Meeting. More details will be presented at the meeting itself (abstract 8000).

Study investigators enrolled 1503 patients from February 2011 through April 2014. They performed the specified interim analysis in January 2016.

Patients were 65 years or younger, and all received bortezomib-based induction therapy followed by stem cell collection. Investigators then randomized 1266 patients to receive either VMP (n=754) or HDM plus single or double ASCT (n=512).

Patients underwent a second randomization to either 2 cycles of bortezomib-based consolidation or no consolidation therapy.

All patients received lenalidomide maintenance until disease progression. The primary endpoint was PFS after the first randomization.

Results

PFS was significantly longer in patients who had received a transplant, with a hazard ratio (HR) of 0.76, 95% confidence interval (CI) of 0.61-0.94, and P value of 0.01.

This benefit held true for patients with revised ISS stage III (HR=0.52, 95% CI 0.32-0.84, P=0.01).

And patients with high-risk cytogenetics also retained the benefit (HR=0.72, 95% CI 0.54-0.97, P=0.03). High-risk was defined as t(4;14), del(17p), del(1p), or gain of 1q.

Investigators also performed a multivariate analysis and found randomization to the HDM arm to be an independent predictor of prolonged PFS (HR=0.61, 95% CI 0.45-0.82, P=0.001).

There was no significant difference between the 2 arms in terms of stringent complete response and complete response.

However, when very good partial response was included in the best-response analysis, patients in the transplant arm fared significantly better (P<0.0001) than patients in the VMP arm—84% and 74%, respectively.

Investigators have not yet completed the interim data analysis related to the second randomization. The study is ongoing, and future analyses will include overall survival, toxicity, quality of life, and other measures.

This study was funded by the Haemato Oncology Foundation for Adults in the Netherlands (HOVON).

Transplant preparation

Photo by Chad McNeeley

CHICAGO—An interim analysis of a large, phase 3 study has confirmed that upfront autologous stem cell transplantation (ASCT) is still the preferred

treatment for newly diagnosed, young multiple myeloma (MM) patients, even in the age of novel agents such as bortezomib.

Investigators compared 4 cycles of bortezomib-melphalan-prednisone (VMP) with high-dose melphalan (HDM) and single or double ASCT, depending upon the policy of the treating institution.

At a median follow-up of 24 months, the 3-year progression-free survival (PFS) was significantly better for patients who had received ASCT.

Michele Cavo, MD, of Seràgnoli Institute of Hematology in Bologna, Italy, reported the results of this first interim analysis of the European Myeloma Network trial (EMN/HO95 MM) at a press briefing preceding the 2016 ASCO Annual Meeting. More details will be presented at the meeting itself (abstract 8000).

Study investigators enrolled 1503 patients from February 2011 through April 2014. They performed the specified interim analysis in January 2016.

Patients were 65 years or younger, and all received bortezomib-based induction therapy followed by stem cell collection. Investigators then randomized 1266 patients to receive either VMP (n=754) or HDM plus single or double ASCT (n=512).

Patients underwent a second randomization to either 2 cycles of bortezomib-based consolidation or no consolidation therapy.

All patients received lenalidomide maintenance until disease progression. The primary endpoint was PFS after the first randomization.

Results

PFS was significantly longer in patients who had received a transplant, with a hazard ratio (HR) of 0.76, 95% confidence interval (CI) of 0.61-0.94, and P value of 0.01.

This benefit held true for patients with revised ISS stage III (HR=0.52, 95% CI 0.32-0.84, P=0.01).

And patients with high-risk cytogenetics also retained the benefit (HR=0.72, 95% CI 0.54-0.97, P=0.03). High-risk was defined as t(4;14), del(17p), del(1p), or gain of 1q.

Investigators also performed a multivariate analysis and found randomization to the HDM arm to be an independent predictor of prolonged PFS (HR=0.61, 95% CI 0.45-0.82, P=0.001).

There was no significant difference between the 2 arms in terms of stringent complete response and complete response.

However, when very good partial response was included in the best-response analysis, patients in the transplant arm fared significantly better (P<0.0001) than patients in the VMP arm—84% and 74%, respectively.

Investigators have not yet completed the interim data analysis related to the second randomization. The study is ongoing, and future analyses will include overall survival, toxicity, quality of life, and other measures.

This study was funded by the Haemato Oncology Foundation for Adults in the Netherlands (HOVON).

Transplant preparation

Photo by Chad McNeeley

CHICAGO—An interim analysis of a large, phase 3 study has confirmed that upfront autologous stem cell transplantation (ASCT) is still the preferred

treatment for newly diagnosed, young multiple myeloma (MM) patients, even in the age of novel agents such as bortezomib.

Investigators compared 4 cycles of bortezomib-melphalan-prednisone (VMP) with high-dose melphalan (HDM) and single or double ASCT, depending upon the policy of the treating institution.

At a median follow-up of 24 months, the 3-year progression-free survival (PFS) was significantly better for patients who had received ASCT.

Michele Cavo, MD, of Seràgnoli Institute of Hematology in Bologna, Italy, reported the results of this first interim analysis of the European Myeloma Network trial (EMN/HO95 MM) at a press briefing preceding the 2016 ASCO Annual Meeting. More details will be presented at the meeting itself (abstract 8000).

Study investigators enrolled 1503 patients from February 2011 through April 2014. They performed the specified interim analysis in January 2016.

Patients were 65 years or younger, and all received bortezomib-based induction therapy followed by stem cell collection. Investigators then randomized 1266 patients to receive either VMP (n=754) or HDM plus single or double ASCT (n=512).

Patients underwent a second randomization to either 2 cycles of bortezomib-based consolidation or no consolidation therapy.

All patients received lenalidomide maintenance until disease progression. The primary endpoint was PFS after the first randomization.

Results

PFS was significantly longer in patients who had received a transplant, with a hazard ratio (HR) of 0.76, 95% confidence interval (CI) of 0.61-0.94, and P value of 0.01.

This benefit held true for patients with revised ISS stage III (HR=0.52, 95% CI 0.32-0.84, P=0.01).

And patients with high-risk cytogenetics also retained the benefit (HR=0.72, 95% CI 0.54-0.97, P=0.03). High-risk was defined as t(4;14), del(17p), del(1p), or gain of 1q.

Investigators also performed a multivariate analysis and found randomization to the HDM arm to be an independent predictor of prolonged PFS (HR=0.61, 95% CI 0.45-0.82, P=0.001).

There was no significant difference between the 2 arms in terms of stringent complete response and complete response.

However, when very good partial response was included in the best-response analysis, patients in the transplant arm fared significantly better (P<0.0001) than patients in the VMP arm—84% and 74%, respectively.

Investigators have not yet completed the interim data analysis related to the second randomization. The study is ongoing, and future analyses will include overall survival, toxicity, quality of life, and other measures.

This study was funded by the Haemato Oncology Foundation for Adults in the Netherlands (HOVON).

Gut bacteria

A new study suggests the composition of a cancer patient’s intestinal microbiome before treatment may predict his risk of developing a bloodstream infection (BSI) after treatment.

Researchers analyzed fecal samples from patients with non-Hodgkin lymphoma who were set to receive an allogeneic hematopoietic stem cell transplant (allo-HSCT) with myeloablative conditioning.

The team found that patients with less diversity in their fecal samples before this treatment were more likely to develop a BSI after.

Emmanuel Montassier, MD, PhD, of Nantes University Hospital in France, and his colleagues conducted this study and reported the result in Genome Medicine.

A previous study suggested that intestinal domination—when a single bacterial taxon occupies at least 30% of the microbiota—is associated with BSIs in patients undergoing allo-HSCT. However, the role of the intestinal microbiome before treatment was not clear.

So Dr Montassier and his colleagues set out to characterize the fecal microbiome before treatment. To do this, they sequenced the bacterial DNA of fecal samples from 28 patients with non-Hodgkin lymphoma.

The team collected the samples before patients began a 5-day myeloablative conditioning regimen (high-dose carmustine, etoposide, aracytine, and melphalan), followed by allo-HSCT on the seventh day.

Eleven of these patients developed a BSI at a mean of 12 days after sample collection. Two patients (18.2%) developed Enterococcus BSI, 4 (36.4%) developed Escherichia coli BSI, and 5 (45.5%) developed other Gammaproteobacteria BSI.

The researchers said that alpha diversity in samples from these patients was significantly lower than alpha diversity from patients who did not develop a BSI, with reduced evenness (Shannon index, Monte Carlo permuted t-test two-sided P value = 0.004) and reduced richness (Observed species, Monte Carlo permuted t-test two-sided P value = 0.001)

The team also noted that, compared to patients who did not develop a BSI, those who did had decreased abundance of Barnesiellaceae, Coriobacteriaceae, Faecalibacterium, Christensenella, Dehalobacterium, Desulfovibrio, and Sutterella.

Using this information, the researchers developed a BSI risk index that could predict the likelihood of a BSI with 90% sensitivity and specificity.

“This method worked even better than we expected because we found a consistent difference between the gut bacteria in those who developed infections and those who did not,” said study author Dan Knights, PhD, of the University of Minnesota in Minneapolis.

“This research is an early demonstration that we may be able to use the bugs in our gut to predict infections and possibly develop new prognostic models in other diseases.”

Still, the researchers said these findings are based on a limited number of patients treated with the same regimen at a single clinic. So the next step for this research is to validate the findings in a much larger cohort including patients with different cancer types, different treatment types, and from multiple treatment centers.

“We still need to determine if these bacteria are playing any kind of causal role in the infections or if they are simply acting as biomarkers for some other predisposing condition in the patient,” Dr Montassier said.

Gut bacteria

A new study suggests the composition of a cancer patient’s intestinal microbiome before treatment may predict his risk of developing a bloodstream infection (BSI) after treatment.

Researchers analyzed fecal samples from patients with non-Hodgkin lymphoma who were set to receive an allogeneic hematopoietic stem cell transplant (allo-HSCT) with myeloablative conditioning.

The team found that patients with less diversity in their fecal samples before this treatment were more likely to develop a BSI after.

Emmanuel Montassier, MD, PhD, of Nantes University Hospital in France, and his colleagues conducted this study and reported the result in Genome Medicine.

A previous study suggested that intestinal domination—when a single bacterial taxon occupies at least 30% of the microbiota—is associated with BSIs in patients undergoing allo-HSCT. However, the role of the intestinal microbiome before treatment was not clear.

So Dr Montassier and his colleagues set out to characterize the fecal microbiome before treatment. To do this, they sequenced the bacterial DNA of fecal samples from 28 patients with non-Hodgkin lymphoma.

The team collected the samples before patients began a 5-day myeloablative conditioning regimen (high-dose carmustine, etoposide, aracytine, and melphalan), followed by allo-HSCT on the seventh day.

Eleven of these patients developed a BSI at a mean of 12 days after sample collection. Two patients (18.2%) developed Enterococcus BSI, 4 (36.4%) developed Escherichia coli BSI, and 5 (45.5%) developed other Gammaproteobacteria BSI.

The researchers said that alpha diversity in samples from these patients was significantly lower than alpha diversity from patients who did not develop a BSI, with reduced evenness (Shannon index, Monte Carlo permuted t-test two-sided P value = 0.004) and reduced richness (Observed species, Monte Carlo permuted t-test two-sided P value = 0.001)

The team also noted that, compared to patients who did not develop a BSI, those who did had decreased abundance of Barnesiellaceae, Coriobacteriaceae, Faecalibacterium, Christensenella, Dehalobacterium, Desulfovibrio, and Sutterella.

Using this information, the researchers developed a BSI risk index that could predict the likelihood of a BSI with 90% sensitivity and specificity.

“This method worked even better than we expected because we found a consistent difference between the gut bacteria in those who developed infections and those who did not,” said study author Dan Knights, PhD, of the University of Minnesota in Minneapolis.

“This research is an early demonstration that we may be able to use the bugs in our gut to predict infections and possibly develop new prognostic models in other diseases.”

Still, the researchers said these findings are based on a limited number of patients treated with the same regimen at a single clinic. So the next step for this research is to validate the findings in a much larger cohort including patients with different cancer types, different treatment types, and from multiple treatment centers.

“We still need to determine if these bacteria are playing any kind of causal role in the infections or if they are simply acting as biomarkers for some other predisposing condition in the patient,” Dr Montassier said.

Gut bacteria

A new study suggests the composition of a cancer patient’s intestinal microbiome before treatment may predict his risk of developing a bloodstream infection (BSI) after treatment.

Researchers analyzed fecal samples from patients with non-Hodgkin lymphoma who were set to receive an allogeneic hematopoietic stem cell transplant (allo-HSCT) with myeloablative conditioning.

The team found that patients with less diversity in their fecal samples before this treatment were more likely to develop a BSI after.

Emmanuel Montassier, MD, PhD, of Nantes University Hospital in France, and his colleagues conducted this study and reported the result in Genome Medicine.

A previous study suggested that intestinal domination—when a single bacterial taxon occupies at least 30% of the microbiota—is associated with BSIs in patients undergoing allo-HSCT. However, the role of the intestinal microbiome before treatment was not clear.

So Dr Montassier and his colleagues set out to characterize the fecal microbiome before treatment. To do this, they sequenced the bacterial DNA of fecal samples from 28 patients with non-Hodgkin lymphoma.

The team collected the samples before patients began a 5-day myeloablative conditioning regimen (high-dose carmustine, etoposide, aracytine, and melphalan), followed by allo-HSCT on the seventh day.

Eleven of these patients developed a BSI at a mean of 12 days after sample collection. Two patients (18.2%) developed Enterococcus BSI, 4 (36.4%) developed Escherichia coli BSI, and 5 (45.5%) developed other Gammaproteobacteria BSI.

The researchers said that alpha diversity in samples from these patients was significantly lower than alpha diversity from patients who did not develop a BSI, with reduced evenness (Shannon index, Monte Carlo permuted t-test two-sided P value = 0.004) and reduced richness (Observed species, Monte Carlo permuted t-test two-sided P value = 0.001)

The team also noted that, compared to patients who did not develop a BSI, those who did had decreased abundance of Barnesiellaceae, Coriobacteriaceae, Faecalibacterium, Christensenella, Dehalobacterium, Desulfovibrio, and Sutterella.

Using this information, the researchers developed a BSI risk index that could predict the likelihood of a BSI with 90% sensitivity and specificity.

“This method worked even better than we expected because we found a consistent difference between the gut bacteria in those who developed infections and those who did not,” said study author Dan Knights, PhD, of the University of Minnesota in Minneapolis.

“This research is an early demonstration that we may be able to use the bugs in our gut to predict infections and possibly develop new prognostic models in other diseases.”

Still, the researchers said these findings are based on a limited number of patients treated with the same regimen at a single clinic. So the next step for this research is to validate the findings in a much larger cohort including patients with different cancer types, different treatment types, and from multiple treatment centers.

“We still need to determine if these bacteria are playing any kind of causal role in the infections or if they are simply acting as biomarkers for some other predisposing condition in the patient,” Dr Montassier said.

Drug release in a cancer cell

Image courtesy of PNAS

The primary method used to test compounds for anticancer activity in vitro may produce inaccurate results, according to researchers.

Therefore, they have developed a new metric to evaluate a compound’s effect on cell proliferation—the drug-induced proliferation (DIP) rate.

They believe this metric, described in Nature Methods, overcomes the time-dependent bias of traditional proliferation assays.

“More than 90% of candidate cancer drugs fail in late-stage clinical trials, costing hundreds of millions of dollars,” said study author Vito Quaranta, MD, of Vanderbilt University School of Medicine in Nashville, Tennessee.

“The flawed in vitro drug discovery metric may not be the only responsible factor, but it may be worth pursuing an estimate of its impact.”

For more than 30 years, scientists have evaluated the ability of a compound to kill cells by adding the compound and counting how many cells are alive after 72 hours.

However, these proliferation assays, which measure cell number at a single time point, don’t take into account the bias introduced by exponential cell proliferation, even in the presence of the drug, said study author Darren Tyson, PhD, of Vanderbilt University School of Medicine.

“Cells are not uniform,” added Dr Quaranta. “They all proliferate exponentially but at different rates. At 72 hours, some cells will have doubled 3 times, and others will not have doubled at all.”

In addition, he noted, drugs don’t all behave the same way on every cell line. For example, a drug might have an immediate effect on one cell line and a delayed effect on another.

Therefore, he and his colleagues used a systems biology approach to demonstrate the time-dependent bias in static proliferation assays and to develop the time-independent DIP rate metric.

The researchers evaluated the responses of 4 different melanoma cell lines to the drug vemurafenib, currently used to treat melanoma, with the standard metric and with the DIP rate.

In one cell line, the team found a stark disagreement between the two metrics.

“The static metric says that the cell line is very sensitive to vemurafenib,” said Leonard Harris, PhD, of Vanderbilt University School of Medicine.

“However, our analysis shows this is not the case. A brief period of drug sensitivity, quickly followed by rebound, fools the static metric but not the DIP rate.”

The findings “suggest we should expect melanoma tumors treated with this drug to come back, and that’s what has happened, puzzling investigators,” Dr Quaranta said. “DIP rate analyses may help solve this conundrum, leading to better treatment strategies.”

These findings have particular importance in light of recent international efforts to generate data sets that include the responses of “thousands of cell lines to hundreds of compounds,” Dr Quaranta said.

The Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) databases include drug response data along with genomic and proteomic data that detail each cell line’s molecular makeup.

“The idea is to look for statistical correlations—these particular cell lines with this particular makeup are sensitive to these types of compounds—to use these large databases as discovery tools for new therapeutic targets in cancer,” Dr Quaranta said. “If the metric by which you’ve evaluated the drug sensitivity of the cells is wrong, your statistical correlations are basically no good.”

Drug release in a cancer cell

Image courtesy of PNAS

The primary method used to test compounds for anticancer activity in vitro may produce inaccurate results, according to researchers.

Therefore, they have developed a new metric to evaluate a compound’s effect on cell proliferation—the drug-induced proliferation (DIP) rate.

They believe this metric, described in Nature Methods, overcomes the time-dependent bias of traditional proliferation assays.

“More than 90% of candidate cancer drugs fail in late-stage clinical trials, costing hundreds of millions of dollars,” said study author Vito Quaranta, MD, of Vanderbilt University School of Medicine in Nashville, Tennessee.

“The flawed in vitro drug discovery metric may not be the only responsible factor, but it may be worth pursuing an estimate of its impact.”

For more than 30 years, scientists have evaluated the ability of a compound to kill cells by adding the compound and counting how many cells are alive after 72 hours.

However, these proliferation assays, which measure cell number at a single time point, don’t take into account the bias introduced by exponential cell proliferation, even in the presence of the drug, said study author Darren Tyson, PhD, of Vanderbilt University School of Medicine.

“Cells are not uniform,” added Dr Quaranta. “They all proliferate exponentially but at different rates. At 72 hours, some cells will have doubled 3 times, and others will not have doubled at all.”

In addition, he noted, drugs don’t all behave the same way on every cell line. For example, a drug might have an immediate effect on one cell line and a delayed effect on another.

Therefore, he and his colleagues used a systems biology approach to demonstrate the time-dependent bias in static proliferation assays and to develop the time-independent DIP rate metric.

The researchers evaluated the responses of 4 different melanoma cell lines to the drug vemurafenib, currently used to treat melanoma, with the standard metric and with the DIP rate.

In one cell line, the team found a stark disagreement between the two metrics.

“The static metric says that the cell line is very sensitive to vemurafenib,” said Leonard Harris, PhD, of Vanderbilt University School of Medicine.

“However, our analysis shows this is not the case. A brief period of drug sensitivity, quickly followed by rebound, fools the static metric but not the DIP rate.”

The findings “suggest we should expect melanoma tumors treated with this drug to come back, and that’s what has happened, puzzling investigators,” Dr Quaranta said. “DIP rate analyses may help solve this conundrum, leading to better treatment strategies.”

These findings have particular importance in light of recent international efforts to generate data sets that include the responses of “thousands of cell lines to hundreds of compounds,” Dr Quaranta said.

The Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) databases include drug response data along with genomic and proteomic data that detail each cell line’s molecular makeup.

“The idea is to look for statistical correlations—these particular cell lines with this particular makeup are sensitive to these types of compounds—to use these large databases as discovery tools for new therapeutic targets in cancer,” Dr Quaranta said. “If the metric by which you’ve evaluated the drug sensitivity of the cells is wrong, your statistical correlations are basically no good.”

Drug release in a cancer cell

Image courtesy of PNAS

The primary method used to test compounds for anticancer activity in vitro may produce inaccurate results, according to researchers.

Therefore, they have developed a new metric to evaluate a compound’s effect on cell proliferation—the drug-induced proliferation (DIP) rate.

They believe this metric, described in Nature Methods, overcomes the time-dependent bias of traditional proliferation assays.

“More than 90% of candidate cancer drugs fail in late-stage clinical trials, costing hundreds of millions of dollars,” said study author Vito Quaranta, MD, of Vanderbilt University School of Medicine in Nashville, Tennessee.

“The flawed in vitro drug discovery metric may not be the only responsible factor, but it may be worth pursuing an estimate of its impact.”

For more than 30 years, scientists have evaluated the ability of a compound to kill cells by adding the compound and counting how many cells are alive after 72 hours.

However, these proliferation assays, which measure cell number at a single time point, don’t take into account the bias introduced by exponential cell proliferation, even in the presence of the drug, said study author Darren Tyson, PhD, of Vanderbilt University School of Medicine.

“Cells are not uniform,” added Dr Quaranta. “They all proliferate exponentially but at different rates. At 72 hours, some cells will have doubled 3 times, and others will not have doubled at all.”

In addition, he noted, drugs don’t all behave the same way on every cell line. For example, a drug might have an immediate effect on one cell line and a delayed effect on another.

Therefore, he and his colleagues used a systems biology approach to demonstrate the time-dependent bias in static proliferation assays and to develop the time-independent DIP rate metric.

The researchers evaluated the responses of 4 different melanoma cell lines to the drug vemurafenib, currently used to treat melanoma, with the standard metric and with the DIP rate.

In one cell line, the team found a stark disagreement between the two metrics.

“The static metric says that the cell line is very sensitive to vemurafenib,” said Leonard Harris, PhD, of Vanderbilt University School of Medicine.

“However, our analysis shows this is not the case. A brief period of drug sensitivity, quickly followed by rebound, fools the static metric but not the DIP rate.”

The findings “suggest we should expect melanoma tumors treated with this drug to come back, and that’s what has happened, puzzling investigators,” Dr Quaranta said. “DIP rate analyses may help solve this conundrum, leading to better treatment strategies.”

These findings have particular importance in light of recent international efforts to generate data sets that include the responses of “thousands of cell lines to hundreds of compounds,” Dr Quaranta said.

The Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) databases include drug response data along with genomic and proteomic data that detail each cell line’s molecular makeup.

“The idea is to look for statistical correlations—these particular cell lines with this particular makeup are sensitive to these types of compounds—to use these large databases as discovery tools for new therapeutic targets in cancer,” Dr Quaranta said. “If the metric by which you’ve evaluated the drug sensitivity of the cells is wrong, your statistical correlations are basically no good.”

Woman exercising in a park

Photo by Peter Griffin

ORLANDO, FL—Frailty after hematopoietic stem cell transplant (HSCT), while associated with higher mortality, is not necessarily a function of age, according to investigators studying the impact of frailty on transplant outcomes.

Instead, other factors, such as increasing time from transplant, employment status, medical leave or disability, and limitations of social activities, were significantly associated with higher odds of frailty.

The investigators prospectively studied 96 HSCT recipients, age 40 and older, to determine the prevalence of frailty in HSCT populations and its impact on outcomes, including early post-transplant non-relapse mortality (NRM).

Mukta Arora, MD, of the University of Minnesota in Minneapolis, reported the findings at the 2015 ASH Annual Meeting (abstract 388*).

The investigators defined frailty as the presence of 3 or more of the following criteria: low grip strength, exhaustion, slowed walking speed, low physical activity, and unintentional weight loss. They defined pre-frailty as having 1 or 2 of these characteristics.

The investigators conducted multi-domain geriatric assessments of patients prior to HSCT and after transplant at 100 days, 6 months, and 1 year. The assessment included function, comorbidity, cognition, psychological state, social activity/support, nutritional status, and demographic, transplant, and disease-related information.

Forty-eight patients were in the younger age group (40–59), and 48 were in the older age group (60–74). All had undergone HSCT between February 2014 and April 2015.

Patient demographics

Patients in the younger group were a median age of 54 (range, 40–59) at transplant. Sixty-five percent were male, 58% had an autologous transplant, and 79% received myeloablative conditioning.

Patients in the older group were a median age of 65 (range, 60–73) at transplant. Fifty-four percent were male, 46% had an autologous transplant, and 46% had myeloablative conditioning.

The difference between the older and younger groups in their conditioning regimen was significant (P<0.01).

The groups were comparable in terms of the HSCT comorbidity index but were significantly different in employment status (P<0.01).

“As expected,” Dr Arora said, “there were more patients who were retired in the older group.”

In the younger group, 31% were employed, 3% retired, 56% on medical leave or disabled, and 10% unemployed.

In the older group, 6% were employed, 62% retired, 28% on medical leave or disabled, and 4% unemployed.

“There was no difference in the social activity and social support scores between the 2 groups,” Dr Arora observed.

Frailty assessments

In the younger group, at baseline, the prevalence of pre-frailty was 47%, and the prevalence of frailty was 11%. At 6 months after HSCT, the prevalence of pre-frailty was 45%, and the prevalence of frailty was 41% (P<0.01).

In the older group, at baseline, the prevalence of pre-frailty was 42%, and the prevalence of frailty was 6%. At 6 months, the prevalence of pre-frailty was 44%, and the prevalence of frailty was 38% (P<0.01).

The investigators then estimated the predictors of frailty.

Significant predictors of frailty included time since HSCT (odds ratio [OR]=3.7, 95% CI: 1.9-7.2, P<0.01), employment status (retired: OR=7.3, 95% CI 1.2 – 46.2, P=0.03), on medical leave or disabled (OR=11.2, 95% CI: 1.8 – 67.7, P=0.01), limitations in social activities (OR=1.04, 95% CI: 1.01 – 1.08, P=0.01), and baseline pre-frailty (OR=3.1, 95% CI: 2.3 – 45.5, P<0.01).

Allogeneic transplant was associated with higher odds of frailty than autologous (OR=3.1, 95% CI: 0.9 – 10.2), although it did not reach significance (P=0.06).

Investigators next estimated the impact of frailty or pre-frailty on NRM and identified a trend toward increased NRM in frail patients.

The 46 patients classified as not frail at baseline had a 7% cumulative incidence of NRM (P=0.07). The 42 patients classified as pre-frail had a 23% cumulative incidence of NRM, while the 8 patients classified as frail at baseline had a 28% cumulative incidence of NRM.

“So, to conclude, in this early study, frailty was noted in 8% and pre-frailty in 44% of the transplant population prior to transplant, and was not dependent on age,” Dr Arora said. “Frailty is a transitional state and appears to reflect a dynamic progression from robustness to functional decline with time since [HSCT].”

Because frailty is associated with higher mortality, the investigators believe vulnerable populations should be identified and their need for specific interventions defined.

This research was funded by the Leukemia & Lymphoma Society.

*Data in the abstract differ from the presentation.

Woman exercising in a park

Photo by Peter Griffin

ORLANDO, FL—Frailty after hematopoietic stem cell transplant (HSCT), while associated with higher mortality, is not necessarily a function of age, according to investigators studying the impact of frailty on transplant outcomes.

Instead, other factors, such as increasing time from transplant, employment status, medical leave or disability, and limitations of social activities, were significantly associated with higher odds of frailty.

The investigators prospectively studied 96 HSCT recipients, age 40 and older, to determine the prevalence of frailty in HSCT populations and its impact on outcomes, including early post-transplant non-relapse mortality (NRM).

Mukta Arora, MD, of the University of Minnesota in Minneapolis, reported the findings at the 2015 ASH Annual Meeting (abstract 388*).

The investigators defined frailty as the presence of 3 or more of the following criteria: low grip strength, exhaustion, slowed walking speed, low physical activity, and unintentional weight loss. They defined pre-frailty as having 1 or 2 of these characteristics.

The investigators conducted multi-domain geriatric assessments of patients prior to HSCT and after transplant at 100 days, 6 months, and 1 year. The assessment included function, comorbidity, cognition, psychological state, social activity/support, nutritional status, and demographic, transplant, and disease-related information.

Forty-eight patients were in the younger age group (40–59), and 48 were in the older age group (60–74). All had undergone HSCT between February 2014 and April 2015.

Patient demographics

Patients in the younger group were a median age of 54 (range, 40–59) at transplant. Sixty-five percent were male, 58% had an autologous transplant, and 79% received myeloablative conditioning.

Patients in the older group were a median age of 65 (range, 60–73) at transplant. Fifty-four percent were male, 46% had an autologous transplant, and 46% had myeloablative conditioning.

The difference between the older and younger groups in their conditioning regimen was significant (P<0.01).

The groups were comparable in terms of the HSCT comorbidity index but were significantly different in employment status (P<0.01).

“As expected,” Dr Arora said, “there were more patients who were retired in the older group.”

In the younger group, 31% were employed, 3% retired, 56% on medical leave or disabled, and 10% unemployed.

In the older group, 6% were employed, 62% retired, 28% on medical leave or disabled, and 4% unemployed.

“There was no difference in the social activity and social support scores between the 2 groups,” Dr Arora observed.

Frailty assessments

In the younger group, at baseline, the prevalence of pre-frailty was 47%, and the prevalence of frailty was 11%. At 6 months after HSCT, the prevalence of pre-frailty was 45%, and the prevalence of frailty was 41% (P<0.01).

In the older group, at baseline, the prevalence of pre-frailty was 42%, and the prevalence of frailty was 6%. At 6 months, the prevalence of pre-frailty was 44%, and the prevalence of frailty was 38% (P<0.01).

The investigators then estimated the predictors of frailty.

Significant predictors of frailty included time since HSCT (odds ratio [OR]=3.7, 95% CI: 1.9-7.2, P<0.01), employment status (retired: OR=7.3, 95% CI 1.2 – 46.2, P=0.03), on medical leave or disabled (OR=11.2, 95% CI: 1.8 – 67.7, P=0.01), limitations in social activities (OR=1.04, 95% CI: 1.01 – 1.08, P=0.01), and baseline pre-frailty (OR=3.1, 95% CI: 2.3 – 45.5, P<0.01).

Allogeneic transplant was associated with higher odds of frailty than autologous (OR=3.1, 95% CI: 0.9 – 10.2), although it did not reach significance (P=0.06).

Investigators next estimated the impact of frailty or pre-frailty on NRM and identified a trend toward increased NRM in frail patients.

The 46 patients classified as not frail at baseline had a 7% cumulative incidence of NRM (P=0.07). The 42 patients classified as pre-frail had a 23% cumulative incidence of NRM, while the 8 patients classified as frail at baseline had a 28% cumulative incidence of NRM.

“So, to conclude, in this early study, frailty was noted in 8% and pre-frailty in 44% of the transplant population prior to transplant, and was not dependent on age,” Dr Arora said. “Frailty is a transitional state and appears to reflect a dynamic progression from robustness to functional decline with time since [HSCT].”

Because frailty is associated with higher mortality, the investigators believe vulnerable populations should be identified and their need for specific interventions defined.

This research was funded by the Leukemia & Lymphoma Society.

*Data in the abstract differ from the presentation.

Woman exercising in a park

Photo by Peter Griffin

ORLANDO, FL—Frailty after hematopoietic stem cell transplant (HSCT), while associated with higher mortality, is not necessarily a function of age, according to investigators studying the impact of frailty on transplant outcomes.

Instead, other factors, such as increasing time from transplant, employment status, medical leave or disability, and limitations of social activities, were significantly associated with higher odds of frailty.

The investigators prospectively studied 96 HSCT recipients, age 40 and older, to determine the prevalence of frailty in HSCT populations and its impact on outcomes, including early post-transplant non-relapse mortality (NRM).

Mukta Arora, MD, of the University of Minnesota in Minneapolis, reported the findings at the 2015 ASH Annual Meeting (abstract 388*).

The investigators defined frailty as the presence of 3 or more of the following criteria: low grip strength, exhaustion, slowed walking speed, low physical activity, and unintentional weight loss. They defined pre-frailty as having 1 or 2 of these characteristics.

The investigators conducted multi-domain geriatric assessments of patients prior to HSCT and after transplant at 100 days, 6 months, and 1 year. The assessment included function, comorbidity, cognition, psychological state, social activity/support, nutritional status, and demographic, transplant, and disease-related information.

Forty-eight patients were in the younger age group (40–59), and 48 were in the older age group (60–74). All had undergone HSCT between February 2014 and April 2015.

Patient demographics

Patients in the younger group were a median age of 54 (range, 40–59) at transplant. Sixty-five percent were male, 58% had an autologous transplant, and 79% received myeloablative conditioning.

Patients in the older group were a median age of 65 (range, 60–73) at transplant. Fifty-four percent were male, 46% had an autologous transplant, and 46% had myeloablative conditioning.

The difference between the older and younger groups in their conditioning regimen was significant (P<0.01).

The groups were comparable in terms of the HSCT comorbidity index but were significantly different in employment status (P<0.01).

“As expected,” Dr Arora said, “there were more patients who were retired in the older group.”

In the younger group, 31% were employed, 3% retired, 56% on medical leave or disabled, and 10% unemployed.

In the older group, 6% were employed, 62% retired, 28% on medical leave or disabled, and 4% unemployed.

“There was no difference in the social activity and social support scores between the 2 groups,” Dr Arora observed.

Frailty assessments

In the younger group, at baseline, the prevalence of pre-frailty was 47%, and the prevalence of frailty was 11%. At 6 months after HSCT, the prevalence of pre-frailty was 45%, and the prevalence of frailty was 41% (P<0.01).

In the older group, at baseline, the prevalence of pre-frailty was 42%, and the prevalence of frailty was 6%. At 6 months, the prevalence of pre-frailty was 44%, and the prevalence of frailty was 38% (P<0.01).

The investigators then estimated the predictors of frailty.

Significant predictors of frailty included time since HSCT (odds ratio [OR]=3.7, 95% CI: 1.9-7.2, P<0.01), employment status (retired: OR=7.3, 95% CI 1.2 – 46.2, P=0.03), on medical leave or disabled (OR=11.2, 95% CI: 1.8 – 67.7, P=0.01), limitations in social activities (OR=1.04, 95% CI: 1.01 – 1.08, P=0.01), and baseline pre-frailty (OR=3.1, 95% CI: 2.3 – 45.5, P<0.01).

Allogeneic transplant was associated with higher odds of frailty than autologous (OR=3.1, 95% CI: 0.9 – 10.2), although it did not reach significance (P=0.06).

Investigators next estimated the impact of frailty or pre-frailty on NRM and identified a trend toward increased NRM in frail patients.

The 46 patients classified as not frail at baseline had a 7% cumulative incidence of NRM (P=0.07). The 42 patients classified as pre-frail had a 23% cumulative incidence of NRM, while the 8 patients classified as frail at baseline had a 28% cumulative incidence of NRM.

“So, to conclude, in this early study, frailty was noted in 8% and pre-frailty in 44% of the transplant population prior to transplant, and was not dependent on age,” Dr Arora said. “Frailty is a transitional state and appears to reflect a dynamic progression from robustness to functional decline with time since [HSCT].”

Because frailty is associated with higher mortality, the investigators believe vulnerable populations should be identified and their need for specific interventions defined.

This research was funded by the Leukemia & Lymphoma Society.

*Data in the abstract differ from the presentation.