Leukemia, Myelodysplasia, Transplantation

of Colorado Cancer Center

New research suggests that, in the US, early deaths from childhood cancer may be more common than clinical trials suggest.

Researchers found the rate of death within 1 month of diagnosis was higher among patients included in a large national database than among patients enrolled in phase 3 trials.

The data also indicated that early death is more likely in cancer patients under the age of 1 and those belonging to minority racial and ethnic groups.

Adam Green, MD, of the University of Colorado Anschutz Medical Campus in Aurora, and his colleagues conducted this research and reported the results in the Journal of Clinical Oncology.

The researchers analyzed data from the Surveillance, Epidemiology and End Results (SEER) database, which collects about 15% of all cancer outcomes across the US (representing a geographic and socioeconomic cross-section).

The team identified 36,337 patients with pediatric cancer (ages 0 to 19) diagnosed between 1992 and 2011. Of these patients, 555 (1.5%) died within 1 month of diagnosis.

Young age

Overall, the strongest predictor of early death was age below 1 year. The odds ratio (OR) was 4.36 for these patients (P<0.001), 0.75 for patients age 1 to 4, 0.78 for patients age 5 to 9, 1.00 (reference) for those age 10 to 14, and 1.69 for those age 15 to 19.

For hematologic malignancies, the adjusted OR (adjusted by poverty, unemployment, education, and year of diagnosis) was 4.32 for patients younger than 1 (P<0.001), 0.76 for patients age 1 to 4, 0.79 for patients age 5 to 9, 1.00 for those age 10 to 14, and 1.76 for those age 15 to 19 (P=0.002).

“In general, babies are just challenging, clinically, because they can’t tell you what they’re feeling,” Dr Green noted. “Parents and physicians have to pick the ones with cancer from the ones with a cold, without the patient being able to tell you about symptoms that could be diagnostic.”

“Babies tend to get aggressive cancers, it’s hard to tell when they’re getting sick, and some are even born with cancers that have already progressed. These factors combine to make very young age the strongest predictor of early death in our study.”

Race/ethnicity

Black race and Hispanic ethnicity also predicted early death. The OR was 1.48 for black race, 1.00 for white race (reference), and 1.09 for “other” races (P=0.102). The OR was 1.39 for Hispanic patients and 1.00 (reference) for non-Hispanic patients (P=0.007).

For hematologic malignancies, the adjusted OR was 1.68 for black patients (P=0.01) and 1.44 for patients of other, non-white races. The adjusted OR was 1.48 for Hispanic patients (P=0.009).

Dr Green said he hopes future studies will be able to determine the factors responsible for these disparities.

Higher death rates

Dr Green and his colleagues also found the rate of early death due to pediatric cancers is higher than reported in clinical trials, and this was true for all cancer subtypes assessed.

“Most of what we know about outcomes for cancer patients come from clinical trials, which have much more thorough reporting rules than cancer treated outside trials,” Dr Green said. “However, these kids in our study aren’t surviving long enough to join clinical trials.”

The researchers looked at a phase 3 trial (COG AAML0531) of pediatric patients with acute myeloid leukemia (AML) who were studied from August 2006 to June 2010. The early death rate in this trial was 1.6% (16/1022).

In contrast, the SEER database showed an early death rate for pediatric AML patients of 5.9% (15/256) during the same period as the trial and 6.2% (106/1698) for the period from 1992 to 2011. This is almost 4 times as high as the death rate in the trial.

The same effect was observed for acute lymphoblastic leukemia (ALL).

The early death rate for non-infant ALL was 0.7% (13/1790) in a trial (POG 9900) conducted from April 2000 to April 2005, 1.6% (30/1823) in the SEER data covering the same time period, and 1.3% (94/7353) in the SEER data from 1992 to 2011.

For infant ALL, the rates were 2.0% (3/149) in a trial (COG AALL0631) conducted from January 2008 to June 2014, 5.0% (2/40) in the SEER data during the trial period, and 5.4% (12/223) in the SEER data from 1992 to 2011.

“I had a hunch this was a bigger problem than we thought,” Dr Green said. “Now we see that is indeed the case.”

of Colorado Cancer Center

New research suggests that, in the US, early deaths from childhood cancer may be more common than clinical trials suggest.

Researchers found the rate of death within 1 month of diagnosis was higher among patients included in a large national database than among patients enrolled in phase 3 trials.

The data also indicated that early death is more likely in cancer patients under the age of 1 and those belonging to minority racial and ethnic groups.

Adam Green, MD, of the University of Colorado Anschutz Medical Campus in Aurora, and his colleagues conducted this research and reported the results in the Journal of Clinical Oncology.

The researchers analyzed data from the Surveillance, Epidemiology and End Results (SEER) database, which collects about 15% of all cancer outcomes across the US (representing a geographic and socioeconomic cross-section).

The team identified 36,337 patients with pediatric cancer (ages 0 to 19) diagnosed between 1992 and 2011. Of these patients, 555 (1.5%) died within 1 month of diagnosis.

Young age

Overall, the strongest predictor of early death was age below 1 year. The odds ratio (OR) was 4.36 for these patients (P<0.001), 0.75 for patients age 1 to 4, 0.78 for patients age 5 to 9, 1.00 (reference) for those age 10 to 14, and 1.69 for those age 15 to 19.

For hematologic malignancies, the adjusted OR (adjusted by poverty, unemployment, education, and year of diagnosis) was 4.32 for patients younger than 1 (P<0.001), 0.76 for patients age 1 to 4, 0.79 for patients age 5 to 9, 1.00 for those age 10 to 14, and 1.76 for those age 15 to 19 (P=0.002).

“In general, babies are just challenging, clinically, because they can’t tell you what they’re feeling,” Dr Green noted. “Parents and physicians have to pick the ones with cancer from the ones with a cold, without the patient being able to tell you about symptoms that could be diagnostic.”

“Babies tend to get aggressive cancers, it’s hard to tell when they’re getting sick, and some are even born with cancers that have already progressed. These factors combine to make very young age the strongest predictor of early death in our study.”

Race/ethnicity

Black race and Hispanic ethnicity also predicted early death. The OR was 1.48 for black race, 1.00 for white race (reference), and 1.09 for “other” races (P=0.102). The OR was 1.39 for Hispanic patients and 1.00 (reference) for non-Hispanic patients (P=0.007).

For hematologic malignancies, the adjusted OR was 1.68 for black patients (P=0.01) and 1.44 for patients of other, non-white races. The adjusted OR was 1.48 for Hispanic patients (P=0.009).

Dr Green said he hopes future studies will be able to determine the factors responsible for these disparities.

Higher death rates

Dr Green and his colleagues also found the rate of early death due to pediatric cancers is higher than reported in clinical trials, and this was true for all cancer subtypes assessed.

“Most of what we know about outcomes for cancer patients come from clinical trials, which have much more thorough reporting rules than cancer treated outside trials,” Dr Green said. “However, these kids in our study aren’t surviving long enough to join clinical trials.”

The researchers looked at a phase 3 trial (COG AAML0531) of pediatric patients with acute myeloid leukemia (AML) who were studied from August 2006 to June 2010. The early death rate in this trial was 1.6% (16/1022).

In contrast, the SEER database showed an early death rate for pediatric AML patients of 5.9% (15/256) during the same period as the trial and 6.2% (106/1698) for the period from 1992 to 2011. This is almost 4 times as high as the death rate in the trial.

The same effect was observed for acute lymphoblastic leukemia (ALL).

The early death rate for non-infant ALL was 0.7% (13/1790) in a trial (POG 9900) conducted from April 2000 to April 2005, 1.6% (30/1823) in the SEER data covering the same time period, and 1.3% (94/7353) in the SEER data from 1992 to 2011.

For infant ALL, the rates were 2.0% (3/149) in a trial (COG AALL0631) conducted from January 2008 to June 2014, 5.0% (2/40) in the SEER data during the trial period, and 5.4% (12/223) in the SEER data from 1992 to 2011.

“I had a hunch this was a bigger problem than we thought,” Dr Green said. “Now we see that is indeed the case.”

of Colorado Cancer Center

New research suggests that, in the US, early deaths from childhood cancer may be more common than clinical trials suggest.

Researchers found the rate of death within 1 month of diagnosis was higher among patients included in a large national database than among patients enrolled in phase 3 trials.

The data also indicated that early death is more likely in cancer patients under the age of 1 and those belonging to minority racial and ethnic groups.

Adam Green, MD, of the University of Colorado Anschutz Medical Campus in Aurora, and his colleagues conducted this research and reported the results in the Journal of Clinical Oncology.

The researchers analyzed data from the Surveillance, Epidemiology and End Results (SEER) database, which collects about 15% of all cancer outcomes across the US (representing a geographic and socioeconomic cross-section).

The team identified 36,337 patients with pediatric cancer (ages 0 to 19) diagnosed between 1992 and 2011. Of these patients, 555 (1.5%) died within 1 month of diagnosis.

Young age

Overall, the strongest predictor of early death was age below 1 year. The odds ratio (OR) was 4.36 for these patients (P<0.001), 0.75 for patients age 1 to 4, 0.78 for patients age 5 to 9, 1.00 (reference) for those age 10 to 14, and 1.69 for those age 15 to 19.

For hematologic malignancies, the adjusted OR (adjusted by poverty, unemployment, education, and year of diagnosis) was 4.32 for patients younger than 1 (P<0.001), 0.76 for patients age 1 to 4, 0.79 for patients age 5 to 9, 1.00 for those age 10 to 14, and 1.76 for those age 15 to 19 (P=0.002).

“In general, babies are just challenging, clinically, because they can’t tell you what they’re feeling,” Dr Green noted. “Parents and physicians have to pick the ones with cancer from the ones with a cold, without the patient being able to tell you about symptoms that could be diagnostic.”

“Babies tend to get aggressive cancers, it’s hard to tell when they’re getting sick, and some are even born with cancers that have already progressed. These factors combine to make very young age the strongest predictor of early death in our study.”

Race/ethnicity

Black race and Hispanic ethnicity also predicted early death. The OR was 1.48 for black race, 1.00 for white race (reference), and 1.09 for “other” races (P=0.102). The OR was 1.39 for Hispanic patients and 1.00 (reference) for non-Hispanic patients (P=0.007).

For hematologic malignancies, the adjusted OR was 1.68 for black patients (P=0.01) and 1.44 for patients of other, non-white races. The adjusted OR was 1.48 for Hispanic patients (P=0.009).

Dr Green said he hopes future studies will be able to determine the factors responsible for these disparities.

Higher death rates

Dr Green and his colleagues also found the rate of early death due to pediatric cancers is higher than reported in clinical trials, and this was true for all cancer subtypes assessed.

“Most of what we know about outcomes for cancer patients come from clinical trials, which have much more thorough reporting rules than cancer treated outside trials,” Dr Green said. “However, these kids in our study aren’t surviving long enough to join clinical trials.”

The researchers looked at a phase 3 trial (COG AAML0531) of pediatric patients with acute myeloid leukemia (AML) who were studied from August 2006 to June 2010. The early death rate in this trial was 1.6% (16/1022).

In contrast, the SEER database showed an early death rate for pediatric AML patients of 5.9% (15/256) during the same period as the trial and 6.2% (106/1698) for the period from 1992 to 2011. This is almost 4 times as high as the death rate in the trial.

The same effect was observed for acute lymphoblastic leukemia (ALL).

The early death rate for non-infant ALL was 0.7% (13/1790) in a trial (POG 9900) conducted from April 2000 to April 2005, 1.6% (30/1823) in the SEER data covering the same time period, and 1.3% (94/7353) in the SEER data from 1992 to 2011.

For infant ALL, the rates were 2.0% (3/149) in a trial (COG AALL0631) conducted from January 2008 to June 2014, 5.0% (2/40) in the SEER data during the trial period, and 5.4% (12/223) in the SEER data from 1992 to 2011.

“I had a hunch this was a bigger problem than we thought,” Dr Green said. “Now we see that is indeed the case.”

Photo courtesy of Amgen

Blinatumomab proved more effective than chemotherapy in a phase 3 trial of adults with Ph-negative, relapsed/refractory B-cell precursor acute lymphoblastic leukemia (B-ALL).

Blinatumomab produced higher remission rates and nearly doubled overall survival (OS) when compared to standard care, which encompassed 4 different chemotherapy regimens (investigator’s choice).

The incidence of grade 3 or higher adverse events (AEs) was higher for patients who received chemotherapy, but the incidence of serious AEs was higher in the blinatumomab arm.

These results were published in NEJM. The trial, known as TOWER, was sponsored by Amgen, the company developing blinatumomab.

“Results from the TOWER study reinforce the potential of this single-agent, bispecific T-cell engager immunotherapy, which helped a higher percentage of patients achieve minimal residual disease response versus standard of care chemotherapy, highlighting the depth and quality of remissions achieved,” said study author Hagop M. Kantarjian, MD, of The University of Texas MD Anderson Cancer Center in Houston.

Treatment

TOWER enrolled 405 patients with Ph-negative, relapsed/refractory B-ALL, 376 of whom ultimately received treatment.

The patients received blinatumomab (n=267) or investigator’s choice of 1 of 4 protocol-defined standard chemotherapy regimens (n=109):

• FLAG (fludarabine, high-dose cytarabine arabinoside, and granulocyte-colony stimulating factor), with or without an anthracycline (n=49, 45%)
• A high-dose cytarabine arabinoside-based regimen (n=19, 17%)
• A high-dose methotrexate-based regimen (n=22, 20%)
• A clofarabine-based regimen (n=19, 17%).

Patients who received blinatumomab received it as a continuous infusion, 4 weeks on and 2 weeks off, at 9 µg/day for 7 days, then 28 µg/day on weeks 2-4. They received 2 cycles of induction, which was followed by 3 cycles of consolidation if they had ≤5% blasts.

If patients still had ≤5% blasts after consolidation, they received up to 12 months of blinatumomab maintenance. Maintenance was a continuous infusion, 4 weeks on and 8 weeks off, at 28 µg/day.

Patients in the blinatumomab arm received a median of 2 cycles of therapy (range, 1-9). And patients in the chemotherapy arm received a median of 1 cycle (range, 1 to 4).

Thirty-two percent of patients in the blinatumomab arm received consolidation, as did 3% of patients in the chemotherapy arm.

Patients

Patient characteristics were similar between the treatment arms. The mean age was 41 in both arms (range, 18-80). Nearly 60% of patients in both arms were male.

About 40% of patients in the blinatumomab arm and 50% in the chemotherapy arm had not received any prior salvage regimens.

Thirty-five percent of patients in the blinatumomab arm and 34% in the chemotherapy arm had an allogeneic hematopoietic stem cell transplant (allo-HSCT) prior to study enrollment. Seventeen percent and 20%, respectively, relapsed after HSCT.

Forty-two percent and 40%, respectively, were refractory to primary or salvage therapy. Twenty-eight percent of patients in both arms were in their first relapse, and their first remission had lasted less than 12 months. Twelve percent of patients in both arms had an untreated second or greater relapse.

Remission

Within 12 weeks of treatment initiation, complete remission (CR) rates were significantly higher in the blinatumomab arm than the chemotherapy arm. (This was in the intent-to-treat population, which included 271 patients in the blinatumomab arm and 134 patients in the chemotherapy arm.)

The rate of CR with full hematologic recovery was 34% in the blinatumomab arm and 16% in the chemotherapy arm (P<0.001). The rate of CR with full, partial, or incomplete hematologic recovery was 44% and 25%, respectively (P<0.001).

Among patients who achieved a CR with full, partial, or incomplete hematologic recovery, 76% of those in the blinatumomab arm and 48% of those in the chemotherapy arm were negative for minimal residual disease.

Survival

At a median follow-up of 11.7 months for the blinatumomab arm and 11.8 months for the chemotherapy arm, the OS was significantly longer in the blinatumomab arm.

The median OS was 7.7 months and 4.0 months, respectively (hazard ratio for death=0.71, P=0.01).

The improvement in OS with blinatumomab was consistent across subgroups, regardless of age, prior salvage therapy, or prior allo-HSCT.

The investigators also considered the effect that post-treatment allo-HSCT might have on OS. Sixty-five patients in the blinatumomab arm and 32 in the chemotherapy arm went on to receive an allo-HSCT (24% of patients in both arms).

When the investigators censored for post-treatment allo-HSCT, the median OS was 6.9 months in the blinatumomab arm and 3.9 months in the chemotherapy arm (hazard ratio=0.66, P=0.004).

Safety

Nearly all patients in both arms (99%) experienced AEs. Grade 3 or higher AEs occurred in 87% of patients in the blinatumomab arm and 92% of those in the chemotherapy arm. Serious AEs occurred in 62% and 45%, respectively.

Grade 3 or higher AEs of interest, according to the researchers, were infection (34% with blinatumomab and 52% with chemotherapy), neutropenia (38% and 58%, respectively), elevated liver enzymes (13% and 15%, respectively), neurologic events (9% and 8%, respectively), cytokine release syndrome (5% and 0%, respectively), infusion reactions (3% and 1%, respectively), and lymphopenia (2% and 4%, respectively).

Fatal AEs occurred in 19% of patients in the blinatumomab arm and 17% of those in the chemotherapy arm.

Fatal AEs that occurred in at least 1% of patients in either arm (blinatumomab and chemotherapy, respectively) were sepsis (3% and 4%), septic shock (2% and 0%), multiorgan failure (1% and 0%), respiratory failure (<1% and 2%), and bacteremia (0% and 2%). 

Photo courtesy of Amgen

Blinatumomab proved more effective than chemotherapy in a phase 3 trial of adults with Ph-negative, relapsed/refractory B-cell precursor acute lymphoblastic leukemia (B-ALL).

Blinatumomab produced higher remission rates and nearly doubled overall survival (OS) when compared to standard care, which encompassed 4 different chemotherapy regimens (investigator’s choice).

The incidence of grade 3 or higher adverse events (AEs) was higher for patients who received chemotherapy, but the incidence of serious AEs was higher in the blinatumomab arm.

These results were published in NEJM. The trial, known as TOWER, was sponsored by Amgen, the company developing blinatumomab.

“Results from the TOWER study reinforce the potential of this single-agent, bispecific T-cell engager immunotherapy, which helped a higher percentage of patients achieve minimal residual disease response versus standard of care chemotherapy, highlighting the depth and quality of remissions achieved,” said study author Hagop M. Kantarjian, MD, of The University of Texas MD Anderson Cancer Center in Houston.

Treatment

TOWER enrolled 405 patients with Ph-negative, relapsed/refractory B-ALL, 376 of whom ultimately received treatment.

The patients received blinatumomab (n=267) or investigator’s choice of 1 of 4 protocol-defined standard chemotherapy regimens (n=109):

• FLAG (fludarabine, high-dose cytarabine arabinoside, and granulocyte-colony stimulating factor), with or without an anthracycline (n=49, 45%)
• A high-dose cytarabine arabinoside-based regimen (n=19, 17%)
• A high-dose methotrexate-based regimen (n=22, 20%)
• A clofarabine-based regimen (n=19, 17%).

Patients who received blinatumomab received it as a continuous infusion, 4 weeks on and 2 weeks off, at 9 µg/day for 7 days, then 28 µg/day on weeks 2-4. They received 2 cycles of induction, which was followed by 3 cycles of consolidation if they had ≤5% blasts.

If patients still had ≤5% blasts after consolidation, they received up to 12 months of blinatumomab maintenance. Maintenance was a continuous infusion, 4 weeks on and 8 weeks off, at 28 µg/day.

Patients in the blinatumomab arm received a median of 2 cycles of therapy (range, 1-9). And patients in the chemotherapy arm received a median of 1 cycle (range, 1 to 4).

Thirty-two percent of patients in the blinatumomab arm received consolidation, as did 3% of patients in the chemotherapy arm.

Patients

Patient characteristics were similar between the treatment arms. The mean age was 41 in both arms (range, 18-80). Nearly 60% of patients in both arms were male.

About 40% of patients in the blinatumomab arm and 50% in the chemotherapy arm had not received any prior salvage regimens.

Thirty-five percent of patients in the blinatumomab arm and 34% in the chemotherapy arm had an allogeneic hematopoietic stem cell transplant (allo-HSCT) prior to study enrollment. Seventeen percent and 20%, respectively, relapsed after HSCT.

Forty-two percent and 40%, respectively, were refractory to primary or salvage therapy. Twenty-eight percent of patients in both arms were in their first relapse, and their first remission had lasted less than 12 months. Twelve percent of patients in both arms had an untreated second or greater relapse.

Remission

Within 12 weeks of treatment initiation, complete remission (CR) rates were significantly higher in the blinatumomab arm than the chemotherapy arm. (This was in the intent-to-treat population, which included 271 patients in the blinatumomab arm and 134 patients in the chemotherapy arm.)

The rate of CR with full hematologic recovery was 34% in the blinatumomab arm and 16% in the chemotherapy arm (P<0.001). The rate of CR with full, partial, or incomplete hematologic recovery was 44% and 25%, respectively (P<0.001).

Among patients who achieved a CR with full, partial, or incomplete hematologic recovery, 76% of those in the blinatumomab arm and 48% of those in the chemotherapy arm were negative for minimal residual disease.

Survival

At a median follow-up of 11.7 months for the blinatumomab arm and 11.8 months for the chemotherapy arm, the OS was significantly longer in the blinatumomab arm.

The median OS was 7.7 months and 4.0 months, respectively (hazard ratio for death=0.71, P=0.01).

The improvement in OS with blinatumomab was consistent across subgroups, regardless of age, prior salvage therapy, or prior allo-HSCT.

The investigators also considered the effect that post-treatment allo-HSCT might have on OS. Sixty-five patients in the blinatumomab arm and 32 in the chemotherapy arm went on to receive an allo-HSCT (24% of patients in both arms).

When the investigators censored for post-treatment allo-HSCT, the median OS was 6.9 months in the blinatumomab arm and 3.9 months in the chemotherapy arm (hazard ratio=0.66, P=0.004).

Safety

Nearly all patients in both arms (99%) experienced AEs. Grade 3 or higher AEs occurred in 87% of patients in the blinatumomab arm and 92% of those in the chemotherapy arm. Serious AEs occurred in 62% and 45%, respectively.

Grade 3 or higher AEs of interest, according to the researchers, were infection (34% with blinatumomab and 52% with chemotherapy), neutropenia (38% and 58%, respectively), elevated liver enzymes (13% and 15%, respectively), neurologic events (9% and 8%, respectively), cytokine release syndrome (5% and 0%, respectively), infusion reactions (3% and 1%, respectively), and lymphopenia (2% and 4%, respectively).

Fatal AEs occurred in 19% of patients in the blinatumomab arm and 17% of those in the chemotherapy arm.

Fatal AEs that occurred in at least 1% of patients in either arm (blinatumomab and chemotherapy, respectively) were sepsis (3% and 4%), septic shock (2% and 0%), multiorgan failure (1% and 0%), respiratory failure (<1% and 2%), and bacteremia (0% and 2%). 

Photo courtesy of Amgen

Blinatumomab proved more effective than chemotherapy in a phase 3 trial of adults with Ph-negative, relapsed/refractory B-cell precursor acute lymphoblastic leukemia (B-ALL).

Blinatumomab produced higher remission rates and nearly doubled overall survival (OS) when compared to standard care, which encompassed 4 different chemotherapy regimens (investigator’s choice).

The incidence of grade 3 or higher adverse events (AEs) was higher for patients who received chemotherapy, but the incidence of serious AEs was higher in the blinatumomab arm.

These results were published in NEJM. The trial, known as TOWER, was sponsored by Amgen, the company developing blinatumomab.

“Results from the TOWER study reinforce the potential of this single-agent, bispecific T-cell engager immunotherapy, which helped a higher percentage of patients achieve minimal residual disease response versus standard of care chemotherapy, highlighting the depth and quality of remissions achieved,” said study author Hagop M. Kantarjian, MD, of The University of Texas MD Anderson Cancer Center in Houston.

Treatment

TOWER enrolled 405 patients with Ph-negative, relapsed/refractory B-ALL, 376 of whom ultimately received treatment.

The patients received blinatumomab (n=267) or investigator’s choice of 1 of 4 protocol-defined standard chemotherapy regimens (n=109):

• FLAG (fludarabine, high-dose cytarabine arabinoside, and granulocyte-colony stimulating factor), with or without an anthracycline (n=49, 45%)
• A high-dose cytarabine arabinoside-based regimen (n=19, 17%)
• A high-dose methotrexate-based regimen (n=22, 20%)
• A clofarabine-based regimen (n=19, 17%).

Patients who received blinatumomab received it as a continuous infusion, 4 weeks on and 2 weeks off, at 9 µg/day for 7 days, then 28 µg/day on weeks 2-4. They received 2 cycles of induction, which was followed by 3 cycles of consolidation if they had ≤5% blasts.

If patients still had ≤5% blasts after consolidation, they received up to 12 months of blinatumomab maintenance. Maintenance was a continuous infusion, 4 weeks on and 8 weeks off, at 28 µg/day.

Patients in the blinatumomab arm received a median of 2 cycles of therapy (range, 1-9). And patients in the chemotherapy arm received a median of 1 cycle (range, 1 to 4).

Thirty-two percent of patients in the blinatumomab arm received consolidation, as did 3% of patients in the chemotherapy arm.

Patients

Patient characteristics were similar between the treatment arms. The mean age was 41 in both arms (range, 18-80). Nearly 60% of patients in both arms were male.

About 40% of patients in the blinatumomab arm and 50% in the chemotherapy arm had not received any prior salvage regimens.

Thirty-five percent of patients in the blinatumomab arm and 34% in the chemotherapy arm had an allogeneic hematopoietic stem cell transplant (allo-HSCT) prior to study enrollment. Seventeen percent and 20%, respectively, relapsed after HSCT.

Forty-two percent and 40%, respectively, were refractory to primary or salvage therapy. Twenty-eight percent of patients in both arms were in their first relapse, and their first remission had lasted less than 12 months. Twelve percent of patients in both arms had an untreated second or greater relapse.

Remission

Within 12 weeks of treatment initiation, complete remission (CR) rates were significantly higher in the blinatumomab arm than the chemotherapy arm. (This was in the intent-to-treat population, which included 271 patients in the blinatumomab arm and 134 patients in the chemotherapy arm.)

The rate of CR with full hematologic recovery was 34% in the blinatumomab arm and 16% in the chemotherapy arm (P<0.001). The rate of CR with full, partial, or incomplete hematologic recovery was 44% and 25%, respectively (P<0.001).

Among patients who achieved a CR with full, partial, or incomplete hematologic recovery, 76% of those in the blinatumomab arm and 48% of those in the chemotherapy arm were negative for minimal residual disease.

Survival

At a median follow-up of 11.7 months for the blinatumomab arm and 11.8 months for the chemotherapy arm, the OS was significantly longer in the blinatumomab arm.

The median OS was 7.7 months and 4.0 months, respectively (hazard ratio for death=0.71, P=0.01).

The improvement in OS with blinatumomab was consistent across subgroups, regardless of age, prior salvage therapy, or prior allo-HSCT.

The investigators also considered the effect that post-treatment allo-HSCT might have on OS. Sixty-five patients in the blinatumomab arm and 32 in the chemotherapy arm went on to receive an allo-HSCT (24% of patients in both arms).

When the investigators censored for post-treatment allo-HSCT, the median OS was 6.9 months in the blinatumomab arm and 3.9 months in the chemotherapy arm (hazard ratio=0.66, P=0.004).

Safety

Nearly all patients in both arms (99%) experienced AEs. Grade 3 or higher AEs occurred in 87% of patients in the blinatumomab arm and 92% of those in the chemotherapy arm. Serious AEs occurred in 62% and 45%, respectively.

Grade 3 or higher AEs of interest, according to the researchers, were infection (34% with blinatumomab and 52% with chemotherapy), neutropenia (38% and 58%, respectively), elevated liver enzymes (13% and 15%, respectively), neurologic events (9% and 8%, respectively), cytokine release syndrome (5% and 0%, respectively), infusion reactions (3% and 1%, respectively), and lymphopenia (2% and 4%, respectively).

Fatal AEs occurred in 19% of patients in the blinatumomab arm and 17% of those in the chemotherapy arm.

Fatal AEs that occurred in at least 1% of patients in either arm (blinatumomab and chemotherapy, respectively) were sepsis (3% and 4%), septic shock (2% and 0%), multiorgan failure (1% and 0%), respiratory failure (<1% and 2%), and bacteremia (0% and 2%). 

ORLANDO – Allogeneic hematopoietic stem cell transplantation using a matched donor is a valid treatment option – and potential cure – for leukemias with markers of both myeloid and lymphoid lineages, or mixed phenotype acute leukemias, according to findings from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (ALWP-EBMT) database.

Treatment outcomes at 3 years in 519 patients from the database who received an allogeneic transplant (allo-HCT) for mixed-phenotype acute leukemia (MPAL) between 2000 and 2014 and were transplanted in complete remission (CR1) included an overall survival of 56.3%, a leukemia-free survival of 46.5%, a relapse incidence of 31.4%, a nonrelapse mortality of 22.1%, and an incidence of chronic graft-versus-host disease (GVHD) of 37.5%, Reinhold Munker, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

“The outcome in this large adult study is pretty favorable based upon 519 patients; 45%-65% can expect overall survival at 5 years,” he said.

The median age of the study subjects was 38.1 years (range, 18-75). Transplants were from a matched sibling donor in 54.5% of cases, and from a matched unrelated donor in 45.5% of cases. Myeloablative conditioning was used in 400 patients and included only chemotherapy in 140 patients and chemotherapy with total body irradiation in 260 patients. The remaining patients received nonmyeloablative conditioning, said Dr. Munker of Tulane University, New Orleans.

The source of stem cells was bone marrow in 26% of patients, and peripheral blood in 73%. Grade II-IV acute GVHD developed in 32.5% of patients. Median follow-up was 32 months, he noted.

In univariate analysis, age at transplant was strongly associated with leukemia-free survival, nonrelapse mortality, relapse incidence, and overall survival. The best outcomes were among those aged 18-35 years. The nonrelapse mortality rate and overall survival rate were lower for transplants done in 2005-2014 vs. 2000-2004 (20% vs 33.2% and 58.3 vs 44.7%, respectively). No differences in outcomes were found between related and unrelated donors, but chronic GVHD was more common with female donors and male recipients, with no in vivo T-cell depletion, and with use of peripheral blood stem cells – findings which are not unexpected, Dr. Munker noted.

Use of myeloablative conditioning with total-body irradiation correlated with a lower relapse incidence and with better leukemia-free survival vs. both myeloablative conditioning with only chemotherapy and reduced-intensity conditioning, he said.

In multivariate analysis, younger age and more recent year of transplant were associated with a better leukemia-free survival and overall survival, and use of myeloablative conditioning with total-body irradiation was associated with better leukemia-free survival and with a trend for higher overall survival.

MPALs are rare, accounting for only 2%-5% of all acute leukemias, Dr. Munker said, noting that prognosis is considered to be intermediate in children and unfavorable in adults.

The diagnostic criteria for MPAL were revised by the World Health Organization (WHO) in 2008 and accepted by most centers, but until recently data were lacking with respect to the recommended treatment strategy of induction regimens similar to those used in acute lymphoblastic leukemia, and consolidation by allogeneic transplant, he explained.

However, the Center for International Blood and Marrow Transplant Research last year published a series of 95 cases showing encouraging long-term survival with allo-HCT in MPAL patients with a median age of 20 years.

The current findings confirm and extend those prior findings, Dr. Munker said.

Dr. Munker reported having no disclosures.

[email protected]

ORLANDO – Allogeneic hematopoietic stem cell transplantation using a matched donor is a valid treatment option – and potential cure – for leukemias with markers of both myeloid and lymphoid lineages, or mixed phenotype acute leukemias, according to findings from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (ALWP-EBMT) database.

Treatment outcomes at 3 years in 519 patients from the database who received an allogeneic transplant (allo-HCT) for mixed-phenotype acute leukemia (MPAL) between 2000 and 2014 and were transplanted in complete remission (CR1) included an overall survival of 56.3%, a leukemia-free survival of 46.5%, a relapse incidence of 31.4%, a nonrelapse mortality of 22.1%, and an incidence of chronic graft-versus-host disease (GVHD) of 37.5%, Reinhold Munker, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

“The outcome in this large adult study is pretty favorable based upon 519 patients; 45%-65% can expect overall survival at 5 years,” he said.

The median age of the study subjects was 38.1 years (range, 18-75). Transplants were from a matched sibling donor in 54.5% of cases, and from a matched unrelated donor in 45.5% of cases. Myeloablative conditioning was used in 400 patients and included only chemotherapy in 140 patients and chemotherapy with total body irradiation in 260 patients. The remaining patients received nonmyeloablative conditioning, said Dr. Munker of Tulane University, New Orleans.

The source of stem cells was bone marrow in 26% of patients, and peripheral blood in 73%. Grade II-IV acute GVHD developed in 32.5% of patients. Median follow-up was 32 months, he noted.

In univariate analysis, age at transplant was strongly associated with leukemia-free survival, nonrelapse mortality, relapse incidence, and overall survival. The best outcomes were among those aged 18-35 years. The nonrelapse mortality rate and overall survival rate were lower for transplants done in 2005-2014 vs. 2000-2004 (20% vs 33.2% and 58.3 vs 44.7%, respectively). No differences in outcomes were found between related and unrelated donors, but chronic GVHD was more common with female donors and male recipients, with no in vivo T-cell depletion, and with use of peripheral blood stem cells – findings which are not unexpected, Dr. Munker noted.

Use of myeloablative conditioning with total-body irradiation correlated with a lower relapse incidence and with better leukemia-free survival vs. both myeloablative conditioning with only chemotherapy and reduced-intensity conditioning, he said.

In multivariate analysis, younger age and more recent year of transplant were associated with a better leukemia-free survival and overall survival, and use of myeloablative conditioning with total-body irradiation was associated with better leukemia-free survival and with a trend for higher overall survival.

MPALs are rare, accounting for only 2%-5% of all acute leukemias, Dr. Munker said, noting that prognosis is considered to be intermediate in children and unfavorable in adults.

The diagnostic criteria for MPAL were revised by the World Health Organization (WHO) in 2008 and accepted by most centers, but until recently data were lacking with respect to the recommended treatment strategy of induction regimens similar to those used in acute lymphoblastic leukemia, and consolidation by allogeneic transplant, he explained.

However, the Center for International Blood and Marrow Transplant Research last year published a series of 95 cases showing encouraging long-term survival with allo-HCT in MPAL patients with a median age of 20 years.

The current findings confirm and extend those prior findings, Dr. Munker said.

Dr. Munker reported having no disclosures.

[email protected]

ORLANDO – Allogeneic hematopoietic stem cell transplantation using a matched donor is a valid treatment option – and potential cure – for leukemias with markers of both myeloid and lymphoid lineages, or mixed phenotype acute leukemias, according to findings from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (ALWP-EBMT) database.

Treatment outcomes at 3 years in 519 patients from the database who received an allogeneic transplant (allo-HCT) for mixed-phenotype acute leukemia (MPAL) between 2000 and 2014 and were transplanted in complete remission (CR1) included an overall survival of 56.3%, a leukemia-free survival of 46.5%, a relapse incidence of 31.4%, a nonrelapse mortality of 22.1%, and an incidence of chronic graft-versus-host disease (GVHD) of 37.5%, Reinhold Munker, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

“The outcome in this large adult study is pretty favorable based upon 519 patients; 45%-65% can expect overall survival at 5 years,” he said.

The median age of the study subjects was 38.1 years (range, 18-75). Transplants were from a matched sibling donor in 54.5% of cases, and from a matched unrelated donor in 45.5% of cases. Myeloablative conditioning was used in 400 patients and included only chemotherapy in 140 patients and chemotherapy with total body irradiation in 260 patients. The remaining patients received nonmyeloablative conditioning, said Dr. Munker of Tulane University, New Orleans.

The source of stem cells was bone marrow in 26% of patients, and peripheral blood in 73%. Grade II-IV acute GVHD developed in 32.5% of patients. Median follow-up was 32 months, he noted.

In univariate analysis, age at transplant was strongly associated with leukemia-free survival, nonrelapse mortality, relapse incidence, and overall survival. The best outcomes were among those aged 18-35 years. The nonrelapse mortality rate and overall survival rate were lower for transplants done in 2005-2014 vs. 2000-2004 (20% vs 33.2% and 58.3 vs 44.7%, respectively). No differences in outcomes were found between related and unrelated donors, but chronic GVHD was more common with female donors and male recipients, with no in vivo T-cell depletion, and with use of peripheral blood stem cells – findings which are not unexpected, Dr. Munker noted.

Use of myeloablative conditioning with total-body irradiation correlated with a lower relapse incidence and with better leukemia-free survival vs. both myeloablative conditioning with only chemotherapy and reduced-intensity conditioning, he said.

In multivariate analysis, younger age and more recent year of transplant were associated with a better leukemia-free survival and overall survival, and use of myeloablative conditioning with total-body irradiation was associated with better leukemia-free survival and with a trend for higher overall survival.

MPALs are rare, accounting for only 2%-5% of all acute leukemias, Dr. Munker said, noting that prognosis is considered to be intermediate in children and unfavorable in adults.

The diagnostic criteria for MPAL were revised by the World Health Organization (WHO) in 2008 and accepted by most centers, but until recently data were lacking with respect to the recommended treatment strategy of induction regimens similar to those used in acute lymphoblastic leukemia, and consolidation by allogeneic transplant, he explained.

However, the Center for International Blood and Marrow Transplant Research last year published a series of 95 cases showing encouraging long-term survival with allo-HCT in MPAL patients with a median age of 20 years.

The current findings confirm and extend those prior findings, Dr. Munker said.

Dr. Munker reported having no disclosures.

[email protected]

ORLANDO – Minimal residual disease (MRD) measured before and after allogeneic hematopoietic stem cell transplantation (HCT) is a powerful predictor of survival in children with acute lymphoblastic leukemia (ALL), according to a review of hundreds of cases from around the world.

The findings could have implications for using minimal residual disease measures to guide posttransplant interventions, Michael A. Pulsipher, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

“MRD pretransplant was a very powerful predictor of outcomes. MRD posttransplant highlights individual patients at risk,” Dr. Pulsipher said. Results comparing reverse transcriptase–polymerase chain reaction with flow cytometry require validation by direct comparison in the same patient cohort, but “the new risk scores ... very nicely predict outcomes both pre- and post-transplant and can guide study planning and patient counseling.”

A total of 2,960 bone marrow MRD measurements were performed in the 747 patients included in the study. MRD was assessed prior to HCT and on or near days 30, 60, 100, 180, and 365 and beyond after HCT.

Patients were grouped for analysis according to MRD level: Group 1 had no detectable MRD, group 2 had low detectable MRD levels (less than 10E-4, or 0.01% by flow cytometry), and group 3 had high detectable MRD levels (10E-4 or higher). A second analysis compared findings in those tested by flow cytometry and those tested by real-time quantitative PCR (RQ-PCR), said Dr. Pulsipher of Children’s Hospital Los Angeles.

In 648 patients with pre-HCT MRD measurements available, the 4-year probability of event-free survival was 62%, 67%, and 37% for groups 1, 2, and 3, respectively. Group 3 – the high MRD level group – had 2.47 times the increased hazard ratio for relapse and 1.67 times the increased risk of treatment-related mortality, Dr. Pulsipher said, adding that pre-HCT MRD and remission status both significantly influenced survival, while age, sex, relapse site, cytogenetics, donor type, and stem cell source did not influence outcome.

Post-HCT MRD values were analyzed as time-dependent covariates.

“As time went by more and more, any detectable level of MRD led to a very poor prognosis, whereas patients arriving at day 365 with no detectable MRD had exceptional prognosis with survival approaching 90%,” he said.

Specifically, the 4-year probability of event-free survival for groups 1, 2, and 3, respectively, were 59%, 65%, and 43% at day 30; 64%, 47%, and 36% at day 60; 65%, 69%, and 44% at day 90; 79%, 40%, and 12% at day 180; and 87%, 36%, and 25% at day 365.

Of note, a very significant interaction was seen between acute graft-versus-host disease (GVHD) and MRD, Dr. Pulsipher said, explaining that patients who were MRD positive and had developed GVHD had a significant decrease in the cumulative incidence of relapse, compared with those with no GVHD.

“This translated into improved event-free survival with patients post transplant, who were MRD-positive [and] developing GVHD, still having a reasonable chance of survival, whereas patients post transplant who had MRD measured who did not develop GVHD had a very poor chance of survival,” he added.

Additionally, based on detailed multivariate analysis including a number of clinical factors, risk predictive scores were developed for event-free survival risk at 18 months or cumulative incidence of relapse at 18 months. Multiple scores were developed for each, but, as an example of factors that had an important effect on outcomes, patients with very early pretransplant relapse (those who went into remission but relapsed within 18 months) or with greater than 2nd relapse had a high risk for poor event-free survival. Mismatched donors and unrelated cord-blood stem cell transplant recipients also had high risk, he said, noting that, “of course, MRD had a significant effect” and was the most important factor prior to transplant.

These patients, who had a 4-point or greater risk score, were the poorest risk group, with survival that was less than 50%, as opposed to better risk groups that exceeded 90%, he said.

“A score of greater than 5 could identify 80% of patients who were going to relapse after transplant, and of course, event-free and overall survival in those patients were very poor,” he added.

As time went by, the early risk of GVHD diminished somewhat, as did the risk of mismatched donors.

“Most of the risk was associated with any MRD detection,” he said.

Flow cytometry and RQ-PCR levels of at least 10-4 were highly predictive of relapse at all pre- and post-HCT time points; however, RQ-PCR values between 10-4 and 10-3, in cases where adequate numbers were available for comparison, better predicted relapse as compared with flow cytometry results.

For example, before HCT, hazard ratios were 1.26 and 2.41 with flow cytometry vs. RQ-PCR. At day 30, the hazard ratios were 1.33 and 2.53, and at day 365, they were 3.54 and 31.84, Dr. Pulsipher reported.

The findings provide important information for improving outcomes in children with high-risk ALL undergoing HCT, he said.

“Older prognostic models for relapsed and refractory high-risk ALL have focused on timing and location of relapse, as well as disease phenotype. But it is clear that, in order to treat children with very high risk ALL with transplantation, MRD has become the most important thing to look at in the pretreatment setting. The challenges that we face in assessing MRD, however, have been hampered by the fact that we have differing MRD measurements,” he said, noting that RQ-PCR is often used in Europe, while flow cytometry is more often used in the United States. As such, direct comparisons are lacking, as are T-cell and posttransplant data.

The current study represents a “tremendous effort” by international collaborators to address these shortcoming, he said.

“This is a great opportunity, as our goal, of course, is to avoid futility in transplantation, but, more importantly, to find opportunities to identify groups for which we can improve our outcomes,” he added.

Patients included in the study were treated in Europe, North America, and Australia and were transplanted during Sept. 1999-May 2016. Most were in first or second remission, and most (586) had pre-B ALL. A notable 145 had T-cell ALL – “more than ever has been analyzed previously” – and 16 had B-lineage or biphenotypic ALL. About half were under age 10 years, 62% were boys, and stem cell sources were typical, although 20% received a cord blood transplant.

Dr. Pulsipher reported serving as an advisor and/or consultant for Chimerix, Novartis, Jazz Pharmaceutical, and receiving housing support from Medac Pharma for an educational meeting.

[email protected]

ORLANDO – Minimal residual disease (MRD) measured before and after allogeneic hematopoietic stem cell transplantation (HCT) is a powerful predictor of survival in children with acute lymphoblastic leukemia (ALL), according to a review of hundreds of cases from around the world.

The findings could have implications for using minimal residual disease measures to guide posttransplant interventions, Michael A. Pulsipher, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

“MRD pretransplant was a very powerful predictor of outcomes. MRD posttransplant highlights individual patients at risk,” Dr. Pulsipher said. Results comparing reverse transcriptase–polymerase chain reaction with flow cytometry require validation by direct comparison in the same patient cohort, but “the new risk scores ... very nicely predict outcomes both pre- and post-transplant and can guide study planning and patient counseling.”

A total of 2,960 bone marrow MRD measurements were performed in the 747 patients included in the study. MRD was assessed prior to HCT and on or near days 30, 60, 100, 180, and 365 and beyond after HCT.

Patients were grouped for analysis according to MRD level: Group 1 had no detectable MRD, group 2 had low detectable MRD levels (less than 10E-4, or 0.01% by flow cytometry), and group 3 had high detectable MRD levels (10E-4 or higher). A second analysis compared findings in those tested by flow cytometry and those tested by real-time quantitative PCR (RQ-PCR), said Dr. Pulsipher of Children’s Hospital Los Angeles.

In 648 patients with pre-HCT MRD measurements available, the 4-year probability of event-free survival was 62%, 67%, and 37% for groups 1, 2, and 3, respectively. Group 3 – the high MRD level group – had 2.47 times the increased hazard ratio for relapse and 1.67 times the increased risk of treatment-related mortality, Dr. Pulsipher said, adding that pre-HCT MRD and remission status both significantly influenced survival, while age, sex, relapse site, cytogenetics, donor type, and stem cell source did not influence outcome.

Post-HCT MRD values were analyzed as time-dependent covariates.

“As time went by more and more, any detectable level of MRD led to a very poor prognosis, whereas patients arriving at day 365 with no detectable MRD had exceptional prognosis with survival approaching 90%,” he said.

Specifically, the 4-year probability of event-free survival for groups 1, 2, and 3, respectively, were 59%, 65%, and 43% at day 30; 64%, 47%, and 36% at day 60; 65%, 69%, and 44% at day 90; 79%, 40%, and 12% at day 180; and 87%, 36%, and 25% at day 365.

Of note, a very significant interaction was seen between acute graft-versus-host disease (GVHD) and MRD, Dr. Pulsipher said, explaining that patients who were MRD positive and had developed GVHD had a significant decrease in the cumulative incidence of relapse, compared with those with no GVHD.

“This translated into improved event-free survival with patients post transplant, who were MRD-positive [and] developing GVHD, still having a reasonable chance of survival, whereas patients post transplant who had MRD measured who did not develop GVHD had a very poor chance of survival,” he added.

Additionally, based on detailed multivariate analysis including a number of clinical factors, risk predictive scores were developed for event-free survival risk at 18 months or cumulative incidence of relapse at 18 months. Multiple scores were developed for each, but, as an example of factors that had an important effect on outcomes, patients with very early pretransplant relapse (those who went into remission but relapsed within 18 months) or with greater than 2nd relapse had a high risk for poor event-free survival. Mismatched donors and unrelated cord-blood stem cell transplant recipients also had high risk, he said, noting that, “of course, MRD had a significant effect” and was the most important factor prior to transplant.

These patients, who had a 4-point or greater risk score, were the poorest risk group, with survival that was less than 50%, as opposed to better risk groups that exceeded 90%, he said.

“A score of greater than 5 could identify 80% of patients who were going to relapse after transplant, and of course, event-free and overall survival in those patients were very poor,” he added.

As time went by, the early risk of GVHD diminished somewhat, as did the risk of mismatched donors.

“Most of the risk was associated with any MRD detection,” he said.

Flow cytometry and RQ-PCR levels of at least 10-4 were highly predictive of relapse at all pre- and post-HCT time points; however, RQ-PCR values between 10-4 and 10-3, in cases where adequate numbers were available for comparison, better predicted relapse as compared with flow cytometry results.

For example, before HCT, hazard ratios were 1.26 and 2.41 with flow cytometry vs. RQ-PCR. At day 30, the hazard ratios were 1.33 and 2.53, and at day 365, they were 3.54 and 31.84, Dr. Pulsipher reported.

The findings provide important information for improving outcomes in children with high-risk ALL undergoing HCT, he said.

“Older prognostic models for relapsed and refractory high-risk ALL have focused on timing and location of relapse, as well as disease phenotype. But it is clear that, in order to treat children with very high risk ALL with transplantation, MRD has become the most important thing to look at in the pretreatment setting. The challenges that we face in assessing MRD, however, have been hampered by the fact that we have differing MRD measurements,” he said, noting that RQ-PCR is often used in Europe, while flow cytometry is more often used in the United States. As such, direct comparisons are lacking, as are T-cell and posttransplant data.

The current study represents a “tremendous effort” by international collaborators to address these shortcoming, he said.

“This is a great opportunity, as our goal, of course, is to avoid futility in transplantation, but, more importantly, to find opportunities to identify groups for which we can improve our outcomes,” he added.

Patients included in the study were treated in Europe, North America, and Australia and were transplanted during Sept. 1999-May 2016. Most were in first or second remission, and most (586) had pre-B ALL. A notable 145 had T-cell ALL – “more than ever has been analyzed previously” – and 16 had B-lineage or biphenotypic ALL. About half were under age 10 years, 62% were boys, and stem cell sources were typical, although 20% received a cord blood transplant.

Dr. Pulsipher reported serving as an advisor and/or consultant for Chimerix, Novartis, Jazz Pharmaceutical, and receiving housing support from Medac Pharma for an educational meeting.

[email protected]

ORLANDO – Minimal residual disease (MRD) measured before and after allogeneic hematopoietic stem cell transplantation (HCT) is a powerful predictor of survival in children with acute lymphoblastic leukemia (ALL), according to a review of hundreds of cases from around the world.

The findings could have implications for using minimal residual disease measures to guide posttransplant interventions, Michael A. Pulsipher, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

“MRD pretransplant was a very powerful predictor of outcomes. MRD posttransplant highlights individual patients at risk,” Dr. Pulsipher said. Results comparing reverse transcriptase–polymerase chain reaction with flow cytometry require validation by direct comparison in the same patient cohort, but “the new risk scores ... very nicely predict outcomes both pre- and post-transplant and can guide study planning and patient counseling.”

A total of 2,960 bone marrow MRD measurements were performed in the 747 patients included in the study. MRD was assessed prior to HCT and on or near days 30, 60, 100, 180, and 365 and beyond after HCT.

Patients were grouped for analysis according to MRD level: Group 1 had no detectable MRD, group 2 had low detectable MRD levels (less than 10E-4, or 0.01% by flow cytometry), and group 3 had high detectable MRD levels (10E-4 or higher). A second analysis compared findings in those tested by flow cytometry and those tested by real-time quantitative PCR (RQ-PCR), said Dr. Pulsipher of Children’s Hospital Los Angeles.

In 648 patients with pre-HCT MRD measurements available, the 4-year probability of event-free survival was 62%, 67%, and 37% for groups 1, 2, and 3, respectively. Group 3 – the high MRD level group – had 2.47 times the increased hazard ratio for relapse and 1.67 times the increased risk of treatment-related mortality, Dr. Pulsipher said, adding that pre-HCT MRD and remission status both significantly influenced survival, while age, sex, relapse site, cytogenetics, donor type, and stem cell source did not influence outcome.

Post-HCT MRD values were analyzed as time-dependent covariates.

“As time went by more and more, any detectable level of MRD led to a very poor prognosis, whereas patients arriving at day 365 with no detectable MRD had exceptional prognosis with survival approaching 90%,” he said.

Specifically, the 4-year probability of event-free survival for groups 1, 2, and 3, respectively, were 59%, 65%, and 43% at day 30; 64%, 47%, and 36% at day 60; 65%, 69%, and 44% at day 90; 79%, 40%, and 12% at day 180; and 87%, 36%, and 25% at day 365.

Of note, a very significant interaction was seen between acute graft-versus-host disease (GVHD) and MRD, Dr. Pulsipher said, explaining that patients who were MRD positive and had developed GVHD had a significant decrease in the cumulative incidence of relapse, compared with those with no GVHD.

“This translated into improved event-free survival with patients post transplant, who were MRD-positive [and] developing GVHD, still having a reasonable chance of survival, whereas patients post transplant who had MRD measured who did not develop GVHD had a very poor chance of survival,” he added.

Additionally, based on detailed multivariate analysis including a number of clinical factors, risk predictive scores were developed for event-free survival risk at 18 months or cumulative incidence of relapse at 18 months. Multiple scores were developed for each, but, as an example of factors that had an important effect on outcomes, patients with very early pretransplant relapse (those who went into remission but relapsed within 18 months) or with greater than 2nd relapse had a high risk for poor event-free survival. Mismatched donors and unrelated cord-blood stem cell transplant recipients also had high risk, he said, noting that, “of course, MRD had a significant effect” and was the most important factor prior to transplant.

These patients, who had a 4-point or greater risk score, were the poorest risk group, with survival that was less than 50%, as opposed to better risk groups that exceeded 90%, he said.

“A score of greater than 5 could identify 80% of patients who were going to relapse after transplant, and of course, event-free and overall survival in those patients were very poor,” he added.

As time went by, the early risk of GVHD diminished somewhat, as did the risk of mismatched donors.

“Most of the risk was associated with any MRD detection,” he said.

Flow cytometry and RQ-PCR levels of at least 10-4 were highly predictive of relapse at all pre- and post-HCT time points; however, RQ-PCR values between 10-4 and 10-3, in cases where adequate numbers were available for comparison, better predicted relapse as compared with flow cytometry results.

For example, before HCT, hazard ratios were 1.26 and 2.41 with flow cytometry vs. RQ-PCR. At day 30, the hazard ratios were 1.33 and 2.53, and at day 365, they were 3.54 and 31.84, Dr. Pulsipher reported.

The findings provide important information for improving outcomes in children with high-risk ALL undergoing HCT, he said.

“Older prognostic models for relapsed and refractory high-risk ALL have focused on timing and location of relapse, as well as disease phenotype. But it is clear that, in order to treat children with very high risk ALL with transplantation, MRD has become the most important thing to look at in the pretreatment setting. The challenges that we face in assessing MRD, however, have been hampered by the fact that we have differing MRD measurements,” he said, noting that RQ-PCR is often used in Europe, while flow cytometry is more often used in the United States. As such, direct comparisons are lacking, as are T-cell and posttransplant data.

The current study represents a “tremendous effort” by international collaborators to address these shortcoming, he said.

“This is a great opportunity, as our goal, of course, is to avoid futility in transplantation, but, more importantly, to find opportunities to identify groups for which we can improve our outcomes,” he added.

Patients included in the study were treated in Europe, North America, and Australia and were transplanted during Sept. 1999-May 2016. Most were in first or second remission, and most (586) had pre-B ALL. A notable 145 had T-cell ALL – “more than ever has been analyzed previously” – and 16 had B-lineage or biphenotypic ALL. About half were under age 10 years, 62% were boys, and stem cell sources were typical, although 20% received a cord blood transplant.

Dr. Pulsipher reported serving as an advisor and/or consultant for Chimerix, Novartis, Jazz Pharmaceutical, and receiving housing support from Medac Pharma for an educational meeting.

[email protected]

Image from NIAID

After 2 clinical holds in 2016 and 5 patient deaths, the Seattle biotech Juno Therapeutics is shutting down the phase 2 ROCKET trial of JCAR015.

The chimeric antigen receptor (CAR) T-cell therapy JCAR015 was being tested in adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

“We have decided not to move forward . . . at this time,” CEO Hans Bishop said in a statement, “even though it generated important learnings for us and the immunotherapy field.”

He said the company remains “committed to developing better treatment for patients battling ALL.”

The first clinical hold of the ROCKET trial occurred in July after 2 patients died. The company attributed the deaths primarily to the addition of fludarabine to the regimen.

Juno removed fludarabine from the treatment protocol, the clinical hold was lifted, and the trial resumed.

Then, in November, 2 more patients died from cerebral edema, and the trial was put on hold once again.

One patient had died earlier in 2016, totaling 5 patient deaths from cerebral edema, although the earliest death was not necessarily related to treatment, the company stated.

Juno attributed the deaths to multiple factors, including the patients’ treatment history and treatment received at the beginning of the trial.

Juno plans to start a new adult ALL trial in 2018. The therapy, they say, is more similar to JCAR017, which is being tested in pediatric patients.

ROCKET is not the first trial of JCAR015 to be placed on hold.

In 2014, after 2 patients died of cytokine release syndrome, the phase 1 trial was placed on clinical hold.

Juno made changes to the enrollment criteria and dosing, and the hold was lifted. Results from this trial were presented at ASCO 2015 and ASCO 2016.

Image from NIAID

After 2 clinical holds in 2016 and 5 patient deaths, the Seattle biotech Juno Therapeutics is shutting down the phase 2 ROCKET trial of JCAR015.

The chimeric antigen receptor (CAR) T-cell therapy JCAR015 was being tested in adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

“We have decided not to move forward . . . at this time,” CEO Hans Bishop said in a statement, “even though it generated important learnings for us and the immunotherapy field.”

He said the company remains “committed to developing better treatment for patients battling ALL.”

The first clinical hold of the ROCKET trial occurred in July after 2 patients died. The company attributed the deaths primarily to the addition of fludarabine to the regimen.

Juno removed fludarabine from the treatment protocol, the clinical hold was lifted, and the trial resumed.

Then, in November, 2 more patients died from cerebral edema, and the trial was put on hold once again.

One patient had died earlier in 2016, totaling 5 patient deaths from cerebral edema, although the earliest death was not necessarily related to treatment, the company stated.

Juno attributed the deaths to multiple factors, including the patients’ treatment history and treatment received at the beginning of the trial.

Juno plans to start a new adult ALL trial in 2018. The therapy, they say, is more similar to JCAR017, which is being tested in pediatric patients.

ROCKET is not the first trial of JCAR015 to be placed on hold.

In 2014, after 2 patients died of cytokine release syndrome, the phase 1 trial was placed on clinical hold.

Juno made changes to the enrollment criteria and dosing, and the hold was lifted. Results from this trial were presented at ASCO 2015 and ASCO 2016.

Image from NIAID

After 2 clinical holds in 2016 and 5 patient deaths, the Seattle biotech Juno Therapeutics is shutting down the phase 2 ROCKET trial of JCAR015.

The chimeric antigen receptor (CAR) T-cell therapy JCAR015 was being tested in adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

“We have decided not to move forward . . . at this time,” CEO Hans Bishop said in a statement, “even though it generated important learnings for us and the immunotherapy field.”

He said the company remains “committed to developing better treatment for patients battling ALL.”

The first clinical hold of the ROCKET trial occurred in July after 2 patients died. The company attributed the deaths primarily to the addition of fludarabine to the regimen.

Juno removed fludarabine from the treatment protocol, the clinical hold was lifted, and the trial resumed.

Then, in November, 2 more patients died from cerebral edema, and the trial was put on hold once again.

One patient had died earlier in 2016, totaling 5 patient deaths from cerebral edema, although the earliest death was not necessarily related to treatment, the company stated.

Juno attributed the deaths to multiple factors, including the patients’ treatment history and treatment received at the beginning of the trial.

Juno plans to start a new adult ALL trial in 2018. The therapy, they say, is more similar to JCAR017, which is being tested in pediatric patients.

ROCKET is not the first trial of JCAR015 to be placed on hold.

In 2014, after 2 patients died of cytokine release syndrome, the phase 1 trial was placed on clinical hold.

Juno made changes to the enrollment criteria and dosing, and the hold was lifted. Results from this trial were presented at ASCO 2015 and ASCO 2016.

Photo by Petr Kratochvil

Exercise and/or psychological therapy work better than medications to reduce cancer-related fatigue, according to research published in JAMA Oncology.

Researchers conducted a review and meta-analysis of more than 113 studies and found that exercise and psychological interventions, as well as a combination of both, were associated with reduced fatigue during and after cancer treatment.

However, pharmaceutical interventions were not associated with the same magnitude of improvement.

The researchers therefore concluded that exercise and psychological therapy should be recommended over medications.

“If a cancer patient is having trouble with fatigue, rather than looking for extra cups of coffee, a nap, or a pharmaceutical solution, consider a 15-minute walk,” said study author Karen Mustian, PhD, of the University of Rochester Medical Center in Rochester, New York.

“It’s a really simple concept, but it’s very hard for patients and the medical community to wrap their heads around it because these interventions have not been front-and-center in the past. Our research gives clinicians a valuable asset to alleviate cancer-related fatigue.”

Dr Mustian and her colleagues reached their conclusions after analyzing data from 113 randomized clinical trials testing various treatments for cancer-related fatigue.

There were 11,525 patients enrolled in these studies. Nearly half (46.9%) were women with breast cancer. Ten studies focused on other types of cancer and enrolled only men.

Dr Mustian and her colleagues performed a meta-analysis to establish and compare the mean weighted effect sizes (WESs) of the fatigue treatments.

The team found that exercise alone—whether aerobic or anaerobic—reduced cancer-related fatigue most significantly. The WES was 0.30 (95% CI, 0.25-0.36; P<0.001).

Psychological interventions—such as therapy designed to provide education, change personal behavior, and adapt the way a person thinks about his or her circumstances—also improved fatigue. The WES was 0.27 (95% CI, 0.21-0.330.30; P<0.001).

A combination of psychological interventions and exercise had a significant improvement on fatigue as well. The WES was 0.26 (95% CI, 0.13-0.38; P<0.001).

However, the drugs tested for treating cancer-related fatigue—paroxetine hydrochloride, modafinil, armodafinil, methylphenidate hydrochloride, dexymethylphenidate, dexamphetamine, and methylprednisolone—were not as effective as the other interventions. The WES was 0.09 (95% CI, 0.00-0.19; P=0.05).

“The literature bears out that these drugs don’t work very well, although they are continually prescribed,” Dr Mustian said. “Cancer patients already take a lot of medications, and they all come with risks and side effects. So any time you can subtract a pharmaceutical from the picture it usually benefits patients.”

Photo by Petr Kratochvil

Exercise and/or psychological therapy work better than medications to reduce cancer-related fatigue, according to research published in JAMA Oncology.

Researchers conducted a review and meta-analysis of more than 113 studies and found that exercise and psychological interventions, as well as a combination of both, were associated with reduced fatigue during and after cancer treatment.

However, pharmaceutical interventions were not associated with the same magnitude of improvement.

The researchers therefore concluded that exercise and psychological therapy should be recommended over medications.

“If a cancer patient is having trouble with fatigue, rather than looking for extra cups of coffee, a nap, or a pharmaceutical solution, consider a 15-minute walk,” said study author Karen Mustian, PhD, of the University of Rochester Medical Center in Rochester, New York.

“It’s a really simple concept, but it’s very hard for patients and the medical community to wrap their heads around it because these interventions have not been front-and-center in the past. Our research gives clinicians a valuable asset to alleviate cancer-related fatigue.”

Dr Mustian and her colleagues reached their conclusions after analyzing data from 113 randomized clinical trials testing various treatments for cancer-related fatigue.

There were 11,525 patients enrolled in these studies. Nearly half (46.9%) were women with breast cancer. Ten studies focused on other types of cancer and enrolled only men.

Dr Mustian and her colleagues performed a meta-analysis to establish and compare the mean weighted effect sizes (WESs) of the fatigue treatments.

The team found that exercise alone—whether aerobic or anaerobic—reduced cancer-related fatigue most significantly. The WES was 0.30 (95% CI, 0.25-0.36; P<0.001).

Psychological interventions—such as therapy designed to provide education, change personal behavior, and adapt the way a person thinks about his or her circumstances—also improved fatigue. The WES was 0.27 (95% CI, 0.21-0.330.30; P<0.001).

A combination of psychological interventions and exercise had a significant improvement on fatigue as well. The WES was 0.26 (95% CI, 0.13-0.38; P<0.001).

However, the drugs tested for treating cancer-related fatigue—paroxetine hydrochloride, modafinil, armodafinil, methylphenidate hydrochloride, dexymethylphenidate, dexamphetamine, and methylprednisolone—were not as effective as the other interventions. The WES was 0.09 (95% CI, 0.00-0.19; P=0.05).

“The literature bears out that these drugs don’t work very well, although they are continually prescribed,” Dr Mustian said. “Cancer patients already take a lot of medications, and they all come with risks and side effects. So any time you can subtract a pharmaceutical from the picture it usually benefits patients.”

Photo by Petr Kratochvil

Exercise and/or psychological therapy work better than medications to reduce cancer-related fatigue, according to research published in JAMA Oncology.

Researchers conducted a review and meta-analysis of more than 113 studies and found that exercise and psychological interventions, as well as a combination of both, were associated with reduced fatigue during and after cancer treatment.

However, pharmaceutical interventions were not associated with the same magnitude of improvement.

The researchers therefore concluded that exercise and psychological therapy should be recommended over medications.

“If a cancer patient is having trouble with fatigue, rather than looking for extra cups of coffee, a nap, or a pharmaceutical solution, consider a 15-minute walk,” said study author Karen Mustian, PhD, of the University of Rochester Medical Center in Rochester, New York.

“It’s a really simple concept, but it’s very hard for patients and the medical community to wrap their heads around it because these interventions have not been front-and-center in the past. Our research gives clinicians a valuable asset to alleviate cancer-related fatigue.”

Dr Mustian and her colleagues reached their conclusions after analyzing data from 113 randomized clinical trials testing various treatments for cancer-related fatigue.

There were 11,525 patients enrolled in these studies. Nearly half (46.9%) were women with breast cancer. Ten studies focused on other types of cancer and enrolled only men.

Dr Mustian and her colleagues performed a meta-analysis to establish and compare the mean weighted effect sizes (WESs) of the fatigue treatments.

The team found that exercise alone—whether aerobic or anaerobic—reduced cancer-related fatigue most significantly. The WES was 0.30 (95% CI, 0.25-0.36; P<0.001).

Psychological interventions—such as therapy designed to provide education, change personal behavior, and adapt the way a person thinks about his or her circumstances—also improved fatigue. The WES was 0.27 (95% CI, 0.21-0.330.30; P<0.001).

A combination of psychological interventions and exercise had a significant improvement on fatigue as well. The WES was 0.26 (95% CI, 0.13-0.38; P<0.001).

However, the drugs tested for treating cancer-related fatigue—paroxetine hydrochloride, modafinil, armodafinil, methylphenidate hydrochloride, dexymethylphenidate, dexamphetamine, and methylprednisolone—were not as effective as the other interventions. The WES was 0.09 (95% CI, 0.00-0.19; P=0.05).

“The literature bears out that these drugs don’t work very well, although they are continually prescribed,” Dr Mustian said. “Cancer patients already take a lot of medications, and they all come with risks and side effects. So any time you can subtract a pharmaceutical from the picture it usually benefits patients.”

ORLANDO – Patients with advanced hematologic malignancies of B-cell lineage had robust immune responses following infusion of a chimeric antigen receptor (CAR)–T-cell construct designed to deliver a specific balance of antigens, investigators reported.

Adults with relapsed or refractory B-lineage acute myeloid leukemia (ALL), non–Hodgkin lymphoma (NHL), and chronic lymphocytic leukemia (CLL) who received a CAR-T cell construct consisting of autologous CD4-positive and CD-8-positive T cells that were transduced separately, recombined, and then delivered in a single infusion had comparatively high overall response and complete response rates, reported Cameron Turtle, MBBS, PhD, from the Fred Hutchinson Cancer Research Center in Seattle.

“We know that patients have a highly variable CD4 to CD8 ratio, so by actually controlling this and separately transducing, expanding, and then reformulating in this defined composition, we’re able to eliminate one source of variability in CAR-T cell products,” Dr. Turtle said at the ASCO-SITC Clinical Immuno-Oncology Symposium.

In preclinical studies, an even balance of CD4-positive and CD8-positive central memory T cells or naive T cells evoked more potent immune responses against B-cell malignancies in mice than CD19-positive cells, he explained

To see whether this would also hold true in humans, the investigators enrolled into a phase I/II trial adults with relapsed/refractory B-cell malignancies, including ALL (36 patients), NHL (41), and CLL (24). No patients were excluded on the basis of either absolute lymphocyte, circulating tumors cells, history of stem cell transplant, or results of in vitro test expansions.

All patients underwent leukapheresis for harvesting of T-cells, and populations of CD4- and CD8-positive cells were separated and transduced with a lentiviral vector to express a CD19 CAR and a truncated human epidermal growth factor receptor that allowed tracing of the transduced cells via flow cytometry. The patients underwent lymphodepleting chemotherapy with cyclophosphamide (for the earliest patients), or cyclophosphamide plus fludarabine. Fifteen days after leukapheresis, the separated, transduced, and expanded cells were combined and delivered back to patients in a single infusion at one of three dose levels: 2 x 105, 2 x 106, or 2 x 107 CAR-T cells/kg.
 

ALL results

Two of the 36 patients with ALL died from complications of the CAR-T cell infusion process prior to evaluation. The 34 remaining patients all had morphologic bone marrow complete responses (CR). Of this group, 32 also had bone marrow CR on flow cytometry.

Using immunoglobulin H (IgH) deep sequencing in a subset of 20 patients 3 weeks after CAR-T cell infusion, the investigators could not detect the malignant IgH index clone in 13 of the patients, and found fewer than 10 copies in the bone marrow of 5 patients.

Six of seven patients with extramedullary disease at baseline had a complete response. The remaining patient in this group had an equivocal PET scan result, and experienced a relapse 2 months after assessment.

The investigators also determined that the lymphodepletion regimen may affect overall results, based on the finding that 10 of 12 patients who received cyclophosphamide alone achieved a CR, but seven of these 10 patients had a relapse within a few months. Of these seven patients. five received a second T-cell infusion, but none had significant T-cell expansion. The investigators traced the failure of the second attempt to a CD8-mediated transgene immune response to a murine single-chain variable fragment used in the construct.

For subsequent patients, they altered the lymphodepletion regimen to include fludarabine to prevent priming of the anti-CAR transgenic immune response. This modification resulted in improved progression-free survival and overall survival for subsequent patients receiving a second infusion, Dr. Turtle said.
 

NHL results

Of the 41 patients with NHL, 30 (73%) had aggressive histologies, including diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, T-cell/histiocyte-rich large B-cell, and Burkitt lymphomas, and 11 (27%) had indolent histologies, including mantle cell and follicular lymphomas. Most of the patients had received multiple prior lines of therapy, and 19 (46%) had undergone either an autologous or allogeneic stem cell transplant.

Of the 39 evaluable patients who completed therapy, the overall response rate was 67%, including 13 (39%) with CR. Dr. Turtle noted that the CR rate was substantially higher among patients who received cyclophosphamide and fludarabine lymphodepletion, compared with cyclophosphamide alone.

There were also a few responses, including two CRs, among patients with indolent histologies, he said.

CLL, safety results

All 24 patients with CLL had previously received ibrutinib (Imbruvica). Of this group, 19 either had no significant responses to the drug, inactivating mutations, or intolerable toxicities. All but 1 of the 24 patients also had high-risk cytogenetics.

Of the 16 ibrutinib-refractory patients who were evaluable for restaging, 14 had no evidence of disease in bone marrow by flow cytometry at 4 weeks. The overall response rate in this group was 69%, which included four CRs.

Among a majority of all patients, toxicity with the CAR-T cell therapy was mild to moderate. Early cytokine changes appeared to be predictive of serious adverse events such as the cytokine release syndrome, a finding that may allow clinicians to intervene early to prevent complications, Dr. Turtle said.

In the CAR-T cell therapy, “multiple things affect the response and toxicity, including CAR T-cell dose, disease burden, the anti-CAR transgene immune response and the lymphodepletion regimen, not to mention other patient factors that we’re still sorting out,” he commented.

The trial was funded by the National Institutes of Health, Life Science Development Fund, Juno Therapeutics and the Bezos Family Foundation. Dr. Turtle disclosed consultancy, honoraria, and/or research funding from Juno Therapeutics and Seattle Genetics.

ORLANDO – Patients with advanced hematologic malignancies of B-cell lineage had robust immune responses following infusion of a chimeric antigen receptor (CAR)–T-cell construct designed to deliver a specific balance of antigens, investigators reported.

Adults with relapsed or refractory B-lineage acute myeloid leukemia (ALL), non–Hodgkin lymphoma (NHL), and chronic lymphocytic leukemia (CLL) who received a CAR-T cell construct consisting of autologous CD4-positive and CD-8-positive T cells that were transduced separately, recombined, and then delivered in a single infusion had comparatively high overall response and complete response rates, reported Cameron Turtle, MBBS, PhD, from the Fred Hutchinson Cancer Research Center in Seattle.

“We know that patients have a highly variable CD4 to CD8 ratio, so by actually controlling this and separately transducing, expanding, and then reformulating in this defined composition, we’re able to eliminate one source of variability in CAR-T cell products,” Dr. Turtle said at the ASCO-SITC Clinical Immuno-Oncology Symposium.

In preclinical studies, an even balance of CD4-positive and CD8-positive central memory T cells or naive T cells evoked more potent immune responses against B-cell malignancies in mice than CD19-positive cells, he explained

To see whether this would also hold true in humans, the investigators enrolled into a phase I/II trial adults with relapsed/refractory B-cell malignancies, including ALL (36 patients), NHL (41), and CLL (24). No patients were excluded on the basis of either absolute lymphocyte, circulating tumors cells, history of stem cell transplant, or results of in vitro test expansions.

All patients underwent leukapheresis for harvesting of T-cells, and populations of CD4- and CD8-positive cells were separated and transduced with a lentiviral vector to express a CD19 CAR and a truncated human epidermal growth factor receptor that allowed tracing of the transduced cells via flow cytometry. The patients underwent lymphodepleting chemotherapy with cyclophosphamide (for the earliest patients), or cyclophosphamide plus fludarabine. Fifteen days after leukapheresis, the separated, transduced, and expanded cells were combined and delivered back to patients in a single infusion at one of three dose levels: 2 x 105, 2 x 106, or 2 x 107 CAR-T cells/kg.
 

ALL results

Two of the 36 patients with ALL died from complications of the CAR-T cell infusion process prior to evaluation. The 34 remaining patients all had morphologic bone marrow complete responses (CR). Of this group, 32 also had bone marrow CR on flow cytometry.

Using immunoglobulin H (IgH) deep sequencing in a subset of 20 patients 3 weeks after CAR-T cell infusion, the investigators could not detect the malignant IgH index clone in 13 of the patients, and found fewer than 10 copies in the bone marrow of 5 patients.

Six of seven patients with extramedullary disease at baseline had a complete response. The remaining patient in this group had an equivocal PET scan result, and experienced a relapse 2 months after assessment.

The investigators also determined that the lymphodepletion regimen may affect overall results, based on the finding that 10 of 12 patients who received cyclophosphamide alone achieved a CR, but seven of these 10 patients had a relapse within a few months. Of these seven patients. five received a second T-cell infusion, but none had significant T-cell expansion. The investigators traced the failure of the second attempt to a CD8-mediated transgene immune response to a murine single-chain variable fragment used in the construct.

For subsequent patients, they altered the lymphodepletion regimen to include fludarabine to prevent priming of the anti-CAR transgenic immune response. This modification resulted in improved progression-free survival and overall survival for subsequent patients receiving a second infusion, Dr. Turtle said.
 

NHL results

Of the 41 patients with NHL, 30 (73%) had aggressive histologies, including diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, T-cell/histiocyte-rich large B-cell, and Burkitt lymphomas, and 11 (27%) had indolent histologies, including mantle cell and follicular lymphomas. Most of the patients had received multiple prior lines of therapy, and 19 (46%) had undergone either an autologous or allogeneic stem cell transplant.

Of the 39 evaluable patients who completed therapy, the overall response rate was 67%, including 13 (39%) with CR. Dr. Turtle noted that the CR rate was substantially higher among patients who received cyclophosphamide and fludarabine lymphodepletion, compared with cyclophosphamide alone.

There were also a few responses, including two CRs, among patients with indolent histologies, he said.

CLL, safety results

All 24 patients with CLL had previously received ibrutinib (Imbruvica). Of this group, 19 either had no significant responses to the drug, inactivating mutations, or intolerable toxicities. All but 1 of the 24 patients also had high-risk cytogenetics.

Of the 16 ibrutinib-refractory patients who were evaluable for restaging, 14 had no evidence of disease in bone marrow by flow cytometry at 4 weeks. The overall response rate in this group was 69%, which included four CRs.

Among a majority of all patients, toxicity with the CAR-T cell therapy was mild to moderate. Early cytokine changes appeared to be predictive of serious adverse events such as the cytokine release syndrome, a finding that may allow clinicians to intervene early to prevent complications, Dr. Turtle said.

In the CAR-T cell therapy, “multiple things affect the response and toxicity, including CAR T-cell dose, disease burden, the anti-CAR transgene immune response and the lymphodepletion regimen, not to mention other patient factors that we’re still sorting out,” he commented.

The trial was funded by the National Institutes of Health, Life Science Development Fund, Juno Therapeutics and the Bezos Family Foundation. Dr. Turtle disclosed consultancy, honoraria, and/or research funding from Juno Therapeutics and Seattle Genetics.

ORLANDO – Patients with advanced hematologic malignancies of B-cell lineage had robust immune responses following infusion of a chimeric antigen receptor (CAR)–T-cell construct designed to deliver a specific balance of antigens, investigators reported.

Adults with relapsed or refractory B-lineage acute myeloid leukemia (ALL), non–Hodgkin lymphoma (NHL), and chronic lymphocytic leukemia (CLL) who received a CAR-T cell construct consisting of autologous CD4-positive and CD-8-positive T cells that were transduced separately, recombined, and then delivered in a single infusion had comparatively high overall response and complete response rates, reported Cameron Turtle, MBBS, PhD, from the Fred Hutchinson Cancer Research Center in Seattle.

“We know that patients have a highly variable CD4 to CD8 ratio, so by actually controlling this and separately transducing, expanding, and then reformulating in this defined composition, we’re able to eliminate one source of variability in CAR-T cell products,” Dr. Turtle said at the ASCO-SITC Clinical Immuno-Oncology Symposium.

In preclinical studies, an even balance of CD4-positive and CD8-positive central memory T cells or naive T cells evoked more potent immune responses against B-cell malignancies in mice than CD19-positive cells, he explained

To see whether this would also hold true in humans, the investigators enrolled into a phase I/II trial adults with relapsed/refractory B-cell malignancies, including ALL (36 patients), NHL (41), and CLL (24). No patients were excluded on the basis of either absolute lymphocyte, circulating tumors cells, history of stem cell transplant, or results of in vitro test expansions.

All patients underwent leukapheresis for harvesting of T-cells, and populations of CD4- and CD8-positive cells were separated and transduced with a lentiviral vector to express a CD19 CAR and a truncated human epidermal growth factor receptor that allowed tracing of the transduced cells via flow cytometry. The patients underwent lymphodepleting chemotherapy with cyclophosphamide (for the earliest patients), or cyclophosphamide plus fludarabine. Fifteen days after leukapheresis, the separated, transduced, and expanded cells were combined and delivered back to patients in a single infusion at one of three dose levels: 2 x 105, 2 x 106, or 2 x 107 CAR-T cells/kg.
 

ALL results

Two of the 36 patients with ALL died from complications of the CAR-T cell infusion process prior to evaluation. The 34 remaining patients all had morphologic bone marrow complete responses (CR). Of this group, 32 also had bone marrow CR on flow cytometry.

Using immunoglobulin H (IgH) deep sequencing in a subset of 20 patients 3 weeks after CAR-T cell infusion, the investigators could not detect the malignant IgH index clone in 13 of the patients, and found fewer than 10 copies in the bone marrow of 5 patients.

Six of seven patients with extramedullary disease at baseline had a complete response. The remaining patient in this group had an equivocal PET scan result, and experienced a relapse 2 months after assessment.

The investigators also determined that the lymphodepletion regimen may affect overall results, based on the finding that 10 of 12 patients who received cyclophosphamide alone achieved a CR, but seven of these 10 patients had a relapse within a few months. Of these seven patients. five received a second T-cell infusion, but none had significant T-cell expansion. The investigators traced the failure of the second attempt to a CD8-mediated transgene immune response to a murine single-chain variable fragment used in the construct.

For subsequent patients, they altered the lymphodepletion regimen to include fludarabine to prevent priming of the anti-CAR transgenic immune response. This modification resulted in improved progression-free survival and overall survival for subsequent patients receiving a second infusion, Dr. Turtle said.
 

NHL results

Of the 41 patients with NHL, 30 (73%) had aggressive histologies, including diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, T-cell/histiocyte-rich large B-cell, and Burkitt lymphomas, and 11 (27%) had indolent histologies, including mantle cell and follicular lymphomas. Most of the patients had received multiple prior lines of therapy, and 19 (46%) had undergone either an autologous or allogeneic stem cell transplant.

Of the 39 evaluable patients who completed therapy, the overall response rate was 67%, including 13 (39%) with CR. Dr. Turtle noted that the CR rate was substantially higher among patients who received cyclophosphamide and fludarabine lymphodepletion, compared with cyclophosphamide alone.

There were also a few responses, including two CRs, among patients with indolent histologies, he said.

CLL, safety results

All 24 patients with CLL had previously received ibrutinib (Imbruvica). Of this group, 19 either had no significant responses to the drug, inactivating mutations, or intolerable toxicities. All but 1 of the 24 patients also had high-risk cytogenetics.

Of the 16 ibrutinib-refractory patients who were evaluable for restaging, 14 had no evidence of disease in bone marrow by flow cytometry at 4 weeks. The overall response rate in this group was 69%, which included four CRs.

Among a majority of all patients, toxicity with the CAR-T cell therapy was mild to moderate. Early cytokine changes appeared to be predictive of serious adverse events such as the cytokine release syndrome, a finding that may allow clinicians to intervene early to prevent complications, Dr. Turtle said.

In the CAR-T cell therapy, “multiple things affect the response and toxicity, including CAR T-cell dose, disease burden, the anti-CAR transgene immune response and the lymphodepletion regimen, not to mention other patient factors that we’re still sorting out,” he commented.

The trial was funded by the National Institutes of Health, Life Science Development Fund, Juno Therapeutics and the Bezos Family Foundation. Dr. Turtle disclosed consultancy, honoraria, and/or research funding from Juno Therapeutics and Seattle Genetics.

AML cells

The US Food and Drug Administration (FDA) has granted priority review for the new drug application (NDA) for enasidenib (AG-221), an inhibitor of mutant IDH2.

The drug is under review for the treatment of patients with relapsed or refractory acute myeloid leukemia (AML) with an IDH2 mutation.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10-month period.

The NDA for enasidenib has been given a Prescription Drug User Fee Act action date of August 30, 2017.

Enasidenib is being developed by Celgene Corporation and Agios Pharmaceuticals.

Phase 1/2 trial

The NDA submission for enasidenib is based on results from AG221-C-001, a single-arm, phase 1/2 study of the drug in patients with advanced hematologic malignancies with an IDH2 mutation.

Early data from the relapsed or refractory AML patients in this study were presented at the 2015 ASH Annual Meeting. (The presentation included updated data that differ from the data in the abstract.)

The trial included a dose-escalation phase and 5 expansion cohorts. The first 4 expansion cohorts had completed enrollment as of the presentation.

• Arm 1: 25 patients with IDH2-mutant-positive relapsed or refractory AML age ≥60 years, or any patient with AML regardless of age who relapsed after a bone marrow transplant (BMT)
• Arm 2: 25 patients with IDH2-mutant-positive relapsed or refractory AML age <60 years, excluding patients with AML who relapsed after a BMT
• Arm 3: 25 patients with IDH2-mutant-positive untreated AML age ≥60 years who decline standard of care chemotherapy
• Arm 4: 25 patients with IDH2-mutant-positive advanced hematologic malignancies not eligible for arms 1 to 3
• Arm 5: The phase 2 portion of the trial included 125 patients with IDH2-mutant-positive AML who were in second or later relapse, refractory to second-line induction or reinduction treatment, or  relapsed after allogeneic transplant.

The data reported at ASH were from patients receiving enasidenib administered from 50-mg to 650-mg total daily doses in the dose-escalation arm and 100 mg once daily in the first 4 expansion arms, as of September 1, 2015.

The median age of these patients was 69 (range, 19-100). Patients with relapsed or refractory AML received a median of 2 prior lines of therapy (range, 1-6).

Safety data

A safety analysis was conducted for all 231 treated patients. As of the ASH presentation, a maximum tolerated dose of enasidenib had not been reached.

The majority of adverse events were mild to moderate, with the most common being nausea, diarrhea, fatigue, and febrile neutropenia.

Twenty-three percent of patients had treatment-related serious adverse events—notably, differentiation syndrome (4%), leukocytosis (4%), and nausea (2%).

Drug-related grade 5 serious adverse events include atrial flutter (n=1), cardiac tamponade (n=1), pericardial effusion (n=1), and respiratory failure (n=1).

Efficacy Data

Seventy-nine of the 209 response-evaluable patients achieved investigator-assessed objective responses, for an overall response rate of 38%.

There were 37 (18%) complete remissions (CR), 3 CRs with incomplete platelet recovery (CRp), 14 marrow CRs (mCR), 3 CRs with incomplete hematologic recovery (CRi), and 22 partial remissions (PR).

Of the 159 patients with relapsed or refractory AML, 59 (37%) achieved an objective response, including 29 (18%) CRs, 1 CRp, 9 mCRs, 3 CRis, and 17 PRs.

Of the 24 patients with AML who declined standard of care chemotherapy, 10 achieved an objective response, including 4 CRs, 1 CRp, 1 mCR, and 4 PRs.

The median duration of response was 6.9 months in patients with relapsed or refractory AML.

Responding relapsed/refractory AML patients were on study treatment for up to 18 months. The median duration of treatment was 6.8 months (range, 1.8 to 18 months).

AML cells

The US Food and Drug Administration (FDA) has granted priority review for the new drug application (NDA) for enasidenib (AG-221), an inhibitor of mutant IDH2.

The drug is under review for the treatment of patients with relapsed or refractory acute myeloid leukemia (AML) with an IDH2 mutation.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10-month period.

The NDA for enasidenib has been given a Prescription Drug User Fee Act action date of August 30, 2017.

Enasidenib is being developed by Celgene Corporation and Agios Pharmaceuticals.

Phase 1/2 trial

The NDA submission for enasidenib is based on results from AG221-C-001, a single-arm, phase 1/2 study of the drug in patients with advanced hematologic malignancies with an IDH2 mutation.

Early data from the relapsed or refractory AML patients in this study were presented at the 2015 ASH Annual Meeting. (The presentation included updated data that differ from the data in the abstract.)

The trial included a dose-escalation phase and 5 expansion cohorts. The first 4 expansion cohorts had completed enrollment as of the presentation.

• Arm 1: 25 patients with IDH2-mutant-positive relapsed or refractory AML age ≥60 years, or any patient with AML regardless of age who relapsed after a bone marrow transplant (BMT)
• Arm 2: 25 patients with IDH2-mutant-positive relapsed or refractory AML age <60 years, excluding patients with AML who relapsed after a BMT
• Arm 3: 25 patients with IDH2-mutant-positive untreated AML age ≥60 years who decline standard of care chemotherapy
• Arm 4: 25 patients with IDH2-mutant-positive advanced hematologic malignancies not eligible for arms 1 to 3
• Arm 5: The phase 2 portion of the trial included 125 patients with IDH2-mutant-positive AML who were in second or later relapse, refractory to second-line induction or reinduction treatment, or  relapsed after allogeneic transplant.

The data reported at ASH were from patients receiving enasidenib administered from 50-mg to 650-mg total daily doses in the dose-escalation arm and 100 mg once daily in the first 4 expansion arms, as of September 1, 2015.

The median age of these patients was 69 (range, 19-100). Patients with relapsed or refractory AML received a median of 2 prior lines of therapy (range, 1-6).

Safety data

A safety analysis was conducted for all 231 treated patients. As of the ASH presentation, a maximum tolerated dose of enasidenib had not been reached.

The majority of adverse events were mild to moderate, with the most common being nausea, diarrhea, fatigue, and febrile neutropenia.

Twenty-three percent of patients had treatment-related serious adverse events—notably, differentiation syndrome (4%), leukocytosis (4%), and nausea (2%).

Drug-related grade 5 serious adverse events include atrial flutter (n=1), cardiac tamponade (n=1), pericardial effusion (n=1), and respiratory failure (n=1).

Efficacy Data

Seventy-nine of the 209 response-evaluable patients achieved investigator-assessed objective responses, for an overall response rate of 38%.

There were 37 (18%) complete remissions (CR), 3 CRs with incomplete platelet recovery (CRp), 14 marrow CRs (mCR), 3 CRs with incomplete hematologic recovery (CRi), and 22 partial remissions (PR).

Of the 159 patients with relapsed or refractory AML, 59 (37%) achieved an objective response, including 29 (18%) CRs, 1 CRp, 9 mCRs, 3 CRis, and 17 PRs.

Of the 24 patients with AML who declined standard of care chemotherapy, 10 achieved an objective response, including 4 CRs, 1 CRp, 1 mCR, and 4 PRs.

The median duration of response was 6.9 months in patients with relapsed or refractory AML.

Responding relapsed/refractory AML patients were on study treatment for up to 18 months. The median duration of treatment was 6.8 months (range, 1.8 to 18 months).

AML cells

The US Food and Drug Administration (FDA) has granted priority review for the new drug application (NDA) for enasidenib (AG-221), an inhibitor of mutant IDH2.

The drug is under review for the treatment of patients with relapsed or refractory acute myeloid leukemia (AML) with an IDH2 mutation.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10-month period.

The NDA for enasidenib has been given a Prescription Drug User Fee Act action date of August 30, 2017.

Enasidenib is being developed by Celgene Corporation and Agios Pharmaceuticals.

Phase 1/2 trial

The NDA submission for enasidenib is based on results from AG221-C-001, a single-arm, phase 1/2 study of the drug in patients with advanced hematologic malignancies with an IDH2 mutation.

Early data from the relapsed or refractory AML patients in this study were presented at the 2015 ASH Annual Meeting. (The presentation included updated data that differ from the data in the abstract.)

The trial included a dose-escalation phase and 5 expansion cohorts. The first 4 expansion cohorts had completed enrollment as of the presentation.

• Arm 1: 25 patients with IDH2-mutant-positive relapsed or refractory AML age ≥60 years, or any patient with AML regardless of age who relapsed after a bone marrow transplant (BMT)
• Arm 2: 25 patients with IDH2-mutant-positive relapsed or refractory AML age <60 years, excluding patients with AML who relapsed after a BMT
• Arm 3: 25 patients with IDH2-mutant-positive untreated AML age ≥60 years who decline standard of care chemotherapy
• Arm 4: 25 patients with IDH2-mutant-positive advanced hematologic malignancies not eligible for arms 1 to 3
• Arm 5: The phase 2 portion of the trial included 125 patients with IDH2-mutant-positive AML who were in second or later relapse, refractory to second-line induction or reinduction treatment, or  relapsed after allogeneic transplant.

The data reported at ASH were from patients receiving enasidenib administered from 50-mg to 650-mg total daily doses in the dose-escalation arm and 100 mg once daily in the first 4 expansion arms, as of September 1, 2015.

The median age of these patients was 69 (range, 19-100). Patients with relapsed or refractory AML received a median of 2 prior lines of therapy (range, 1-6).

Safety data

A safety analysis was conducted for all 231 treated patients. As of the ASH presentation, a maximum tolerated dose of enasidenib had not been reached.

The majority of adverse events were mild to moderate, with the most common being nausea, diarrhea, fatigue, and febrile neutropenia.

Twenty-three percent of patients had treatment-related serious adverse events—notably, differentiation syndrome (4%), leukocytosis (4%), and nausea (2%).

Drug-related grade 5 serious adverse events include atrial flutter (n=1), cardiac tamponade (n=1), pericardial effusion (n=1), and respiratory failure (n=1).

Efficacy Data

Seventy-nine of the 209 response-evaluable patients achieved investigator-assessed objective responses, for an overall response rate of 38%.

There were 37 (18%) complete remissions (CR), 3 CRs with incomplete platelet recovery (CRp), 14 marrow CRs (mCR), 3 CRs with incomplete hematologic recovery (CRi), and 22 partial remissions (PR).

Of the 159 patients with relapsed or refractory AML, 59 (37%) achieved an objective response, including 29 (18%) CRs, 1 CRp, 9 mCRs, 3 CRis, and 17 PRs.

Of the 24 patients with AML who declined standard of care chemotherapy, 10 achieved an objective response, including 4 CRs, 1 CRp, 1 mCR, and 4 PRs.

The median duration of response was 6.9 months in patients with relapsed or refractory AML.

Responding relapsed/refractory AML patients were on study treatment for up to 18 months. The median duration of treatment was 6.8 months (range, 1.8 to 18 months).

Blinatumomab proved superior to standard chemotherapy for relapsed or refractory acute lymphoblastic leukemia (ALL), based on results of an international phase III trial reported online March 2 in the New England Journal of Medicine.

The trial was halted early when an interim analysis revealed the clear benefit with blinatumomab, Hagop Kantarjian, MD, chair of the department of leukemia, University of Texas MD Anderson Cancer Center, Houston, and his associates wrote.

The manufacturer-sponsored open-label study included 376 adults with Ph-negative B-cell precursor ALL that was either refractory to primary induction therapy or to salvage with intensive combination chemotherapy, first relapse with the first remission lasting less than 12 months, second or greater relapse, or relapse at any time after allogeneic stem cell transplantation.

Study participants were randomly assigned to receive either blinatumomab (267 patients) or the investigator’s choice of one of four protocol-defined regimens of standard chemotherapy (109 patients) and were followed at 101 medical centers in 21 countries for a median of 11 months.

For each 6-week cycle of blinatumomab therapy, patients received treatment for 4 weeks (9 mcg blinatumomab per day during week 1 of induction cycle one and 28 mcg/day thereafter, by continuous infusion) and then no treatment for 2 weeks.

Maintenance treatment with blinatumomab was given as a 4-week continuous infusion every 12 weeks.

At the interim analysis – when 75% of the total number of planned deaths for the final analysis had occurred – the monitoring committee recommended that the trial be stopped early because of the benefit observed with blinatumomab therapy. Median overall survival was significantly longer with blinatumomab (7.7 months) than with chemotherapy (4 months), with a hazard ratio for death of 0.71. The estimated survival at 6 months was 54% with blinatumomab and 39% with chemotherapy.

Remission rates also favored blinatumomab: Rates of complete remission with full hematologic recovery were 34% vs. 16% and rates of complete remission with full, partial, or incomplete hematologic recovery were 44% vs. 25%.

In addition, the median duration of remission was 7.3 months with blinatumomab and 4.6 months with chemotherapy. And 6-month estimates of event-free survival were 31% vs. 12%. These survival and remission benefits were consistent across all subgroups of patients and persisted in several sensitivity analyses, the investigators said (N Engl J Med. 2017 Mar 2. doi: 10.1056/nejmOA1609783).

A total of 24% of the patients in the blinatumomab group and 24% of the patients in the chemotherapy group underwent allogeneic stem cell transplantation, with comparable outcomes and death rates.

Serious adverse events occurred in 62% of patients receiving blinatumomab and in 45% of those receiving chemotherapy, including fatal adverse events in 19% and 17%, respectively. The fatal events were considered to be related to treatment in 3% of the blinatumomab group and in 7% of the chemotherapy group. Rates of treatment discontinuation from an adverse event were 12% and 8%, respectively.

Patient-reported health status and quality of life improved with blinatumomab but worsened with chemotherapy.

“Given the previous exposure of these patients to myelosuppressive and immunosuppressive treatments, the activity of an immune-based therapy such as blinatumomab, which depends on functioning T cells for its activity, provides encouragement that responses may be further enhanced and made durable with additional immune activation strategies,” Dr. Kantarjian and his associates noted.

Dr. Kantarjian reported receiving research support from Amgen, Pfizer, Bristol-Myers Squibb, Novartis, and ARIAD; his associates reported ties to numerous industry sources.

Blinatumomab proved superior to standard chemotherapy for relapsed or refractory acute lymphoblastic leukemia (ALL), based on results of an international phase III trial reported online March 2 in the New England Journal of Medicine.

The trial was halted early when an interim analysis revealed the clear benefit with blinatumomab, Hagop Kantarjian, MD, chair of the department of leukemia, University of Texas MD Anderson Cancer Center, Houston, and his associates wrote.

The manufacturer-sponsored open-label study included 376 adults with Ph-negative B-cell precursor ALL that was either refractory to primary induction therapy or to salvage with intensive combination chemotherapy, first relapse with the first remission lasting less than 12 months, second or greater relapse, or relapse at any time after allogeneic stem cell transplantation.

Study participants were randomly assigned to receive either blinatumomab (267 patients) or the investigator’s choice of one of four protocol-defined regimens of standard chemotherapy (109 patients) and were followed at 101 medical centers in 21 countries for a median of 11 months.

For each 6-week cycle of blinatumomab therapy, patients received treatment for 4 weeks (9 mcg blinatumomab per day during week 1 of induction cycle one and 28 mcg/day thereafter, by continuous infusion) and then no treatment for 2 weeks.

Maintenance treatment with blinatumomab was given as a 4-week continuous infusion every 12 weeks.

At the interim analysis – when 75% of the total number of planned deaths for the final analysis had occurred – the monitoring committee recommended that the trial be stopped early because of the benefit observed with blinatumomab therapy. Median overall survival was significantly longer with blinatumomab (7.7 months) than with chemotherapy (4 months), with a hazard ratio for death of 0.71. The estimated survival at 6 months was 54% with blinatumomab and 39% with chemotherapy.

Remission rates also favored blinatumomab: Rates of complete remission with full hematologic recovery were 34% vs. 16% and rates of complete remission with full, partial, or incomplete hematologic recovery were 44% vs. 25%.

In addition, the median duration of remission was 7.3 months with blinatumomab and 4.6 months with chemotherapy. And 6-month estimates of event-free survival were 31% vs. 12%. These survival and remission benefits were consistent across all subgroups of patients and persisted in several sensitivity analyses, the investigators said (N Engl J Med. 2017 Mar 2. doi: 10.1056/nejmOA1609783).

A total of 24% of the patients in the blinatumomab group and 24% of the patients in the chemotherapy group underwent allogeneic stem cell transplantation, with comparable outcomes and death rates.

Serious adverse events occurred in 62% of patients receiving blinatumomab and in 45% of those receiving chemotherapy, including fatal adverse events in 19% and 17%, respectively. The fatal events were considered to be related to treatment in 3% of the blinatumomab group and in 7% of the chemotherapy group. Rates of treatment discontinuation from an adverse event were 12% and 8%, respectively.

Patient-reported health status and quality of life improved with blinatumomab but worsened with chemotherapy.

“Given the previous exposure of these patients to myelosuppressive and immunosuppressive treatments, the activity of an immune-based therapy such as blinatumomab, which depends on functioning T cells for its activity, provides encouragement that responses may be further enhanced and made durable with additional immune activation strategies,” Dr. Kantarjian and his associates noted.

Dr. Kantarjian reported receiving research support from Amgen, Pfizer, Bristol-Myers Squibb, Novartis, and ARIAD; his associates reported ties to numerous industry sources.

Blinatumomab proved superior to standard chemotherapy for relapsed or refractory acute lymphoblastic leukemia (ALL), based on results of an international phase III trial reported online March 2 in the New England Journal of Medicine.

The trial was halted early when an interim analysis revealed the clear benefit with blinatumomab, Hagop Kantarjian, MD, chair of the department of leukemia, University of Texas MD Anderson Cancer Center, Houston, and his associates wrote.

The manufacturer-sponsored open-label study included 376 adults with Ph-negative B-cell precursor ALL that was either refractory to primary induction therapy or to salvage with intensive combination chemotherapy, first relapse with the first remission lasting less than 12 months, second or greater relapse, or relapse at any time after allogeneic stem cell transplantation.

Study participants were randomly assigned to receive either blinatumomab (267 patients) or the investigator’s choice of one of four protocol-defined regimens of standard chemotherapy (109 patients) and were followed at 101 medical centers in 21 countries for a median of 11 months.

For each 6-week cycle of blinatumomab therapy, patients received treatment for 4 weeks (9 mcg blinatumomab per day during week 1 of induction cycle one and 28 mcg/day thereafter, by continuous infusion) and then no treatment for 2 weeks.

Maintenance treatment with blinatumomab was given as a 4-week continuous infusion every 12 weeks.

At the interim analysis – when 75% of the total number of planned deaths for the final analysis had occurred – the monitoring committee recommended that the trial be stopped early because of the benefit observed with blinatumomab therapy. Median overall survival was significantly longer with blinatumomab (7.7 months) than with chemotherapy (4 months), with a hazard ratio for death of 0.71. The estimated survival at 6 months was 54% with blinatumomab and 39% with chemotherapy.

Remission rates also favored blinatumomab: Rates of complete remission with full hematologic recovery were 34% vs. 16% and rates of complete remission with full, partial, or incomplete hematologic recovery were 44% vs. 25%.

In addition, the median duration of remission was 7.3 months with blinatumomab and 4.6 months with chemotherapy. And 6-month estimates of event-free survival were 31% vs. 12%. These survival and remission benefits were consistent across all subgroups of patients and persisted in several sensitivity analyses, the investigators said (N Engl J Med. 2017 Mar 2. doi: 10.1056/nejmOA1609783).

A total of 24% of the patients in the blinatumomab group and 24% of the patients in the chemotherapy group underwent allogeneic stem cell transplantation, with comparable outcomes and death rates.

Serious adverse events occurred in 62% of patients receiving blinatumomab and in 45% of those receiving chemotherapy, including fatal adverse events in 19% and 17%, respectively. The fatal events were considered to be related to treatment in 3% of the blinatumomab group and in 7% of the chemotherapy group. Rates of treatment discontinuation from an adverse event were 12% and 8%, respectively.

Patient-reported health status and quality of life improved with blinatumomab but worsened with chemotherapy.

“Given the previous exposure of these patients to myelosuppressive and immunosuppressive treatments, the activity of an immune-based therapy such as blinatumomab, which depends on functioning T cells for its activity, provides encouragement that responses may be further enhanced and made durable with additional immune activation strategies,” Dr. Kantarjian and his associates noted.

Dr. Kantarjian reported receiving research support from Amgen, Pfizer, Bristol-Myers Squibb, Novartis, and ARIAD; his associates reported ties to numerous industry sources.

Photo by Steven Fruitsmaak

ORLANDO, FL—A single, 4 mg-dose of the bisphosphonate zoledronic acid (ZA) prior to allogeneic hematopoietic stem cell transplant (HSCT) prevents femoral neck (FN) bone loss at day 100 in patients with lymphoid or myeloid malignancies, according to new research.

The study also suggests that patients who receive risk-adapted ZA therapy after transplant can experience significant reductions in bone loss between days 100 and 365.

However, patients with acute and chronic graft-versus-host disease (GVHD) continue to be at risk of bone loss.

Eric Wong, of the Royal Melbourne Hospital in Parkville, Australia, presented these findings at the 2017 BMT Tandem Meetings (abstract 53) on behalf of the Australasian Leukaemia and Lymphoma Group.

“Previous studies have demonstrated that efforts to prevent bone loss through calcium and vitamin D supplementation as well as hormone-replacement therapy alone have been ineffective in preventing bone loss,” Wong explained.

And monthly pamidronate begun prior to HSCT reduces, but does not prevent, FN bone density loss.

So Wong and his colleagues began a trial of ZA, which is approximately 100-fold more potent than pamidronate.

Study design

The researchers enrolled 82 patients into the phase 2 ALLG BM07 trial. All patients received a single shot of ZA prior to HSCT conditioning.

All patients also received vitamin D and calcium supplements, and pre-menopausal women received hormone replacement therapy.

Depending on their risk of bone loss, patients received individualized ZA therapy after transplant. Researchers assessed the patients’ bone density at days 100, 180, 270, and 365 post-HSCT. Patients at high risk of bone loss received additional doses of ZA.

Risks for bone loss included bone mineral density (BMD) reduction of 5% or greater compared to baseline, prednisolone exposure of 1 mg/kg/d or greater for 2 weeks, or prednisolone exposure of 10 mg/d or more for 6 weeks

The primary endpoint of the study was the change in FN BMD at days 100 and 365 after HSCT compared to baseline.

The researchers also compared patients’ FN BMD with 35 untreated historical controls assessed at the same time points.

Patient characteristics

Seventy patients were alive and had not relapsed at day 100. Most (87%) were 60 years or younger, 60% were male, 53% had myeloid disease, 43% lymphoid, and 4% other disease.

“The most common indications for transplant were acute myeloid leukemia and acute lymphoblastic leukemia,” Wong said, “which, together, formed over 50% of the entire cohort.”

Seventy percent of patients were ECOG status 0 or 1, and 30% were 2 or greater.

Most (59%) had received myeloablative conditioning, the predominant regimens being busulfan/cyclophosphamide or cyclophosphamide/total-body irradiation. And the most common reduced-intensity conditioning regimen was fludarabine/melphalan.

Fifty-six percent of patients had a sibling donor, and 43% had a matched unrelated donor.

Thirty-eight percent of patients developed acute GVHD—19% grade 1, and 19% grade 2 to 3.

“Of note,” Wong said, “no patient developed grade 4 acute GVHD.”

Patients received a median of 2 ZA doses (range, 1–4), including the pre-transplant dose.

Sixty patients received at least 1 dose of ZA between day 100 and day 365, including 33% who received multiple doses.

At day 100, 33 patients received additional ZA. At day 180, 27 patients received additional ZA, including 8 patients who did not have it at day 100. And at day 270, 18 patients had additional ZA, including 1 patient who had no additional ZA at earlier time points.

Results

At day 100, there was no statistically significant change in FN bone density compared with baseline. The mean change was -2.6% (range, -6.6% to 1.4%).

For patients with acute GVHD, however, the change in bone density was significant (P=0.03). Patients with grade 1-2 GVHD had a mean change of -1.6% ± 3.7%, and patients with grade 3-4 GVHD had a mean change of -8.5% ± 11.2%.

Sixty-five patients were available for the day 365 efficacy analysis.

Bone density did not change significantly between day 100 and 365 for the entire group.

“By day 365,” Wong noted, “there was a net loss of bone density of -2.9%.”

But by day 365, patients with extensive chronic GVHD had significantly more bone loss compared with patients who had no chronic GVHD (P=0.03).

Age, sex, duration of cyclosporine, and mean steroid dose were not associated with a change in bone density at day 100 or 365, although there was a trend for an association between high steroid exposure and increased bone loss (P=0.07).

When the researchers compared the patients to untreated historical controls, patients who received ZA had significantly less bone loss at day 100  (P=0.001) and day 365 (P<0.0001).

The researchers observed no serious adverse events with ZA.

Wong concluded that patients with extensive GVHD are a “high-risk cohort that needs augmented therapies.”

Photo by Steven Fruitsmaak

ORLANDO, FL—A single, 4 mg-dose of the bisphosphonate zoledronic acid (ZA) prior to allogeneic hematopoietic stem cell transplant (HSCT) prevents femoral neck (FN) bone loss at day 100 in patients with lymphoid or myeloid malignancies, according to new research.

The study also suggests that patients who receive risk-adapted ZA therapy after transplant can experience significant reductions in bone loss between days 100 and 365.

However, patients with acute and chronic graft-versus-host disease (GVHD) continue to be at risk of bone loss.

Eric Wong, of the Royal Melbourne Hospital in Parkville, Australia, presented these findings at the 2017 BMT Tandem Meetings (abstract 53) on behalf of the Australasian Leukaemia and Lymphoma Group.

“Previous studies have demonstrated that efforts to prevent bone loss through calcium and vitamin D supplementation as well as hormone-replacement therapy alone have been ineffective in preventing bone loss,” Wong explained.

And monthly pamidronate begun prior to HSCT reduces, but does not prevent, FN bone density loss.

So Wong and his colleagues began a trial of ZA, which is approximately 100-fold more potent than pamidronate.

Study design

The researchers enrolled 82 patients into the phase 2 ALLG BM07 trial. All patients received a single shot of ZA prior to HSCT conditioning.

All patients also received vitamin D and calcium supplements, and pre-menopausal women received hormone replacement therapy.

Depending on their risk of bone loss, patients received individualized ZA therapy after transplant. Researchers assessed the patients’ bone density at days 100, 180, 270, and 365 post-HSCT. Patients at high risk of bone loss received additional doses of ZA.

Risks for bone loss included bone mineral density (BMD) reduction of 5% or greater compared to baseline, prednisolone exposure of 1 mg/kg/d or greater for 2 weeks, or prednisolone exposure of 10 mg/d or more for 6 weeks

The primary endpoint of the study was the change in FN BMD at days 100 and 365 after HSCT compared to baseline.

The researchers also compared patients’ FN BMD with 35 untreated historical controls assessed at the same time points.

Patient characteristics

Seventy patients were alive and had not relapsed at day 100. Most (87%) were 60 years or younger, 60% were male, 53% had myeloid disease, 43% lymphoid, and 4% other disease.

“The most common indications for transplant were acute myeloid leukemia and acute lymphoblastic leukemia,” Wong said, “which, together, formed over 50% of the entire cohort.”

Seventy percent of patients were ECOG status 0 or 1, and 30% were 2 or greater.

Most (59%) had received myeloablative conditioning, the predominant regimens being busulfan/cyclophosphamide or cyclophosphamide/total-body irradiation. And the most common reduced-intensity conditioning regimen was fludarabine/melphalan.

Fifty-six percent of patients had a sibling donor, and 43% had a matched unrelated donor.

Thirty-eight percent of patients developed acute GVHD—19% grade 1, and 19% grade 2 to 3.

“Of note,” Wong said, “no patient developed grade 4 acute GVHD.”

Patients received a median of 2 ZA doses (range, 1–4), including the pre-transplant dose.

Sixty patients received at least 1 dose of ZA between day 100 and day 365, including 33% who received multiple doses.

At day 100, 33 patients received additional ZA. At day 180, 27 patients received additional ZA, including 8 patients who did not have it at day 100. And at day 270, 18 patients had additional ZA, including 1 patient who had no additional ZA at earlier time points.

Results

At day 100, there was no statistically significant change in FN bone density compared with baseline. The mean change was -2.6% (range, -6.6% to 1.4%).

For patients with acute GVHD, however, the change in bone density was significant (P=0.03). Patients with grade 1-2 GVHD had a mean change of -1.6% ± 3.7%, and patients with grade 3-4 GVHD had a mean change of -8.5% ± 11.2%.

Sixty-five patients were available for the day 365 efficacy analysis.

Bone density did not change significantly between day 100 and 365 for the entire group.

“By day 365,” Wong noted, “there was a net loss of bone density of -2.9%.”

But by day 365, patients with extensive chronic GVHD had significantly more bone loss compared with patients who had no chronic GVHD (P=0.03).

Age, sex, duration of cyclosporine, and mean steroid dose were not associated with a change in bone density at day 100 or 365, although there was a trend for an association between high steroid exposure and increased bone loss (P=0.07).

When the researchers compared the patients to untreated historical controls, patients who received ZA had significantly less bone loss at day 100  (P=0.001) and day 365 (P<0.0001).

The researchers observed no serious adverse events with ZA.

Wong concluded that patients with extensive GVHD are a “high-risk cohort that needs augmented therapies.”

Photo by Steven Fruitsmaak

ORLANDO, FL—A single, 4 mg-dose of the bisphosphonate zoledronic acid (ZA) prior to allogeneic hematopoietic stem cell transplant (HSCT) prevents femoral neck (FN) bone loss at day 100 in patients with lymphoid or myeloid malignancies, according to new research.

The study also suggests that patients who receive risk-adapted ZA therapy after transplant can experience significant reductions in bone loss between days 100 and 365.

However, patients with acute and chronic graft-versus-host disease (GVHD) continue to be at risk of bone loss.

Eric Wong, of the Royal Melbourne Hospital in Parkville, Australia, presented these findings at the 2017 BMT Tandem Meetings (abstract 53) on behalf of the Australasian Leukaemia and Lymphoma Group.

“Previous studies have demonstrated that efforts to prevent bone loss through calcium and vitamin D supplementation as well as hormone-replacement therapy alone have been ineffective in preventing bone loss,” Wong explained.

And monthly pamidronate begun prior to HSCT reduces, but does not prevent, FN bone density loss.

So Wong and his colleagues began a trial of ZA, which is approximately 100-fold more potent than pamidronate.

Study design

The researchers enrolled 82 patients into the phase 2 ALLG BM07 trial. All patients received a single shot of ZA prior to HSCT conditioning.

All patients also received vitamin D and calcium supplements, and pre-menopausal women received hormone replacement therapy.

Depending on their risk of bone loss, patients received individualized ZA therapy after transplant. Researchers assessed the patients’ bone density at days 100, 180, 270, and 365 post-HSCT. Patients at high risk of bone loss received additional doses of ZA.

Risks for bone loss included bone mineral density (BMD) reduction of 5% or greater compared to baseline, prednisolone exposure of 1 mg/kg/d or greater for 2 weeks, or prednisolone exposure of 10 mg/d or more for 6 weeks

The primary endpoint of the study was the change in FN BMD at days 100 and 365 after HSCT compared to baseline.

The researchers also compared patients’ FN BMD with 35 untreated historical controls assessed at the same time points.

Patient characteristics

Seventy patients were alive and had not relapsed at day 100. Most (87%) were 60 years or younger, 60% were male, 53% had myeloid disease, 43% lymphoid, and 4% other disease.

“The most common indications for transplant were acute myeloid leukemia and acute lymphoblastic leukemia,” Wong said, “which, together, formed over 50% of the entire cohort.”

Seventy percent of patients were ECOG status 0 or 1, and 30% were 2 or greater.

Most (59%) had received myeloablative conditioning, the predominant regimens being busulfan/cyclophosphamide or cyclophosphamide/total-body irradiation. And the most common reduced-intensity conditioning regimen was fludarabine/melphalan.

Fifty-six percent of patients had a sibling donor, and 43% had a matched unrelated donor.

Thirty-eight percent of patients developed acute GVHD—19% grade 1, and 19% grade 2 to 3.

“Of note,” Wong said, “no patient developed grade 4 acute GVHD.”

Patients received a median of 2 ZA doses (range, 1–4), including the pre-transplant dose.

Sixty patients received at least 1 dose of ZA between day 100 and day 365, including 33% who received multiple doses.

At day 100, 33 patients received additional ZA. At day 180, 27 patients received additional ZA, including 8 patients who did not have it at day 100. And at day 270, 18 patients had additional ZA, including 1 patient who had no additional ZA at earlier time points.

Results

At day 100, there was no statistically significant change in FN bone density compared with baseline. The mean change was -2.6% (range, -6.6% to 1.4%).

For patients with acute GVHD, however, the change in bone density was significant (P=0.03). Patients with grade 1-2 GVHD had a mean change of -1.6% ± 3.7%, and patients with grade 3-4 GVHD had a mean change of -8.5% ± 11.2%.

Sixty-five patients were available for the day 365 efficacy analysis.

Bone density did not change significantly between day 100 and 365 for the entire group.

“By day 365,” Wong noted, “there was a net loss of bone density of -2.9%.”

But by day 365, patients with extensive chronic GVHD had significantly more bone loss compared with patients who had no chronic GVHD (P=0.03).

Age, sex, duration of cyclosporine, and mean steroid dose were not associated with a change in bone density at day 100 or 365, although there was a trend for an association between high steroid exposure and increased bone loss (P=0.07).

When the researchers compared the patients to untreated historical controls, patients who received ZA had significantly less bone loss at day 100  (P=0.001) and day 365 (P<0.0001).

The researchers observed no serious adverse events with ZA.

Wong concluded that patients with extensive GVHD are a “high-risk cohort that needs augmented therapies.”