Hematology Times

Researcher placing PCR tubes

in a thermal cycler

Photo by Karl Mumm

Measuring expression of the gene TJP1 could help determine which multiple myeloma (MM) patients are most likely to benefit from treatment with proteasome inhibitors (PIs), according to a study published in Cancer Cell.

Investigators found that TJP1 enhanced PI sensitivity in vitro and in vivo.

When they analyzed patient data, the team found that high TJP1 expression in patients’ MM cells was associated with a significantly higher likelihood of responding to bortezomib and a longer response duration.

“Proteasome inhibitors form the cornerstone of our standard therapy for multiple myeloma,” said study author Robert Orlowski, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“However, no biomarkers have been clinically validated that can identify patients most likely to respond to this treatment. Our findings provide a rationale for use of TJP1 as the first biomarker to select patients who are most and least likely to benefit from proteasome inhibitors.”

At the start of this study, Dr Orlowski and his colleagues examined gene-expression profiles of ANBL-6 and KAS-6/1 wild-type and bortezomib-resistant MM cells and found that TJP1 was downregulated in the resistant cells.

To further study the role of TJP1 in PI resistance, the investigators conducted experiments with RPMI 8226 and U266 MM cell lines (models that expressed high TJP1 levels) and MOLP-8 (a model that expressed low levels).

They found that knocking down TJP1 in RPMI 8226 and U266 cells with short hairpin RNA (shRNA) preserved the cells’ viability after exposure to bortezomib or carfilzomib. On the other hand, TJP1 overexpression sensitized MOLP-8 cells to the PIs.

In mice, RPMI 8226/TJP1 shRNA tumors were less sensitive to bortezomib than RPMI 8226/control tumors. And mice with MOLP-8/TJP1 shRNA tumors had a greater reduction in tumor growth after bortezomib treatment than MOLP-8/control mice.

Further investigation revealed that TJP1 modulates signaling through a pathway involving EGFR, JAK1, and STAT3. This finding supports the hypothesis that plasma cells expressing low TJP1 levels have both high EGFR/JAK1/STAT3 activity and high proteasome content.

“Therefore, these plasma cells were resistant to proteasome inhibitors,” Dr Orlowski explained. “Moreover, they demonstrated a previously unknown role for EGFR signaling in myeloma and for STAT3 in controlling the level of proteasomes in cells and, therefore, the cell’s ability to break down proteins.”

“This study allows us to identify promising future directions to overcome proteasome inhibitor resistance in patients with high signaling through the EGFR/JAK1/STAT3 pathway by offering combination therapies such as bortezomib with either the EGFR inhibitor erlotinib or a JAK1 inhibitor such as ruxolitinib.”

Finally, Dr Orlowski and his colleagues found that patients whose MM cells expressed low TJP1 levels were significantly less likely to achieve a response or benefit from bortezomib.

Patients who achieved a response after bortezomib across multiple studies had significantly higher TJP1 expression than nonresponders. And patients with the highest TJP1 expression levels had the longest time to progression.

Researcher placing PCR tubes

in a thermal cycler

Photo by Karl Mumm

Measuring expression of the gene TJP1 could help determine which multiple myeloma (MM) patients are most likely to benefit from treatment with proteasome inhibitors (PIs), according to a study published in Cancer Cell.

Investigators found that TJP1 enhanced PI sensitivity in vitro and in vivo.

When they analyzed patient data, the team found that high TJP1 expression in patients’ MM cells was associated with a significantly higher likelihood of responding to bortezomib and a longer response duration.

“Proteasome inhibitors form the cornerstone of our standard therapy for multiple myeloma,” said study author Robert Orlowski, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“However, no biomarkers have been clinically validated that can identify patients most likely to respond to this treatment. Our findings provide a rationale for use of TJP1 as the first biomarker to select patients who are most and least likely to benefit from proteasome inhibitors.”

At the start of this study, Dr Orlowski and his colleagues examined gene-expression profiles of ANBL-6 and KAS-6/1 wild-type and bortezomib-resistant MM cells and found that TJP1 was downregulated in the resistant cells.

To further study the role of TJP1 in PI resistance, the investigators conducted experiments with RPMI 8226 and U266 MM cell lines (models that expressed high TJP1 levels) and MOLP-8 (a model that expressed low levels).

They found that knocking down TJP1 in RPMI 8226 and U266 cells with short hairpin RNA (shRNA) preserved the cells’ viability after exposure to bortezomib or carfilzomib. On the other hand, TJP1 overexpression sensitized MOLP-8 cells to the PIs.

In mice, RPMI 8226/TJP1 shRNA tumors were less sensitive to bortezomib than RPMI 8226/control tumors. And mice with MOLP-8/TJP1 shRNA tumors had a greater reduction in tumor growth after bortezomib treatment than MOLP-8/control mice.

Further investigation revealed that TJP1 modulates signaling through a pathway involving EGFR, JAK1, and STAT3. This finding supports the hypothesis that plasma cells expressing low TJP1 levels have both high EGFR/JAK1/STAT3 activity and high proteasome content.

“Therefore, these plasma cells were resistant to proteasome inhibitors,” Dr Orlowski explained. “Moreover, they demonstrated a previously unknown role for EGFR signaling in myeloma and for STAT3 in controlling the level of proteasomes in cells and, therefore, the cell’s ability to break down proteins.”

“This study allows us to identify promising future directions to overcome proteasome inhibitor resistance in patients with high signaling through the EGFR/JAK1/STAT3 pathway by offering combination therapies such as bortezomib with either the EGFR inhibitor erlotinib or a JAK1 inhibitor such as ruxolitinib.”

Finally, Dr Orlowski and his colleagues found that patients whose MM cells expressed low TJP1 levels were significantly less likely to achieve a response or benefit from bortezomib.

Patients who achieved a response after bortezomib across multiple studies had significantly higher TJP1 expression than nonresponders. And patients with the highest TJP1 expression levels had the longest time to progression.

Researcher placing PCR tubes

in a thermal cycler

Photo by Karl Mumm

Measuring expression of the gene TJP1 could help determine which multiple myeloma (MM) patients are most likely to benefit from treatment with proteasome inhibitors (PIs), according to a study published in Cancer Cell.

Investigators found that TJP1 enhanced PI sensitivity in vitro and in vivo.

When they analyzed patient data, the team found that high TJP1 expression in patients’ MM cells was associated with a significantly higher likelihood of responding to bortezomib and a longer response duration.

“Proteasome inhibitors form the cornerstone of our standard therapy for multiple myeloma,” said study author Robert Orlowski, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“However, no biomarkers have been clinically validated that can identify patients most likely to respond to this treatment. Our findings provide a rationale for use of TJP1 as the first biomarker to select patients who are most and least likely to benefit from proteasome inhibitors.”

At the start of this study, Dr Orlowski and his colleagues examined gene-expression profiles of ANBL-6 and KAS-6/1 wild-type and bortezomib-resistant MM cells and found that TJP1 was downregulated in the resistant cells.

To further study the role of TJP1 in PI resistance, the investigators conducted experiments with RPMI 8226 and U266 MM cell lines (models that expressed high TJP1 levels) and MOLP-8 (a model that expressed low levels).

They found that knocking down TJP1 in RPMI 8226 and U266 cells with short hairpin RNA (shRNA) preserved the cells’ viability after exposure to bortezomib or carfilzomib. On the other hand, TJP1 overexpression sensitized MOLP-8 cells to the PIs.

In mice, RPMI 8226/TJP1 shRNA tumors were less sensitive to bortezomib than RPMI 8226/control tumors. And mice with MOLP-8/TJP1 shRNA tumors had a greater reduction in tumor growth after bortezomib treatment than MOLP-8/control mice.

Further investigation revealed that TJP1 modulates signaling through a pathway involving EGFR, JAK1, and STAT3. This finding supports the hypothesis that plasma cells expressing low TJP1 levels have both high EGFR/JAK1/STAT3 activity and high proteasome content.

“Therefore, these plasma cells were resistant to proteasome inhibitors,” Dr Orlowski explained. “Moreover, they demonstrated a previously unknown role for EGFR signaling in myeloma and for STAT3 in controlling the level of proteasomes in cells and, therefore, the cell’s ability to break down proteins.”

“This study allows us to identify promising future directions to overcome proteasome inhibitor resistance in patients with high signaling through the EGFR/JAK1/STAT3 pathway by offering combination therapies such as bortezomib with either the EGFR inhibitor erlotinib or a JAK1 inhibitor such as ruxolitinib.”

Finally, Dr Orlowski and his colleagues found that patients whose MM cells expressed low TJP1 levels were significantly less likely to achieve a response or benefit from bortezomib.

Patients who achieved a response after bortezomib across multiple studies had significantly higher TJP1 expression than nonresponders. And patients with the highest TJP1 expression levels had the longest time to progression.

Doctor with a clipboard

A recent cancer diagnosis is associated with an increased risk for mental health disorders and increased use of psychiatric medications, according to a large, nationwide study conducted in Sweden.

Overall, there was an increased risk of mental health disorders from 10 months before a cancer diagnosis that peaked during the first week after diagnosis and decreased after that, although the risk remained elevated at 10 years after diagnosis.

In addition, there was an increased use of psychiatric medications from 1 month before cancer diagnosis that peaked at about 3 months after diagnosis and remained elevated 2 years after diagnosis.

Donghao Lu, MD, of the Karolinska Institutet in Stockholm, Sweden and colleagues conducted this study and reported the results in JAMA Oncology.

The study included 304,118 patients with cancer and 3,041,174 cancer-free individuals randomly selected from the Swedish population for comparison.

The researchers investigated changes in risk for several common and potentially stress-related mental disorders—including depression, anxiety, substance abuse, somatoform/conversion disorder, and stress reaction/adjustment disorder—from the cancer diagnostic workup through to post-diagnosis.

They found the relative rate for all of the mental disorders studied started to increase from 10 months before cancer diagnosis, with a hazard ratio [HR] of 1.1 (95%CI, 1.1-1.2).

The rate peaked during the first week after diagnosis, with an HR of 6.7 (95%CI, 6.1-7.4). It decreased rapidly thereafter but was still elevated 10 years after diagnosis, with an HR of 1.1 (95%CI, 1.1-1.2).

The rate elevation was clear for all of the main cancers, including hematologic malignancies, except for nonmelanoma skin cancer.

Among the cancer patients, the mental disorder with the highest cumulative incidence was depression. This was followed by anxiety and stress reaction/adjustment disorder.

When compared to controls, the cancer patients had a higher cumulative incidence of most of the mental disorders. The exception was somatoform/conversion disorder.

The researchers also examined the use of psychiatric medications for patients with cancer to assess milder mental health conditions and symptoms.

The team found an increased use of psychiatric medications in cancer patients compared to controls, from 1 month before diagnosis—12.2% vs 11.7% (P=0.04)—that peaked at about 3 months after diagnosis—18.1% vs 11.9% (P<0.001)—and was still elevated 2 years after diagnosis—15.4% vs 12.7% (P<0.001).

The researchers said the results of this study support the existing guidelines of integrating psychological management into cancer care and call for extended vigilance for multiple mental disorders starting from the time of the cancer diagnostic workup.

Doctor with a clipboard

A recent cancer diagnosis is associated with an increased risk for mental health disorders and increased use of psychiatric medications, according to a large, nationwide study conducted in Sweden.

Overall, there was an increased risk of mental health disorders from 10 months before a cancer diagnosis that peaked during the first week after diagnosis and decreased after that, although the risk remained elevated at 10 years after diagnosis.

In addition, there was an increased use of psychiatric medications from 1 month before cancer diagnosis that peaked at about 3 months after diagnosis and remained elevated 2 years after diagnosis.

Donghao Lu, MD, of the Karolinska Institutet in Stockholm, Sweden and colleagues conducted this study and reported the results in JAMA Oncology.

The study included 304,118 patients with cancer and 3,041,174 cancer-free individuals randomly selected from the Swedish population for comparison.

The researchers investigated changes in risk for several common and potentially stress-related mental disorders—including depression, anxiety, substance abuse, somatoform/conversion disorder, and stress reaction/adjustment disorder—from the cancer diagnostic workup through to post-diagnosis.

They found the relative rate for all of the mental disorders studied started to increase from 10 months before cancer diagnosis, with a hazard ratio [HR] of 1.1 (95%CI, 1.1-1.2).

The rate peaked during the first week after diagnosis, with an HR of 6.7 (95%CI, 6.1-7.4). It decreased rapidly thereafter but was still elevated 10 years after diagnosis, with an HR of 1.1 (95%CI, 1.1-1.2).

The rate elevation was clear for all of the main cancers, including hematologic malignancies, except for nonmelanoma skin cancer.

Among the cancer patients, the mental disorder with the highest cumulative incidence was depression. This was followed by anxiety and stress reaction/adjustment disorder.

When compared to controls, the cancer patients had a higher cumulative incidence of most of the mental disorders. The exception was somatoform/conversion disorder.

The researchers also examined the use of psychiatric medications for patients with cancer to assess milder mental health conditions and symptoms.

The team found an increased use of psychiatric medications in cancer patients compared to controls, from 1 month before diagnosis—12.2% vs 11.7% (P=0.04)—that peaked at about 3 months after diagnosis—18.1% vs 11.9% (P<0.001)—and was still elevated 2 years after diagnosis—15.4% vs 12.7% (P<0.001).

The researchers said the results of this study support the existing guidelines of integrating psychological management into cancer care and call for extended vigilance for multiple mental disorders starting from the time of the cancer diagnostic workup.

Doctor with a clipboard

A recent cancer diagnosis is associated with an increased risk for mental health disorders and increased use of psychiatric medications, according to a large, nationwide study conducted in Sweden.

Overall, there was an increased risk of mental health disorders from 10 months before a cancer diagnosis that peaked during the first week after diagnosis and decreased after that, although the risk remained elevated at 10 years after diagnosis.

In addition, there was an increased use of psychiatric medications from 1 month before cancer diagnosis that peaked at about 3 months after diagnosis and remained elevated 2 years after diagnosis.

Donghao Lu, MD, of the Karolinska Institutet in Stockholm, Sweden and colleagues conducted this study and reported the results in JAMA Oncology.

The study included 304,118 patients with cancer and 3,041,174 cancer-free individuals randomly selected from the Swedish population for comparison.

The researchers investigated changes in risk for several common and potentially stress-related mental disorders—including depression, anxiety, substance abuse, somatoform/conversion disorder, and stress reaction/adjustment disorder—from the cancer diagnostic workup through to post-diagnosis.

They found the relative rate for all of the mental disorders studied started to increase from 10 months before cancer diagnosis, with a hazard ratio [HR] of 1.1 (95%CI, 1.1-1.2).

The rate peaked during the first week after diagnosis, with an HR of 6.7 (95%CI, 6.1-7.4). It decreased rapidly thereafter but was still elevated 10 years after diagnosis, with an HR of 1.1 (95%CI, 1.1-1.2).

The rate elevation was clear for all of the main cancers, including hematologic malignancies, except for nonmelanoma skin cancer.

Among the cancer patients, the mental disorder with the highest cumulative incidence was depression. This was followed by anxiety and stress reaction/adjustment disorder.

When compared to controls, the cancer patients had a higher cumulative incidence of most of the mental disorders. The exception was somatoform/conversion disorder.

The researchers also examined the use of psychiatric medications for patients with cancer to assess milder mental health conditions and symptoms.

The team found an increased use of psychiatric medications in cancer patients compared to controls, from 1 month before diagnosis—12.2% vs 11.7% (P=0.04)—that peaked at about 3 months after diagnosis—18.1% vs 11.9% (P<0.001)—and was still elevated 2 years after diagnosis—15.4% vs 12.7% (P<0.001).

The researchers said the results of this study support the existing guidelines of integrating psychological management into cancer care and call for extended vigilance for multiple mental disorders starting from the time of the cancer diagnostic workup.

Prescription medications

Photo courtesy of the CDC

New orally administered cancer drugs are much more expensive in their first year on the market than such drugs launched about 15 years ago, according to a study published in JAMA Oncology.

The research showed that a month of treatment with orally administered cancer drugs introduced in 2014 was, on average, 6 times more expensive at launch than monthly treatment costs for such drugs introduced in 2000, after adjusting for inflation.

In addition, most existing therapies had substantial price increases from the time they were launched to 2014.

“The major trend here is that these products are just getting more expensive over time,” said study author Stacie Dusetzina, PhD, of the University of North Carolina at Chapel Hill.

For this study, Dr Dusetzina evaluated what commercial health insurance companies and patients paid for prescription fills—before rebates and discounts—for 32 orally administered cancer drugs from 2000 to 2014. The information came from the TruvenHealth MarketScan Commercial Claims and Encounters database.

The data showed that orally administered drugs approved in 2000 cost an average of $1869 (95% CI, $1648-$2121) per month, compared to $11,325 (95% CI, $10 989-$11 671) for those approved in 2014.

When Dr Dusetzina compared changes in spending by year from a product’s launch to 2014, she observed increases in most of the drugs studied.

The drugs with the largest increases in monthly spending were thalidomide, which increased from $1869 to $7564 ($5695) and imatinib, which increased from $3346 to $8479 ($5133).

However, 2 drugs showed decreases in mean monthly spending between their launch and 2014. Monthly spending for lenalidomide decreased from $10,109 to $9640 ($469), and monthly spending for vorinostat decreased from $9755 to $7592 ($2163).

Dr Dusetzina pointed out that the amount patients pay for these drugs depends on their healthcare benefits. However, the high prices are being passed along to patients more and more, potentially affecting the patients’ access to these drugs.

“Patients are increasingly taking on the burden of paying for these high-cost specialty drugs as plans move toward use of higher deductibles and co-insurance—where a patient will pay a percentage of the drug cost rather than a flat copay,” Dr Dusetzina said.

She noted that while this study did account for payments by commercial health plans, it did not account for spending by Medicaid and Medicare, which may differ. In addition, only the products that were dispensed and reimbursed by commercial health plans were included, which may have excluded rarely used or recently approved products.

Prescription medications

Photo courtesy of the CDC

New orally administered cancer drugs are much more expensive in their first year on the market than such drugs launched about 15 years ago, according to a study published in JAMA Oncology.

The research showed that a month of treatment with orally administered cancer drugs introduced in 2014 was, on average, 6 times more expensive at launch than monthly treatment costs for such drugs introduced in 2000, after adjusting for inflation.

In addition, most existing therapies had substantial price increases from the time they were launched to 2014.

“The major trend here is that these products are just getting more expensive over time,” said study author Stacie Dusetzina, PhD, of the University of North Carolina at Chapel Hill.

For this study, Dr Dusetzina evaluated what commercial health insurance companies and patients paid for prescription fills—before rebates and discounts—for 32 orally administered cancer drugs from 2000 to 2014. The information came from the TruvenHealth MarketScan Commercial Claims and Encounters database.

The data showed that orally administered drugs approved in 2000 cost an average of $1869 (95% CI, $1648-$2121) per month, compared to $11,325 (95% CI, $10 989-$11 671) for those approved in 2014.

When Dr Dusetzina compared changes in spending by year from a product’s launch to 2014, she observed increases in most of the drugs studied.

The drugs with the largest increases in monthly spending were thalidomide, which increased from $1869 to $7564 ($5695) and imatinib, which increased from $3346 to $8479 ($5133).

However, 2 drugs showed decreases in mean monthly spending between their launch and 2014. Monthly spending for lenalidomide decreased from $10,109 to $9640 ($469), and monthly spending for vorinostat decreased from $9755 to $7592 ($2163).

Dr Dusetzina pointed out that the amount patients pay for these drugs depends on their healthcare benefits. However, the high prices are being passed along to patients more and more, potentially affecting the patients’ access to these drugs.

“Patients are increasingly taking on the burden of paying for these high-cost specialty drugs as plans move toward use of higher deductibles and co-insurance—where a patient will pay a percentage of the drug cost rather than a flat copay,” Dr Dusetzina said.

She noted that while this study did account for payments by commercial health plans, it did not account for spending by Medicaid and Medicare, which may differ. In addition, only the products that were dispensed and reimbursed by commercial health plans were included, which may have excluded rarely used or recently approved products.

Prescription medications

Photo courtesy of the CDC

New orally administered cancer drugs are much more expensive in their first year on the market than such drugs launched about 15 years ago, according to a study published in JAMA Oncology.

The research showed that a month of treatment with orally administered cancer drugs introduced in 2014 was, on average, 6 times more expensive at launch than monthly treatment costs for such drugs introduced in 2000, after adjusting for inflation.

In addition, most existing therapies had substantial price increases from the time they were launched to 2014.

“The major trend here is that these products are just getting more expensive over time,” said study author Stacie Dusetzina, PhD, of the University of North Carolina at Chapel Hill.

For this study, Dr Dusetzina evaluated what commercial health insurance companies and patients paid for prescription fills—before rebates and discounts—for 32 orally administered cancer drugs from 2000 to 2014. The information came from the TruvenHealth MarketScan Commercial Claims and Encounters database.

The data showed that orally administered drugs approved in 2000 cost an average of $1869 (95% CI, $1648-$2121) per month, compared to $11,325 (95% CI, $10 989-$11 671) for those approved in 2014.

When Dr Dusetzina compared changes in spending by year from a product’s launch to 2014, she observed increases in most of the drugs studied.

The drugs with the largest increases in monthly spending were thalidomide, which increased from $1869 to $7564 ($5695) and imatinib, which increased from $3346 to $8479 ($5133).

However, 2 drugs showed decreases in mean monthly spending between their launch and 2014. Monthly spending for lenalidomide decreased from $10,109 to $9640 ($469), and monthly spending for vorinostat decreased from $9755 to $7592 ($2163).

Dr Dusetzina pointed out that the amount patients pay for these drugs depends on their healthcare benefits. However, the high prices are being passed along to patients more and more, potentially affecting the patients’ access to these drugs.

“Patients are increasingly taking on the burden of paying for these high-cost specialty drugs as plans move toward use of higher deductibles and co-insurance—where a patient will pay a percentage of the drug cost rather than a flat copay,” Dr Dusetzina said.

She noted that while this study did account for payments by commercial health plans, it did not account for spending by Medicaid and Medicare, which may differ. In addition, only the products that were dispensed and reimbursed by commercial health plans were included, which may have excluded rarely used or recently approved products.

Cameron Turtle, MBBS, PhD

Photo courtesy of

Fred Hutch News Service

Researchers say they have conducted the first trial of CD19-directed chimeric antigen receptor (CAR) T-cell therapy in which CD4+ and CD8+ cells were administered in equal proportions.

And the assurance that each patient received the same mixture of cells allowed the team to draw clear conclusions about the effects of administering CAR T-cell therapy at different doses.

The researchers detailed these conclusions in The Journal of Clinical Investigation.

This phase 1/2 trial (NCT01865617) was funded, in part, by Juno Therapeutics, the company developing the CAR T-cell therapy as JCAR014.

The work was also funded by the National Cancer Institute, private philanthropists, and the Life Sciences Discovery Fund.

Patients and treatment

The researchers reported data on 32 patients who had relapsed or refractory, CD19+ B-cell acute lymphoblastic leukemia and a median age of 40 (range, 20–73). Two of these patients were excluded due to complications prior to receiving treatment.

The 30 patients who were treated in this study had received a median of 3 prior intensive chemotherapy regimens (range, 1–11). Eleven patients had failed a hematopoietic stem cell transplant (HSCT). And all patients had detectable disease in the bone marrow, extramedullary sites, or cerebrospinal fluid at baseline.

To create the CAR T-cell therapy, the researchers modified CD8+ and CD4+ T-cell subsets separately to express a CD19-targeted CAR incorporating 4-1BB and CD3ζ signaling domains. The cells were then formulated in a defined ratio of CD4+:CD8+ CAR T cells.

Patients underwent lymphodepletion with a cyclophosphamide-based regimen (alone or with fludarabine or etoposide) and then received CAR T cells 48 to 96 hours later. The CAR T cells were given at 3 dose levels—2 × 10⁵/kg (DL1), 2 × 10⁶/kg (DL2), and 2 × 10⁷/kg (DL3).

Toxicity

The first 2 patients who received CAR T-cell therapy at DL3 developed severe toxicities, including 1 patient who died. So DL3 was not given to any subsequent patients.

Two patients died after CAR T-cell infusion. One patient had severe cytokine release syndrome (CRS) and multiorgan failure and died on day 3. The other patient had transient severe CRS with irreversible neurologic toxicity and died on day 122.

The most common adverse event observed in the first 14 days after CAR T-cell infusion was CRS, which occurred in 25 patients. Seven patients had severe CRS that put them in the intensive care unit.

However, for the patients treated at DL1 and DL2, dexamethasone alone or with tocilizumab resolved CRS.

Fifteen patients developed severe neurotoxicity (grade 3 or higher), either with CRS or after it resolved. For all but 1 patient (the aforementioned patient who died), neurologic symptoms and signs resolved.

Response

One patient died before response assessment, so 29 patients were evaluable. Twenty-seven of these patients (93%) achieved bone marrow remission by flow cytometry.

Of the 2 patients who did not achieve a complete response (CR), 1 underwent an allogeneic HSCT after receiving CAR T cells. After HSCT, she relapsed, was re-enrolled on the trial, and achieved a CR after receiving a higher dose of CAR T cells (DL2).

Twenty-five patients (86%) achieved a CR without evidence of minimal residual disease by flow cytometry and conventional karyotyping, FISH, or QPCR.

“Patients who come onto the trial have really limited options for treatment,” said study author Cameron Turtle, MBBS, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

“They have refractory acute leukemia. So the fact that we’re getting so many into remission is giving these people a way forward.”

Unfortunately, not all patients stayed in CR. Some relapsed and were treated again with CAR T cells, and 2 patients relapsed with leukemias that were immune to the CAR T cells. The researchers said it is still too early to know the long-term outcomes of the therapy.

“This is just the beginning,” Dr Turtle said. “It sounds fantastic to say that we get over 90% remissions, but there’s so much more work to do make sure they’re durable remissions, to work out who’s going to benefit the most, and extend this work to other diseases.”

Lessons learned

The researchers said that, because these CAR T cells had a defined CD4+:CD8+ composition, this study provides the first clear evidence of the relationships between the CAR T-cell dose patients receive and their outcomes after infusion.

The team found that high doses of CAR T cells and high tumor burden increase the risks of severe CRS and neurotoxicity. However, certain biomarkers can identify patients at the highest risk of toxicity.

Levels of IL-6, IFN-γ, and TNF-α on the first day after CAR T-cell infusion were significantly higher in patients who later developed severe neurotoxicity. Levels of these biomarkers were also higher in patients who were later sent to the intensive care unit.

Furthermore, risk-stratified CAR T-cell dosing based on bone marrow disease burden decreased toxicity.

The researchers also said they observed CD8+ T-cell-mediated anti-CAR transgene product immune responses in some patients, which limited CAR T-cell persistence and increased the risk of relapse.

And including fludarabine in the lymphodepletion regimen resulted in better CAR T-cell persistence and disease-free survival than when cyclophosphamide was given alone or with etoposide.

Cameron Turtle, MBBS, PhD

Photo courtesy of

Fred Hutch News Service

Researchers say they have conducted the first trial of CD19-directed chimeric antigen receptor (CAR) T-cell therapy in which CD4+ and CD8+ cells were administered in equal proportions.

And the assurance that each patient received the same mixture of cells allowed the team to draw clear conclusions about the effects of administering CAR T-cell therapy at different doses.

The researchers detailed these conclusions in The Journal of Clinical Investigation.

This phase 1/2 trial (NCT01865617) was funded, in part, by Juno Therapeutics, the company developing the CAR T-cell therapy as JCAR014.

The work was also funded by the National Cancer Institute, private philanthropists, and the Life Sciences Discovery Fund.

Patients and treatment

The researchers reported data on 32 patients who had relapsed or refractory, CD19+ B-cell acute lymphoblastic leukemia and a median age of 40 (range, 20–73). Two of these patients were excluded due to complications prior to receiving treatment.

The 30 patients who were treated in this study had received a median of 3 prior intensive chemotherapy regimens (range, 1–11). Eleven patients had failed a hematopoietic stem cell transplant (HSCT). And all patients had detectable disease in the bone marrow, extramedullary sites, or cerebrospinal fluid at baseline.

To create the CAR T-cell therapy, the researchers modified CD8+ and CD4+ T-cell subsets separately to express a CD19-targeted CAR incorporating 4-1BB and CD3ζ signaling domains. The cells were then formulated in a defined ratio of CD4+:CD8+ CAR T cells.

Patients underwent lymphodepletion with a cyclophosphamide-based regimen (alone or with fludarabine or etoposide) and then received CAR T cells 48 to 96 hours later. The CAR T cells were given at 3 dose levels—2 × 10⁵/kg (DL1), 2 × 10⁶/kg (DL2), and 2 × 10⁷/kg (DL3).

Toxicity

The first 2 patients who received CAR T-cell therapy at DL3 developed severe toxicities, including 1 patient who died. So DL3 was not given to any subsequent patients.

Two patients died after CAR T-cell infusion. One patient had severe cytokine release syndrome (CRS) and multiorgan failure and died on day 3. The other patient had transient severe CRS with irreversible neurologic toxicity and died on day 122.

The most common adverse event observed in the first 14 days after CAR T-cell infusion was CRS, which occurred in 25 patients. Seven patients had severe CRS that put them in the intensive care unit.

However, for the patients treated at DL1 and DL2, dexamethasone alone or with tocilizumab resolved CRS.

Fifteen patients developed severe neurotoxicity (grade 3 or higher), either with CRS or after it resolved. For all but 1 patient (the aforementioned patient who died), neurologic symptoms and signs resolved.

Response

One patient died before response assessment, so 29 patients were evaluable. Twenty-seven of these patients (93%) achieved bone marrow remission by flow cytometry.

Of the 2 patients who did not achieve a complete response (CR), 1 underwent an allogeneic HSCT after receiving CAR T cells. After HSCT, she relapsed, was re-enrolled on the trial, and achieved a CR after receiving a higher dose of CAR T cells (DL2).

Twenty-five patients (86%) achieved a CR without evidence of minimal residual disease by flow cytometry and conventional karyotyping, FISH, or QPCR.

“Patients who come onto the trial have really limited options for treatment,” said study author Cameron Turtle, MBBS, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

“They have refractory acute leukemia. So the fact that we’re getting so many into remission is giving these people a way forward.”

Unfortunately, not all patients stayed in CR. Some relapsed and were treated again with CAR T cells, and 2 patients relapsed with leukemias that were immune to the CAR T cells. The researchers said it is still too early to know the long-term outcomes of the therapy.

“This is just the beginning,” Dr Turtle said. “It sounds fantastic to say that we get over 90% remissions, but there’s so much more work to do make sure they’re durable remissions, to work out who’s going to benefit the most, and extend this work to other diseases.”

Lessons learned

The researchers said that, because these CAR T cells had a defined CD4+:CD8+ composition, this study provides the first clear evidence of the relationships between the CAR T-cell dose patients receive and their outcomes after infusion.

The team found that high doses of CAR T cells and high tumor burden increase the risks of severe CRS and neurotoxicity. However, certain biomarkers can identify patients at the highest risk of toxicity.

Levels of IL-6, IFN-γ, and TNF-α on the first day after CAR T-cell infusion were significantly higher in patients who later developed severe neurotoxicity. Levels of these biomarkers were also higher in patients who were later sent to the intensive care unit.

Furthermore, risk-stratified CAR T-cell dosing based on bone marrow disease burden decreased toxicity.

The researchers also said they observed CD8+ T-cell-mediated anti-CAR transgene product immune responses in some patients, which limited CAR T-cell persistence and increased the risk of relapse.

And including fludarabine in the lymphodepletion regimen resulted in better CAR T-cell persistence and disease-free survival than when cyclophosphamide was given alone or with etoposide.

Cameron Turtle, MBBS, PhD

Photo courtesy of

Fred Hutch News Service

Researchers say they have conducted the first trial of CD19-directed chimeric antigen receptor (CAR) T-cell therapy in which CD4+ and CD8+ cells were administered in equal proportions.

And the assurance that each patient received the same mixture of cells allowed the team to draw clear conclusions about the effects of administering CAR T-cell therapy at different doses.

The researchers detailed these conclusions in The Journal of Clinical Investigation.

This phase 1/2 trial (NCT01865617) was funded, in part, by Juno Therapeutics, the company developing the CAR T-cell therapy as JCAR014.

The work was also funded by the National Cancer Institute, private philanthropists, and the Life Sciences Discovery Fund.

Patients and treatment

The researchers reported data on 32 patients who had relapsed or refractory, CD19+ B-cell acute lymphoblastic leukemia and a median age of 40 (range, 20–73). Two of these patients were excluded due to complications prior to receiving treatment.

The 30 patients who were treated in this study had received a median of 3 prior intensive chemotherapy regimens (range, 1–11). Eleven patients had failed a hematopoietic stem cell transplant (HSCT). And all patients had detectable disease in the bone marrow, extramedullary sites, or cerebrospinal fluid at baseline.

To create the CAR T-cell therapy, the researchers modified CD8+ and CD4+ T-cell subsets separately to express a CD19-targeted CAR incorporating 4-1BB and CD3ζ signaling domains. The cells were then formulated in a defined ratio of CD4+:CD8+ CAR T cells.

Patients underwent lymphodepletion with a cyclophosphamide-based regimen (alone or with fludarabine or etoposide) and then received CAR T cells 48 to 96 hours later. The CAR T cells were given at 3 dose levels—2 × 10⁵/kg (DL1), 2 × 10⁶/kg (DL2), and 2 × 10⁷/kg (DL3).

Toxicity

The first 2 patients who received CAR T-cell therapy at DL3 developed severe toxicities, including 1 patient who died. So DL3 was not given to any subsequent patients.

Two patients died after CAR T-cell infusion. One patient had severe cytokine release syndrome (CRS) and multiorgan failure and died on day 3. The other patient had transient severe CRS with irreversible neurologic toxicity and died on day 122.

The most common adverse event observed in the first 14 days after CAR T-cell infusion was CRS, which occurred in 25 patients. Seven patients had severe CRS that put them in the intensive care unit.

However, for the patients treated at DL1 and DL2, dexamethasone alone or with tocilizumab resolved CRS.

Fifteen patients developed severe neurotoxicity (grade 3 or higher), either with CRS or after it resolved. For all but 1 patient (the aforementioned patient who died), neurologic symptoms and signs resolved.

Response

One patient died before response assessment, so 29 patients were evaluable. Twenty-seven of these patients (93%) achieved bone marrow remission by flow cytometry.

Of the 2 patients who did not achieve a complete response (CR), 1 underwent an allogeneic HSCT after receiving CAR T cells. After HSCT, she relapsed, was re-enrolled on the trial, and achieved a CR after receiving a higher dose of CAR T cells (DL2).

Twenty-five patients (86%) achieved a CR without evidence of minimal residual disease by flow cytometry and conventional karyotyping, FISH, or QPCR.

“Patients who come onto the trial have really limited options for treatment,” said study author Cameron Turtle, MBBS, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

“They have refractory acute leukemia. So the fact that we’re getting so many into remission is giving these people a way forward.”

Unfortunately, not all patients stayed in CR. Some relapsed and were treated again with CAR T cells, and 2 patients relapsed with leukemias that were immune to the CAR T cells. The researchers said it is still too early to know the long-term outcomes of the therapy.

“This is just the beginning,” Dr Turtle said. “It sounds fantastic to say that we get over 90% remissions, but there’s so much more work to do make sure they’re durable remissions, to work out who’s going to benefit the most, and extend this work to other diseases.”

Lessons learned

The researchers said that, because these CAR T cells had a defined CD4+:CD8+ composition, this study provides the first clear evidence of the relationships between the CAR T-cell dose patients receive and their outcomes after infusion.

The team found that high doses of CAR T cells and high tumor burden increase the risks of severe CRS and neurotoxicity. However, certain biomarkers can identify patients at the highest risk of toxicity.

Levels of IL-6, IFN-γ, and TNF-α on the first day after CAR T-cell infusion were significantly higher in patients who later developed severe neurotoxicity. Levels of these biomarkers were also higher in patients who were later sent to the intensive care unit.

Furthermore, risk-stratified CAR T-cell dosing based on bone marrow disease burden decreased toxicity.

The researchers also said they observed CD8+ T-cell-mediated anti-CAR transgene product immune responses in some patients, which limited CAR T-cell persistence and increased the risk of relapse.

And including fludarabine in the lymphodepletion regimen resulted in better CAR T-cell persistence and disease-free survival than when cyclophosphamide was given alone or with etoposide.

Cord blood donation

Photo courtesy of NHS

New research suggests an RNA-binding protein can be used to expand hematopoietic stem cells (HSCs) derived from umbilical cord blood.

Investigators found the protein, Musashi-2 (MSI2), regulates the function and development of cord-blood derived HSCs, and overexpressing MSI2 can significantly expand both short-term and long-term repopulating HSCs.

“By expanding the stem cells as we have done, many more donated [cord blood] samples could now be used for transplants,” said Kristin Hope, PhD, of McMaster University in Hamilton, Ontario, Canada.

“Providing enhanced numbers of stem cells for transplantation could alleviate some of the current post-transplantation complications and allow for faster recoveries, in turn, reducing overall healthcare costs and wait times for newly diagnosed patients seeking treatment.”

Dr Hope and her colleagues described this exploration of HSC expansion in Nature.

The team first found that expression of MSI2 messenger RNA was elevated in primitive cord blood hematopoietic stem and progenitor cells (HSPCs), but it decreased during differentiation.

They then found that overexpressing MSI2 enhances the activity of cord blood progenitors in vitro and increases the number of short-term repopulating HSCs in vitro and in vivo.

During in vitro culture, MSI2-overexpressing cells were 2.3-fold more abundant than control cells at 7 days and 6-fold more abundant at 21 days. After 7 days, MSI2-overexpressing cells showed a cumulative 9.3-fold increase in colony-forming cells but no changes in cell cycling or death.

MSI2-overexpressing short-term repopulating cells (STRCs) yielded 1.8-fold more primitive CD34+ cells than control STRCs. And the MSI2-overexpressing STRCs prompted a 17-fold increase in functional STRCs.

Furthermore, 100% of mice transplanted with MSI2-overexpressing STRCs were engrafted at 6.5 weeks, compared to 50% of mice transplanted with control STRCs.

Additional transplant experiments showed that MSI2 overexpression also impacted long-term HSCs (LT-HSCs). Compared to control cells, MSI2-overexpressing cells increased the percentage of GFP+ HSCs in the bone marrow 4.6-fold and the frequency of LT-HSCs 3.5-fold.

The researchers said the increase in LT-HSC frequency corresponded to MSI2-overexpressing GFP+ HSCs having expanded in mice 2.4-fold over input. With control HSCs, on the other hand, there was a 1.5-fold decrease.

In ex vivo culture, MSI2 overexpression induced a cumulative 23-fold expansion of secondary LT-HSCs when compared to control LT-HSCs.

Finally, the researchers performed a global analysis of MSI2–RNA interactions and found that MSI2 mediates HSPC self-renewal and ex vivo expansion by coordinating the post-transcriptional regulation of proteins belonging to a shared self-renewal regulatory pathway.

“We’ve really shone a light on the way these stem cells work,” Dr Hope said. “We now understand how they operate at a completely new level, and that provides us with a serious advantage in determining how to maximize these stem cells in therapeutics. With this newfound ability to control the regeneration of these cells, more people will be able to get the treatment they need.”

Cord blood donation

Photo courtesy of NHS

New research suggests an RNA-binding protein can be used to expand hematopoietic stem cells (HSCs) derived from umbilical cord blood.

Investigators found the protein, Musashi-2 (MSI2), regulates the function and development of cord-blood derived HSCs, and overexpressing MSI2 can significantly expand both short-term and long-term repopulating HSCs.

“By expanding the stem cells as we have done, many more donated [cord blood] samples could now be used for transplants,” said Kristin Hope, PhD, of McMaster University in Hamilton, Ontario, Canada.

“Providing enhanced numbers of stem cells for transplantation could alleviate some of the current post-transplantation complications and allow for faster recoveries, in turn, reducing overall healthcare costs and wait times for newly diagnosed patients seeking treatment.”

Dr Hope and her colleagues described this exploration of HSC expansion in Nature.

The team first found that expression of MSI2 messenger RNA was elevated in primitive cord blood hematopoietic stem and progenitor cells (HSPCs), but it decreased during differentiation.

They then found that overexpressing MSI2 enhances the activity of cord blood progenitors in vitro and increases the number of short-term repopulating HSCs in vitro and in vivo.

During in vitro culture, MSI2-overexpressing cells were 2.3-fold more abundant than control cells at 7 days and 6-fold more abundant at 21 days. After 7 days, MSI2-overexpressing cells showed a cumulative 9.3-fold increase in colony-forming cells but no changes in cell cycling or death.

MSI2-overexpressing short-term repopulating cells (STRCs) yielded 1.8-fold more primitive CD34+ cells than control STRCs. And the MSI2-overexpressing STRCs prompted a 17-fold increase in functional STRCs.

Furthermore, 100% of mice transplanted with MSI2-overexpressing STRCs were engrafted at 6.5 weeks, compared to 50% of mice transplanted with control STRCs.

Additional transplant experiments showed that MSI2 overexpression also impacted long-term HSCs (LT-HSCs). Compared to control cells, MSI2-overexpressing cells increased the percentage of GFP+ HSCs in the bone marrow 4.6-fold and the frequency of LT-HSCs 3.5-fold.

The researchers said the increase in LT-HSC frequency corresponded to MSI2-overexpressing GFP+ HSCs having expanded in mice 2.4-fold over input. With control HSCs, on the other hand, there was a 1.5-fold decrease.

In ex vivo culture, MSI2 overexpression induced a cumulative 23-fold expansion of secondary LT-HSCs when compared to control LT-HSCs.

Finally, the researchers performed a global analysis of MSI2–RNA interactions and found that MSI2 mediates HSPC self-renewal and ex vivo expansion by coordinating the post-transcriptional regulation of proteins belonging to a shared self-renewal regulatory pathway.

“We’ve really shone a light on the way these stem cells work,” Dr Hope said. “We now understand how they operate at a completely new level, and that provides us with a serious advantage in determining how to maximize these stem cells in therapeutics. With this newfound ability to control the regeneration of these cells, more people will be able to get the treatment they need.”

Cord blood donation

Photo courtesy of NHS

New research suggests an RNA-binding protein can be used to expand hematopoietic stem cells (HSCs) derived from umbilical cord blood.

Investigators found the protein, Musashi-2 (MSI2), regulates the function and development of cord-blood derived HSCs, and overexpressing MSI2 can significantly expand both short-term and long-term repopulating HSCs.

“By expanding the stem cells as we have done, many more donated [cord blood] samples could now be used for transplants,” said Kristin Hope, PhD, of McMaster University in Hamilton, Ontario, Canada.

“Providing enhanced numbers of stem cells for transplantation could alleviate some of the current post-transplantation complications and allow for faster recoveries, in turn, reducing overall healthcare costs and wait times for newly diagnosed patients seeking treatment.”

Dr Hope and her colleagues described this exploration of HSC expansion in Nature.

The team first found that expression of MSI2 messenger RNA was elevated in primitive cord blood hematopoietic stem and progenitor cells (HSPCs), but it decreased during differentiation.

They then found that overexpressing MSI2 enhances the activity of cord blood progenitors in vitro and increases the number of short-term repopulating HSCs in vitro and in vivo.

During in vitro culture, MSI2-overexpressing cells were 2.3-fold more abundant than control cells at 7 days and 6-fold more abundant at 21 days. After 7 days, MSI2-overexpressing cells showed a cumulative 9.3-fold increase in colony-forming cells but no changes in cell cycling or death.

MSI2-overexpressing short-term repopulating cells (STRCs) yielded 1.8-fold more primitive CD34+ cells than control STRCs. And the MSI2-overexpressing STRCs prompted a 17-fold increase in functional STRCs.

Furthermore, 100% of mice transplanted with MSI2-overexpressing STRCs were engrafted at 6.5 weeks, compared to 50% of mice transplanted with control STRCs.

Additional transplant experiments showed that MSI2 overexpression also impacted long-term HSCs (LT-HSCs). Compared to control cells, MSI2-overexpressing cells increased the percentage of GFP+ HSCs in the bone marrow 4.6-fold and the frequency of LT-HSCs 3.5-fold.

The researchers said the increase in LT-HSC frequency corresponded to MSI2-overexpressing GFP+ HSCs having expanded in mice 2.4-fold over input. With control HSCs, on the other hand, there was a 1.5-fold decrease.

In ex vivo culture, MSI2 overexpression induced a cumulative 23-fold expansion of secondary LT-HSCs when compared to control LT-HSCs.

Finally, the researchers performed a global analysis of MSI2–RNA interactions and found that MSI2 mediates HSPC self-renewal and ex vivo expansion by coordinating the post-transcriptional regulation of proteins belonging to a shared self-renewal regulatory pathway.

“We’ve really shone a light on the way these stem cells work,” Dr Hope said. “We now understand how they operate at a completely new level, and that provides us with a serious advantage in determining how to maximize these stem cells in therapeutics. With this newfound ability to control the regeneration of these cells, more people will be able to get the treatment they need.”

Red blood cells

Image courtesy of NHLBI

The US Food and Drug Administration (FDA) has approved the use of a powder formulation of ferric pyrophosphate citrate (Triferic powder packet) to maintain hemoglobin in adult patients with hemodialysis-dependent chronic kidney disease.

The FDA previously approved ferric pyrophosphate citrate solution (Triferic) in ampule form. It is an iron-replacement drug intended to treat anemia in chronic kidney disease patients receiving hemodialysis.

Triferic is delivered to hemodialysis patients via dialysate, replacing the ongoing iron loss that occurs during their dialysis treatment. The drug is added to the bicarbonate concentrate on-site at the dialysis clinic.

Once in dialysate, Triferic crosses the dialyzer membrane and enters the blood, where it immediately binds to transferrin and is transported to the erythroid precursor cells to be incorporated into hemoglobin.

Triferic is designed to deliver sufficient iron to the bone marrow and maintain hemoglobin without increasing iron stores.

“We are pleased to obtain this FDA approval for the Triferic powder packet,” said Robert L. Chioini, founder, chairman, and chief executive officer of Rockwell Medical, Inc., makers of Triferic.

“The Triferic powder packet is similar to the size of a packet of sugar. It is much smaller and lighter than the current Triferic liquid ampule, and it enables us to place 3-times greater the number of units in an even smaller carton.”

“This presentation is much more convenient for customers, as it reduces storage space and requires fewer reorders to maintain inventory. We expect it to be commercially available shortly.”

Red blood cells

Image courtesy of NHLBI

The US Food and Drug Administration (FDA) has approved the use of a powder formulation of ferric pyrophosphate citrate (Triferic powder packet) to maintain hemoglobin in adult patients with hemodialysis-dependent chronic kidney disease.

The FDA previously approved ferric pyrophosphate citrate solution (Triferic) in ampule form. It is an iron-replacement drug intended to treat anemia in chronic kidney disease patients receiving hemodialysis.

Triferic is delivered to hemodialysis patients via dialysate, replacing the ongoing iron loss that occurs during their dialysis treatment. The drug is added to the bicarbonate concentrate on-site at the dialysis clinic.

Once in dialysate, Triferic crosses the dialyzer membrane and enters the blood, where it immediately binds to transferrin and is transported to the erythroid precursor cells to be incorporated into hemoglobin.

Triferic is designed to deliver sufficient iron to the bone marrow and maintain hemoglobin without increasing iron stores.

“We are pleased to obtain this FDA approval for the Triferic powder packet,” said Robert L. Chioini, founder, chairman, and chief executive officer of Rockwell Medical, Inc., makers of Triferic.

“The Triferic powder packet is similar to the size of a packet of sugar. It is much smaller and lighter than the current Triferic liquid ampule, and it enables us to place 3-times greater the number of units in an even smaller carton.”

“This presentation is much more convenient for customers, as it reduces storage space and requires fewer reorders to maintain inventory. We expect it to be commercially available shortly.”

Red blood cells

Image courtesy of NHLBI

The US Food and Drug Administration (FDA) has approved the use of a powder formulation of ferric pyrophosphate citrate (Triferic powder packet) to maintain hemoglobin in adult patients with hemodialysis-dependent chronic kidney disease.

The FDA previously approved ferric pyrophosphate citrate solution (Triferic) in ampule form. It is an iron-replacement drug intended to treat anemia in chronic kidney disease patients receiving hemodialysis.

Triferic is delivered to hemodialysis patients via dialysate, replacing the ongoing iron loss that occurs during their dialysis treatment. The drug is added to the bicarbonate concentrate on-site at the dialysis clinic.

Once in dialysate, Triferic crosses the dialyzer membrane and enters the blood, where it immediately binds to transferrin and is transported to the erythroid precursor cells to be incorporated into hemoglobin.

Triferic is designed to deliver sufficient iron to the bone marrow and maintain hemoglobin without increasing iron stores.

“We are pleased to obtain this FDA approval for the Triferic powder packet,” said Robert L. Chioini, founder, chairman, and chief executive officer of Rockwell Medical, Inc., makers of Triferic.

“The Triferic powder packet is similar to the size of a packet of sugar. It is much smaller and lighter than the current Triferic liquid ampule, and it enables us to place 3-times greater the number of units in an even smaller carton.”

“This presentation is much more convenient for customers, as it reduces storage space and requires fewer reorders to maintain inventory. We expect it to be commercially available shortly.”

miR-22

Image by Su Jung Song

The microRNA miR-22 is “an essential antitumor gatekeeper” in acute myeloid leukemia (AML), researchers have reported in Nature Communications.

The team found that miR-22 was significantly downregulated in  AML, and forced expression of miR-22 produced antileukemic effects in AML cells

and mouse models of the disease.

Futhermore, nanoparticles carrying miR-22 oligonucleotides appeared to cure AML in some mice.

“Previous research has shown that microRNA miR-22 is linked to breast cancer and other blood disorders [myelodysplastic syndromes], which sometimes turn into AML,” said study author Jianjun Chen, PhD, of the University of Cincinnati in Ohio.

“But we found in this study that it could be an essential antitumor gatekeeper in AML when it is downregulated. When we forced miR-22 expression, we saw difficulty in leukemia cells developing, growing, and thriving.”

Dr Chen and his colleagues first found that miR-22 was significantly downregulated (P<0.05) in samples from AML patients, when compared with normal CD34+ hematopoietic stem/progenitor cells, CD33+ myeloid progenitor cells, and mononuclear cells. The set of AML samples included MLL, t(15;17), t(8;21), and inv(16) AML.

When the researchers forced expression of miR-22 in human AML cells, they found the microRNA significantly inhibited cell viability, growth, and proliferation, while promoting apoptosis.

The team also investigated the role of miR-22 in colony formation induced by MLL-AF10/t(10;11), PML-RARA/t(15;17), and AML1-ETO9a/t(8;21). They found that forced expression of miR-22 significantly inhibited colony formation induced by all of these oncogenic fusion genes.

In mice, forced expression of miR-22 blocked MLL-AF9-mediated leukemogenesis and MLL-AF10-mediated leukemogenesis.

Forced expression of miR-22 also inhibited progression of AML induced by MLL-AF9, AE9a, or FLT3-ITD/NPM1c+ in secondary recipient mice. The researchers said this resulted in “largely normal” morphologies in the peripheral blood, bone marrow, spleen, and liver tissues of these mice.

In addition, the team found that nanoparticles carrying miR-22 oligonucleotides significantly delayed AML progression in secondary recipient mice with MLL-AF9 and AE9a-induced AML. At least 40% of the mice appeared to be completely cured.

In a xenotransplantation model, miR-22 nanoparticles significantly delayed AML progression induced by human MV4;11/t(4;11) cells.

Further investigation into the role miR-22 plays in AML revealed that 3 oncogenes—CRTC1, FLT3, and MYCBP—are “functionally important” targets of miR-22 in AML. And miR-22 represses the CREB and MYC signaling pathways.

The researchers also found DNA copy-number loss in the miR-22 gene locus in AML cases, and they discovered the expression of miR-22 is epigenetically repressed in AML.

“The downregulation, or decreased output, of miR-22 in AML is caused by the loss of the number of DNA being copied and/or stopping their expression through a pathway called TET1/GFI1/EZH2/SIN3A,” Dr Chen explained.

“Our study uncovers a previously unappreciated signaling pathway—TET1/GFI1/EZH2/SIN3A/miR-22/CREB-MYC—and provides new insights into genetic mechanisms causing and progressing AML and also highlights the clinical potential of miR-22-based AML therapy. More research on this pathway and ways to target it are necessary.”

miR-22

Image by Su Jung Song

The microRNA miR-22 is “an essential antitumor gatekeeper” in acute myeloid leukemia (AML), researchers have reported in Nature Communications.

The team found that miR-22 was significantly downregulated in  AML, and forced expression of miR-22 produced antileukemic effects in AML cells

and mouse models of the disease.

Futhermore, nanoparticles carrying miR-22 oligonucleotides appeared to cure AML in some mice.

“Previous research has shown that microRNA miR-22 is linked to breast cancer and other blood disorders [myelodysplastic syndromes], which sometimes turn into AML,” said study author Jianjun Chen, PhD, of the University of Cincinnati in Ohio.

“But we found in this study that it could be an essential antitumor gatekeeper in AML when it is downregulated. When we forced miR-22 expression, we saw difficulty in leukemia cells developing, growing, and thriving.”

Dr Chen and his colleagues first found that miR-22 was significantly downregulated (P<0.05) in samples from AML patients, when compared with normal CD34+ hematopoietic stem/progenitor cells, CD33+ myeloid progenitor cells, and mononuclear cells. The set of AML samples included MLL, t(15;17), t(8;21), and inv(16) AML.

When the researchers forced expression of miR-22 in human AML cells, they found the microRNA significantly inhibited cell viability, growth, and proliferation, while promoting apoptosis.

The team also investigated the role of miR-22 in colony formation induced by MLL-AF10/t(10;11), PML-RARA/t(15;17), and AML1-ETO9a/t(8;21). They found that forced expression of miR-22 significantly inhibited colony formation induced by all of these oncogenic fusion genes.

In mice, forced expression of miR-22 blocked MLL-AF9-mediated leukemogenesis and MLL-AF10-mediated leukemogenesis.

Forced expression of miR-22 also inhibited progression of AML induced by MLL-AF9, AE9a, or FLT3-ITD/NPM1c+ in secondary recipient mice. The researchers said this resulted in “largely normal” morphologies in the peripheral blood, bone marrow, spleen, and liver tissues of these mice.

In addition, the team found that nanoparticles carrying miR-22 oligonucleotides significantly delayed AML progression in secondary recipient mice with MLL-AF9 and AE9a-induced AML. At least 40% of the mice appeared to be completely cured.

In a xenotransplantation model, miR-22 nanoparticles significantly delayed AML progression induced by human MV4;11/t(4;11) cells.

Further investigation into the role miR-22 plays in AML revealed that 3 oncogenes—CRTC1, FLT3, and MYCBP—are “functionally important” targets of miR-22 in AML. And miR-22 represses the CREB and MYC signaling pathways.

The researchers also found DNA copy-number loss in the miR-22 gene locus in AML cases, and they discovered the expression of miR-22 is epigenetically repressed in AML.

“The downregulation, or decreased output, of miR-22 in AML is caused by the loss of the number of DNA being copied and/or stopping their expression through a pathway called TET1/GFI1/EZH2/SIN3A,” Dr Chen explained.

“Our study uncovers a previously unappreciated signaling pathway—TET1/GFI1/EZH2/SIN3A/miR-22/CREB-MYC—and provides new insights into genetic mechanisms causing and progressing AML and also highlights the clinical potential of miR-22-based AML therapy. More research on this pathway and ways to target it are necessary.”

miR-22

Image by Su Jung Song

The microRNA miR-22 is “an essential antitumor gatekeeper” in acute myeloid leukemia (AML), researchers have reported in Nature Communications.

The team found that miR-22 was significantly downregulated in  AML, and forced expression of miR-22 produced antileukemic effects in AML cells

and mouse models of the disease.

Futhermore, nanoparticles carrying miR-22 oligonucleotides appeared to cure AML in some mice.

“Previous research has shown that microRNA miR-22 is linked to breast cancer and other blood disorders [myelodysplastic syndromes], which sometimes turn into AML,” said study author Jianjun Chen, PhD, of the University of Cincinnati in Ohio.

“But we found in this study that it could be an essential antitumor gatekeeper in AML when it is downregulated. When we forced miR-22 expression, we saw difficulty in leukemia cells developing, growing, and thriving.”

Dr Chen and his colleagues first found that miR-22 was significantly downregulated (P<0.05) in samples from AML patients, when compared with normal CD34+ hematopoietic stem/progenitor cells, CD33+ myeloid progenitor cells, and mononuclear cells. The set of AML samples included MLL, t(15;17), t(8;21), and inv(16) AML.

When the researchers forced expression of miR-22 in human AML cells, they found the microRNA significantly inhibited cell viability, growth, and proliferation, while promoting apoptosis.

The team also investigated the role of miR-22 in colony formation induced by MLL-AF10/t(10;11), PML-RARA/t(15;17), and AML1-ETO9a/t(8;21). They found that forced expression of miR-22 significantly inhibited colony formation induced by all of these oncogenic fusion genes.

In mice, forced expression of miR-22 blocked MLL-AF9-mediated leukemogenesis and MLL-AF10-mediated leukemogenesis.

Forced expression of miR-22 also inhibited progression of AML induced by MLL-AF9, AE9a, or FLT3-ITD/NPM1c+ in secondary recipient mice. The researchers said this resulted in “largely normal” morphologies in the peripheral blood, bone marrow, spleen, and liver tissues of these mice.

In addition, the team found that nanoparticles carrying miR-22 oligonucleotides significantly delayed AML progression in secondary recipient mice with MLL-AF9 and AE9a-induced AML. At least 40% of the mice appeared to be completely cured.

In a xenotransplantation model, miR-22 nanoparticles significantly delayed AML progression induced by human MV4;11/t(4;11) cells.

Further investigation into the role miR-22 plays in AML revealed that 3 oncogenes—CRTC1, FLT3, and MYCBP—are “functionally important” targets of miR-22 in AML. And miR-22 represses the CREB and MYC signaling pathways.

The researchers also found DNA copy-number loss in the miR-22 gene locus in AML cases, and they discovered the expression of miR-22 is epigenetically repressed in AML.

“The downregulation, or decreased output, of miR-22 in AML is caused by the loss of the number of DNA being copied and/or stopping their expression through a pathway called TET1/GFI1/EZH2/SIN3A,” Dr Chen explained.

“Our study uncovers a previously unappreciated signaling pathway—TET1/GFI1/EZH2/SIN3A/miR-22/CREB-MYC—and provides new insights into genetic mechanisms causing and progressing AML and also highlights the clinical potential of miR-22-based AML therapy. More research on this pathway and ways to target it are necessary.”

Red blood cells

Researchers say they have used a rational design approach to create a safer variant of the drug erythropoietin (EPO).

This “targeted EPO” effectively stimulated red blood cell production in mice and had a minimal impact on platelets.

The team believes this approach could allow for the use of higher restorative doses of EPO without platelet-mediated side effects, and it might improve drug pharmacokinetics.

Devin Burrill, PhD, of the Wyss Institute for Biologically Inspired Engineering at Harvard University in Boston, Massachusetts, and his colleagues described the approach in PNAS.

The researchers noted that EPO has been widely used to treat anemia, but the drug also poses a risk of thrombotic complications. To combat this problem, the team set out to design a more effective, multi-part drug molecule.

“Compared to currently available EPO drugs, our molecule is engineered to prevent EPO from binding to and activating cells that promote side effects such as blood clotting or tumor growth,” said Jeffrey Way, PhD, also of the Wyss Institute.

“This cell-targeted EPO approach demonstrates a new theoretical basis for the rational design of engineered protein fusion drugs.”

To create their drug, the researchers first mutated EPO to reduce its ability to bind to EPO receptors.

Then, using a chain of amino acids as a flexible linker, they attached mutated EPO to an antibody fragment that specifically binds the human red blood cell marker glycophorin A (huGYPA). This antibody fragment binds to red blood cell precursors while avoiding other types of blood cells.

When the team’s fusion protein molecules were delivered to huGYPA transgenic mice, the antibody fragments piloted toward and bound to the membranes of red blood cell precursors, towing along EPO molecules on the other end of their linkers.

In such close proximity to the surface of the cells, a high concentration of tethered EPO bounced around until it ultimately toggled into place on the cells’ receptors. In this way, red blood cell production was increased with only minimal effects on platelets.

“Our rational design strategy is unique compared to current industry approaches,” Dr Burrill said. “Our goal is to use our method to advance predictive drug design and minimize the time between drug concept and commercialization.”

“The principles of synthetic biology influenced our efforts,” added James Collins, PhD, of the Wyss Institute.

“In drug development, the focus is typically on increasing the strength of interaction with a drug target, but, here, we found that weakening an interaction was useful. This illustrates how we need to adopt alternative, non-traditional approaches if we want to build complex, multi-part therapeutics.”

The researchers said this specific, cell-targeted approach could be applied quite broadly. In addition to “targeted EPO,” the team has developed “targeted interferon-alfa.”

Red blood cells

Researchers say they have used a rational design approach to create a safer variant of the drug erythropoietin (EPO).

This “targeted EPO” effectively stimulated red blood cell production in mice and had a minimal impact on platelets.

The team believes this approach could allow for the use of higher restorative doses of EPO without platelet-mediated side effects, and it might improve drug pharmacokinetics.

Devin Burrill, PhD, of the Wyss Institute for Biologically Inspired Engineering at Harvard University in Boston, Massachusetts, and his colleagues described the approach in PNAS.

The researchers noted that EPO has been widely used to treat anemia, but the drug also poses a risk of thrombotic complications. To combat this problem, the team set out to design a more effective, multi-part drug molecule.

“Compared to currently available EPO drugs, our molecule is engineered to prevent EPO from binding to and activating cells that promote side effects such as blood clotting or tumor growth,” said Jeffrey Way, PhD, also of the Wyss Institute.

“This cell-targeted EPO approach demonstrates a new theoretical basis for the rational design of engineered protein fusion drugs.”

To create their drug, the researchers first mutated EPO to reduce its ability to bind to EPO receptors.

Then, using a chain of amino acids as a flexible linker, they attached mutated EPO to an antibody fragment that specifically binds the human red blood cell marker glycophorin A (huGYPA). This antibody fragment binds to red blood cell precursors while avoiding other types of blood cells.

When the team’s fusion protein molecules were delivered to huGYPA transgenic mice, the antibody fragments piloted toward and bound to the membranes of red blood cell precursors, towing along EPO molecules on the other end of their linkers.

In such close proximity to the surface of the cells, a high concentration of tethered EPO bounced around until it ultimately toggled into place on the cells’ receptors. In this way, red blood cell production was increased with only minimal effects on platelets.

“Our rational design strategy is unique compared to current industry approaches,” Dr Burrill said. “Our goal is to use our method to advance predictive drug design and minimize the time between drug concept and commercialization.”

“The principles of synthetic biology influenced our efforts,” added James Collins, PhD, of the Wyss Institute.

“In drug development, the focus is typically on increasing the strength of interaction with a drug target, but, here, we found that weakening an interaction was useful. This illustrates how we need to adopt alternative, non-traditional approaches if we want to build complex, multi-part therapeutics.”

The researchers said this specific, cell-targeted approach could be applied quite broadly. In addition to “targeted EPO,” the team has developed “targeted interferon-alfa.”

Red blood cells

Researchers say they have used a rational design approach to create a safer variant of the drug erythropoietin (EPO).

This “targeted EPO” effectively stimulated red blood cell production in mice and had a minimal impact on platelets.

The team believes this approach could allow for the use of higher restorative doses of EPO without platelet-mediated side effects, and it might improve drug pharmacokinetics.

Devin Burrill, PhD, of the Wyss Institute for Biologically Inspired Engineering at Harvard University in Boston, Massachusetts, and his colleagues described the approach in PNAS.

The researchers noted that EPO has been widely used to treat anemia, but the drug also poses a risk of thrombotic complications. To combat this problem, the team set out to design a more effective, multi-part drug molecule.

“Compared to currently available EPO drugs, our molecule is engineered to prevent EPO from binding to and activating cells that promote side effects such as blood clotting or tumor growth,” said Jeffrey Way, PhD, also of the Wyss Institute.

“This cell-targeted EPO approach demonstrates a new theoretical basis for the rational design of engineered protein fusion drugs.”

To create their drug, the researchers first mutated EPO to reduce its ability to bind to EPO receptors.

Then, using a chain of amino acids as a flexible linker, they attached mutated EPO to an antibody fragment that specifically binds the human red blood cell marker glycophorin A (huGYPA). This antibody fragment binds to red blood cell precursors while avoiding other types of blood cells.

When the team’s fusion protein molecules were delivered to huGYPA transgenic mice, the antibody fragments piloted toward and bound to the membranes of red blood cell precursors, towing along EPO molecules on the other end of their linkers.

In such close proximity to the surface of the cells, a high concentration of tethered EPO bounced around until it ultimately toggled into place on the cells’ receptors. In this way, red blood cell production was increased with only minimal effects on platelets.

“Our rational design strategy is unique compared to current industry approaches,” Dr Burrill said. “Our goal is to use our method to advance predictive drug design and minimize the time between drug concept and commercialization.”

“The principles of synthetic biology influenced our efforts,” added James Collins, PhD, of the Wyss Institute.

“In drug development, the focus is typically on increasing the strength of interaction with a drug target, but, here, we found that weakening an interaction was useful. This illustrates how we need to adopt alternative, non-traditional approaches if we want to build complex, multi-part therapeutics.”

The researchers said this specific, cell-targeted approach could be applied quite broadly. In addition to “targeted EPO,” the team has developed “targeted interferon-alfa.”

Pregnant woman

Photo by Nina Matthews

New research suggests a mother’s birthplace may affect the risk of certain cancers for Hispanic children.

The study showed that children of Hispanic mothers who were not born in the US had lower risks of brain cancers, neuroblastoma, and Wilms tumor, when compared to children of US-born Hispanic mothers and non-Hispanic white mothers born in the US.

However, all Hispanic children, regardless of where their mothers were born, had higher risks of acute leukemias and Hodgkin lymphoma but a lower risk of non-Hodgkin lymphoma (NHL).

Julia E. Heck, PhD, of the University of California, Los Angeles, and her colleagues reported these findings in JAMA Pediatrics.

The researchers used California birth records to identify children born from 1983 through 2011. Information on cancer cases came from California Cancer Registry records from 1988 to 2012.

The team restricted their analysis to children of US-born white, US-born Hispanic, and non-US-born Hispanic mothers. The study included 13,666 cases of children diagnosed with cancer before the age of 6 and 15,513,718 children who served as control subjects.

To assess the hazard ratios (HRs) for various cancers, the researchers used children of non-Hispanic white mothers as a reference (HR=1.00) and compared them to the children of non-US-born Hispanic mothers and US-born Hispanic mothers.

For children of non-US-born Hispanic mothers, the HR was 0.50 for glioma, 0.43 for astrocytoma, 0.47 for neuroblastoma, and 0.70 for Wilms tumor. For children of US-born Hispanic mothers, the HR was 0.71 for glioma, 0.62 for astrocytoma, 0.66 for neuroblastoma, and 0.88 for Wilms tumor.

When compared to non-Hispanic white children, Hispanic children had an increased risk of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and Hodgkin lymphoma but lower risks of NHL and Burkitt lymphoma.

For children of US-born Hispanic mothers, the HR was 1.20 for ALL, 1.28 for AML, 2.49 for Hodgkin lymphoma, 0.79 for NHL, and 0.69 for Burkitt lymphoma.

For children of non-US-born Hispanic mothers, the HR was 1.06 for ALL, 1.05 for AML, 2.35 for Hodgkin lymphoma, 0.76 for NHL, and 0.73 for Burkitt lymphoma.

The researchers said the differences observed between children of US-born and non-US-born Hispanic mothers may be explained by lifestyle differences and varying environmental exposures.

These factors may explain the differences in cancer incidence between Hispanic children and white children as well, but the differences may also be a result of genetic variation and infection exposures early in life.

Pregnant woman

Photo by Nina Matthews

New research suggests a mother’s birthplace may affect the risk of certain cancers for Hispanic children.

The study showed that children of Hispanic mothers who were not born in the US had lower risks of brain cancers, neuroblastoma, and Wilms tumor, when compared to children of US-born Hispanic mothers and non-Hispanic white mothers born in the US.

However, all Hispanic children, regardless of where their mothers were born, had higher risks of acute leukemias and Hodgkin lymphoma but a lower risk of non-Hodgkin lymphoma (NHL).

Julia E. Heck, PhD, of the University of California, Los Angeles, and her colleagues reported these findings in JAMA Pediatrics.

The researchers used California birth records to identify children born from 1983 through 2011. Information on cancer cases came from California Cancer Registry records from 1988 to 2012.

The team restricted their analysis to children of US-born white, US-born Hispanic, and non-US-born Hispanic mothers. The study included 13,666 cases of children diagnosed with cancer before the age of 6 and 15,513,718 children who served as control subjects.

To assess the hazard ratios (HRs) for various cancers, the researchers used children of non-Hispanic white mothers as a reference (HR=1.00) and compared them to the children of non-US-born Hispanic mothers and US-born Hispanic mothers.

For children of non-US-born Hispanic mothers, the HR was 0.50 for glioma, 0.43 for astrocytoma, 0.47 for neuroblastoma, and 0.70 for Wilms tumor. For children of US-born Hispanic mothers, the HR was 0.71 for glioma, 0.62 for astrocytoma, 0.66 for neuroblastoma, and 0.88 for Wilms tumor.

When compared to non-Hispanic white children, Hispanic children had an increased risk of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and Hodgkin lymphoma but lower risks of NHL and Burkitt lymphoma.

For children of US-born Hispanic mothers, the HR was 1.20 for ALL, 1.28 for AML, 2.49 for Hodgkin lymphoma, 0.79 for NHL, and 0.69 for Burkitt lymphoma.

For children of non-US-born Hispanic mothers, the HR was 1.06 for ALL, 1.05 for AML, 2.35 for Hodgkin lymphoma, 0.76 for NHL, and 0.73 for Burkitt lymphoma.

The researchers said the differences observed between children of US-born and non-US-born Hispanic mothers may be explained by lifestyle differences and varying environmental exposures.

These factors may explain the differences in cancer incidence between Hispanic children and white children as well, but the differences may also be a result of genetic variation and infection exposures early in life.

Pregnant woman

Photo by Nina Matthews

New research suggests a mother’s birthplace may affect the risk of certain cancers for Hispanic children.

The study showed that children of Hispanic mothers who were not born in the US had lower risks of brain cancers, neuroblastoma, and Wilms tumor, when compared to children of US-born Hispanic mothers and non-Hispanic white mothers born in the US.

However, all Hispanic children, regardless of where their mothers were born, had higher risks of acute leukemias and Hodgkin lymphoma but a lower risk of non-Hodgkin lymphoma (NHL).

Julia E. Heck, PhD, of the University of California, Los Angeles, and her colleagues reported these findings in JAMA Pediatrics.

The researchers used California birth records to identify children born from 1983 through 2011. Information on cancer cases came from California Cancer Registry records from 1988 to 2012.

The team restricted their analysis to children of US-born white, US-born Hispanic, and non-US-born Hispanic mothers. The study included 13,666 cases of children diagnosed with cancer before the age of 6 and 15,513,718 children who served as control subjects.

To assess the hazard ratios (HRs) for various cancers, the researchers used children of non-Hispanic white mothers as a reference (HR=1.00) and compared them to the children of non-US-born Hispanic mothers and US-born Hispanic mothers.

For children of non-US-born Hispanic mothers, the HR was 0.50 for glioma, 0.43 for astrocytoma, 0.47 for neuroblastoma, and 0.70 for Wilms tumor. For children of US-born Hispanic mothers, the HR was 0.71 for glioma, 0.62 for astrocytoma, 0.66 for neuroblastoma, and 0.88 for Wilms tumor.

When compared to non-Hispanic white children, Hispanic children had an increased risk of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and Hodgkin lymphoma but lower risks of NHL and Burkitt lymphoma.

For children of US-born Hispanic mothers, the HR was 1.20 for ALL, 1.28 for AML, 2.49 for Hodgkin lymphoma, 0.79 for NHL, and 0.69 for Burkitt lymphoma.

For children of non-US-born Hispanic mothers, the HR was 1.06 for ALL, 1.05 for AML, 2.35 for Hodgkin lymphoma, 0.76 for NHL, and 0.73 for Burkitt lymphoma.

The researchers said the differences observed between children of US-born and non-US-born Hispanic mothers may be explained by lifestyle differences and varying environmental exposures.

These factors may explain the differences in cancer incidence between Hispanic children and white children as well, but the differences may also be a result of genetic variation and infection exposures early in life.

ALL patient

Photo by Bill Branson

High-dose methotrexate (MTX) is more effective than escalating doses of MTX for young patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL), according to a study published in the Journal of Clinical Oncology.

Patients who received high-dose MTX during interim maintenance 1 had significantly better event-free survival (EFS) than those who received escalating MTX.

In addition, the study showed that substituting dexamethasone for prednisone during induction was beneficial for younger—but not older—patients.

The high-dose MTX protocol outlined in this study, and the use of dexamethasone in younger patients, has become the standard practice for the treatment of high-risk ALL patients in North America.

Prior to the release of the initial study results, which were first presented last year at the ASCO Annual Meeting, the standard of care for high-risk ALL patients in North America was escalating MTX.

“One of the improvements in outcome for ALL overall has been using methotrexate in a more intense fashion, by giving higher doses,” said study investigator William L. Carroll, MD, of NYU Langone Medical Center in New York, New York.

“We designed this study to compare high-dose and escalating methotrexate to determine the best way to use this drug to increase the survival of high-risk ALL patients.”

Treatment

Between January 2004 and January 2011, Dr Carroll and his colleagues enrolled 3154 patients, ages 1 to 30, with newly diagnosed, high-risk B-ALL. After exclusions, 2914 patients were randomized to treatment.

Using a 2 × 2 factorial design, the patients were randomized to receive dexamethasone for 14 days or prednisone for 28 days during induction and high-dose MTX or Capizzi escalating-dose MTX plus pegaspargase during interim maintenance 1.

So the treatment groups were as follows:

• Prednisone and escalating MTX (n=926)
• Prednisone and high-dose MTX (n=926)
• Dexamethasone and escalating MTX (n=535)
• Dexamethasone and high-dose MTX (n=527).

MTX results

At the planned interim analysis, the 5-year EFS was 82% among patients who received high-dose MTX and 75.4% among those who received escalating MTX (P=0.006).

The final data showed 5-year EFS rates of 79.6% and 75.2%, respectively (P=0.008) and 5-year overall survival rates of 88.9% and 86.1%, respectively (P=0.025).

There was a higher rate of febrile neutropenia during interim maintenance 1 among patients who received escalating MTX than among those who received high-dose MTX—8.3% and 5.1%, respectively (P=0.003).

There were 5 cases of ischemic cerebrovascular toxicity among patients who received high-dose MTX and none among the patients who received escalating MTX (P=0.03).

But there were no other significant differences in adverse events between the high-dose and escalating-dose MTX groups.

Corticosteroid results

Patients age 10 and older saw no benefit from dexamethasone, and, in fact, were at much higher risk of developing osteonecrosis. Because of this risk, the corticosteroid induction arm of this study was closed early, in 2008.

However, the investigators found that patients younger than age 10 did benefit from dexamethasone exposure.

Specifically, patients under 10 who received dexamethasone and high-dose MTX had significantly better EFS than patients who received the other 3 treatment regimens.

The 5-year EFS rate was 91.2% in the dexamethasone and high-dose MTX arm, 83.2% in the dexamethasone and escalating MTX arm, 80.8% in the prednisone and high-dose MTX arm, and 82.1% in the prednisone and escalating MTX arm (P=0.015).

For patients of all ages, there was a higher rate of febrile neutropenia during induction among patients who received dexamethasone than among those who received prednisone—18.2% and 11.0%, respectively (P<0.001).

Patients who received dexamethasone also had a higher rate of infections/infestations—29.4% and 20.3%, respectively (P<0.001).

However, there was no significant difference in induction death rate—1.9% and 1.8%, respectively (P=0.87). The same was true when the investigators looked only at patients younger than 10 (P=0.71) or at patients 10 and older (P=0.69).

Among patients ages 10 and older who participated in the induction corticosteroid randomization before it was closed, the 5-year cumulative incidence of osteonecrosis was 24.3% for patients who received dexamethasone and 15.9% for those who received prednisone (P=0.001).

There were no other significant differences in adverse events between the 2 corticosteroid regimens.

ALL patient

Photo by Bill Branson

High-dose methotrexate (MTX) is more effective than escalating doses of MTX for young patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL), according to a study published in the Journal of Clinical Oncology.

Patients who received high-dose MTX during interim maintenance 1 had significantly better event-free survival (EFS) than those who received escalating MTX.

In addition, the study showed that substituting dexamethasone for prednisone during induction was beneficial for younger—but not older—patients.

The high-dose MTX protocol outlined in this study, and the use of dexamethasone in younger patients, has become the standard practice for the treatment of high-risk ALL patients in North America.

Prior to the release of the initial study results, which were first presented last year at the ASCO Annual Meeting, the standard of care for high-risk ALL patients in North America was escalating MTX.

“One of the improvements in outcome for ALL overall has been using methotrexate in a more intense fashion, by giving higher doses,” said study investigator William L. Carroll, MD, of NYU Langone Medical Center in New York, New York.

“We designed this study to compare high-dose and escalating methotrexate to determine the best way to use this drug to increase the survival of high-risk ALL patients.”

Treatment

Between January 2004 and January 2011, Dr Carroll and his colleagues enrolled 3154 patients, ages 1 to 30, with newly diagnosed, high-risk B-ALL. After exclusions, 2914 patients were randomized to treatment.

Using a 2 × 2 factorial design, the patients were randomized to receive dexamethasone for 14 days or prednisone for 28 days during induction and high-dose MTX or Capizzi escalating-dose MTX plus pegaspargase during interim maintenance 1.

So the treatment groups were as follows:

• Prednisone and escalating MTX (n=926)
• Prednisone and high-dose MTX (n=926)
• Dexamethasone and escalating MTX (n=535)
• Dexamethasone and high-dose MTX (n=527).

MTX results

At the planned interim analysis, the 5-year EFS was 82% among patients who received high-dose MTX and 75.4% among those who received escalating MTX (P=0.006).

The final data showed 5-year EFS rates of 79.6% and 75.2%, respectively (P=0.008) and 5-year overall survival rates of 88.9% and 86.1%, respectively (P=0.025).

There was a higher rate of febrile neutropenia during interim maintenance 1 among patients who received escalating MTX than among those who received high-dose MTX—8.3% and 5.1%, respectively (P=0.003).

There were 5 cases of ischemic cerebrovascular toxicity among patients who received high-dose MTX and none among the patients who received escalating MTX (P=0.03).

But there were no other significant differences in adverse events between the high-dose and escalating-dose MTX groups.

Corticosteroid results

Patients age 10 and older saw no benefit from dexamethasone, and, in fact, were at much higher risk of developing osteonecrosis. Because of this risk, the corticosteroid induction arm of this study was closed early, in 2008.

However, the investigators found that patients younger than age 10 did benefit from dexamethasone exposure.

Specifically, patients under 10 who received dexamethasone and high-dose MTX had significantly better EFS than patients who received the other 3 treatment regimens.

The 5-year EFS rate was 91.2% in the dexamethasone and high-dose MTX arm, 83.2% in the dexamethasone and escalating MTX arm, 80.8% in the prednisone and high-dose MTX arm, and 82.1% in the prednisone and escalating MTX arm (P=0.015).

For patients of all ages, there was a higher rate of febrile neutropenia during induction among patients who received dexamethasone than among those who received prednisone—18.2% and 11.0%, respectively (P<0.001).

Patients who received dexamethasone also had a higher rate of infections/infestations—29.4% and 20.3%, respectively (P<0.001).

However, there was no significant difference in induction death rate—1.9% and 1.8%, respectively (P=0.87). The same was true when the investigators looked only at patients younger than 10 (P=0.71) or at patients 10 and older (P=0.69).

Among patients ages 10 and older who participated in the induction corticosteroid randomization before it was closed, the 5-year cumulative incidence of osteonecrosis was 24.3% for patients who received dexamethasone and 15.9% for those who received prednisone (P=0.001).

There were no other significant differences in adverse events between the 2 corticosteroid regimens.

ALL patient

Photo by Bill Branson

High-dose methotrexate (MTX) is more effective than escalating doses of MTX for young patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL), according to a study published in the Journal of Clinical Oncology.

Patients who received high-dose MTX during interim maintenance 1 had significantly better event-free survival (EFS) than those who received escalating MTX.

In addition, the study showed that substituting dexamethasone for prednisone during induction was beneficial for younger—but not older—patients.

The high-dose MTX protocol outlined in this study, and the use of dexamethasone in younger patients, has become the standard practice for the treatment of high-risk ALL patients in North America.

Prior to the release of the initial study results, which were first presented last year at the ASCO Annual Meeting, the standard of care for high-risk ALL patients in North America was escalating MTX.

“One of the improvements in outcome for ALL overall has been using methotrexate in a more intense fashion, by giving higher doses,” said study investigator William L. Carroll, MD, of NYU Langone Medical Center in New York, New York.

“We designed this study to compare high-dose and escalating methotrexate to determine the best way to use this drug to increase the survival of high-risk ALL patients.”

Treatment

Between January 2004 and January 2011, Dr Carroll and his colleagues enrolled 3154 patients, ages 1 to 30, with newly diagnosed, high-risk B-ALL. After exclusions, 2914 patients were randomized to treatment.

Using a 2 × 2 factorial design, the patients were randomized to receive dexamethasone for 14 days or prednisone for 28 days during induction and high-dose MTX or Capizzi escalating-dose MTX plus pegaspargase during interim maintenance 1.

So the treatment groups were as follows:

• Prednisone and escalating MTX (n=926)
• Prednisone and high-dose MTX (n=926)
• Dexamethasone and escalating MTX (n=535)
• Dexamethasone and high-dose MTX (n=527).

MTX results

At the planned interim analysis, the 5-year EFS was 82% among patients who received high-dose MTX and 75.4% among those who received escalating MTX (P=0.006).

The final data showed 5-year EFS rates of 79.6% and 75.2%, respectively (P=0.008) and 5-year overall survival rates of 88.9% and 86.1%, respectively (P=0.025).

There was a higher rate of febrile neutropenia during interim maintenance 1 among patients who received escalating MTX than among those who received high-dose MTX—8.3% and 5.1%, respectively (P=0.003).

There were 5 cases of ischemic cerebrovascular toxicity among patients who received high-dose MTX and none among the patients who received escalating MTX (P=0.03).

But there were no other significant differences in adverse events between the high-dose and escalating-dose MTX groups.

Corticosteroid results

Patients age 10 and older saw no benefit from dexamethasone, and, in fact, were at much higher risk of developing osteonecrosis. Because of this risk, the corticosteroid induction arm of this study was closed early, in 2008.

However, the investigators found that patients younger than age 10 did benefit from dexamethasone exposure.

Specifically, patients under 10 who received dexamethasone and high-dose MTX had significantly better EFS than patients who received the other 3 treatment regimens.

The 5-year EFS rate was 91.2% in the dexamethasone and high-dose MTX arm, 83.2% in the dexamethasone and escalating MTX arm, 80.8% in the prednisone and high-dose MTX arm, and 82.1% in the prednisone and escalating MTX arm (P=0.015).

For patients of all ages, there was a higher rate of febrile neutropenia during induction among patients who received dexamethasone than among those who received prednisone—18.2% and 11.0%, respectively (P<0.001).

Patients who received dexamethasone also had a higher rate of infections/infestations—29.4% and 20.3%, respectively (P<0.001).

However, there was no significant difference in induction death rate—1.9% and 1.8%, respectively (P=0.87). The same was true when the investigators looked only at patients younger than 10 (P=0.71) or at patients 10 and older (P=0.69).

Among patients ages 10 and older who participated in the induction corticosteroid randomization before it was closed, the 5-year cumulative incidence of osteonecrosis was 24.3% for patients who received dexamethasone and 15.9% for those who received prednisone (P=0.001).

There were no other significant differences in adverse events between the 2 corticosteroid regimens.