Transplantation

The US Food and Drug Administration (FDA) has approved the leukocyte growth factor Zarxio (filgrastim-sndz), the first biosimilar product to be approved in the US.

A biosimilar product is approved based on data showing that it is highly similar to an already-approved biological product.

Sandoz Inc’s Zarxio is biosimilar to Amgen Inc’s Neupogen (filgrastim), which was originally licensed in 1991. Zarxio is now approved for the same indications as Neupogen.

Zarxio can be prescribed for:

• patients with cancer receiving myelosuppressive chemotherapy
• patients with acute myeloid leukemia receiving induction or consolidation chemotherapy
• patients with cancer undergoing bone marrow transplant
• patients undergoing autologous peripheral blood progenitor cell collection and therapy
• patients with severe chronic neutropenia.

Zarxio is marketed as Zarzio outside the US. The biosimilar is available in more than 60 countries worldwide.

“Biosimilars will provide access to important therapies for patients who need them,” said FDA Commissioner Margaret A. Hamburg, MD.

“Patients and the healthcare community can be confident that biosimilar products approved by the FDA meet the agency’s rigorous safety, efficacy, and quality standards.”

Zarxio data

The FDA’s approval of Zarxio is based on a review of evidence that included structural and functional characterization, in vivo data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrates Zarxio is biosimilar to Neupogen.

The PIONEER study was the final piece of data the FDA used to approve Zarxio as biosimilar to Neupogen. The data was sufficient to allow extrapolation of the use of Zarxio to all indications of Neupogen.

In the PIONEER study, Zarxio and Neupogen both produced the expected reduction in the duration of severe neutropenia in cancer patients undergoing myelosuppressive chemotherapy—1.17 and 1.20 days, respectively.

The mean time to absolute neutrophil count recovery in cycle 1 was also similar—1.8 ± 0.97 days in the Zarxio arm and 1.7 ± 0.81 days in the Neupogen arm. No immunogenicity or antibodies against rhG-CSF were detected throughout the study.

The most common side effects of Zarxio are aching in the bones or muscles and redness, swelling, or itching at the injection site. Serious side effects may include spleen rupture; serious allergic reactions that may cause rash, shortness of breath, wheezing and/or swelling around the mouth and eyes; fast pulse and sweating; and acute respiratory distress syndrome.

About biosimilar approval

The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was passed as part of the Affordable Care Act that President Barack Obama signed into law in March 2010. The BPCI Act created an abbreviated licensure pathway for biological products shown to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product, known as the reference product.

This abbreviated licensure pathway under section 351(k) of the Public Health Service Act permits reliance on certain existing scientific knowledge about the safety and effectiveness of the reference product, and it enables a biosimilar biological product to be licensed based on less than a full complement of product-specific preclinical and clinical data.

A biosimilar product can only be approved by the FDA if it has the same mechanism(s) of action, route(s) of administration, dosage form(s) and strength(s) as the reference product, and only for the indication(s) and condition(s) of use that have been approved for the reference product. The facilities where biosimilars are manufactured must also meet the FDA’s standards.

There must be no clinically meaningful differences between the biosimilar and the reference product in terms of safety and effectiveness. Only minor differences in clinically inactive components are allowable.

Zarxio has been approved as a biosimilar, not an interchangeable product. Under the BPCI Act, a biological product that has been approved as “interchangeable” may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product.

For Zarxio’s approval, the FDA has designated a placeholder nonproprietary name for this product as “filgrastim-sndz.” The provision of a placeholder nonproprietary name should not be viewed as reflective of the agency’s decision on a comprehensive naming policy for biosimilars and other biological products.

While the FDA has not yet issued draft guidance on how current and future biological products marketed in the US should be named, the agency intends to do so in the near future.

For more details on Zarxio, see the full prescribing information.

The US Food and Drug Administration (FDA) has approved the leukocyte growth factor Zarxio (filgrastim-sndz), the first biosimilar product to be approved in the US.

A biosimilar product is approved based on data showing that it is highly similar to an already-approved biological product.

Sandoz Inc’s Zarxio is biosimilar to Amgen Inc’s Neupogen (filgrastim), which was originally licensed in 1991. Zarxio is now approved for the same indications as Neupogen.

Zarxio can be prescribed for:

• patients with cancer receiving myelosuppressive chemotherapy
• patients with acute myeloid leukemia receiving induction or consolidation chemotherapy
• patients with cancer undergoing bone marrow transplant
• patients undergoing autologous peripheral blood progenitor cell collection and therapy
• patients with severe chronic neutropenia.

Zarxio is marketed as Zarzio outside the US. The biosimilar is available in more than 60 countries worldwide.

“Biosimilars will provide access to important therapies for patients who need them,” said FDA Commissioner Margaret A. Hamburg, MD.

“Patients and the healthcare community can be confident that biosimilar products approved by the FDA meet the agency’s rigorous safety, efficacy, and quality standards.”

Zarxio data

The FDA’s approval of Zarxio is based on a review of evidence that included structural and functional characterization, in vivo data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrates Zarxio is biosimilar to Neupogen.

The PIONEER study was the final piece of data the FDA used to approve Zarxio as biosimilar to Neupogen. The data was sufficient to allow extrapolation of the use of Zarxio to all indications of Neupogen.

In the PIONEER study, Zarxio and Neupogen both produced the expected reduction in the duration of severe neutropenia in cancer patients undergoing myelosuppressive chemotherapy—1.17 and 1.20 days, respectively.

The mean time to absolute neutrophil count recovery in cycle 1 was also similar—1.8 ± 0.97 days in the Zarxio arm and 1.7 ± 0.81 days in the Neupogen arm. No immunogenicity or antibodies against rhG-CSF were detected throughout the study.

The most common side effects of Zarxio are aching in the bones or muscles and redness, swelling, or itching at the injection site. Serious side effects may include spleen rupture; serious allergic reactions that may cause rash, shortness of breath, wheezing and/or swelling around the mouth and eyes; fast pulse and sweating; and acute respiratory distress syndrome.

About biosimilar approval

The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was passed as part of the Affordable Care Act that President Barack Obama signed into law in March 2010. The BPCI Act created an abbreviated licensure pathway for biological products shown to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product, known as the reference product.

This abbreviated licensure pathway under section 351(k) of the Public Health Service Act permits reliance on certain existing scientific knowledge about the safety and effectiveness of the reference product, and it enables a biosimilar biological product to be licensed based on less than a full complement of product-specific preclinical and clinical data.

A biosimilar product can only be approved by the FDA if it has the same mechanism(s) of action, route(s) of administration, dosage form(s) and strength(s) as the reference product, and only for the indication(s) and condition(s) of use that have been approved for the reference product. The facilities where biosimilars are manufactured must also meet the FDA’s standards.

There must be no clinically meaningful differences between the biosimilar and the reference product in terms of safety and effectiveness. Only minor differences in clinically inactive components are allowable.

Zarxio has been approved as a biosimilar, not an interchangeable product. Under the BPCI Act, a biological product that has been approved as “interchangeable” may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product.

For Zarxio’s approval, the FDA has designated a placeholder nonproprietary name for this product as “filgrastim-sndz.” The provision of a placeholder nonproprietary name should not be viewed as reflective of the agency’s decision on a comprehensive naming policy for biosimilars and other biological products.

While the FDA has not yet issued draft guidance on how current and future biological products marketed in the US should be named, the agency intends to do so in the near future.

For more details on Zarxio, see the full prescribing information.

The US Food and Drug Administration (FDA) has approved the leukocyte growth factor Zarxio (filgrastim-sndz), the first biosimilar product to be approved in the US.

A biosimilar product is approved based on data showing that it is highly similar to an already-approved biological product.

Sandoz Inc’s Zarxio is biosimilar to Amgen Inc’s Neupogen (filgrastim), which was originally licensed in 1991. Zarxio is now approved for the same indications as Neupogen.

Zarxio can be prescribed for:

• patients with cancer receiving myelosuppressive chemotherapy
• patients with acute myeloid leukemia receiving induction or consolidation chemotherapy
• patients with cancer undergoing bone marrow transplant
• patients undergoing autologous peripheral blood progenitor cell collection and therapy
• patients with severe chronic neutropenia.

Zarxio is marketed as Zarzio outside the US. The biosimilar is available in more than 60 countries worldwide.

“Biosimilars will provide access to important therapies for patients who need them,” said FDA Commissioner Margaret A. Hamburg, MD.

“Patients and the healthcare community can be confident that biosimilar products approved by the FDA meet the agency’s rigorous safety, efficacy, and quality standards.”

Zarxio data

The FDA’s approval of Zarxio is based on a review of evidence that included structural and functional characterization, in vivo data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrates Zarxio is biosimilar to Neupogen.

The PIONEER study was the final piece of data the FDA used to approve Zarxio as biosimilar to Neupogen. The data was sufficient to allow extrapolation of the use of Zarxio to all indications of Neupogen.

In the PIONEER study, Zarxio and Neupogen both produced the expected reduction in the duration of severe neutropenia in cancer patients undergoing myelosuppressive chemotherapy—1.17 and 1.20 days, respectively.

The mean time to absolute neutrophil count recovery in cycle 1 was also similar—1.8 ± 0.97 days in the Zarxio arm and 1.7 ± 0.81 days in the Neupogen arm. No immunogenicity or antibodies against rhG-CSF were detected throughout the study.

The most common side effects of Zarxio are aching in the bones or muscles and redness, swelling, or itching at the injection site. Serious side effects may include spleen rupture; serious allergic reactions that may cause rash, shortness of breath, wheezing and/or swelling around the mouth and eyes; fast pulse and sweating; and acute respiratory distress syndrome.

About biosimilar approval

The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was passed as part of the Affordable Care Act that President Barack Obama signed into law in March 2010. The BPCI Act created an abbreviated licensure pathway for biological products shown to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product, known as the reference product.

This abbreviated licensure pathway under section 351(k) of the Public Health Service Act permits reliance on certain existing scientific knowledge about the safety and effectiveness of the reference product, and it enables a biosimilar biological product to be licensed based on less than a full complement of product-specific preclinical and clinical data.

A biosimilar product can only be approved by the FDA if it has the same mechanism(s) of action, route(s) of administration, dosage form(s) and strength(s) as the reference product, and only for the indication(s) and condition(s) of use that have been approved for the reference product. The facilities where biosimilars are manufactured must also meet the FDA’s standards.

There must be no clinically meaningful differences between the biosimilar and the reference product in terms of safety and effectiveness. Only minor differences in clinically inactive components are allowable.

Zarxio has been approved as a biosimilar, not an interchangeable product. Under the BPCI Act, a biological product that has been approved as “interchangeable” may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product.

For Zarxio’s approval, the FDA has designated a placeholder nonproprietary name for this product as “filgrastim-sndz.” The provision of a placeholder nonproprietary name should not be viewed as reflective of the agency’s decision on a comprehensive naming policy for biosimilars and other biological products.

While the FDA has not yet issued draft guidance on how current and future biological products marketed in the US should be named, the agency intends to do so in the near future.

For more details on Zarxio, see the full prescribing information.

Saad S. Kenderian

Photo courtesy of

BMT Tandem Meetings

SAN DIEGO—Researchers have developed a “biodegradable” chimeric antigen receptor (CAR) T-cell therapy that could potentially serve as a preparative regimen for acute myeloid leukemia (AML) patients undergoing allogeneic transplant.

The team created CAR T cells that target CD33 (CART33) and modified them with RNA so the cells would stop expressing CARs over time.

In mouse models of AML, the RNA-CART33 cells had an antileukemic effect and induced myeloablation.

The cells also stopped expressing CARs by the 2-week mark, which would allow for engraftment after allogeneic transplant, according to the researchers.

Saad S. Kenderian, MD, of the University of Pennsylvania in Philadelphia, presented this research at the 2015 BMT Tandem Meetings as one of the meeting’s “Best Abstracts” (abstract 1). The research was funded by Novartis.

“Allogeneic transplantation is the only potentially curative option in relapsed/refractory AML,” Dr Kenderian noted. “Outcomes are poor if patients are transplanted in residual disease  . . . , and these patients are often considered transplant-ineligible. Therefore, novel therapies are desperately needed.”

With this in mind, Dr Kenderian and his colleagues set out to develop a CAR T-cell therapy targeting CD33, which is expressed on AML blasts.

The researchers created a CAR from the anti-CD33 single-chain fragment variable of gemtuzumab ozogamicin, 41BB costimulation, CD3ζ signaling domain, and a lentiviral (LV) vector. They transduced T cells with this construct and expanded them in culture using anti-CD3/CD28 magnetic beads.

The team then tested these CART33 cells in NSGS mice engrafted with primary AML blasts. The mice received CART33 cells, another CAR T-cell therapy known as CART123, or control T cells.

At 4 weeks, mice that had received CART33 or CART123 cells were entirely leukemia-free, but the disease continued to progress in mice that received control T cells.

Likewise, when the experiment ended at 200 days, survival was 100% among mice that received CART33 or CART123, but all of the control mice had died. And at 200 days, CAR T cells were still circulating in the CART33- and CART123-treated mice.

Next, the researchers administered CART33 cells to HIS-NSG mice engrafted with human bone marrow and found the treatment resulted in myeloablation. There was a significant reduction of CD34-positive cells in mice that received CART33 compared to mice that received control T cells or no treatment.

“So based on our preclinical data, when we treat refractory AML with lentivirally transduced CART33, that will result in myeloablation, eradication of AML, and persistence of these CARs,” Dr Kenderian said.

“If allogeneic transplantation is performed at this aplastic stage, it will likely lead to rejection of the graft by persisting CAR therapy, which also means that elimination of CARs is necessary prior to stem cell infusion.”

So the researchers decided to create a transiently expressed, mRNA-modified CAR based on CART33. They electroporated T cells with this construct, and the cells expressed CARs for up to 6 days.

In experiments with the MOLM14 cell line, RNA-modified CART33 cells exhibited transient but comparable killing ability as LV-transduced CART33.

The researchers then tested RNA-CART33 in combination with chemotherapy in vivo. They transplanted NSG mice with MOLM14 and treated them with cyclophosphamide plus RNA-CART33 or cyclophosphamide plus control T cells.

Combination RNA-CART33 and chemotherapy prompted stronger, more durable antileukemic activity than cyclophosphamide and control T cells. Furthermore, there was a significant improvement in survival among RNA-CART33-treated mice (P=0.01).

Finally, Dr Kenderian and his colleagues tested the effect of RNA-CART33 on hematopoiesis. The team treated NSGS mice with busulfan and transplanted them with T-cell-depleted bone marrow. Following engraftment, mice received RNA-CART33 cells, LV-CART33 cells, or control T cells.

The researchers followed the mice for 2 weeks and found that both RNA-CART33 and LV-CART33 induced myeloablation. And at 14 days, LV-CART33-treated mice were still expressing CARs, but RNA-CART33-treated mice were not.

“Based on our preclinical data, if we treat refractory AML with RNA-modified CART33, that results in myeloablation, anti-AML activity, and biodegradable, non-persisting CARs,” Dr Kenderian summarized.

“If allogeneic transplantation follows at this stage, it will likely lead to engraftment. Therefore, we conclude from this study that RNA-CART33 could be incorporated in novel conditioning regimens and will be tested in pilot phase 1 studies.”

Saad S. Kenderian

Photo courtesy of

BMT Tandem Meetings

SAN DIEGO—Researchers have developed a “biodegradable” chimeric antigen receptor (CAR) T-cell therapy that could potentially serve as a preparative regimen for acute myeloid leukemia (AML) patients undergoing allogeneic transplant.

The team created CAR T cells that target CD33 (CART33) and modified them with RNA so the cells would stop expressing CARs over time.

In mouse models of AML, the RNA-CART33 cells had an antileukemic effect and induced myeloablation.

The cells also stopped expressing CARs by the 2-week mark, which would allow for engraftment after allogeneic transplant, according to the researchers.

Saad S. Kenderian, MD, of the University of Pennsylvania in Philadelphia, presented this research at the 2015 BMT Tandem Meetings as one of the meeting’s “Best Abstracts” (abstract 1). The research was funded by Novartis.

“Allogeneic transplantation is the only potentially curative option in relapsed/refractory AML,” Dr Kenderian noted. “Outcomes are poor if patients are transplanted in residual disease  . . . , and these patients are often considered transplant-ineligible. Therefore, novel therapies are desperately needed.”

With this in mind, Dr Kenderian and his colleagues set out to develop a CAR T-cell therapy targeting CD33, which is expressed on AML blasts.

The researchers created a CAR from the anti-CD33 single-chain fragment variable of gemtuzumab ozogamicin, 41BB costimulation, CD3ζ signaling domain, and a lentiviral (LV) vector. They transduced T cells with this construct and expanded them in culture using anti-CD3/CD28 magnetic beads.

The team then tested these CART33 cells in NSGS mice engrafted with primary AML blasts. The mice received CART33 cells, another CAR T-cell therapy known as CART123, or control T cells.

At 4 weeks, mice that had received CART33 or CART123 cells were entirely leukemia-free, but the disease continued to progress in mice that received control T cells.

Likewise, when the experiment ended at 200 days, survival was 100% among mice that received CART33 or CART123, but all of the control mice had died. And at 200 days, CAR T cells were still circulating in the CART33- and CART123-treated mice.

Next, the researchers administered CART33 cells to HIS-NSG mice engrafted with human bone marrow and found the treatment resulted in myeloablation. There was a significant reduction of CD34-positive cells in mice that received CART33 compared to mice that received control T cells or no treatment.

“So based on our preclinical data, when we treat refractory AML with lentivirally transduced CART33, that will result in myeloablation, eradication of AML, and persistence of these CARs,” Dr Kenderian said.

“If allogeneic transplantation is performed at this aplastic stage, it will likely lead to rejection of the graft by persisting CAR therapy, which also means that elimination of CARs is necessary prior to stem cell infusion.”

So the researchers decided to create a transiently expressed, mRNA-modified CAR based on CART33. They electroporated T cells with this construct, and the cells expressed CARs for up to 6 days.

In experiments with the MOLM14 cell line, RNA-modified CART33 cells exhibited transient but comparable killing ability as LV-transduced CART33.

The researchers then tested RNA-CART33 in combination with chemotherapy in vivo. They transplanted NSG mice with MOLM14 and treated them with cyclophosphamide plus RNA-CART33 or cyclophosphamide plus control T cells.

Combination RNA-CART33 and chemotherapy prompted stronger, more durable antileukemic activity than cyclophosphamide and control T cells. Furthermore, there was a significant improvement in survival among RNA-CART33-treated mice (P=0.01).

Finally, Dr Kenderian and his colleagues tested the effect of RNA-CART33 on hematopoiesis. The team treated NSGS mice with busulfan and transplanted them with T-cell-depleted bone marrow. Following engraftment, mice received RNA-CART33 cells, LV-CART33 cells, or control T cells.

The researchers followed the mice for 2 weeks and found that both RNA-CART33 and LV-CART33 induced myeloablation. And at 14 days, LV-CART33-treated mice were still expressing CARs, but RNA-CART33-treated mice were not.

“Based on our preclinical data, if we treat refractory AML with RNA-modified CART33, that results in myeloablation, anti-AML activity, and biodegradable, non-persisting CARs,” Dr Kenderian summarized.

“If allogeneic transplantation follows at this stage, it will likely lead to engraftment. Therefore, we conclude from this study that RNA-CART33 could be incorporated in novel conditioning regimens and will be tested in pilot phase 1 studies.”

Saad S. Kenderian

Photo courtesy of

BMT Tandem Meetings

SAN DIEGO—Researchers have developed a “biodegradable” chimeric antigen receptor (CAR) T-cell therapy that could potentially serve as a preparative regimen for acute myeloid leukemia (AML) patients undergoing allogeneic transplant.

The team created CAR T cells that target CD33 (CART33) and modified them with RNA so the cells would stop expressing CARs over time.

In mouse models of AML, the RNA-CART33 cells had an antileukemic effect and induced myeloablation.

The cells also stopped expressing CARs by the 2-week mark, which would allow for engraftment after allogeneic transplant, according to the researchers.

Saad S. Kenderian, MD, of the University of Pennsylvania in Philadelphia, presented this research at the 2015 BMT Tandem Meetings as one of the meeting’s “Best Abstracts” (abstract 1). The research was funded by Novartis.

“Allogeneic transplantation is the only potentially curative option in relapsed/refractory AML,” Dr Kenderian noted. “Outcomes are poor if patients are transplanted in residual disease  . . . , and these patients are often considered transplant-ineligible. Therefore, novel therapies are desperately needed.”

With this in mind, Dr Kenderian and his colleagues set out to develop a CAR T-cell therapy targeting CD33, which is expressed on AML blasts.

The researchers created a CAR from the anti-CD33 single-chain fragment variable of gemtuzumab ozogamicin, 41BB costimulation, CD3ζ signaling domain, and a lentiviral (LV) vector. They transduced T cells with this construct and expanded them in culture using anti-CD3/CD28 magnetic beads.

The team then tested these CART33 cells in NSGS mice engrafted with primary AML blasts. The mice received CART33 cells, another CAR T-cell therapy known as CART123, or control T cells.

At 4 weeks, mice that had received CART33 or CART123 cells were entirely leukemia-free, but the disease continued to progress in mice that received control T cells.

Likewise, when the experiment ended at 200 days, survival was 100% among mice that received CART33 or CART123, but all of the control mice had died. And at 200 days, CAR T cells were still circulating in the CART33- and CART123-treated mice.

Next, the researchers administered CART33 cells to HIS-NSG mice engrafted with human bone marrow and found the treatment resulted in myeloablation. There was a significant reduction of CD34-positive cells in mice that received CART33 compared to mice that received control T cells or no treatment.

“So based on our preclinical data, when we treat refractory AML with lentivirally transduced CART33, that will result in myeloablation, eradication of AML, and persistence of these CARs,” Dr Kenderian said.

“If allogeneic transplantation is performed at this aplastic stage, it will likely lead to rejection of the graft by persisting CAR therapy, which also means that elimination of CARs is necessary prior to stem cell infusion.”

So the researchers decided to create a transiently expressed, mRNA-modified CAR based on CART33. They electroporated T cells with this construct, and the cells expressed CARs for up to 6 days.

In experiments with the MOLM14 cell line, RNA-modified CART33 cells exhibited transient but comparable killing ability as LV-transduced CART33.

The researchers then tested RNA-CART33 in combination with chemotherapy in vivo. They transplanted NSG mice with MOLM14 and treated them with cyclophosphamide plus RNA-CART33 or cyclophosphamide plus control T cells.

Combination RNA-CART33 and chemotherapy prompted stronger, more durable antileukemic activity than cyclophosphamide and control T cells. Furthermore, there was a significant improvement in survival among RNA-CART33-treated mice (P=0.01).

Finally, Dr Kenderian and his colleagues tested the effect of RNA-CART33 on hematopoiesis. The team treated NSGS mice with busulfan and transplanted them with T-cell-depleted bone marrow. Following engraftment, mice received RNA-CART33 cells, LV-CART33 cells, or control T cells.

The researchers followed the mice for 2 weeks and found that both RNA-CART33 and LV-CART33 induced myeloablation. And at 14 days, LV-CART33-treated mice were still expressing CARs, but RNA-CART33-treated mice were not.

“Based on our preclinical data, if we treat refractory AML with RNA-modified CART33, that results in myeloablation, anti-AML activity, and biodegradable, non-persisting CARs,” Dr Kenderian summarized.

“If allogeneic transplantation follows at this stage, it will likely lead to engraftment. Therefore, we conclude from this study that RNA-CART33 could be incorporated in novel conditioning regimens and will be tested in pilot phase 1 studies.”

Lab mouse

Cells derived from placenta can increase blood counts after hematopoietic stem cell transplant (HSCT), preclinical research suggests.

Investigators evaluated PLX-R18, a product consisting of mesenchymal-like adherent stromal cells derived from full-term human placentas, in mice undergoing HSCT.

Mice that received PLX-R18 in conjunction with HSCT had significantly faster hematopoietic recovery than mice that received placebo with their transplants.

Pluristem Therapeutics, Inc., the company developing PLX-R18, recently announced these results.

The study included 78 irradiated mice divided into 4 groups. One group received a transplant of 4 million HSCs plus an intra-muscular (IM) injection of 1 million PLX-R18 cells on days 1 and 10. A second group received 8 million HSCs plus an IM injection of 1 million PLX-R18 cells on days 1 and 10.

The first control group received 4 million HSCs plus an IM injection of placebo on days 1 and 10. And the second control group received 8 million HSCs plus an IM injection of placebo on days 1 and 10.

The investigators performed complete blood counts on day 9 after HSCT and the first dose of PLX-R18 or placebo, on day 16 after the second dose of PLX-R18 or placebo, and on day 23.

Nine days after transplantation with a low dose of HSCs (4 million) and concurrent administration of either PLX-R18 or placebo, mice treated with PLX-R18 had statistically significant increases in platelets and granulocytes when compared to controls (P=0.0059 and P=0.0267, respectively).

PLX-R18-treated mice also had more lymphocytes and total white blood cells, but these increases were not statistically significant.

Nine days after transplantation with a high dose of HSCs (8 million) and concurrent administration of either PLX-R18 or placebo, mice treated with PLX-R18 had statistically significant increases in platelet levels (P=0.0015).

One week later, at 16 days after a low-dose HSCT, mice treated with PLX-R18 had more platelets than controls, although the difference wasn’t significant.

Also on day 16, mice treated with PLX-R18 and a high dose of HSCs had statistically significant increases in platelets, granulocytes, and total white blood cells compared to controls (P=0.0053, P=0.0122, and P=0.0262 respectively).

On day 23, there were no significant differences in the number of cells between the treatment groups.

Taking these results together, the investigators concluded that PLX-R18 cells can significantly accelerate the recovery of several components of normal blood counts.

“A statistically significant increase in blood counts soon after bone marrow transplant is very meaningful,” said Reuven Or, MD, of Hadassah Medical Center in Haifa, Israel.

“We were particularly encouraged to see that the administration of PLX-R18 cells resulted in the greatest early improvement when using a lower dose of bone marrow cells. This means we could one day potentially achieve success with lower bone marrow transplant doses, thus addressing both treatment costs and donor availability.”

Lab mouse

Cells derived from placenta can increase blood counts after hematopoietic stem cell transplant (HSCT), preclinical research suggests.

Investigators evaluated PLX-R18, a product consisting of mesenchymal-like adherent stromal cells derived from full-term human placentas, in mice undergoing HSCT.

Mice that received PLX-R18 in conjunction with HSCT had significantly faster hematopoietic recovery than mice that received placebo with their transplants.

Pluristem Therapeutics, Inc., the company developing PLX-R18, recently announced these results.

The study included 78 irradiated mice divided into 4 groups. One group received a transplant of 4 million HSCs plus an intra-muscular (IM) injection of 1 million PLX-R18 cells on days 1 and 10. A second group received 8 million HSCs plus an IM injection of 1 million PLX-R18 cells on days 1 and 10.

The first control group received 4 million HSCs plus an IM injection of placebo on days 1 and 10. And the second control group received 8 million HSCs plus an IM injection of placebo on days 1 and 10.

The investigators performed complete blood counts on day 9 after HSCT and the first dose of PLX-R18 or placebo, on day 16 after the second dose of PLX-R18 or placebo, and on day 23.

Nine days after transplantation with a low dose of HSCs (4 million) and concurrent administration of either PLX-R18 or placebo, mice treated with PLX-R18 had statistically significant increases in platelets and granulocytes when compared to controls (P=0.0059 and P=0.0267, respectively).

PLX-R18-treated mice also had more lymphocytes and total white blood cells, but these increases were not statistically significant.

Nine days after transplantation with a high dose of HSCs (8 million) and concurrent administration of either PLX-R18 or placebo, mice treated with PLX-R18 had statistically significant increases in platelet levels (P=0.0015).

One week later, at 16 days after a low-dose HSCT, mice treated with PLX-R18 had more platelets than controls, although the difference wasn’t significant.

Also on day 16, mice treated with PLX-R18 and a high dose of HSCs had statistically significant increases in platelets, granulocytes, and total white blood cells compared to controls (P=0.0053, P=0.0122, and P=0.0262 respectively).

On day 23, there were no significant differences in the number of cells between the treatment groups.

Taking these results together, the investigators concluded that PLX-R18 cells can significantly accelerate the recovery of several components of normal blood counts.

“A statistically significant increase in blood counts soon after bone marrow transplant is very meaningful,” said Reuven Or, MD, of Hadassah Medical Center in Haifa, Israel.

“We were particularly encouraged to see that the administration of PLX-R18 cells resulted in the greatest early improvement when using a lower dose of bone marrow cells. This means we could one day potentially achieve success with lower bone marrow transplant doses, thus addressing both treatment costs and donor availability.”

Lab mouse

Cells derived from placenta can increase blood counts after hematopoietic stem cell transplant (HSCT), preclinical research suggests.

Investigators evaluated PLX-R18, a product consisting of mesenchymal-like adherent stromal cells derived from full-term human placentas, in mice undergoing HSCT.

Mice that received PLX-R18 in conjunction with HSCT had significantly faster hematopoietic recovery than mice that received placebo with their transplants.

Pluristem Therapeutics, Inc., the company developing PLX-R18, recently announced these results.

The study included 78 irradiated mice divided into 4 groups. One group received a transplant of 4 million HSCs plus an intra-muscular (IM) injection of 1 million PLX-R18 cells on days 1 and 10. A second group received 8 million HSCs plus an IM injection of 1 million PLX-R18 cells on days 1 and 10.

The first control group received 4 million HSCs plus an IM injection of placebo on days 1 and 10. And the second control group received 8 million HSCs plus an IM injection of placebo on days 1 and 10.

The investigators performed complete blood counts on day 9 after HSCT and the first dose of PLX-R18 or placebo, on day 16 after the second dose of PLX-R18 or placebo, and on day 23.

Nine days after transplantation with a low dose of HSCs (4 million) and concurrent administration of either PLX-R18 or placebo, mice treated with PLX-R18 had statistically significant increases in platelets and granulocytes when compared to controls (P=0.0059 and P=0.0267, respectively).

PLX-R18-treated mice also had more lymphocytes and total white blood cells, but these increases were not statistically significant.

Nine days after transplantation with a high dose of HSCs (8 million) and concurrent administration of either PLX-R18 or placebo, mice treated with PLX-R18 had statistically significant increases in platelet levels (P=0.0015).

One week later, at 16 days after a low-dose HSCT, mice treated with PLX-R18 had more platelets than controls, although the difference wasn’t significant.

Also on day 16, mice treated with PLX-R18 and a high dose of HSCs had statistically significant increases in platelets, granulocytes, and total white blood cells compared to controls (P=0.0053, P=0.0122, and P=0.0262 respectively).

On day 23, there were no significant differences in the number of cells between the treatment groups.

Taking these results together, the investigators concluded that PLX-R18 cells can significantly accelerate the recovery of several components of normal blood counts.

“A statistically significant increase in blood counts soon after bone marrow transplant is very meaningful,” said Reuven Or, MD, of Hadassah Medical Center in Haifa, Israel.

“We were particularly encouraged to see that the administration of PLX-R18 cells resulted in the greatest early improvement when using a lower dose of bone marrow cells. This means we could one day potentially achieve success with lower bone marrow transplant doses, thus addressing both treatment costs and donor availability.”

Preparing for HSCT

Photo by Chad McNeeley

SAN DIEGO—Results of 3 studies appear to support the use of defibrotide in patients who develop hepatic veno-occlusive disease (VOD) after hematopoietic stem cell transplant (HSCT).

Defibrotide is the sodium salt of a complex mixture of single-stranded oligodeoxyribonucleotides derived from porcine mucosal DNA. It has antithrombotic, anti-inflammatory, and anti-ischemic properties.

The drug is already approved in Europe to treat VOD and is under investigation for this indication in the US.

Researchers presented data from 3 studies showing promising results with defibrotide at the 2015 BMT Tandem Meetings. The studies were sponsored by Jazz Pharmaceuticals, the company developing defibrotide.

T-IND study

Paul G. Richardson, MD, of the Dana-Farber Cancer Institute in Boston, presented data from an ongoing treatment investigational new drug (T-IND) study (abstract 111*).

The study included 641 patients with VOD who received at least one dose of defibrotide—279 who had severe VOD with multi-organ failure (MOF), 247 who had VOD without MOF, and 526 who had undergone HSCT.

Twenty-one percent of patients had at least 1 treatment-related adverse event (AE). Common treatment-related AEs included hypotension (13%), respiratory failure (8%), diarrhea (8%), pyrexia (7%), pulmonary hemorrhage (7%), renal failure (7%), vomiting (6%), gastrointestinal hemorrhage (6%), hypoxia (6%), epistaxis (5%), and nausea (5%).

At day 100 in post-HSCT patients, the overall survival rate was 52%. The rate was 45% among patients with MOF, and 60% among patients without MOF.

Dr Richardson concluded that defibrotide was generally well-tolerated, and the survival results were favorable. He noted that the higher survival rate in patients without MOF indicates a need to study the impact of treatment earlier in the course of VOD.

NNT study

Dr Richardson also presented data from a number needed to treat (NNT) analysis from a historically controlled, phase 3 trial in patients undergoing HSCT (abstract 112).

For this study, researchers used data from the phase 3 trial to evaluate the NNT with defibrotide to achieve 1 complete response (CR) or to prevent 1 death at day 100 after HSCT in patients with severe VOD (n=102) compared with untreated, historical controls (n=32).

At 100 days, 23.5% of patients in the defibrotide cohort had a CR, compared to 9.4% of historical controls (P=0.013). Survival at 100 days was 38.2% in the defibrotide cohort and 25% among historical controls (P=0.034).

Based on these data, the NNT to achieve 1 CR with defibrotide by day 100 was 7, and the NNT to prevent 1 death at day 100 was 8.

Dr Richardson concluded that defibrotide demonstrated improved CR and survival in patients with severe VOD. And the NNTs with defibrotide are comparable to or lower than those with other therapeutic medical interventions in critical care.

Compassionate use program

Selim Corbacioglu, MD, of the University of Regensburg in Germany, presented final results of an international compassionate use program for defibrotide (abstract 109).

The program included 710 patients who received at least 1 documented dose of defibrotide. In all, 628 patients had undergone HSCT, 429 had severe VOD, and 292 had MOF.

Twenty-eight percent of patients discontinued treatment with defibrotide. Fifty-three percent of patients had AEs, 18% of which were possibly treatment-related. These were primarily gastrointestinal hemorrhage (2%), hemorrhage (1%), and pulmonary hemorrhage (1%).

At day 100 (post-HSCT, chemotherapy, or radiation), the survival rate was 54%. Survival varied according to defibrotide dose. It was 43% for the 10 mg/kg/day group, 58% for the 25 mg/kg/day group, 54% for the 40 mg/kg/day group, 61% for the 60/80 mg/kg/day group, and 51% for patients whose dose was unknown.

Dr Corbacioglu noted that the side-effect profile and the survival rates in this program were consistent with those observed in prior defibrotide studies. And these data support 25 mg/kg/day as the optimal dose of the drug.

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

Preparing for HSCT

Photo by Chad McNeeley

SAN DIEGO—Results of 3 studies appear to support the use of defibrotide in patients who develop hepatic veno-occlusive disease (VOD) after hematopoietic stem cell transplant (HSCT).

Defibrotide is the sodium salt of a complex mixture of single-stranded oligodeoxyribonucleotides derived from porcine mucosal DNA. It has antithrombotic, anti-inflammatory, and anti-ischemic properties.

The drug is already approved in Europe to treat VOD and is under investigation for this indication in the US.

Researchers presented data from 3 studies showing promising results with defibrotide at the 2015 BMT Tandem Meetings. The studies were sponsored by Jazz Pharmaceuticals, the company developing defibrotide.

T-IND study

Paul G. Richardson, MD, of the Dana-Farber Cancer Institute in Boston, presented data from an ongoing treatment investigational new drug (T-IND) study (abstract 111*).

The study included 641 patients with VOD who received at least one dose of defibrotide—279 who had severe VOD with multi-organ failure (MOF), 247 who had VOD without MOF, and 526 who had undergone HSCT.

Twenty-one percent of patients had at least 1 treatment-related adverse event (AE). Common treatment-related AEs included hypotension (13%), respiratory failure (8%), diarrhea (8%), pyrexia (7%), pulmonary hemorrhage (7%), renal failure (7%), vomiting (6%), gastrointestinal hemorrhage (6%), hypoxia (6%), epistaxis (5%), and nausea (5%).

At day 100 in post-HSCT patients, the overall survival rate was 52%. The rate was 45% among patients with MOF, and 60% among patients without MOF.

Dr Richardson concluded that defibrotide was generally well-tolerated, and the survival results were favorable. He noted that the higher survival rate in patients without MOF indicates a need to study the impact of treatment earlier in the course of VOD.

NNT study

Dr Richardson also presented data from a number needed to treat (NNT) analysis from a historically controlled, phase 3 trial in patients undergoing HSCT (abstract 112).

For this study, researchers used data from the phase 3 trial to evaluate the NNT with defibrotide to achieve 1 complete response (CR) or to prevent 1 death at day 100 after HSCT in patients with severe VOD (n=102) compared with untreated, historical controls (n=32).

At 100 days, 23.5% of patients in the defibrotide cohort had a CR, compared to 9.4% of historical controls (P=0.013). Survival at 100 days was 38.2% in the defibrotide cohort and 25% among historical controls (P=0.034).

Based on these data, the NNT to achieve 1 CR with defibrotide by day 100 was 7, and the NNT to prevent 1 death at day 100 was 8.

Dr Richardson concluded that defibrotide demonstrated improved CR and survival in patients with severe VOD. And the NNTs with defibrotide are comparable to or lower than those with other therapeutic medical interventions in critical care.

Compassionate use program

Selim Corbacioglu, MD, of the University of Regensburg in Germany, presented final results of an international compassionate use program for defibrotide (abstract 109).

The program included 710 patients who received at least 1 documented dose of defibrotide. In all, 628 patients had undergone HSCT, 429 had severe VOD, and 292 had MOF.

Twenty-eight percent of patients discontinued treatment with defibrotide. Fifty-three percent of patients had AEs, 18% of which were possibly treatment-related. These were primarily gastrointestinal hemorrhage (2%), hemorrhage (1%), and pulmonary hemorrhage (1%).

At day 100 (post-HSCT, chemotherapy, or radiation), the survival rate was 54%. Survival varied according to defibrotide dose. It was 43% for the 10 mg/kg/day group, 58% for the 25 mg/kg/day group, 54% for the 40 mg/kg/day group, 61% for the 60/80 mg/kg/day group, and 51% for patients whose dose was unknown.

Dr Corbacioglu noted that the side-effect profile and the survival rates in this program were consistent with those observed in prior defibrotide studies. And these data support 25 mg/kg/day as the optimal dose of the drug.

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

Preparing for HSCT

Photo by Chad McNeeley

SAN DIEGO—Results of 3 studies appear to support the use of defibrotide in patients who develop hepatic veno-occlusive disease (VOD) after hematopoietic stem cell transplant (HSCT).

Defibrotide is the sodium salt of a complex mixture of single-stranded oligodeoxyribonucleotides derived from porcine mucosal DNA. It has antithrombotic, anti-inflammatory, and anti-ischemic properties.

The drug is already approved in Europe to treat VOD and is under investigation for this indication in the US.

Researchers presented data from 3 studies showing promising results with defibrotide at the 2015 BMT Tandem Meetings. The studies were sponsored by Jazz Pharmaceuticals, the company developing defibrotide.

T-IND study

Paul G. Richardson, MD, of the Dana-Farber Cancer Institute in Boston, presented data from an ongoing treatment investigational new drug (T-IND) study (abstract 111*).

The study included 641 patients with VOD who received at least one dose of defibrotide—279 who had severe VOD with multi-organ failure (MOF), 247 who had VOD without MOF, and 526 who had undergone HSCT.

Twenty-one percent of patients had at least 1 treatment-related adverse event (AE). Common treatment-related AEs included hypotension (13%), respiratory failure (8%), diarrhea (8%), pyrexia (7%), pulmonary hemorrhage (7%), renal failure (7%), vomiting (6%), gastrointestinal hemorrhage (6%), hypoxia (6%), epistaxis (5%), and nausea (5%).

At day 100 in post-HSCT patients, the overall survival rate was 52%. The rate was 45% among patients with MOF, and 60% among patients without MOF.

Dr Richardson concluded that defibrotide was generally well-tolerated, and the survival results were favorable. He noted that the higher survival rate in patients without MOF indicates a need to study the impact of treatment earlier in the course of VOD.

NNT study

Dr Richardson also presented data from a number needed to treat (NNT) analysis from a historically controlled, phase 3 trial in patients undergoing HSCT (abstract 112).

For this study, researchers used data from the phase 3 trial to evaluate the NNT with defibrotide to achieve 1 complete response (CR) or to prevent 1 death at day 100 after HSCT in patients with severe VOD (n=102) compared with untreated, historical controls (n=32).

At 100 days, 23.5% of patients in the defibrotide cohort had a CR, compared to 9.4% of historical controls (P=0.013). Survival at 100 days was 38.2% in the defibrotide cohort and 25% among historical controls (P=0.034).

Based on these data, the NNT to achieve 1 CR with defibrotide by day 100 was 7, and the NNT to prevent 1 death at day 100 was 8.

Dr Richardson concluded that defibrotide demonstrated improved CR and survival in patients with severe VOD. And the NNTs with defibrotide are comparable to or lower than those with other therapeutic medical interventions in critical care.

Compassionate use program

Selim Corbacioglu, MD, of the University of Regensburg in Germany, presented final results of an international compassionate use program for defibrotide (abstract 109).

The program included 710 patients who received at least 1 documented dose of defibrotide. In all, 628 patients had undergone HSCT, 429 had severe VOD, and 292 had MOF.

Twenty-eight percent of patients discontinued treatment with defibrotide. Fifty-three percent of patients had AEs, 18% of which were possibly treatment-related. These were primarily gastrointestinal hemorrhage (2%), hemorrhage (1%), and pulmonary hemorrhage (1%).

At day 100 (post-HSCT, chemotherapy, or radiation), the survival rate was 54%. Survival varied according to defibrotide dose. It was 43% for the 10 mg/kg/day group, 58% for the 25 mg/kg/day group, 54% for the 40 mg/kg/day group, 61% for the 60/80 mg/kg/day group, and 51% for patients whose dose was unknown.

Dr Corbacioglu noted that the side-effect profile and the survival rates in this program were consistent with those observed in prior defibrotide studies. And these data support 25 mg/kg/day as the optimal dose of the drug.

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

Blood donation

Photo by Charles Haymond

The US Food and Drug Administration (FDA) has granted breakthrough designation to a therapy consisting of cytotoxic T lymphocytes activated against Epstein-Barr virus (EBV-CTLs).

The treatment is intended for use in patients with rituximab-refractory, EBV-associated lymphoproliferative disease (EBV-LPD), which occurs after allogeneic hematopoietic stem cell transplant.

EBV-CTLs consist of T cells collected from third-party donors.

The T cells are exposed to antigens, expanded, characterized, and stored for future use in an appropriate, partially HLA-matched patient.

In the context of EBV-LPD, the EBV-CTLs are able to target and destroy cancer cells expressing EBV.

“The receipt of breakthrough therapy designation brings us one step closer to our ultimate goal of making EBV-CTL available to all patients with EBV-LPD, a serious and life-threatening condition with limited treatment options,” said Richard O’Reilly, MD, Chair of the Department of Pediatrics and Chief of the Pediatric Bone Marrow Transplant Service at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, New York.

MSKCC is developing EBV-CTLs in conjunction with Atara Biotherapeutics, Inc.

Breakthrough therapy designation for EBV-CTLs was based on data from 2 clinical trials of EBV-CTLs conducted at MSKCC.

Data from these studies have been submitted for presentation at an upcoming medical conference. Results of a phase 1/2 study of EBV-CTLs were previously presented at the APHON 37th Annual Conference and Exhibit in 2013.

The FDA’s breakthrough therapy designation is designed to expedite the development and review of new drugs for the treatment of serious or life-threatening conditions.

To qualify for this designation, a drug must show credible evidence of a substantial improvement on a clinically significant endpoint over available therapies, or over placebo if there is no available therapy, or in a study that compares the new treatment plus the standard of care to the standard of care alone.

The designation confers several benefits, including intensive FDA guidance and eligibility for submission of a rolling biologic license application.

Blood donation

Photo by Charles Haymond

The US Food and Drug Administration (FDA) has granted breakthrough designation to a therapy consisting of cytotoxic T lymphocytes activated against Epstein-Barr virus (EBV-CTLs).

The treatment is intended for use in patients with rituximab-refractory, EBV-associated lymphoproliferative disease (EBV-LPD), which occurs after allogeneic hematopoietic stem cell transplant.

EBV-CTLs consist of T cells collected from third-party donors.

The T cells are exposed to antigens, expanded, characterized, and stored for future use in an appropriate, partially HLA-matched patient.

In the context of EBV-LPD, the EBV-CTLs are able to target and destroy cancer cells expressing EBV.

“The receipt of breakthrough therapy designation brings us one step closer to our ultimate goal of making EBV-CTL available to all patients with EBV-LPD, a serious and life-threatening condition with limited treatment options,” said Richard O’Reilly, MD, Chair of the Department of Pediatrics and Chief of the Pediatric Bone Marrow Transplant Service at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, New York.

MSKCC is developing EBV-CTLs in conjunction with Atara Biotherapeutics, Inc.

Breakthrough therapy designation for EBV-CTLs was based on data from 2 clinical trials of EBV-CTLs conducted at MSKCC.

Data from these studies have been submitted for presentation at an upcoming medical conference. Results of a phase 1/2 study of EBV-CTLs were previously presented at the APHON 37th Annual Conference and Exhibit in 2013.

The FDA’s breakthrough therapy designation is designed to expedite the development and review of new drugs for the treatment of serious or life-threatening conditions.

To qualify for this designation, a drug must show credible evidence of a substantial improvement on a clinically significant endpoint over available therapies, or over placebo if there is no available therapy, or in a study that compares the new treatment plus the standard of care to the standard of care alone.

The designation confers several benefits, including intensive FDA guidance and eligibility for submission of a rolling biologic license application.

Blood donation

Photo by Charles Haymond

The US Food and Drug Administration (FDA) has granted breakthrough designation to a therapy consisting of cytotoxic T lymphocytes activated against Epstein-Barr virus (EBV-CTLs).

The treatment is intended for use in patients with rituximab-refractory, EBV-associated lymphoproliferative disease (EBV-LPD), which occurs after allogeneic hematopoietic stem cell transplant.

EBV-CTLs consist of T cells collected from third-party donors.

The T cells are exposed to antigens, expanded, characterized, and stored for future use in an appropriate, partially HLA-matched patient.

In the context of EBV-LPD, the EBV-CTLs are able to target and destroy cancer cells expressing EBV.

“The receipt of breakthrough therapy designation brings us one step closer to our ultimate goal of making EBV-CTL available to all patients with EBV-LPD, a serious and life-threatening condition with limited treatment options,” said Richard O’Reilly, MD, Chair of the Department of Pediatrics and Chief of the Pediatric Bone Marrow Transplant Service at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, New York.

MSKCC is developing EBV-CTLs in conjunction with Atara Biotherapeutics, Inc.

Breakthrough therapy designation for EBV-CTLs was based on data from 2 clinical trials of EBV-CTLs conducted at MSKCC.

Data from these studies have been submitted for presentation at an upcoming medical conference. Results of a phase 1/2 study of EBV-CTLs were previously presented at the APHON 37th Annual Conference and Exhibit in 2013.

The FDA’s breakthrough therapy designation is designed to expedite the development and review of new drugs for the treatment of serious or life-threatening conditions.

To qualify for this designation, a drug must show credible evidence of a substantial improvement on a clinically significant endpoint over available therapies, or over placebo if there is no available therapy, or in a study that compares the new treatment plus the standard of care to the standard of care alone.

The designation confers several benefits, including intensive FDA guidance and eligibility for submission of a rolling biologic license application.

Team performing surgery

Photo by Piotr Bodzek

The US Food and Drug Administration (FDA) has granted orphan designation to andexanet alfa for reversing the anticoagulant effect of factor Xa inhibitors in patients experiencing a serious, uncontrolled bleeding event and those who require urgent or emergent surgery.

At present, there is no approved antidote for these patients.

Andexanet alfa is the only compound being studied as a reversal agent for factor Xa inhibitors that directly and specifically corrects anti-factor Xa activity.

The drug is a modified human factor Xa molecule that acts as a decoy to target and sequester both oral and injectable factor Xa inhibitors in the blood. Once bound, the inhibitors are unable to bind to and inhibit native factor Xa, thus allowing for the restoration of normal hemostatic processes.

Andexanet alfa has the potential to address several clinical scenarios where a factor Xa antidote is needed by allowing for flexible and controlled reversal. This can be short-acting, through the administration of an intravenous (IV) bolus, or longer-acting with the addition of an extended infusion.

The FDA previously granted andexanet alfa breakthrough therapy designation, which is intended to expedite the development and review of a drug candidate intended to treat a serious or life-threatening condition.

“Orphan drug designation for andexanet alfa recognizes its potential to address a significant unmet medical need and to advance the field by helping patients who currently have no treatment options,” said Bill Lis, chief executive officer of Portola Pharmaceuticals, the company developing andexanet alfa.

The FDA’s orphan drug designation program provides orphan status to drugs and biologics that are intended for the treatment, diagnosis, or prevention of rare diseases/disorders that currently affect fewer than 200,000 people in the US.

Orphan designation qualifies a company for certain benefits, including an accelerated approval process, 7 years of market exclusivity following the drug’s approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.

Clinical development of andexanet alfa

Researchers are currently evaluating andexanet alfa in 2 randomized, placebo-controlled, phase 3 trials—ANNEXA-A and ANNEXA-R.

They previously reported promising results from the first part of the ANNEXA-A study, a test of andexanet alfa’s ability to reverse the effects of apixaban in healthy subjects when the antidote was given as a single IV bolus.

Researchers also reported favorable results from the first part of the ANNEXA-R study, in which they evaluated andexanet alfa’s ability to reverse the effects of rivaroxaban in healthy subjects when the antidote was given as a single IV bolus.

The second parts of the ANNEXA-A and ANNEXA-R studies are ongoing. The researchers are evaluating the use of andexanet alfa given as a bolus and a continuous infusion.

ANNEXA-4, a phase 4, single-arm, confirmatory study is also ongoing. Researchers are evaluating the drug in patients receiving apixaban, rivaroxaban, edoxaban, or enoxaparin who present with an acute major bleed.

Team performing surgery

Photo by Piotr Bodzek

The US Food and Drug Administration (FDA) has granted orphan designation to andexanet alfa for reversing the anticoagulant effect of factor Xa inhibitors in patients experiencing a serious, uncontrolled bleeding event and those who require urgent or emergent surgery.

At present, there is no approved antidote for these patients.

Andexanet alfa is the only compound being studied as a reversal agent for factor Xa inhibitors that directly and specifically corrects anti-factor Xa activity.

The drug is a modified human factor Xa molecule that acts as a decoy to target and sequester both oral and injectable factor Xa inhibitors in the blood. Once bound, the inhibitors are unable to bind to and inhibit native factor Xa, thus allowing for the restoration of normal hemostatic processes.

Andexanet alfa has the potential to address several clinical scenarios where a factor Xa antidote is needed by allowing for flexible and controlled reversal. This can be short-acting, through the administration of an intravenous (IV) bolus, or longer-acting with the addition of an extended infusion.

The FDA previously granted andexanet alfa breakthrough therapy designation, which is intended to expedite the development and review of a drug candidate intended to treat a serious or life-threatening condition.

“Orphan drug designation for andexanet alfa recognizes its potential to address a significant unmet medical need and to advance the field by helping patients who currently have no treatment options,” said Bill Lis, chief executive officer of Portola Pharmaceuticals, the company developing andexanet alfa.

The FDA’s orphan drug designation program provides orphan status to drugs and biologics that are intended for the treatment, diagnosis, or prevention of rare diseases/disorders that currently affect fewer than 200,000 people in the US.

Orphan designation qualifies a company for certain benefits, including an accelerated approval process, 7 years of market exclusivity following the drug’s approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.

Clinical development of andexanet alfa

Researchers are currently evaluating andexanet alfa in 2 randomized, placebo-controlled, phase 3 trials—ANNEXA-A and ANNEXA-R.

They previously reported promising results from the first part of the ANNEXA-A study, a test of andexanet alfa’s ability to reverse the effects of apixaban in healthy subjects when the antidote was given as a single IV bolus.

Researchers also reported favorable results from the first part of the ANNEXA-R study, in which they evaluated andexanet alfa’s ability to reverse the effects of rivaroxaban in healthy subjects when the antidote was given as a single IV bolus.

The second parts of the ANNEXA-A and ANNEXA-R studies are ongoing. The researchers are evaluating the use of andexanet alfa given as a bolus and a continuous infusion.

ANNEXA-4, a phase 4, single-arm, confirmatory study is also ongoing. Researchers are evaluating the drug in patients receiving apixaban, rivaroxaban, edoxaban, or enoxaparin who present with an acute major bleed.

Team performing surgery

Photo by Piotr Bodzek

The US Food and Drug Administration (FDA) has granted orphan designation to andexanet alfa for reversing the anticoagulant effect of factor Xa inhibitors in patients experiencing a serious, uncontrolled bleeding event and those who require urgent or emergent surgery.

At present, there is no approved antidote for these patients.

Andexanet alfa is the only compound being studied as a reversal agent for factor Xa inhibitors that directly and specifically corrects anti-factor Xa activity.

The drug is a modified human factor Xa molecule that acts as a decoy to target and sequester both oral and injectable factor Xa inhibitors in the blood. Once bound, the inhibitors are unable to bind to and inhibit native factor Xa, thus allowing for the restoration of normal hemostatic processes.

Andexanet alfa has the potential to address several clinical scenarios where a factor Xa antidote is needed by allowing for flexible and controlled reversal. This can be short-acting, through the administration of an intravenous (IV) bolus, or longer-acting with the addition of an extended infusion.

The FDA previously granted andexanet alfa breakthrough therapy designation, which is intended to expedite the development and review of a drug candidate intended to treat a serious or life-threatening condition.

“Orphan drug designation for andexanet alfa recognizes its potential to address a significant unmet medical need and to advance the field by helping patients who currently have no treatment options,” said Bill Lis, chief executive officer of Portola Pharmaceuticals, the company developing andexanet alfa.

The FDA’s orphan drug designation program provides orphan status to drugs and biologics that are intended for the treatment, diagnosis, or prevention of rare diseases/disorders that currently affect fewer than 200,000 people in the US.

Orphan designation qualifies a company for certain benefits, including an accelerated approval process, 7 years of market exclusivity following the drug’s approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.

Clinical development of andexanet alfa

Researchers are currently evaluating andexanet alfa in 2 randomized, placebo-controlled, phase 3 trials—ANNEXA-A and ANNEXA-R.

They previously reported promising results from the first part of the ANNEXA-A study, a test of andexanet alfa’s ability to reverse the effects of apixaban in healthy subjects when the antidote was given as a single IV bolus.

Researchers also reported favorable results from the first part of the ANNEXA-R study, in which they evaluated andexanet alfa’s ability to reverse the effects of rivaroxaban in healthy subjects when the antidote was given as a single IV bolus.

The second parts of the ANNEXA-A and ANNEXA-R studies are ongoing. The researchers are evaluating the use of andexanet alfa given as a bolus and a continuous infusion.

ANNEXA-4, a phase 4, single-arm, confirmatory study is also ongoing. Researchers are evaluating the drug in patients receiving apixaban, rivaroxaban, edoxaban, or enoxaparin who present with an acute major bleed.

Preparing for HSCT

Photo by Chad McNeeley

A retrospective study has shown that, since the 1980s, the world has seen a substantial increase in the use of hematopoietic stem cell transplants (HSCTs) and a significant rise in the number of donor registries.

Still, it seems many patients who would benefit from HSCT do not undergo the procedure due to a chronic shortage of resources and donors.

Dietger Niederwieser, MD, of the University Hospital Leipzig in Germany, and his colleagues recounted these findings in The Lancet Haematology.

Using data collected by the Worldwide Network for Blood and Marrow Transplantation (WBMT), the researchers systematically analyzed the growth of HSCT and changes in its use in 194 WHO member countries since the first HSCT was performed in 1957.

The team also examined the link between macroeconomic factors (eg, gross national income and healthcare expenditure) and transplant frequencies per 10 million inhabitants in each country.

The data showed that about 10,000 HSCTs had been performed by 1985, but that number rose to around 100,000 by 1995. By December 2012, nearly 1 million HSCTs—42% allogeneic and 58% autologous—had been performed at 1516 transplant centers across 75 countries.

Transplants were more common in countries with greater financial resources, more transplant teams, and an unrelated donor infrastructure. Most transplants were performed in Europe (53%), followed by the Americas (31%), South East Asia and the Western Pacific (15%), and the Eastern Mediterranean and Africa (2%).

The use of allogeneic HSCT has grown rapidly in all regions, without any signs of saturation. This likely reflects substantial underuse of this therapy, according to the researchers. And it suggests more patients would have received allogeneic transplants if they were accessible or suitable donors were available.

On the other hand, the researchers found that the number of countries with donor registries increased from 2 in 1987 to 57 in 2012. And the number of volunteer donors rose from 3072 in 1987 to over 22 million in 2012.

The international exchange of stem cell products also increased to more than 10,000 a year between 2006 and 2012, with substantial differences between countries in the amount of stem cells they import or export.

Despite these increases, the researchers noted that there are still too many patients who are unable to find a suitable donor. At any time, more than 37,000 people worldwide are waiting for an HSC donation.

“Patients, many of them children, are facing a life-and-death situation,” Dr Niederwieser said. “Ultimately, they will die if they cannot get the treatment they need. All countries need to provide adequate infrastructure for patients and donors to make sure that everyone who needs a transplant gets one, rather than the present situation in which access remains restricted to countries and people with sufficient resources.”

Preparing for HSCT

Photo by Chad McNeeley

A retrospective study has shown that, since the 1980s, the world has seen a substantial increase in the use of hematopoietic stem cell transplants (HSCTs) and a significant rise in the number of donor registries.

Still, it seems many patients who would benefit from HSCT do not undergo the procedure due to a chronic shortage of resources and donors.

Dietger Niederwieser, MD, of the University Hospital Leipzig in Germany, and his colleagues recounted these findings in The Lancet Haematology.

Using data collected by the Worldwide Network for Blood and Marrow Transplantation (WBMT), the researchers systematically analyzed the growth of HSCT and changes in its use in 194 WHO member countries since the first HSCT was performed in 1957.

The team also examined the link between macroeconomic factors (eg, gross national income and healthcare expenditure) and transplant frequencies per 10 million inhabitants in each country.

The data showed that about 10,000 HSCTs had been performed by 1985, but that number rose to around 100,000 by 1995. By December 2012, nearly 1 million HSCTs—42% allogeneic and 58% autologous—had been performed at 1516 transplant centers across 75 countries.

Transplants were more common in countries with greater financial resources, more transplant teams, and an unrelated donor infrastructure. Most transplants were performed in Europe (53%), followed by the Americas (31%), South East Asia and the Western Pacific (15%), and the Eastern Mediterranean and Africa (2%).

The use of allogeneic HSCT has grown rapidly in all regions, without any signs of saturation. This likely reflects substantial underuse of this therapy, according to the researchers. And it suggests more patients would have received allogeneic transplants if they were accessible or suitable donors were available.

On the other hand, the researchers found that the number of countries with donor registries increased from 2 in 1987 to 57 in 2012. And the number of volunteer donors rose from 3072 in 1987 to over 22 million in 2012.

The international exchange of stem cell products also increased to more than 10,000 a year between 2006 and 2012, with substantial differences between countries in the amount of stem cells they import or export.

Despite these increases, the researchers noted that there are still too many patients who are unable to find a suitable donor. At any time, more than 37,000 people worldwide are waiting for an HSC donation.

“Patients, many of them children, are facing a life-and-death situation,” Dr Niederwieser said. “Ultimately, they will die if they cannot get the treatment they need. All countries need to provide adequate infrastructure for patients and donors to make sure that everyone who needs a transplant gets one, rather than the present situation in which access remains restricted to countries and people with sufficient resources.”

Preparing for HSCT

Photo by Chad McNeeley

A retrospective study has shown that, since the 1980s, the world has seen a substantial increase in the use of hematopoietic stem cell transplants (HSCTs) and a significant rise in the number of donor registries.

Still, it seems many patients who would benefit from HSCT do not undergo the procedure due to a chronic shortage of resources and donors.

Dietger Niederwieser, MD, of the University Hospital Leipzig in Germany, and his colleagues recounted these findings in The Lancet Haematology.

Using data collected by the Worldwide Network for Blood and Marrow Transplantation (WBMT), the researchers systematically analyzed the growth of HSCT and changes in its use in 194 WHO member countries since the first HSCT was performed in 1957.

The team also examined the link between macroeconomic factors (eg, gross national income and healthcare expenditure) and transplant frequencies per 10 million inhabitants in each country.

The data showed that about 10,000 HSCTs had been performed by 1985, but that number rose to around 100,000 by 1995. By December 2012, nearly 1 million HSCTs—42% allogeneic and 58% autologous—had been performed at 1516 transplant centers across 75 countries.

Transplants were more common in countries with greater financial resources, more transplant teams, and an unrelated donor infrastructure. Most transplants were performed in Europe (53%), followed by the Americas (31%), South East Asia and the Western Pacific (15%), and the Eastern Mediterranean and Africa (2%).

The use of allogeneic HSCT has grown rapidly in all regions, without any signs of saturation. This likely reflects substantial underuse of this therapy, according to the researchers. And it suggests more patients would have received allogeneic transplants if they were accessible or suitable donors were available.

On the other hand, the researchers found that the number of countries with donor registries increased from 2 in 1987 to 57 in 2012. And the number of volunteer donors rose from 3072 in 1987 to over 22 million in 2012.

The international exchange of stem cell products also increased to more than 10,000 a year between 2006 and 2012, with substantial differences between countries in the amount of stem cells they import or export.

Despite these increases, the researchers noted that there are still too many patients who are unable to find a suitable donor. At any time, more than 37,000 people worldwide are waiting for an HSC donation.

“Patients, many of them children, are facing a life-and-death situation,” Dr Niederwieser said. “Ultimately, they will die if they cannot get the treatment they need. All countries need to provide adequate infrastructure for patients and donors to make sure that everyone who needs a transplant gets one, rather than the present situation in which access remains restricted to countries and people with sufficient resources.”

Lab mice

Photo by Aaron Logan

Researchers have used a 3D printer to create a carrier that allows for local and sustained delivery of the immunosuppressive drug cyclosporine A (CsA) after cell transplantation.

The carrier is a combination of microspheres and hydrogel. In murine experiments, it delivered a local, sustained load of CsA in an amount that eliminated the need for additional drugs to treat immune rejection.

The researchers described these results in Cell Transplantation.

“Our objective was to show the feasibility of using a subcutaneous, 3D-printed drug delivery system to achieve local and sustained CsA release and to investigate the local immunosuppressive effects of the CsA after cell transplantation,” said study author Dong-Woo Cho, PhD, of the Pohang University of Science and Technology in Korea.

“The improved load-bearing capacity of the combined microsphere and hydrogel system, and its ability to maintain its integrity and shape during the implantation period, helped to deliver a sustained CsA release, preventing the acceleration of the secretion of cytokines related to immune rejection.”

The researchers noted that CsA improves the success rate of transplants, but systemic administration requires high doses that can have severe side effects. The benefit of a carrier is that it provides local drug delivery.

Other research groups have attempted CsA delivery via either microspheres or hydrogels, but most encountered serious problems, such as embolisms or organ damage due to migration of the microspheres from the injection site.

In addition, weak mechanical properties in some delivery systems caused premature dissolution and placed limitations on drug load quantity.

However, Dr Cho’s group said their carrier’s improved structure and load-bearing capacity allowed for sustained release of CsA at the desired site.

Their carrier is a hybrid of a CsA-poly (lactic-co-glycolic) acid microsphere-loaded hydrogel and a polymeric framework, which ensures the carrier can endure external force under physiological conditions.

In in vitro experiments with the carrier, the researchers observed decreased expression of cytokines, which are secreted by spleen cells activated by Concanavalin A and are related to immune rejection.

The team also implanted in mice drug carriers seeded with xenogeneic cells, and they observed significant suppression of T-cell-mediated rejection for 4 weeks.

The researchers believe this study could help overcome existing cell transplantation limitations caused by systemic immunosuppression. They said their carrier could be a promising solution for treating a range of diseases that require cell-based therapy.

Lab mice

Photo by Aaron Logan

Researchers have used a 3D printer to create a carrier that allows for local and sustained delivery of the immunosuppressive drug cyclosporine A (CsA) after cell transplantation.

The carrier is a combination of microspheres and hydrogel. In murine experiments, it delivered a local, sustained load of CsA in an amount that eliminated the need for additional drugs to treat immune rejection.

The researchers described these results in Cell Transplantation.

“Our objective was to show the feasibility of using a subcutaneous, 3D-printed drug delivery system to achieve local and sustained CsA release and to investigate the local immunosuppressive effects of the CsA after cell transplantation,” said study author Dong-Woo Cho, PhD, of the Pohang University of Science and Technology in Korea.

“The improved load-bearing capacity of the combined microsphere and hydrogel system, and its ability to maintain its integrity and shape during the implantation period, helped to deliver a sustained CsA release, preventing the acceleration of the secretion of cytokines related to immune rejection.”

The researchers noted that CsA improves the success rate of transplants, but systemic administration requires high doses that can have severe side effects. The benefit of a carrier is that it provides local drug delivery.

Other research groups have attempted CsA delivery via either microspheres or hydrogels, but most encountered serious problems, such as embolisms or organ damage due to migration of the microspheres from the injection site.

In addition, weak mechanical properties in some delivery systems caused premature dissolution and placed limitations on drug load quantity.

However, Dr Cho’s group said their carrier’s improved structure and load-bearing capacity allowed for sustained release of CsA at the desired site.

Their carrier is a hybrid of a CsA-poly (lactic-co-glycolic) acid microsphere-loaded hydrogel and a polymeric framework, which ensures the carrier can endure external force under physiological conditions.

In in vitro experiments with the carrier, the researchers observed decreased expression of cytokines, which are secreted by spleen cells activated by Concanavalin A and are related to immune rejection.

The team also implanted in mice drug carriers seeded with xenogeneic cells, and they observed significant suppression of T-cell-mediated rejection for 4 weeks.

The researchers believe this study could help overcome existing cell transplantation limitations caused by systemic immunosuppression. They said their carrier could be a promising solution for treating a range of diseases that require cell-based therapy.

Lab mice

Photo by Aaron Logan

Researchers have used a 3D printer to create a carrier that allows for local and sustained delivery of the immunosuppressive drug cyclosporine A (CsA) after cell transplantation.

The carrier is a combination of microspheres and hydrogel. In murine experiments, it delivered a local, sustained load of CsA in an amount that eliminated the need for additional drugs to treat immune rejection.

The researchers described these results in Cell Transplantation.

“Our objective was to show the feasibility of using a subcutaneous, 3D-printed drug delivery system to achieve local and sustained CsA release and to investigate the local immunosuppressive effects of the CsA after cell transplantation,” said study author Dong-Woo Cho, PhD, of the Pohang University of Science and Technology in Korea.

“The improved load-bearing capacity of the combined microsphere and hydrogel system, and its ability to maintain its integrity and shape during the implantation period, helped to deliver a sustained CsA release, preventing the acceleration of the secretion of cytokines related to immune rejection.”

The researchers noted that CsA improves the success rate of transplants, but systemic administration requires high doses that can have severe side effects. The benefit of a carrier is that it provides local drug delivery.

Other research groups have attempted CsA delivery via either microspheres or hydrogels, but most encountered serious problems, such as embolisms or organ damage due to migration of the microspheres from the injection site.

In addition, weak mechanical properties in some delivery systems caused premature dissolution and placed limitations on drug load quantity.

However, Dr Cho’s group said their carrier’s improved structure and load-bearing capacity allowed for sustained release of CsA at the desired site.

Their carrier is a hybrid of a CsA-poly (lactic-co-glycolic) acid microsphere-loaded hydrogel and a polymeric framework, which ensures the carrier can endure external force under physiological conditions.

In in vitro experiments with the carrier, the researchers observed decreased expression of cytokines, which are secreted by spleen cells activated by Concanavalin A and are related to immune rejection.

The team also implanted in mice drug carriers seeded with xenogeneic cells, and they observed significant suppression of T-cell-mediated rejection for 4 weeks.

The researchers believe this study could help overcome existing cell transplantation limitations caused by systemic immunosuppression. They said their carrier could be a promising solution for treating a range of diseases that require cell-based therapy.

Bone marrow harvest

Photo by Chad McNeeley

SAN DIEGO—Haploidentical bone marrow transplant (haplo-BMT) is a feasible option for patients with high-risk hematologic malignancies who don’t have timely access to an HLA-matched donor, according to a speaker at the 2015 BMT Tandem Meetings.

Haplo-BMT using myeloablative conditioning, T-cell replete grafts, and post-transplant cyclophosphamide elicited “excellent” rates of engraftment, graft-vs-host disease (GVHD), and transplant-related mortality, said Heather Symons, MD, of The Johns Hopkins University School of Medicine in Baltimore, Maryland.

Dr Symons presented these results at the meeting as abstract 6*, which was chosen as one of the meeting’s “Best Abstracts.” The research was funded by Otsuka Pharmaceuticals.

Dr Symons and her colleagues conducted a phase 2 study of 96 patients with high-risk hematologic malignancies and a median age of 42 (range, 1-65). Males made up 58% of the population.

Diagnoses included acute and chronic leukemias, lymphomas, multiple myeloma, and myelodysplastic syndromes. Some patients were in complete remission, and some were in chemo-sensitive partial remission. There was also a mix of minimal residual disease positivity and negativity.

“Given the heterogeneity of these patients, we further classified our patients by disease risk index,” Dr Symons said. “We used the revised disease risk index as published by Armand in 2013. The disease risk index, or DRI, assigned patients into overall survival risk groups based on disease type and status.”

So 6 patients had a low DRI, 61 had an intermediate DRI, and 29 had a high DRI.

For most patients (n=73), conditioning consisted of intravenous busulfan (pharmacokinetically adjusted) on days –6 to –3 and cyclophosphamide (50 mg/kg/day) on days –2 and –1. But 23 patients (those with acute lymphocytic leukemia or lymphoblastic lymphoma) received cyclophosphamide (50 mg/kg/day) on days –5 and –4 and total body irradiation (200 cGy twice daily) on days –3 to -1.

All patients received T-cell-replete bone marrow from haploidentical, related donors. The median number of HLA mismatches was 4.

Post-transplant immunosuppression consisted of cyclophosphamide (50 mg/kg/day) on days 3 and 4, followed by mycophenolate mofetil for 30 days and tacrolimus for 6 months.

‘Excellent’ outcomes

The median follow-up was 18 months (range, 3-59). The median time to neutrophil engraftment was 24 days, and the median time to platelet engraftment was 29 days. Ninety-one percent of patients had donor chimerism greater than 95% at day 60.

The cumulative incidence of acute GVHD was 17% for grades 2-4 and 7% for grades 3-4. The cumulative incidence of chronic GHVD was 15%. For moderate-to-severe chronic GVHD, it was 5%.

Twenty-four percent of patients had CMV reactivation, and 22% had hemorrhagic cystitis.

The rate of relapse was 36% at 1 year and 44% at 3 years. The transplant-related mortality rate was 6% at 100 days and 11% at 1 year.

Ten patients died—2 from GVHD, 1 of cardiomyopathy, 2 of veno-occlusive disease, 1 of drug-induced liver injury, 2 due to infection, and 2 of unknown causes.

Overall survival was 72% at 1 year, 57% at 2 years, and 51% at 3 years. Event-free survival was 56% at 1 year, 51% at 2 years, and 47% at 3 years.

A multivariate analysis revealed that overall survival decreased with increasing age and increasing DRI.

Compared to patients younger than 20, the hazard ratio (HR) was 6.3 for patients ages 20 to 50 (P=0.02) and 4.7 for patients older than 50 (P=0.04). Compared to patients with a low or intermediate DRI, the HR was 2.2 for those with a high DRI (P=0.03).

The analysis also indicated that increasing age and donor CMV-positivity conferred worse event-free survival.

Compared to patients younger than 20, the HR was 3.6 for patients ages 20 to 50 (P=0.04) and 4.0 for patients older than 50 (P=0.03). Compared to patients who had a CMV-negative donor, the HR was 2.2 for patients who had a CMV-positive donor (P=0.01).

“In conclusion, myeloablative haploidentical bone marrow transplantation with post-transplantation cyclophosphamide for high-risk hematologic malignancies has excellent rates of engraftment, graft-vs-host disease, and transplant-related mortality, with results that are similar to those described in myeloablative HLA-matched bone marrow transplantation,” Dr Symons said.

“Overall, this seems a feasible option for high-risk patients who lack timely access to an HLA-matched donor and warrants continued study. We are soon to start enrolling patients on a Pediatric Blood & Marrow Transplant Consortium trial using myeloablative conditioning, haploidentical donors, and post-transplantation cyclophosphamide.”

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

Bone marrow harvest

Photo by Chad McNeeley

SAN DIEGO—Haploidentical bone marrow transplant (haplo-BMT) is a feasible option for patients with high-risk hematologic malignancies who don’t have timely access to an HLA-matched donor, according to a speaker at the 2015 BMT Tandem Meetings.

Haplo-BMT using myeloablative conditioning, T-cell replete grafts, and post-transplant cyclophosphamide elicited “excellent” rates of engraftment, graft-vs-host disease (GVHD), and transplant-related mortality, said Heather Symons, MD, of The Johns Hopkins University School of Medicine in Baltimore, Maryland.

Dr Symons presented these results at the meeting as abstract 6*, which was chosen as one of the meeting’s “Best Abstracts.” The research was funded by Otsuka Pharmaceuticals.

Dr Symons and her colleagues conducted a phase 2 study of 96 patients with high-risk hematologic malignancies and a median age of 42 (range, 1-65). Males made up 58% of the population.

Diagnoses included acute and chronic leukemias, lymphomas, multiple myeloma, and myelodysplastic syndromes. Some patients were in complete remission, and some were in chemo-sensitive partial remission. There was also a mix of minimal residual disease positivity and negativity.

“Given the heterogeneity of these patients, we further classified our patients by disease risk index,” Dr Symons said. “We used the revised disease risk index as published by Armand in 2013. The disease risk index, or DRI, assigned patients into overall survival risk groups based on disease type and status.”

So 6 patients had a low DRI, 61 had an intermediate DRI, and 29 had a high DRI.

For most patients (n=73), conditioning consisted of intravenous busulfan (pharmacokinetically adjusted) on days –6 to –3 and cyclophosphamide (50 mg/kg/day) on days –2 and –1. But 23 patients (those with acute lymphocytic leukemia or lymphoblastic lymphoma) received cyclophosphamide (50 mg/kg/day) on days –5 and –4 and total body irradiation (200 cGy twice daily) on days –3 to -1.

All patients received T-cell-replete bone marrow from haploidentical, related donors. The median number of HLA mismatches was 4.

Post-transplant immunosuppression consisted of cyclophosphamide (50 mg/kg/day) on days 3 and 4, followed by mycophenolate mofetil for 30 days and tacrolimus for 6 months.

‘Excellent’ outcomes

The median follow-up was 18 months (range, 3-59). The median time to neutrophil engraftment was 24 days, and the median time to platelet engraftment was 29 days. Ninety-one percent of patients had donor chimerism greater than 95% at day 60.

The cumulative incidence of acute GVHD was 17% for grades 2-4 and 7% for grades 3-4. The cumulative incidence of chronic GHVD was 15%. For moderate-to-severe chronic GVHD, it was 5%.

Twenty-four percent of patients had CMV reactivation, and 22% had hemorrhagic cystitis.

The rate of relapse was 36% at 1 year and 44% at 3 years. The transplant-related mortality rate was 6% at 100 days and 11% at 1 year.

Ten patients died—2 from GVHD, 1 of cardiomyopathy, 2 of veno-occlusive disease, 1 of drug-induced liver injury, 2 due to infection, and 2 of unknown causes.

Overall survival was 72% at 1 year, 57% at 2 years, and 51% at 3 years. Event-free survival was 56% at 1 year, 51% at 2 years, and 47% at 3 years.

A multivariate analysis revealed that overall survival decreased with increasing age and increasing DRI.

Compared to patients younger than 20, the hazard ratio (HR) was 6.3 for patients ages 20 to 50 (P=0.02) and 4.7 for patients older than 50 (P=0.04). Compared to patients with a low or intermediate DRI, the HR was 2.2 for those with a high DRI (P=0.03).

The analysis also indicated that increasing age and donor CMV-positivity conferred worse event-free survival.

Compared to patients younger than 20, the HR was 3.6 for patients ages 20 to 50 (P=0.04) and 4.0 for patients older than 50 (P=0.03). Compared to patients who had a CMV-negative donor, the HR was 2.2 for patients who had a CMV-positive donor (P=0.01).

“In conclusion, myeloablative haploidentical bone marrow transplantation with post-transplantation cyclophosphamide for high-risk hematologic malignancies has excellent rates of engraftment, graft-vs-host disease, and transplant-related mortality, with results that are similar to those described in myeloablative HLA-matched bone marrow transplantation,” Dr Symons said.

“Overall, this seems a feasible option for high-risk patients who lack timely access to an HLA-matched donor and warrants continued study. We are soon to start enrolling patients on a Pediatric Blood & Marrow Transplant Consortium trial using myeloablative conditioning, haploidentical donors, and post-transplantation cyclophosphamide.”

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

Bone marrow harvest

Photo by Chad McNeeley

SAN DIEGO—Haploidentical bone marrow transplant (haplo-BMT) is a feasible option for patients with high-risk hematologic malignancies who don’t have timely access to an HLA-matched donor, according to a speaker at the 2015 BMT Tandem Meetings.

Haplo-BMT using myeloablative conditioning, T-cell replete grafts, and post-transplant cyclophosphamide elicited “excellent” rates of engraftment, graft-vs-host disease (GVHD), and transplant-related mortality, said Heather Symons, MD, of The Johns Hopkins University School of Medicine in Baltimore, Maryland.

Dr Symons presented these results at the meeting as abstract 6*, which was chosen as one of the meeting’s “Best Abstracts.” The research was funded by Otsuka Pharmaceuticals.

Dr Symons and her colleagues conducted a phase 2 study of 96 patients with high-risk hematologic malignancies and a median age of 42 (range, 1-65). Males made up 58% of the population.

Diagnoses included acute and chronic leukemias, lymphomas, multiple myeloma, and myelodysplastic syndromes. Some patients were in complete remission, and some were in chemo-sensitive partial remission. There was also a mix of minimal residual disease positivity and negativity.

“Given the heterogeneity of these patients, we further classified our patients by disease risk index,” Dr Symons said. “We used the revised disease risk index as published by Armand in 2013. The disease risk index, or DRI, assigned patients into overall survival risk groups based on disease type and status.”

So 6 patients had a low DRI, 61 had an intermediate DRI, and 29 had a high DRI.

For most patients (n=73), conditioning consisted of intravenous busulfan (pharmacokinetically adjusted) on days –6 to –3 and cyclophosphamide (50 mg/kg/day) on days –2 and –1. But 23 patients (those with acute lymphocytic leukemia or lymphoblastic lymphoma) received cyclophosphamide (50 mg/kg/day) on days –5 and –4 and total body irradiation (200 cGy twice daily) on days –3 to -1.

All patients received T-cell-replete bone marrow from haploidentical, related donors. The median number of HLA mismatches was 4.

Post-transplant immunosuppression consisted of cyclophosphamide (50 mg/kg/day) on days 3 and 4, followed by mycophenolate mofetil for 30 days and tacrolimus for 6 months.

‘Excellent’ outcomes

The median follow-up was 18 months (range, 3-59). The median time to neutrophil engraftment was 24 days, and the median time to platelet engraftment was 29 days. Ninety-one percent of patients had donor chimerism greater than 95% at day 60.

The cumulative incidence of acute GVHD was 17% for grades 2-4 and 7% for grades 3-4. The cumulative incidence of chronic GHVD was 15%. For moderate-to-severe chronic GVHD, it was 5%.

Twenty-four percent of patients had CMV reactivation, and 22% had hemorrhagic cystitis.

The rate of relapse was 36% at 1 year and 44% at 3 years. The transplant-related mortality rate was 6% at 100 days and 11% at 1 year.

Ten patients died—2 from GVHD, 1 of cardiomyopathy, 2 of veno-occlusive disease, 1 of drug-induced liver injury, 2 due to infection, and 2 of unknown causes.

Overall survival was 72% at 1 year, 57% at 2 years, and 51% at 3 years. Event-free survival was 56% at 1 year, 51% at 2 years, and 47% at 3 years.

A multivariate analysis revealed that overall survival decreased with increasing age and increasing DRI.

Compared to patients younger than 20, the hazard ratio (HR) was 6.3 for patients ages 20 to 50 (P=0.02) and 4.7 for patients older than 50 (P=0.04). Compared to patients with a low or intermediate DRI, the HR was 2.2 for those with a high DRI (P=0.03).

The analysis also indicated that increasing age and donor CMV-positivity conferred worse event-free survival.

Compared to patients younger than 20, the HR was 3.6 for patients ages 20 to 50 (P=0.04) and 4.0 for patients older than 50 (P=0.03). Compared to patients who had a CMV-negative donor, the HR was 2.2 for patients who had a CMV-positive donor (P=0.01).

“In conclusion, myeloablative haploidentical bone marrow transplantation with post-transplantation cyclophosphamide for high-risk hematologic malignancies has excellent rates of engraftment, graft-vs-host disease, and transplant-related mortality, with results that are similar to those described in myeloablative HLA-matched bone marrow transplantation,” Dr Symons said.

“Overall, this seems a feasible option for high-risk patients who lack timely access to an HLA-matched donor and warrants continued study. We are soon to start enrolling patients on a Pediatric Blood & Marrow Transplant Consortium trial using myeloablative conditioning, haploidentical donors, and post-transplantation cyclophosphamide.”

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

PBSC collection

Photo courtesy of Canterbury

District Health Board

SAN DIEGO—New research indicates that older stem cell donors have somewhat poorer overall health before they donate, but their health-related quality of life (HRQOL) post-donation is similar to that of younger donors.

In fact, the older donors included in this study actually fared better than their younger counterparts in some respects.

Galen E. Switzer, PhD, of the University of Pittsburgh in Pennsylvania, presented these results at the 2015 BMT Tandem Meetings (abstract 27*).

“[Older donors] may be at greater physical and psychological risk because of their age and comorbid conditions,” Dr Switzer noted. “So it’s critical for us to understand the health-related quality of life experiences of these donors.”

With that in mind, he and his colleagues evaluated 163 subjects who donated peripheral blood stem cells (PBSCs) to relatives in need of a transplant. The team compared donors over the age of 60 (n=104, median age 66 years) to those aged 18 to 60 (n=59, median age 41 years).

The investigators collected data via structured telephone interviews 2 weeks before PBSC donation and at 4 weeks and 1 year post-donation.

A comparison of sociodemographic factors revealed that older PBSC donors were significantly less likely to be employed (P<0.001) but more likely be white (P=0.009), be married (P=0.044), and have children (P<0.001).

Pre- and post-donation HRQOL

Pre-donation, older donors had significantly poorer physical health (P=0.001) and better mental health (P=0.036) than younger donors. But there was no significant difference between the age groups with regard to the incidence of depression or anxiety.

Similarly, there were no significant differences with regard to ambivalence, satisfaction, or medical concerns about donation. However, older donors were more likely to consult their physician about donation (P=0.049), and they had fewer work/family concerns (P=0.049) than younger donors.

At 4 weeks post-donation, there were no significant differences between the age groups with regard to general physical health, mental health, or any of 12 donation-related symptoms. However, younger donors were significantly more likely to report that donation was painful (P=0.025).

Older donors were significantly less likely to report work/family concerns, such as missing work, family worry, or worry about what others would think (P=0.001). They were less likely to have other donation-related concerns as well, such as worrying about who would pay for the procedure (P=0.034). And they were less likely to say they would feel responsible if the transplant did not have a favorable outcome (P=0.022).

At 1 year post-donation, there were no significant differences between the age groups with regard to overall physical and mental health, depression, ambivalence, satisfaction, 11 of 12 donation side effects, physical difficulty, psychological difficulty, or “other concerns.”

However, older donors reported significantly less anxiety, fewer medical concerns, and fewer work/family concerns (P<0.05 for all). They were also less likely to feel responsible for transplant outcomes and less likely to have problems sleeping, which was 1 of the 12 donation side effects (P<0.05 for both).

“So the overall conclusion, I think, is really reassuring,” Dr Switzer said. “Despite having somewhat poorer overall general physical health at pre-donation, older donors experience similar—and, in some domains, better—donation-related health-related quality of life than younger donors. So they seem to be doing at least as well and, in some domains, better than their younger counterparts.”

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

PBSC collection

Photo courtesy of Canterbury

District Health Board

SAN DIEGO—New research indicates that older stem cell donors have somewhat poorer overall health before they donate, but their health-related quality of life (HRQOL) post-donation is similar to that of younger donors.

In fact, the older donors included in this study actually fared better than their younger counterparts in some respects.

Galen E. Switzer, PhD, of the University of Pittsburgh in Pennsylvania, presented these results at the 2015 BMT Tandem Meetings (abstract 27*).

“[Older donors] may be at greater physical and psychological risk because of their age and comorbid conditions,” Dr Switzer noted. “So it’s critical for us to understand the health-related quality of life experiences of these donors.”

With that in mind, he and his colleagues evaluated 163 subjects who donated peripheral blood stem cells (PBSCs) to relatives in need of a transplant. The team compared donors over the age of 60 (n=104, median age 66 years) to those aged 18 to 60 (n=59, median age 41 years).

The investigators collected data via structured telephone interviews 2 weeks before PBSC donation and at 4 weeks and 1 year post-donation.

A comparison of sociodemographic factors revealed that older PBSC donors were significantly less likely to be employed (P<0.001) but more likely be white (P=0.009), be married (P=0.044), and have children (P<0.001).

Pre- and post-donation HRQOL

Pre-donation, older donors had significantly poorer physical health (P=0.001) and better mental health (P=0.036) than younger donors. But there was no significant difference between the age groups with regard to the incidence of depression or anxiety.

Similarly, there were no significant differences with regard to ambivalence, satisfaction, or medical concerns about donation. However, older donors were more likely to consult their physician about donation (P=0.049), and they had fewer work/family concerns (P=0.049) than younger donors.

At 4 weeks post-donation, there were no significant differences between the age groups with regard to general physical health, mental health, or any of 12 donation-related symptoms. However, younger donors were significantly more likely to report that donation was painful (P=0.025).

Older donors were significantly less likely to report work/family concerns, such as missing work, family worry, or worry about what others would think (P=0.001). They were less likely to have other donation-related concerns as well, such as worrying about who would pay for the procedure (P=0.034). And they were less likely to say they would feel responsible if the transplant did not have a favorable outcome (P=0.022).

At 1 year post-donation, there were no significant differences between the age groups with regard to overall physical and mental health, depression, ambivalence, satisfaction, 11 of 12 donation side effects, physical difficulty, psychological difficulty, or “other concerns.”

However, older donors reported significantly less anxiety, fewer medical concerns, and fewer work/family concerns (P<0.05 for all). They were also less likely to feel responsible for transplant outcomes and less likely to have problems sleeping, which was 1 of the 12 donation side effects (P<0.05 for both).

“So the overall conclusion, I think, is really reassuring,” Dr Switzer said. “Despite having somewhat poorer overall general physical health at pre-donation, older donors experience similar—and, in some domains, better—donation-related health-related quality of life than younger donors. So they seem to be doing at least as well and, in some domains, better than their younger counterparts.”

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

PBSC collection

Photo courtesy of Canterbury

District Health Board

SAN DIEGO—New research indicates that older stem cell donors have somewhat poorer overall health before they donate, but their health-related quality of life (HRQOL) post-donation is similar to that of younger donors.

In fact, the older donors included in this study actually fared better than their younger counterparts in some respects.

Galen E. Switzer, PhD, of the University of Pittsburgh in Pennsylvania, presented these results at the 2015 BMT Tandem Meetings (abstract 27*).

“[Older donors] may be at greater physical and psychological risk because of their age and comorbid conditions,” Dr Switzer noted. “So it’s critical for us to understand the health-related quality of life experiences of these donors.”

With that in mind, he and his colleagues evaluated 163 subjects who donated peripheral blood stem cells (PBSCs) to relatives in need of a transplant. The team compared donors over the age of 60 (n=104, median age 66 years) to those aged 18 to 60 (n=59, median age 41 years).

The investigators collected data via structured telephone interviews 2 weeks before PBSC donation and at 4 weeks and 1 year post-donation.

A comparison of sociodemographic factors revealed that older PBSC donors were significantly less likely to be employed (P<0.001) but more likely be white (P=0.009), be married (P=0.044), and have children (P<0.001).

Pre- and post-donation HRQOL

Pre-donation, older donors had significantly poorer physical health (P=0.001) and better mental health (P=0.036) than younger donors. But there was no significant difference between the age groups with regard to the incidence of depression or anxiety.

Similarly, there were no significant differences with regard to ambivalence, satisfaction, or medical concerns about donation. However, older donors were more likely to consult their physician about donation (P=0.049), and they had fewer work/family concerns (P=0.049) than younger donors.

At 4 weeks post-donation, there were no significant differences between the age groups with regard to general physical health, mental health, or any of 12 donation-related symptoms. However, younger donors were significantly more likely to report that donation was painful (P=0.025).

Older donors were significantly less likely to report work/family concerns, such as missing work, family worry, or worry about what others would think (P=0.001). They were less likely to have other donation-related concerns as well, such as worrying about who would pay for the procedure (P=0.034). And they were less likely to say they would feel responsible if the transplant did not have a favorable outcome (P=0.022).

At 1 year post-donation, there were no significant differences between the age groups with regard to overall physical and mental health, depression, ambivalence, satisfaction, 11 of 12 donation side effects, physical difficulty, psychological difficulty, or “other concerns.”

However, older donors reported significantly less anxiety, fewer medical concerns, and fewer work/family concerns (P<0.05 for all). They were also less likely to feel responsible for transplant outcomes and less likely to have problems sleeping, which was 1 of the 12 donation side effects (P<0.05 for both).

“So the overall conclusion, I think, is really reassuring,” Dr Switzer said. “Despite having somewhat poorer overall general physical health at pre-donation, older donors experience similar—and, in some domains, better—donation-related health-related quality of life than younger donors. So they seem to be doing at least as well and, in some domains, better than their younger counterparts.”

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