Jen Smith

SAN DIEGO—A dual kinase inhibitor shows potential for treating the heterogeneous acute myeloid leukemia (AML) population, researchers say.

The inhibitor, SEL24-B489, targets both PIM and FLT3 mutants. In experiments, it exhibited more consistent activity across AML cell lines than inhibitors directed only at PIM or FLT3.

SEL24-B489 also demonstrated synergistic activity with cytarabine, both in AML cell lines and mouse models of the disease.

The researchers believe these results suggest SEL24-B489 could potentially treat a range of AML patients and might prove effective regardless of FLT3 status.

“When you have a very heterogeneous population of AML patients, some of them have different FLT mutations, and the problem with FLT inhibitors has been the resistance that occurs in the tyrosine kinase domain,” said Krzysztof D. Brzózka, PhD, of Selvita, the Kraków, Poland-based company developing SEL24-B489.

“We believe that since FLT is upstream, and PIM kinases are downstream of the FLT signaling, we will have higher chances

of overcoming resistance because we are targeting the same pathway at 2 independent nodes.”

Dr Brzózka and his colleagues presented research to support this theory at the AACR Annual Meeting 2014 as abstract 1749.*

The researchers evaluated SEL24-B489 in a range of AML cell lines: MV4-11, MOLM-13, MOLM-16, KG-1, CMK, and HL-60. The drug showed “strong cytotoxicity” across the cell lines, independent of FLT3 status.

The team also compared SEL24-B489 to the PIM inhibitor AZD1208 and the FLT3 inhibitor AC220 in MV4-11 cell lines and MOLM-16 cell lines.

In MV4-11 cells, the IC₅₀ was 0.003 μM for AC220, 0.15 μM for SEL24-B489, and 2.24 μM for AZD1208. In MOLM-16 cells, the IC₅₀ was 0.07 μM for AZD1208, 0.1 μM for SEL24-B489, and >10 μM for AC220.

The researchers then evaluated SEL24-B489 in combination with cytarabine.

“The molecule shows very strong synergistic effects with cytarabine, both in vitro and in vivo,” Dr Brzózka said. “The combination index in vitro is approximately 0.1, 0.2. And in vivo, that translates to [nearly] 100% tumor growth inhibition.”

Tumor growth inhibition (TGI) measured 60% when mice received cytarabine alone at 50 mg/kg. TGI was 77% with SEL24-B489 alone at 25 mg/kg and 82% with SEL24-B489 alone at 50 mg/kg.

But with 25 mg/kg of SEL24-B489 and 50 mg/kg of cytarabine, TGI was 89%. And when both drugs were given at 50 mg/kg, TGI was 99%.

The researchers also assessed SEL24-B489 alone in mouse models of AML. In mice injected with MV4-11 cells, SEL24-B489 at 25 mg/kg BID reduced tumor volume by more than 50%, when compared to untreated control mice. And SEL24-B489 at 75 mg/kg BID reduced tumor volume by more than 80%.

In mice injected with MOLM-16 cells, SEL24-B489 at 25 mg/kg BID reduced tumor volume by more than 80%, when compared to untreated control mice. And SEL24-B489 at 75 mg/kg BID reduced tumor volume by more than 100%.

Finally, the team evaluated the safety of SEL24-B489 via repeated 5-day and 10-day toxicology studies in rats.

And they concluded that doses of 100 mg/kg QD x 5 and 25 mg/kg BID x 10 were safe, based on data concerning body weight gain, as well as results of clinical chemistry, hematology, necropsy, and histological analyses.

“Overall, SEL24-B489 has very good oral bioavailability and initial safety profiling,” Dr Brzózka said. “Both in vitro and in vivo, it shows a pretty promising therapeutic index.”

He and his colleagues are now studying SEL24-B489 in dogs, and Selvita is looking for a partner company to help move the drug to phase 1 trials.

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

SAN DIEGO—A dual kinase inhibitor shows potential for treating the heterogeneous acute myeloid leukemia (AML) population, researchers say.

The inhibitor, SEL24-B489, targets both PIM and FLT3 mutants. In experiments, it exhibited more consistent activity across AML cell lines than inhibitors directed only at PIM or FLT3.

SEL24-B489 also demonstrated synergistic activity with cytarabine, both in AML cell lines and mouse models of the disease.

The researchers believe these results suggest SEL24-B489 could potentially treat a range of AML patients and might prove effective regardless of FLT3 status.

“When you have a very heterogeneous population of AML patients, some of them have different FLT mutations, and the problem with FLT inhibitors has been the resistance that occurs in the tyrosine kinase domain,” said Krzysztof D. Brzózka, PhD, of Selvita, the Kraków, Poland-based company developing SEL24-B489.

“We believe that since FLT is upstream, and PIM kinases are downstream of the FLT signaling, we will have higher chances

of overcoming resistance because we are targeting the same pathway at 2 independent nodes.”

Dr Brzózka and his colleagues presented research to support this theory at the AACR Annual Meeting 2014 as abstract 1749.*

The researchers evaluated SEL24-B489 in a range of AML cell lines: MV4-11, MOLM-13, MOLM-16, KG-1, CMK, and HL-60. The drug showed “strong cytotoxicity” across the cell lines, independent of FLT3 status.

The team also compared SEL24-B489 to the PIM inhibitor AZD1208 and the FLT3 inhibitor AC220 in MV4-11 cell lines and MOLM-16 cell lines.

In MV4-11 cells, the IC₅₀ was 0.003 μM for AC220, 0.15 μM for SEL24-B489, and 2.24 μM for AZD1208. In MOLM-16 cells, the IC₅₀ was 0.07 μM for AZD1208, 0.1 μM for SEL24-B489, and >10 μM for AC220.

The researchers then evaluated SEL24-B489 in combination with cytarabine.

“The molecule shows very strong synergistic effects with cytarabine, both in vitro and in vivo,” Dr Brzózka said. “The combination index in vitro is approximately 0.1, 0.2. And in vivo, that translates to [nearly] 100% tumor growth inhibition.”

Tumor growth inhibition (TGI) measured 60% when mice received cytarabine alone at 50 mg/kg. TGI was 77% with SEL24-B489 alone at 25 mg/kg and 82% with SEL24-B489 alone at 50 mg/kg.

But with 25 mg/kg of SEL24-B489 and 50 mg/kg of cytarabine, TGI was 89%. And when both drugs were given at 50 mg/kg, TGI was 99%.

The researchers also assessed SEL24-B489 alone in mouse models of AML. In mice injected with MV4-11 cells, SEL24-B489 at 25 mg/kg BID reduced tumor volume by more than 50%, when compared to untreated control mice. And SEL24-B489 at 75 mg/kg BID reduced tumor volume by more than 80%.

In mice injected with MOLM-16 cells, SEL24-B489 at 25 mg/kg BID reduced tumor volume by more than 80%, when compared to untreated control mice. And SEL24-B489 at 75 mg/kg BID reduced tumor volume by more than 100%.

Finally, the team evaluated the safety of SEL24-B489 via repeated 5-day and 10-day toxicology studies in rats.

And they concluded that doses of 100 mg/kg QD x 5 and 25 mg/kg BID x 10 were safe, based on data concerning body weight gain, as well as results of clinical chemistry, hematology, necropsy, and histological analyses.

“Overall, SEL24-B489 has very good oral bioavailability and initial safety profiling,” Dr Brzózka said. “Both in vitro and in vivo, it shows a pretty promising therapeutic index.”

He and his colleagues are now studying SEL24-B489 in dogs, and Selvita is looking for a partner company to help move the drug to phase 1 trials.

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

SAN DIEGO—A dual kinase inhibitor shows potential for treating the heterogeneous acute myeloid leukemia (AML) population, researchers say.

The inhibitor, SEL24-B489, targets both PIM and FLT3 mutants. In experiments, it exhibited more consistent activity across AML cell lines than inhibitors directed only at PIM or FLT3.

SEL24-B489 also demonstrated synergistic activity with cytarabine, both in AML cell lines and mouse models of the disease.

The researchers believe these results suggest SEL24-B489 could potentially treat a range of AML patients and might prove effective regardless of FLT3 status.

“When you have a very heterogeneous population of AML patients, some of them have different FLT mutations, and the problem with FLT inhibitors has been the resistance that occurs in the tyrosine kinase domain,” said Krzysztof D. Brzózka, PhD, of Selvita, the Kraków, Poland-based company developing SEL24-B489.

“We believe that since FLT is upstream, and PIM kinases are downstream of the FLT signaling, we will have higher chances

of overcoming resistance because we are targeting the same pathway at 2 independent nodes.”

Dr Brzózka and his colleagues presented research to support this theory at the AACR Annual Meeting 2014 as abstract 1749.*

The researchers evaluated SEL24-B489 in a range of AML cell lines: MV4-11, MOLM-13, MOLM-16, KG-1, CMK, and HL-60. The drug showed “strong cytotoxicity” across the cell lines, independent of FLT3 status.

The team also compared SEL24-B489 to the PIM inhibitor AZD1208 and the FLT3 inhibitor AC220 in MV4-11 cell lines and MOLM-16 cell lines.

In MV4-11 cells, the IC₅₀ was 0.003 μM for AC220, 0.15 μM for SEL24-B489, and 2.24 μM for AZD1208. In MOLM-16 cells, the IC₅₀ was 0.07 μM for AZD1208, 0.1 μM for SEL24-B489, and >10 μM for AC220.

The researchers then evaluated SEL24-B489 in combination with cytarabine.

“The molecule shows very strong synergistic effects with cytarabine, both in vitro and in vivo,” Dr Brzózka said. “The combination index in vitro is approximately 0.1, 0.2. And in vivo, that translates to [nearly] 100% tumor growth inhibition.”

Tumor growth inhibition (TGI) measured 60% when mice received cytarabine alone at 50 mg/kg. TGI was 77% with SEL24-B489 alone at 25 mg/kg and 82% with SEL24-B489 alone at 50 mg/kg.

But with 25 mg/kg of SEL24-B489 and 50 mg/kg of cytarabine, TGI was 89%. And when both drugs were given at 50 mg/kg, TGI was 99%.

The researchers also assessed SEL24-B489 alone in mouse models of AML. In mice injected with MV4-11 cells, SEL24-B489 at 25 mg/kg BID reduced tumor volume by more than 50%, when compared to untreated control mice. And SEL24-B489 at 75 mg/kg BID reduced tumor volume by more than 80%.

In mice injected with MOLM-16 cells, SEL24-B489 at 25 mg/kg BID reduced tumor volume by more than 80%, when compared to untreated control mice. And SEL24-B489 at 75 mg/kg BID reduced tumor volume by more than 100%.

Finally, the team evaluated the safety of SEL24-B489 via repeated 5-day and 10-day toxicology studies in rats.

And they concluded that doses of 100 mg/kg QD x 5 and 25 mg/kg BID x 10 were safe, based on data concerning body weight gain, as well as results of clinical chemistry, hematology, necropsy, and histological analyses.

“Overall, SEL24-B489 has very good oral bioavailability and initial safety profiling,” Dr Brzózka said. “Both in vitro and in vivo, it shows a pretty promising therapeutic index.”

He and his colleagues are now studying SEL24-B489 in dogs, and Selvita is looking for a partner company to help move the drug to phase 1 trials.

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

SAN DIEGO—Experiments conducted in the lab and the clinic suggest the enzyme heparanase enhances resistance to chemotherapy in multiple myeloma (MM).

Researchers first found that expression of heparanase, an endoglycosidase that cleaves heparan sulfate, is highly elevated in MM patients after chemotherapy.

The team then used MM cell lines to investigate the mechanism behind this phenomenon.

Their results indicate that, by inhibiting heparanase, we might be able to prevent or delay relapse in MM.

Vishnu Ramani, PhD, of the University of Alabama Birmingham, and his colleagues conducted this research and presented the results at the AACR Annual Meeting 2014 (abstract 1708).

Several years ago, Dr Ramani’s colleagues (in the lab of Ralph Sanderson, PhD) identified heparanase as a master regulator of aggressive MM. Since then, research has suggested that heparanase fuels aggressive MM by upregulating the expression of pro-angiogenic genes, driving osteolysis, upregulating prometastatic molecules, and controlling the tumor microenvironment.

“We have done a lot of work on the biology of how this molecule works in myeloma, but the one thing I was really interested in was its role in drug resistance,” Dr Ramani said.

So he and his colleagues decided to study heparanase levels in 9 MM patients undergoing chemotherapy. The team isolated tumor cells from patients before and after 2 rounds of chemotherapy and compared heparanase levels at the different time points.

“What we find—and this is really remarkable—is that the expression of heparanase over rounds of therapy goes up several thousand-fold, and this is in the majority of patients,” Dr Ramani said. “In 8 out of 9 patients that we studied, at the end of chemotherapy, the cells that survive have extremely high levels of heparanase.”

To gain more insight into this phenomenon, the researchers studied it in MM cell lines. The team introduced bortezomib to RPMI-8226 and CAG cells and found that heparanase levels increased “dramatically” after treatment.

“The treatment is not only increasing the heparanase expression inside the cell,” Dr Ramani explained. “What the cells do is that, if you continue the treatment, they die, but they don’t take the heparanase with them. They leave it out in the media, and this can be taken in by other cells. So this can activate other cells to promote aggressive tumor growth too.”

Additional investigation revealed that the NF-κB pathway plays a role—namely, chemotherapy activates the pathway to upregulate heparanase. But inhibiting NF-κB activity can prevent that increase in heparanase.

The researchers tested the NF-κB inhibitors BAY 11-7085 and BMS345541 in combination with bortezomib. And they found that both agents prevented bortezomib from elevating heparanase expression in CAG cells.

Dr Ramani and his colleagues also evaluated heparanase levels in chemoresistant MM cell lines. Heparanase levels were 4-fold higher in a doxorubicin-resistant MM cell line and 10-fold higher in a melphalan-resistant cell line, when compared to a wild-type MM cell line.

Next, the researchers compared MM cells with high heparanase expression to those with low heparanase expression. And they discovered that high heparanase levels protect cells from chemotherapy.

After treatment with bortezomib, cells with high heparanase expression were significantly more viable than those with low expression (P<0.05). And there was a significantly higher percentage of apoptotic cells among the low-heparanase population compared to the high-heparanase population (P<0.05).

“If you take cells that have high heparanase and another group of cells that have low heparanase and expose both of them to therapy, the cells with high heparanase always survive better because the heparanase upregulates certain pathways, like the MAP kinase pathway, which helps the cells to survive the onslaught of chemotherapy,” Dr Ramani said. “So myeloma cells are actually hijacking the heparanase pathway to survive better after therapy.”

Building upon that finding, the researchers decided to assess whether inhibiting ERK activity might help cells overcome heparanase-mediated chemoresistance. And experiments showed that the ERK inhibitor U0126 can sensitize cells with high heparanase levels to treatment with bortezomib.

To take this research to the next level, Dr Ramani and his colleagues are collaborating with a company called Sigma Tau, which is developing a heparanase inhibitor called SST-0001. A phase 1 study of the drug in MM patients has been completed, and phase 2 studies are currently recruiting patients in Europe.

Dr Ramani is now conducting experiments in mice to determine how the inhibitor might work in combination with chemotherapy and when it should be administered in order to overcome treatment resistance. He is also looking for other molecular pathways that could be involved in heparanase-related treatment resistance.

SAN DIEGO—Experiments conducted in the lab and the clinic suggest the enzyme heparanase enhances resistance to chemotherapy in multiple myeloma (MM).

Researchers first found that expression of heparanase, an endoglycosidase that cleaves heparan sulfate, is highly elevated in MM patients after chemotherapy.

The team then used MM cell lines to investigate the mechanism behind this phenomenon.

Their results indicate that, by inhibiting heparanase, we might be able to prevent or delay relapse in MM.

Vishnu Ramani, PhD, of the University of Alabama Birmingham, and his colleagues conducted this research and presented the results at the AACR Annual Meeting 2014 (abstract 1708).

Several years ago, Dr Ramani’s colleagues (in the lab of Ralph Sanderson, PhD) identified heparanase as a master regulator of aggressive MM. Since then, research has suggested that heparanase fuels aggressive MM by upregulating the expression of pro-angiogenic genes, driving osteolysis, upregulating prometastatic molecules, and controlling the tumor microenvironment.

“We have done a lot of work on the biology of how this molecule works in myeloma, but the one thing I was really interested in was its role in drug resistance,” Dr Ramani said.

So he and his colleagues decided to study heparanase levels in 9 MM patients undergoing chemotherapy. The team isolated tumor cells from patients before and after 2 rounds of chemotherapy and compared heparanase levels at the different time points.

“What we find—and this is really remarkable—is that the expression of heparanase over rounds of therapy goes up several thousand-fold, and this is in the majority of patients,” Dr Ramani said. “In 8 out of 9 patients that we studied, at the end of chemotherapy, the cells that survive have extremely high levels of heparanase.”

To gain more insight into this phenomenon, the researchers studied it in MM cell lines. The team introduced bortezomib to RPMI-8226 and CAG cells and found that heparanase levels increased “dramatically” after treatment.

“The treatment is not only increasing the heparanase expression inside the cell,” Dr Ramani explained. “What the cells do is that, if you continue the treatment, they die, but they don’t take the heparanase with them. They leave it out in the media, and this can be taken in by other cells. So this can activate other cells to promote aggressive tumor growth too.”

Additional investigation revealed that the NF-κB pathway plays a role—namely, chemotherapy activates the pathway to upregulate heparanase. But inhibiting NF-κB activity can prevent that increase in heparanase.

The researchers tested the NF-κB inhibitors BAY 11-7085 and BMS345541 in combination with bortezomib. And they found that both agents prevented bortezomib from elevating heparanase expression in CAG cells.

Dr Ramani and his colleagues also evaluated heparanase levels in chemoresistant MM cell lines. Heparanase levels were 4-fold higher in a doxorubicin-resistant MM cell line and 10-fold higher in a melphalan-resistant cell line, when compared to a wild-type MM cell line.

Next, the researchers compared MM cells with high heparanase expression to those with low heparanase expression. And they discovered that high heparanase levels protect cells from chemotherapy.

After treatment with bortezomib, cells with high heparanase expression were significantly more viable than those with low expression (P<0.05). And there was a significantly higher percentage of apoptotic cells among the low-heparanase population compared to the high-heparanase population (P<0.05).

“If you take cells that have high heparanase and another group of cells that have low heparanase and expose both of them to therapy, the cells with high heparanase always survive better because the heparanase upregulates certain pathways, like the MAP kinase pathway, which helps the cells to survive the onslaught of chemotherapy,” Dr Ramani said. “So myeloma cells are actually hijacking the heparanase pathway to survive better after therapy.”

Building upon that finding, the researchers decided to assess whether inhibiting ERK activity might help cells overcome heparanase-mediated chemoresistance. And experiments showed that the ERK inhibitor U0126 can sensitize cells with high heparanase levels to treatment with bortezomib.

To take this research to the next level, Dr Ramani and his colleagues are collaborating with a company called Sigma Tau, which is developing a heparanase inhibitor called SST-0001. A phase 1 study of the drug in MM patients has been completed, and phase 2 studies are currently recruiting patients in Europe.

Dr Ramani is now conducting experiments in mice to determine how the inhibitor might work in combination with chemotherapy and when it should be administered in order to overcome treatment resistance. He is also looking for other molecular pathways that could be involved in heparanase-related treatment resistance.

SAN DIEGO—Experiments conducted in the lab and the clinic suggest the enzyme heparanase enhances resistance to chemotherapy in multiple myeloma (MM).

Researchers first found that expression of heparanase, an endoglycosidase that cleaves heparan sulfate, is highly elevated in MM patients after chemotherapy.

The team then used MM cell lines to investigate the mechanism behind this phenomenon.

Their results indicate that, by inhibiting heparanase, we might be able to prevent or delay relapse in MM.

Vishnu Ramani, PhD, of the University of Alabama Birmingham, and his colleagues conducted this research and presented the results at the AACR Annual Meeting 2014 (abstract 1708).

Several years ago, Dr Ramani’s colleagues (in the lab of Ralph Sanderson, PhD) identified heparanase as a master regulator of aggressive MM. Since then, research has suggested that heparanase fuels aggressive MM by upregulating the expression of pro-angiogenic genes, driving osteolysis, upregulating prometastatic molecules, and controlling the tumor microenvironment.

“We have done a lot of work on the biology of how this molecule works in myeloma, but the one thing I was really interested in was its role in drug resistance,” Dr Ramani said.

So he and his colleagues decided to study heparanase levels in 9 MM patients undergoing chemotherapy. The team isolated tumor cells from patients before and after 2 rounds of chemotherapy and compared heparanase levels at the different time points.

“What we find—and this is really remarkable—is that the expression of heparanase over rounds of therapy goes up several thousand-fold, and this is in the majority of patients,” Dr Ramani said. “In 8 out of 9 patients that we studied, at the end of chemotherapy, the cells that survive have extremely high levels of heparanase.”

To gain more insight into this phenomenon, the researchers studied it in MM cell lines. The team introduced bortezomib to RPMI-8226 and CAG cells and found that heparanase levels increased “dramatically” after treatment.

“The treatment is not only increasing the heparanase expression inside the cell,” Dr Ramani explained. “What the cells do is that, if you continue the treatment, they die, but they don’t take the heparanase with them. They leave it out in the media, and this can be taken in by other cells. So this can activate other cells to promote aggressive tumor growth too.”

Additional investigation revealed that the NF-κB pathway plays a role—namely, chemotherapy activates the pathway to upregulate heparanase. But inhibiting NF-κB activity can prevent that increase in heparanase.

The researchers tested the NF-κB inhibitors BAY 11-7085 and BMS345541 in combination with bortezomib. And they found that both agents prevented bortezomib from elevating heparanase expression in CAG cells.

Dr Ramani and his colleagues also evaluated heparanase levels in chemoresistant MM cell lines. Heparanase levels were 4-fold higher in a doxorubicin-resistant MM cell line and 10-fold higher in a melphalan-resistant cell line, when compared to a wild-type MM cell line.

Next, the researchers compared MM cells with high heparanase expression to those with low heparanase expression. And they discovered that high heparanase levels protect cells from chemotherapy.

After treatment with bortezomib, cells with high heparanase expression were significantly more viable than those with low expression (P<0.05). And there was a significantly higher percentage of apoptotic cells among the low-heparanase population compared to the high-heparanase population (P<0.05).

“If you take cells that have high heparanase and another group of cells that have low heparanase and expose both of them to therapy, the cells with high heparanase always survive better because the heparanase upregulates certain pathways, like the MAP kinase pathway, which helps the cells to survive the onslaught of chemotherapy,” Dr Ramani said. “So myeloma cells are actually hijacking the heparanase pathway to survive better after therapy.”

Building upon that finding, the researchers decided to assess whether inhibiting ERK activity might help cells overcome heparanase-mediated chemoresistance. And experiments showed that the ERK inhibitor U0126 can sensitize cells with high heparanase levels to treatment with bortezomib.

To take this research to the next level, Dr Ramani and his colleagues are collaborating with a company called Sigma Tau, which is developing a heparanase inhibitor called SST-0001. A phase 1 study of the drug in MM patients has been completed, and phase 2 studies are currently recruiting patients in Europe.

Dr Ramani is now conducting experiments in mice to determine how the inhibitor might work in combination with chemotherapy and when it should be administered in order to overcome treatment resistance. He is also looking for other molecular pathways that could be involved in heparanase-related treatment resistance.

SAN DIEGO—Results of a pilot study suggest an experimental molecule can increase hemoglobin levels in patients with hematologic malignancies who are suffering from anemia.

The molecule, lexaptepid pegol (NOX-H94), is a pegylated L-stereoisomer RNA aptamer that binds and neutralizes hepcidin.

In this phase 2 study, 5 of 12 patients who received lexaptepid pegol experienced a hemoglobin increase of 1 g/dL or greater and qualified as responders.

Researchers presented these results at the AACR Annual Meeting 2014 as abstract 3847. The study was supported by NOXXON Pharma AG, the Berlin, Germany-based company developing lexaptepid pegol.

“Our concept is to treat anemia by inhibiting the activity of hepcidin,” said study investigator Kai Riecke, MD, of NOXXON Pharma.

“Hepcidin regulates iron in the blood. The problem is that, in quite a few tumors, hepcidin reduces iron in the circulation, and, over a long period of time, that leads to iron-restricted anemia.”

So Dr Riecke and his colleagues tested their antihepcidin molecule, lexaptepid pegol, in anemic cancer patients. The team enrolled patients with hemoglobin levels less than 10 g/dL who had been diagnosed with multiple myeloma, chronic lymphocytic leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma.

The patients had a median age of 64 years (range, 35-77). At baseline, the mean hemoglobin was 9.5 ± 0.2 g/dL, the mean serum ferritin was 1067 ± 297 μg/L, the mean serum iron was 34 ± 6 μg/dL, and the mean transferrin saturation was 16.7 ± 3.4%.

The patients received twice-weekly intravenous infusions of lexaptepid pegol for 4 weeks, and the researchers observed patients for 1 month after treatment. Patients were not allowed to receive erythropoiesis-stimulating agents or iron products during the study period.

The results showed increases in hemoglobin of 1 g/dL or greater, which qualified as a response, in 5 of the 12 patients (42%). Three patients achieved a response within 2 weeks of treatment initiation. All 5 patients maintained the increase in hemoglobin throughout the follow-up period.

There was no clear difference in response among the different malignancies, Dr Reike said. But he also noted that, as the study included a small number of patients, it wasn’t really possible for the researchers to make a fair comparison.

In addition to increasing hemoglobin levels, lexaptepid pegol decreased the mean serum ferritin from 1067 μg/L to 815 μg/L in the entire cohort of patients (P=0.014) and from 772 μg/L to 462 μg/L in responders (but this was not significant).

Reticulocyte hemoglobin increased from 22.7 pg to 24.9 pg (P=0.019) in responding patients, but there was no increase in non-responders. (Data for this measurement were only available for 3 of the responders—but all 7 of the non-responders—due to differences in measurement capabilities at the different research sites).

“During the treatment, we saw a very nice increase in reticulocyte hemoglobin, which shows, in these patients, the red blood cells were able to take up iron and build up more hemoglobin,” Dr Riecke said.

The researchers also observed an increase in the mean reticulocyte index in responding patients, from 0.9 to 1.2, although the increase was not significant.

“So this shows that, not only do you have an increase in hemoglobin within each reticulocyte, but you have an increase in the number of reticulocytes—something that we didn’t really expect in the beginning,” Dr Riecke said. “And this may be a sign that the efficacy of erythropoiesis is improved.”

Additionally, responding patients experienced a decrease in soluble transferrin receptor levels, from 10.0 mg/L to 8.6 mg/L, although this was not significant. Soluble transferrin receptor levels remained unchanged in non-responders. (Data for this measurement were only available for 3 of the responders and 4 of the non-responders.)

“The decrease in soluble transferrin receptor levels is a sign that, in the beginning, the cells were very iron-hungry, and then their hunger was satisfied—at least to a certain extent—during the treatment with our drug,” Dr Reike said. “This is a sign that, by reducing hepcidin, more iron is being released into the circulation, and this iron can effectively be used for erythropoiesis.”

Dr Reike added that, although the researchers did observe some adverse effects in the patients, none of these could be clearly attributed to lexaptepid pegol.

Some of the patients did have low blood pressure shortly after treatment, but that may have been influenced by factors other than treatment, he said. Furthermore, in the phase 1 study of lexaptepid pegol in healthy subjects, the only adverse effect that occurred in the treatment arm (and not in the placebo arm) was headache.

Based on these results, NOXXON is now planning—and recruiting for—a study of lexaptepid pegol in dialysis patients.

SAN DIEGO—Results of a pilot study suggest an experimental molecule can increase hemoglobin levels in patients with hematologic malignancies who are suffering from anemia.

The molecule, lexaptepid pegol (NOX-H94), is a pegylated L-stereoisomer RNA aptamer that binds and neutralizes hepcidin.

In this phase 2 study, 5 of 12 patients who received lexaptepid pegol experienced a hemoglobin increase of 1 g/dL or greater and qualified as responders.

Researchers presented these results at the AACR Annual Meeting 2014 as abstract 3847. The study was supported by NOXXON Pharma AG, the Berlin, Germany-based company developing lexaptepid pegol.

“Our concept is to treat anemia by inhibiting the activity of hepcidin,” said study investigator Kai Riecke, MD, of NOXXON Pharma.

“Hepcidin regulates iron in the blood. The problem is that, in quite a few tumors, hepcidin reduces iron in the circulation, and, over a long period of time, that leads to iron-restricted anemia.”

So Dr Riecke and his colleagues tested their antihepcidin molecule, lexaptepid pegol, in anemic cancer patients. The team enrolled patients with hemoglobin levels less than 10 g/dL who had been diagnosed with multiple myeloma, chronic lymphocytic leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma.

The patients had a median age of 64 years (range, 35-77). At baseline, the mean hemoglobin was 9.5 ± 0.2 g/dL, the mean serum ferritin was 1067 ± 297 μg/L, the mean serum iron was 34 ± 6 μg/dL, and the mean transferrin saturation was 16.7 ± 3.4%.

The patients received twice-weekly intravenous infusions of lexaptepid pegol for 4 weeks, and the researchers observed patients for 1 month after treatment. Patients were not allowed to receive erythropoiesis-stimulating agents or iron products during the study period.

The results showed increases in hemoglobin of 1 g/dL or greater, which qualified as a response, in 5 of the 12 patients (42%). Three patients achieved a response within 2 weeks of treatment initiation. All 5 patients maintained the increase in hemoglobin throughout the follow-up period.

There was no clear difference in response among the different malignancies, Dr Reike said. But he also noted that, as the study included a small number of patients, it wasn’t really possible for the researchers to make a fair comparison.

In addition to increasing hemoglobin levels, lexaptepid pegol decreased the mean serum ferritin from 1067 μg/L to 815 μg/L in the entire cohort of patients (P=0.014) and from 772 μg/L to 462 μg/L in responders (but this was not significant).

Reticulocyte hemoglobin increased from 22.7 pg to 24.9 pg (P=0.019) in responding patients, but there was no increase in non-responders. (Data for this measurement were only available for 3 of the responders—but all 7 of the non-responders—due to differences in measurement capabilities at the different research sites).

“During the treatment, we saw a very nice increase in reticulocyte hemoglobin, which shows, in these patients, the red blood cells were able to take up iron and build up more hemoglobin,” Dr Riecke said.

The researchers also observed an increase in the mean reticulocyte index in responding patients, from 0.9 to 1.2, although the increase was not significant.

“So this shows that, not only do you have an increase in hemoglobin within each reticulocyte, but you have an increase in the number of reticulocytes—something that we didn’t really expect in the beginning,” Dr Riecke said. “And this may be a sign that the efficacy of erythropoiesis is improved.”

Additionally, responding patients experienced a decrease in soluble transferrin receptor levels, from 10.0 mg/L to 8.6 mg/L, although this was not significant. Soluble transferrin receptor levels remained unchanged in non-responders. (Data for this measurement were only available for 3 of the responders and 4 of the non-responders.)

“The decrease in soluble transferrin receptor levels is a sign that, in the beginning, the cells were very iron-hungry, and then their hunger was satisfied—at least to a certain extent—during the treatment with our drug,” Dr Reike said. “This is a sign that, by reducing hepcidin, more iron is being released into the circulation, and this iron can effectively be used for erythropoiesis.”

Dr Reike added that, although the researchers did observe some adverse effects in the patients, none of these could be clearly attributed to lexaptepid pegol.

Some of the patients did have low blood pressure shortly after treatment, but that may have been influenced by factors other than treatment, he said. Furthermore, in the phase 1 study of lexaptepid pegol in healthy subjects, the only adverse effect that occurred in the treatment arm (and not in the placebo arm) was headache.

Based on these results, NOXXON is now planning—and recruiting for—a study of lexaptepid pegol in dialysis patients.

SAN DIEGO—Results of a pilot study suggest an experimental molecule can increase hemoglobin levels in patients with hematologic malignancies who are suffering from anemia.

The molecule, lexaptepid pegol (NOX-H94), is a pegylated L-stereoisomer RNA aptamer that binds and neutralizes hepcidin.

In this phase 2 study, 5 of 12 patients who received lexaptepid pegol experienced a hemoglobin increase of 1 g/dL or greater and qualified as responders.

Researchers presented these results at the AACR Annual Meeting 2014 as abstract 3847. The study was supported by NOXXON Pharma AG, the Berlin, Germany-based company developing lexaptepid pegol.

“Our concept is to treat anemia by inhibiting the activity of hepcidin,” said study investigator Kai Riecke, MD, of NOXXON Pharma.

“Hepcidin regulates iron in the blood. The problem is that, in quite a few tumors, hepcidin reduces iron in the circulation, and, over a long period of time, that leads to iron-restricted anemia.”

So Dr Riecke and his colleagues tested their antihepcidin molecule, lexaptepid pegol, in anemic cancer patients. The team enrolled patients with hemoglobin levels less than 10 g/dL who had been diagnosed with multiple myeloma, chronic lymphocytic leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma.

The patients had a median age of 64 years (range, 35-77). At baseline, the mean hemoglobin was 9.5 ± 0.2 g/dL, the mean serum ferritin was 1067 ± 297 μg/L, the mean serum iron was 34 ± 6 μg/dL, and the mean transferrin saturation was 16.7 ± 3.4%.

The patients received twice-weekly intravenous infusions of lexaptepid pegol for 4 weeks, and the researchers observed patients for 1 month after treatment. Patients were not allowed to receive erythropoiesis-stimulating agents or iron products during the study period.

The results showed increases in hemoglobin of 1 g/dL or greater, which qualified as a response, in 5 of the 12 patients (42%). Three patients achieved a response within 2 weeks of treatment initiation. All 5 patients maintained the increase in hemoglobin throughout the follow-up period.

There was no clear difference in response among the different malignancies, Dr Reike said. But he also noted that, as the study included a small number of patients, it wasn’t really possible for the researchers to make a fair comparison.

In addition to increasing hemoglobin levels, lexaptepid pegol decreased the mean serum ferritin from 1067 μg/L to 815 μg/L in the entire cohort of patients (P=0.014) and from 772 μg/L to 462 μg/L in responders (but this was not significant).

Reticulocyte hemoglobin increased from 22.7 pg to 24.9 pg (P=0.019) in responding patients, but there was no increase in non-responders. (Data for this measurement were only available for 3 of the responders—but all 7 of the non-responders—due to differences in measurement capabilities at the different research sites).

“During the treatment, we saw a very nice increase in reticulocyte hemoglobin, which shows, in these patients, the red blood cells were able to take up iron and build up more hemoglobin,” Dr Riecke said.

The researchers also observed an increase in the mean reticulocyte index in responding patients, from 0.9 to 1.2, although the increase was not significant.

“So this shows that, not only do you have an increase in hemoglobin within each reticulocyte, but you have an increase in the number of reticulocytes—something that we didn’t really expect in the beginning,” Dr Riecke said. “And this may be a sign that the efficacy of erythropoiesis is improved.”

Additionally, responding patients experienced a decrease in soluble transferrin receptor levels, from 10.0 mg/L to 8.6 mg/L, although this was not significant. Soluble transferrin receptor levels remained unchanged in non-responders. (Data for this measurement were only available for 3 of the responders and 4 of the non-responders.)

“The decrease in soluble transferrin receptor levels is a sign that, in the beginning, the cells were very iron-hungry, and then their hunger was satisfied—at least to a certain extent—during the treatment with our drug,” Dr Reike said. “This is a sign that, by reducing hepcidin, more iron is being released into the circulation, and this iron can effectively be used for erythropoiesis.”

Dr Reike added that, although the researchers did observe some adverse effects in the patients, none of these could be clearly attributed to lexaptepid pegol.

Some of the patients did have low blood pressure shortly after treatment, but that may have been influenced by factors other than treatment, he said. Furthermore, in the phase 1 study of lexaptepid pegol in healthy subjects, the only adverse effect that occurred in the treatment arm (and not in the placebo arm) was headache.

Based on these results, NOXXON is now planning—and recruiting for—a study of lexaptepid pegol in dialysis patients.

SAN DIEGO—Preclinical research suggests that combining a BET inhibitor with lenalidomide may overcome resistance to bortezomib in mantle cell lymphoma (MCL).

Experiments in MCL cell lines and mouse models of the disease showed that lenalidomide alone is active in bortezomib-resistant cells and tumors.

But the anticancer effects are more pronounced with the addition of the BET inhibitor CPI203.

“So we think that this new combination based on BET inhibition and lenalidomide may be helpful for the design of new therapies in the subset of MCL patients resistant to bortezomib,” said study investigator Gael Roue, PhD, of IDIBAPS in Barcelona, Spain.

Dr Roue and his colleagues presented this research in a poster at the AACR Annual Meeting 2014 (abstract 1691*). The team included researchers from Constellation Pharmaceuticals, the company developing CPI203.

With this research, the investigators wanted to assess the possibility of targeting IRF4 and MYC signaling and overcoming bortezomib resistance with lenalidomide-based therapies.

To that end, they tested lenalidomide in 9 MCL cell lines. They found the drug’s antitumor activity is mediated by inhibition of the plasmacytic differentiation program in bortezomib-resistant MCL.

The team then evaluated the effects of lenalidomide on REC-1 cells injected into SCID mice. And they found that lenalidomide significantly reduced tumor growth compared to vehicle control (P=0.04).

The researchers next injected mice with REC-1 cells and treated them with 50 mg/kg of lenalidomide, 0.15 mg/kg of bortezomib, both agents, or vehicle control. The mice received lenalidomide 5 days a week and bortezomib twice a week for up to 18 days.

Lenalidomide alone significantly reduced tumor volume when compared to control (P=0.04). The same was true of the combination treatment compared to control (P=0.02).

The investigators also noted a 25% increase in MYC expression in cells and tumors that were resistant to bortezomib. So they speculated that inhibiting MYC could increase lenalidomide activity.

“This was the rationale for combining lenalidomide with a BET inhibitor,” Dr Roue said. “BET inhibitors are known to inhibit MYC transcription, to inhibit MYC signaling, in multiple myeloma and lymphoma cells.”

The researchers first evaluated the effects of CPI203 alone. They cultured 9 MCL cell lines and peripheral blood mononuclear cells from 2 healthy donors with increasing concentrations of CPI203 and assessed cytotoxicity, MYC levels, and cell viability.

They found that CPI203 was active in all the cell lines tested, but it didn’t affect the proliferation or viability of the healthy cells. And CPI203 activity was linked to the downregulation of MYC.

The team then tested CPI203 in combination with lenalidomide. They treated REC-1 cells for 72 hours with 0.1 μM to 0.5 μM of CPI203 and/or 1 μM to 5 μM of lenalidomide.

“[W]e observed synergistic activity in vitro, linked to a complete disappearance of MYC and also of IRF4,” Dr Roue said.

Finally, the investigators tested the 2 agents in mice with bortezomib-resistant MCL. The mice were injected with REC-1 cells and randomized to treatment with lenalidomide at 50 mg/kg/day, CPI203 at 2.5 mg/kg BID, both agents, or vehicle control.

“We found that by treating mice with [both agents] for 3 weeks, we reached 80% tumor remission, which was linked to inhibition of mitosis, complete disappearance of MYC and IRF4 protein levels, and induction of apoptosis in about 30% to 40% of the tumors.”

The researchers said these results suggest the lenalidomide-BET inhibitor combination warrants investigation in MCL patients who are refractory to bortezomib.

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

SAN DIEGO—Preclinical research suggests that combining a BET inhibitor with lenalidomide may overcome resistance to bortezomib in mantle cell lymphoma (MCL).

Experiments in MCL cell lines and mouse models of the disease showed that lenalidomide alone is active in bortezomib-resistant cells and tumors.

But the anticancer effects are more pronounced with the addition of the BET inhibitor CPI203.

“So we think that this new combination based on BET inhibition and lenalidomide may be helpful for the design of new therapies in the subset of MCL patients resistant to bortezomib,” said study investigator Gael Roue, PhD, of IDIBAPS in Barcelona, Spain.

Dr Roue and his colleagues presented this research in a poster at the AACR Annual Meeting 2014 (abstract 1691*). The team included researchers from Constellation Pharmaceuticals, the company developing CPI203.

With this research, the investigators wanted to assess the possibility of targeting IRF4 and MYC signaling and overcoming bortezomib resistance with lenalidomide-based therapies.

To that end, they tested lenalidomide in 9 MCL cell lines. They found the drug’s antitumor activity is mediated by inhibition of the plasmacytic differentiation program in bortezomib-resistant MCL.

The team then evaluated the effects of lenalidomide on REC-1 cells injected into SCID mice. And they found that lenalidomide significantly reduced tumor growth compared to vehicle control (P=0.04).

The researchers next injected mice with REC-1 cells and treated them with 50 mg/kg of lenalidomide, 0.15 mg/kg of bortezomib, both agents, or vehicle control. The mice received lenalidomide 5 days a week and bortezomib twice a week for up to 18 days.

Lenalidomide alone significantly reduced tumor volume when compared to control (P=0.04). The same was true of the combination treatment compared to control (P=0.02).

The investigators also noted a 25% increase in MYC expression in cells and tumors that were resistant to bortezomib. So they speculated that inhibiting MYC could increase lenalidomide activity.

“This was the rationale for combining lenalidomide with a BET inhibitor,” Dr Roue said. “BET inhibitors are known to inhibit MYC transcription, to inhibit MYC signaling, in multiple myeloma and lymphoma cells.”

The researchers first evaluated the effects of CPI203 alone. They cultured 9 MCL cell lines and peripheral blood mononuclear cells from 2 healthy donors with increasing concentrations of CPI203 and assessed cytotoxicity, MYC levels, and cell viability.

They found that CPI203 was active in all the cell lines tested, but it didn’t affect the proliferation or viability of the healthy cells. And CPI203 activity was linked to the downregulation of MYC.

The team then tested CPI203 in combination with lenalidomide. They treated REC-1 cells for 72 hours with 0.1 μM to 0.5 μM of CPI203 and/or 1 μM to 5 μM of lenalidomide.

“[W]e observed synergistic activity in vitro, linked to a complete disappearance of MYC and also of IRF4,” Dr Roue said.

Finally, the investigators tested the 2 agents in mice with bortezomib-resistant MCL. The mice were injected with REC-1 cells and randomized to treatment with lenalidomide at 50 mg/kg/day, CPI203 at 2.5 mg/kg BID, both agents, or vehicle control.

“We found that by treating mice with [both agents] for 3 weeks, we reached 80% tumor remission, which was linked to inhibition of mitosis, complete disappearance of MYC and IRF4 protein levels, and induction of apoptosis in about 30% to 40% of the tumors.”

The researchers said these results suggest the lenalidomide-BET inhibitor combination warrants investigation in MCL patients who are refractory to bortezomib.

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

SAN DIEGO—Preclinical research suggests that combining a BET inhibitor with lenalidomide may overcome resistance to bortezomib in mantle cell lymphoma (MCL).

Experiments in MCL cell lines and mouse models of the disease showed that lenalidomide alone is active in bortezomib-resistant cells and tumors.

But the anticancer effects are more pronounced with the addition of the BET inhibitor CPI203.

“So we think that this new combination based on BET inhibition and lenalidomide may be helpful for the design of new therapies in the subset of MCL patients resistant to bortezomib,” said study investigator Gael Roue, PhD, of IDIBAPS in Barcelona, Spain.

Dr Roue and his colleagues presented this research in a poster at the AACR Annual Meeting 2014 (abstract 1691*). The team included researchers from Constellation Pharmaceuticals, the company developing CPI203.

With this research, the investigators wanted to assess the possibility of targeting IRF4 and MYC signaling and overcoming bortezomib resistance with lenalidomide-based therapies.

To that end, they tested lenalidomide in 9 MCL cell lines. They found the drug’s antitumor activity is mediated by inhibition of the plasmacytic differentiation program in bortezomib-resistant MCL.

The team then evaluated the effects of lenalidomide on REC-1 cells injected into SCID mice. And they found that lenalidomide significantly reduced tumor growth compared to vehicle control (P=0.04).

The researchers next injected mice with REC-1 cells and treated them with 50 mg/kg of lenalidomide, 0.15 mg/kg of bortezomib, both agents, or vehicle control. The mice received lenalidomide 5 days a week and bortezomib twice a week for up to 18 days.

Lenalidomide alone significantly reduced tumor volume when compared to control (P=0.04). The same was true of the combination treatment compared to control (P=0.02).

The investigators also noted a 25% increase in MYC expression in cells and tumors that were resistant to bortezomib. So they speculated that inhibiting MYC could increase lenalidomide activity.

“This was the rationale for combining lenalidomide with a BET inhibitor,” Dr Roue said. “BET inhibitors are known to inhibit MYC transcription, to inhibit MYC signaling, in multiple myeloma and lymphoma cells.”

The researchers first evaluated the effects of CPI203 alone. They cultured 9 MCL cell lines and peripheral blood mononuclear cells from 2 healthy donors with increasing concentrations of CPI203 and assessed cytotoxicity, MYC levels, and cell viability.

They found that CPI203 was active in all the cell lines tested, but it didn’t affect the proliferation or viability of the healthy cells. And CPI203 activity was linked to the downregulation of MYC.

The team then tested CPI203 in combination with lenalidomide. They treated REC-1 cells for 72 hours with 0.1 μM to 0.5 μM of CPI203 and/or 1 μM to 5 μM of lenalidomide.

“[W]e observed synergistic activity in vitro, linked to a complete disappearance of MYC and also of IRF4,” Dr Roue said.

Finally, the investigators tested the 2 agents in mice with bortezomib-resistant MCL. The mice were injected with REC-1 cells and randomized to treatment with lenalidomide at 50 mg/kg/day, CPI203 at 2.5 mg/kg BID, both agents, or vehicle control.

“We found that by treating mice with [both agents] for 3 weeks, we reached 80% tumor remission, which was linked to inhibition of mitosis, complete disappearance of MYC and IRF4 protein levels, and induction of apoptosis in about 30% to 40% of the tumors.”

The researchers said these results suggest the lenalidomide-BET inhibitor combination warrants investigation in MCL patients who are refractory to bortezomib.

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

Update: The hold on this trial has been lifted. Click here for additional details.

Memorial Sloan-Kettering Cancer Center has temporarily suspended enrollment in a study of chimeric antigen receptor (CAR) T-cell therapy, due to 2 patient deaths.

The study is an evaluation of CD19-targeted CAR T cells in patients with B-cell acute lymphoblastic leukemia (ALL).

Of the 22 patients enrolled on the study to date, 10 have died. But only 2 of these deaths gave researchers pause and made them question enrollment criteria.

Six deaths were a result of disease relapse or progression, and 2 patients died of complications from stem cell transplant.

The 2 deaths that prompted the suspension of enrollment occurred within 2 weeks of the patients receiving CAR T cells.

“The first of these patients had a prior history of cardiac disease, while the second patient died due to complications associated with persistent seizure activity,” said Renier Brentjens, MD, PhD, of Memorial Sloan-Kettering in New York.

“As a matter of routine review at Sloan-Kettering for adverse events on-study, our center made the decision to pause enrollment and review these 2 patients in greater detail.”

“And as a consequence of this review, we’ve amended the enrollment criteria in regards to comorbidities, thereby excluding patients with cardiac disease, and adjusted the T-cell dose based on the extent of disease, [in the] hope that this modification will reduce the cytokine release syndrome that these patients with morphological disease have experienced.”

The researchers expect the trial to resume enrollment soon.

Some results from this study were recently published in Science Translational Medicine, and Dr Brentjens presented the latest results at the AACR Annual Meeting 2014 in San Diego (abstract CT102*).

Thus far, the researchers have enrolled 22 adult patients who had relapsed or refractory B-ALL, were minimal residual disease-positive, or were in the first complete remission (CR1) at enrollment. Patients in CR1 were monitored and only received CAR T cells if they relapsed.

The remaining patients received re-induction chemotherapy (physician’s choice), followed by CAR T-cell infusion. After treatment, the options were allogeneic transplant, a different salvage therapy, or monitoring.

In all, 20 patients received a CAR T-cell dose of 3 x 10⁶ T cells/kg. Eighty-two percent of patients initially achieved a CR, and 72% had a morphologic CR. The average time to CR was about 24.5 days.

Twelve of the responders were eligible for transplant. Of the 8 patients who ultimately underwent transplant and survived, 1 relapsed, but the rest remain in remission.

Dr Brentjens noted that some patients developed cytokine release syndrome, and this was related to the amount of disease present at the time of CAR T-cell infusion.

“Those patients that had only minimal residual disease at the time of CAR T-cell infusion . . .  less than 5% blasts, generally had either no fever or very transient, low-grade fever,” he said.

“In contrast, all those patients that had morphologic residual disease at the time of CAR T-cell infusion demonstrated a high, persistent spike in fevers . . . , became hypotensive, and required transfer—for additional, closer monitoring—to our ICU.”

The researchers initially treated these patients with high-dose steroids, which reduced cytokine levels in the serum and ameliorated fevers. But it also rapidly reduced T-cell populations to undetectable levels.

Fortunately, another group of researchers subsequently discovered that the monoclonal antibody tocilizumab can treat cytokine release syndrome without inducing this side effect. So Dr Brentjens and his colleagues began using this drug and found it both safe and effective.

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

Update: The hold on this trial has been lifted. Click here for additional details.

Memorial Sloan-Kettering Cancer Center has temporarily suspended enrollment in a study of chimeric antigen receptor (CAR) T-cell therapy, due to 2 patient deaths.

The study is an evaluation of CD19-targeted CAR T cells in patients with B-cell acute lymphoblastic leukemia (ALL).

Of the 22 patients enrolled on the study to date, 10 have died. But only 2 of these deaths gave researchers pause and made them question enrollment criteria.

Six deaths were a result of disease relapse or progression, and 2 patients died of complications from stem cell transplant.

The 2 deaths that prompted the suspension of enrollment occurred within 2 weeks of the patients receiving CAR T cells.

“The first of these patients had a prior history of cardiac disease, while the second patient died due to complications associated with persistent seizure activity,” said Renier Brentjens, MD, PhD, of Memorial Sloan-Kettering in New York.

“As a matter of routine review at Sloan-Kettering for adverse events on-study, our center made the decision to pause enrollment and review these 2 patients in greater detail.”

“And as a consequence of this review, we’ve amended the enrollment criteria in regards to comorbidities, thereby excluding patients with cardiac disease, and adjusted the T-cell dose based on the extent of disease, [in the] hope that this modification will reduce the cytokine release syndrome that these patients with morphological disease have experienced.”

The researchers expect the trial to resume enrollment soon.

Some results from this study were recently published in Science Translational Medicine, and Dr Brentjens presented the latest results at the AACR Annual Meeting 2014 in San Diego (abstract CT102*).

Thus far, the researchers have enrolled 22 adult patients who had relapsed or refractory B-ALL, were minimal residual disease-positive, or were in the first complete remission (CR1) at enrollment. Patients in CR1 were monitored and only received CAR T cells if they relapsed.

The remaining patients received re-induction chemotherapy (physician’s choice), followed by CAR T-cell infusion. After treatment, the options were allogeneic transplant, a different salvage therapy, or monitoring.

In all, 20 patients received a CAR T-cell dose of 3 x 10⁶ T cells/kg. Eighty-two percent of patients initially achieved a CR, and 72% had a morphologic CR. The average time to CR was about 24.5 days.

Twelve of the responders were eligible for transplant. Of the 8 patients who ultimately underwent transplant and survived, 1 relapsed, but the rest remain in remission.

Dr Brentjens noted that some patients developed cytokine release syndrome, and this was related to the amount of disease present at the time of CAR T-cell infusion.

“Those patients that had only minimal residual disease at the time of CAR T-cell infusion . . .  less than 5% blasts, generally had either no fever or very transient, low-grade fever,” he said.

“In contrast, all those patients that had morphologic residual disease at the time of CAR T-cell infusion demonstrated a high, persistent spike in fevers . . . , became hypotensive, and required transfer—for additional, closer monitoring—to our ICU.”

The researchers initially treated these patients with high-dose steroids, which reduced cytokine levels in the serum and ameliorated fevers. But it also rapidly reduced T-cell populations to undetectable levels.

Fortunately, another group of researchers subsequently discovered that the monoclonal antibody tocilizumab can treat cytokine release syndrome without inducing this side effect. So Dr Brentjens and his colleagues began using this drug and found it both safe and effective.

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

Update: The hold on this trial has been lifted. Click here for additional details.

Memorial Sloan-Kettering Cancer Center has temporarily suspended enrollment in a study of chimeric antigen receptor (CAR) T-cell therapy, due to 2 patient deaths.

The study is an evaluation of CD19-targeted CAR T cells in patients with B-cell acute lymphoblastic leukemia (ALL).

Of the 22 patients enrolled on the study to date, 10 have died. But only 2 of these deaths gave researchers pause and made them question enrollment criteria.

Six deaths were a result of disease relapse or progression, and 2 patients died of complications from stem cell transplant.

The 2 deaths that prompted the suspension of enrollment occurred within 2 weeks of the patients receiving CAR T cells.

“The first of these patients had a prior history of cardiac disease, while the second patient died due to complications associated with persistent seizure activity,” said Renier Brentjens, MD, PhD, of Memorial Sloan-Kettering in New York.

“As a matter of routine review at Sloan-Kettering for adverse events on-study, our center made the decision to pause enrollment and review these 2 patients in greater detail.”

“And as a consequence of this review, we’ve amended the enrollment criteria in regards to comorbidities, thereby excluding patients with cardiac disease, and adjusted the T-cell dose based on the extent of disease, [in the] hope that this modification will reduce the cytokine release syndrome that these patients with morphological disease have experienced.”

The researchers expect the trial to resume enrollment soon.

Some results from this study were recently published in Science Translational Medicine, and Dr Brentjens presented the latest results at the AACR Annual Meeting 2014 in San Diego (abstract CT102*).

Thus far, the researchers have enrolled 22 adult patients who had relapsed or refractory B-ALL, were minimal residual disease-positive, or were in the first complete remission (CR1) at enrollment. Patients in CR1 were monitored and only received CAR T cells if they relapsed.

The remaining patients received re-induction chemotherapy (physician’s choice), followed by CAR T-cell infusion. After treatment, the options were allogeneic transplant, a different salvage therapy, or monitoring.

In all, 20 patients received a CAR T-cell dose of 3 x 10⁶ T cells/kg. Eighty-two percent of patients initially achieved a CR, and 72% had a morphologic CR. The average time to CR was about 24.5 days.

Twelve of the responders were eligible for transplant. Of the 8 patients who ultimately underwent transplant and survived, 1 relapsed, but the rest remain in remission.

Dr Brentjens noted that some patients developed cytokine release syndrome, and this was related to the amount of disease present at the time of CAR T-cell infusion.

“Those patients that had only minimal residual disease at the time of CAR T-cell infusion . . .  less than 5% blasts, generally had either no fever or very transient, low-grade fever,” he said.

“In contrast, all those patients that had morphologic residual disease at the time of CAR T-cell infusion demonstrated a high, persistent spike in fevers . . . , became hypotensive, and required transfer—for additional, closer monitoring—to our ICU.”

The researchers initially treated these patients with high-dose steroids, which reduced cytokine levels in the serum and ameliorated fevers. But it also rapidly reduced T-cell populations to undetectable levels.

Fortunately, another group of researchers subsequently discovered that the monoclonal antibody tocilizumab can treat cytokine release syndrome without inducing this side effect. So Dr Brentjens and his colleagues began using this drug and found it both safe and effective.

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

GRAPEVINE, TEXAS—An analysis of more than 8000 patients provides insights regarding HLA disparity that may help optimize outcomes in individuals undergoing unrelated-donor hematopoietic stem cell transplant.

The study showed that a single allele- or antigen-level HLA mismatch (7/8) increased the risk for acute and chronic graft-vs-host disease (GVHD) and worsened survival rates.

However, there were no locus-specific effects on survival, and there was no impact of allele- vs antigen-level mismatch on survival.

In addition, patients with an 8/8 matched graft had an increased risk of acute GVHD if they had a DQB1 mismatch or a DPB1 mismatch. DPB1 mismatch also decreased the risk of relapse, and nonpermissive DPB1 mismatch was associated with worse survival.

“Thus, we believe that consideration of DPB1 in donor selection may permit skewing toward donors with permissive DPB1 mismatch and may improve outcomes,” said study investigator Joseph Pidala, MD, of the H. Lee Moffitt Cancer Center in Tampa, Florida.

He presented these findings at the 2014 BMT Tandem Meetings as abstract 5, which was designated one of the meeting’s “Best Abstracts.”

Patient characteristics

Dr Pidala and his colleagues evaluated data from 8003 adult and pediatric patients who had undergone their first myeloablative, unrelated transplant between 1999 and 2011. The patients had been diagnosed with acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, or myelodysplastic syndrome.

Patients and their donors had high-resolution typing for HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1. Most cases were 8/8 matched (n=5449), followed by 7/8 (n=2071) and 6/8 (n=483).

“Those with a greater extent of HLA mismatch were younger, less likely to be Caucasian, they differed according to disease indication for transplant, and had a greater proportion of advanced disease stage,” Dr Pidala noted.

“Additionally, those with a greater extent of HLA mismatch were more likely to receive bone marrow grafts in comparison to peripheral blood, total body irradiation, and also to receive in vivo T-cell depletion.”

Furthermore, there was a declining proportion of 6/8 match over time. It decreased from 49% (1999-2002) to 37% (2003-2006) to 14% (2007-2011).

Effects of HLA mismatch

In all analyses, the researchers considered findings significant if the P value was less than 0.01.

Compared to an 8/8 matched graft, receiving a 7/8 graft was significantly associated with an increase in acute grade 2-4, acute grade 3-4, and chronic GVHD; higher transplant-related mortality (TRM); lower disease-free survival (DFS) among patients with early stage or intermediate (but not advanced) disease; and lower overall survival (OS) regardless of disease stage.

Receiving a 6/8 graft was significantly associated with an increase in acute grade 2-4 and 3-4 GVHD, increased TRM, decreased DFS (early stage or intermediate disease), and decreased OS (early stage or intermediate disease).

“In no cases did we find [that mismatch had] an impact on the incidence of primary disease relapse,” Dr Pidala said. “Comparing 7/8 to 6/8 cases, we found that those with 7/8 had improved transplant-related mortality and disease-free and overall survival [only] in the context of early stage disease.”

The team also confirmed these findings in an analysis of 5846 unique cases. In this cohort, 2528 patients were 8/8 matched, 882 were 7/8, and 157 were 6/8.

Locus-specific effects

Mismatch at HLA-A (n=743) was significantly associated with an increase in acute grade 2-4/3-4 and chronic GVHD, increased TRM, decreased DFS, and decreased OS.

Mismatch at HLA-B (n=345) was significantly associated with an increase in grade 2-4/3-4 acute GHVD, chronic GVHD, and TRM. And mismatch at HLA-C (n=766) was significantly associated with an increase in acute grade 3-4 GVHD and TRM and a decrease in DFS and OS.

There were no significant differences in the case of DRB1 mismatch. However, Dr Pidala noted that this group had the smallest number of patients, at 217.

“I’d also like to point out that in direct, pair-wise comparisons across the mismatched loci, we did not observe any significant differences in overall survival,” Dr Pidala said. “Similarly, we found no impact of allele- vs antigen-level mismatch on overall survival.”

DP and DQ mismatch

Among 8/8 matched cases, DPB1 mismatch led to a significantly increased risk for acute grade 2-4 and 3-4 GHVD, as well as a significant reduction in the risk of relapse. This was the case whether patients had a single- or double-allele mismatch.

The addition of DQB1 mismatch significantly increased the risk of grade 2-4 acute GVHD among 8/8 matched cases only if it was a single-antigen mismatch.

Neither DPB1 nor DQB1 mismatch had a significant effect on OS, DFS, or TRM in 8/8 matched cases. And neither DPB1 nor DQB1 mismatch had a significant effect on outcomes of patients who received 7/8 matched grafts.

Among 8/8 matched cases, those with permissive DPB1 mismatch had a significantly lower risk of acute grade 2-4 and 3-4 GVHD and a significantly higher risk of relapse than patients with nonpermissive DPB1 mismatch. Patients with nonpermissive mismatch also had significantly higher TRM and significantly lower DFS and OS.

However, there were no significant differences between permissive and nonpermissive mismatches for patients with 7/8 matched grafts.

Treatment implications

Based on these results and those of previous studies, Dr Pidala said we can conclude that 8/8 matched grafts confer better survival than mismatched grafts. And a permissive DPB1 mismatch can further improve survival in 8/8 cases.

Among patients receiving a 7/8 matched graft, it is preferable to identify those with HLA-C 03:03/03:04 mismatches, as these patients appear to have mortality rates comparable to 8/8 matched cases.

Among 7/8 matched cases, we should avoid nonpermissive DPB1 mismatch, having 3 or more low-expression loci mismatches (DP, DQ, DRB3/4/5), and nonpermissive allele combinations and amino acid substitutions.

GRAPEVINE, TEXAS—An analysis of more than 8000 patients provides insights regarding HLA disparity that may help optimize outcomes in individuals undergoing unrelated-donor hematopoietic stem cell transplant.

The study showed that a single allele- or antigen-level HLA mismatch (7/8) increased the risk for acute and chronic graft-vs-host disease (GVHD) and worsened survival rates.

However, there were no locus-specific effects on survival, and there was no impact of allele- vs antigen-level mismatch on survival.

In addition, patients with an 8/8 matched graft had an increased risk of acute GVHD if they had a DQB1 mismatch or a DPB1 mismatch. DPB1 mismatch also decreased the risk of relapse, and nonpermissive DPB1 mismatch was associated with worse survival.

“Thus, we believe that consideration of DPB1 in donor selection may permit skewing toward donors with permissive DPB1 mismatch and may improve outcomes,” said study investigator Joseph Pidala, MD, of the H. Lee Moffitt Cancer Center in Tampa, Florida.

He presented these findings at the 2014 BMT Tandem Meetings as abstract 5, which was designated one of the meeting’s “Best Abstracts.”

Patient characteristics

Dr Pidala and his colleagues evaluated data from 8003 adult and pediatric patients who had undergone their first myeloablative, unrelated transplant between 1999 and 2011. The patients had been diagnosed with acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, or myelodysplastic syndrome.

Patients and their donors had high-resolution typing for HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1. Most cases were 8/8 matched (n=5449), followed by 7/8 (n=2071) and 6/8 (n=483).

“Those with a greater extent of HLA mismatch were younger, less likely to be Caucasian, they differed according to disease indication for transplant, and had a greater proportion of advanced disease stage,” Dr Pidala noted.

“Additionally, those with a greater extent of HLA mismatch were more likely to receive bone marrow grafts in comparison to peripheral blood, total body irradiation, and also to receive in vivo T-cell depletion.”

Furthermore, there was a declining proportion of 6/8 match over time. It decreased from 49% (1999-2002) to 37% (2003-2006) to 14% (2007-2011).

Effects of HLA mismatch

In all analyses, the researchers considered findings significant if the P value was less than 0.01.

Compared to an 8/8 matched graft, receiving a 7/8 graft was significantly associated with an increase in acute grade 2-4, acute grade 3-4, and chronic GVHD; higher transplant-related mortality (TRM); lower disease-free survival (DFS) among patients with early stage or intermediate (but not advanced) disease; and lower overall survival (OS) regardless of disease stage.

Receiving a 6/8 graft was significantly associated with an increase in acute grade 2-4 and 3-4 GVHD, increased TRM, decreased DFS (early stage or intermediate disease), and decreased OS (early stage or intermediate disease).

“In no cases did we find [that mismatch had] an impact on the incidence of primary disease relapse,” Dr Pidala said. “Comparing 7/8 to 6/8 cases, we found that those with 7/8 had improved transplant-related mortality and disease-free and overall survival [only] in the context of early stage disease.”

The team also confirmed these findings in an analysis of 5846 unique cases. In this cohort, 2528 patients were 8/8 matched, 882 were 7/8, and 157 were 6/8.

Locus-specific effects

Mismatch at HLA-A (n=743) was significantly associated with an increase in acute grade 2-4/3-4 and chronic GVHD, increased TRM, decreased DFS, and decreased OS.

Mismatch at HLA-B (n=345) was significantly associated with an increase in grade 2-4/3-4 acute GHVD, chronic GVHD, and TRM. And mismatch at HLA-C (n=766) was significantly associated with an increase in acute grade 3-4 GVHD and TRM and a decrease in DFS and OS.

There were no significant differences in the case of DRB1 mismatch. However, Dr Pidala noted that this group had the smallest number of patients, at 217.

“I’d also like to point out that in direct, pair-wise comparisons across the mismatched loci, we did not observe any significant differences in overall survival,” Dr Pidala said. “Similarly, we found no impact of allele- vs antigen-level mismatch on overall survival.”

DP and DQ mismatch

Among 8/8 matched cases, DPB1 mismatch led to a significantly increased risk for acute grade 2-4 and 3-4 GHVD, as well as a significant reduction in the risk of relapse. This was the case whether patients had a single- or double-allele mismatch.

The addition of DQB1 mismatch significantly increased the risk of grade 2-4 acute GVHD among 8/8 matched cases only if it was a single-antigen mismatch.

Neither DPB1 nor DQB1 mismatch had a significant effect on OS, DFS, or TRM in 8/8 matched cases. And neither DPB1 nor DQB1 mismatch had a significant effect on outcomes of patients who received 7/8 matched grafts.

Among 8/8 matched cases, those with permissive DPB1 mismatch had a significantly lower risk of acute grade 2-4 and 3-4 GVHD and a significantly higher risk of relapse than patients with nonpermissive DPB1 mismatch. Patients with nonpermissive mismatch also had significantly higher TRM and significantly lower DFS and OS.

However, there were no significant differences between permissive and nonpermissive mismatches for patients with 7/8 matched grafts.

Treatment implications

Based on these results and those of previous studies, Dr Pidala said we can conclude that 8/8 matched grafts confer better survival than mismatched grafts. And a permissive DPB1 mismatch can further improve survival in 8/8 cases.

Among patients receiving a 7/8 matched graft, it is preferable to identify those with HLA-C 03:03/03:04 mismatches, as these patients appear to have mortality rates comparable to 8/8 matched cases.

Among 7/8 matched cases, we should avoid nonpermissive DPB1 mismatch, having 3 or more low-expression loci mismatches (DP, DQ, DRB3/4/5), and nonpermissive allele combinations and amino acid substitutions.

GRAPEVINE, TEXAS—An analysis of more than 8000 patients provides insights regarding HLA disparity that may help optimize outcomes in individuals undergoing unrelated-donor hematopoietic stem cell transplant.

The study showed that a single allele- or antigen-level HLA mismatch (7/8) increased the risk for acute and chronic graft-vs-host disease (GVHD) and worsened survival rates.

However, there were no locus-specific effects on survival, and there was no impact of allele- vs antigen-level mismatch on survival.

In addition, patients with an 8/8 matched graft had an increased risk of acute GVHD if they had a DQB1 mismatch or a DPB1 mismatch. DPB1 mismatch also decreased the risk of relapse, and nonpermissive DPB1 mismatch was associated with worse survival.

“Thus, we believe that consideration of DPB1 in donor selection may permit skewing toward donors with permissive DPB1 mismatch and may improve outcomes,” said study investigator Joseph Pidala, MD, of the H. Lee Moffitt Cancer Center in Tampa, Florida.

He presented these findings at the 2014 BMT Tandem Meetings as abstract 5, which was designated one of the meeting’s “Best Abstracts.”

Patient characteristics

Dr Pidala and his colleagues evaluated data from 8003 adult and pediatric patients who had undergone their first myeloablative, unrelated transplant between 1999 and 2011. The patients had been diagnosed with acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, or myelodysplastic syndrome.

Patients and their donors had high-resolution typing for HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1. Most cases were 8/8 matched (n=5449), followed by 7/8 (n=2071) and 6/8 (n=483).

“Those with a greater extent of HLA mismatch were younger, less likely to be Caucasian, they differed according to disease indication for transplant, and had a greater proportion of advanced disease stage,” Dr Pidala noted.

“Additionally, those with a greater extent of HLA mismatch were more likely to receive bone marrow grafts in comparison to peripheral blood, total body irradiation, and also to receive in vivo T-cell depletion.”

Furthermore, there was a declining proportion of 6/8 match over time. It decreased from 49% (1999-2002) to 37% (2003-2006) to 14% (2007-2011).

Effects of HLA mismatch

In all analyses, the researchers considered findings significant if the P value was less than 0.01.

Compared to an 8/8 matched graft, receiving a 7/8 graft was significantly associated with an increase in acute grade 2-4, acute grade 3-4, and chronic GVHD; higher transplant-related mortality (TRM); lower disease-free survival (DFS) among patients with early stage or intermediate (but not advanced) disease; and lower overall survival (OS) regardless of disease stage.

Receiving a 6/8 graft was significantly associated with an increase in acute grade 2-4 and 3-4 GVHD, increased TRM, decreased DFS (early stage or intermediate disease), and decreased OS (early stage or intermediate disease).

“In no cases did we find [that mismatch had] an impact on the incidence of primary disease relapse,” Dr Pidala said. “Comparing 7/8 to 6/8 cases, we found that those with 7/8 had improved transplant-related mortality and disease-free and overall survival [only] in the context of early stage disease.”

The team also confirmed these findings in an analysis of 5846 unique cases. In this cohort, 2528 patients were 8/8 matched, 882 were 7/8, and 157 were 6/8.

Locus-specific effects

Mismatch at HLA-A (n=743) was significantly associated with an increase in acute grade 2-4/3-4 and chronic GVHD, increased TRM, decreased DFS, and decreased OS.

Mismatch at HLA-B (n=345) was significantly associated with an increase in grade 2-4/3-4 acute GHVD, chronic GVHD, and TRM. And mismatch at HLA-C (n=766) was significantly associated with an increase in acute grade 3-4 GVHD and TRM and a decrease in DFS and OS.

There were no significant differences in the case of DRB1 mismatch. However, Dr Pidala noted that this group had the smallest number of patients, at 217.

“I’d also like to point out that in direct, pair-wise comparisons across the mismatched loci, we did not observe any significant differences in overall survival,” Dr Pidala said. “Similarly, we found no impact of allele- vs antigen-level mismatch on overall survival.”

DP and DQ mismatch

Among 8/8 matched cases, DPB1 mismatch led to a significantly increased risk for acute grade 2-4 and 3-4 GHVD, as well as a significant reduction in the risk of relapse. This was the case whether patients had a single- or double-allele mismatch.

The addition of DQB1 mismatch significantly increased the risk of grade 2-4 acute GVHD among 8/8 matched cases only if it was a single-antigen mismatch.

Neither DPB1 nor DQB1 mismatch had a significant effect on OS, DFS, or TRM in 8/8 matched cases. And neither DPB1 nor DQB1 mismatch had a significant effect on outcomes of patients who received 7/8 matched grafts.

Among 8/8 matched cases, those with permissive DPB1 mismatch had a significantly lower risk of acute grade 2-4 and 3-4 GVHD and a significantly higher risk of relapse than patients with nonpermissive DPB1 mismatch. Patients with nonpermissive mismatch also had significantly higher TRM and significantly lower DFS and OS.

However, there were no significant differences between permissive and nonpermissive mismatches for patients with 7/8 matched grafts.

Treatment implications

Based on these results and those of previous studies, Dr Pidala said we can conclude that 8/8 matched grafts confer better survival than mismatched grafts. And a permissive DPB1 mismatch can further improve survival in 8/8 cases.

Among patients receiving a 7/8 matched graft, it is preferable to identify those with HLA-C 03:03/03:04 mismatches, as these patients appear to have mortality rates comparable to 8/8 matched cases.

Among 7/8 matched cases, we should avoid nonpermissive DPB1 mismatch, having 3 or more low-expression loci mismatches (DP, DQ, DRB3/4/5), and nonpermissive allele combinations and amino acid substitutions.

GRAPEVINE, TEXAS—Adding specialized T cells to allogeneic bone marrow transplants can prevent graft-vs-host disease (GVHD) while preserving the graft-vs-tumor (GVT) effect, preclinical research suggests.

Donor-derived CD4+ invariant natural killer T cells (iNKT cells) helped protect mice from developing GVHD and lymphoma, thereby improving their survival.

As human CD4+ iNKT cells can be expanded in vitro, these findings may translate to the clinic, said study investigator Dominik Schneidawind, MD, of Stanford University in California.

Dr Schneidawind discussed this research at the 2014 BMT Tandem Meetings as abstract 2*, which was designated one of the meeting’s “Best Abstracts.”

Improved survival

Dr Schneidawind and his colleagues created a model of allogeneic bone marrow transplant in Balb/c (H-2Kd) mice. The mice were first irradiated with 8 Gy and then received T cell-depleted bone marrow, along with 1 x 10⁶ CD4/CD8 T cells (Tcon) from C57Bl/6 (H-2Kb) donor mice and varying doses of CD4+ iNKT cells: 1 x 10⁴ to 1 x 10⁵.

Mice that received 100,000 CD4+ iNKT cells had significantly improved survival (P=0.002)—and better weight and GVHD scores—compared to mice that received bone marrow grafts alone. But a CD4+ iNKT dose as low as 10,000 cells also conferred a significant improvement in survival (P=0.03).

“In contrast, you need roughly 500,000 to 1 million donor-derived regulatory T cells to achieve a comparable survival benefit in this model of bone marrow transplantation,” Dr Schneidawind noted.

GVT effect

Dr Schneidawind and his colleagues also evaluated the impact of CD4+ iNKT cells on the GVT effect. They used luciferase-transfected BCL1 cells to induce lymphoma development, injecting the cells into mice 1 day before transplant.

Mice that received BCL1 cells, with or without CD4+ iNKT cells, showed increasing bioluminescence imaging (BLI) signals and all died from progressive lymphoma. The mice that received BLC1 and Tcon did not show an increase in BLI signals, but they all died from GVHD.

However, the mice that received BCL1, Tcon, and CD4+ iNKT cells didn’t show any sign of lymphoma or GVHD and survived through the whole experiment (P=0.002).

The investigators conducted the same experiment with the luciferase-positive A20 cell line. And they observed similar results. Mice that received A20 cells, Tcon, and CD4+ iNKT cells showed no sign of lymphoma and had significantly improved survival (P=0.002) over animals that received A20 and Tcon.

“Interestingly, animals that received A20 cells and 50,000 CD4+ iNKT cells only, without Tcon, showed a significant decrease in BLI signal and significantly improved survival,” Dr Schneidawind noted.

“So we conclude from these experiments that CD4+ iNKT cells do not abrogate the Tcon-mediated [GVT] effect but might exert some distinct antitumor activity by themselves.”

Mechanism of GVHD prevention

Lastly, Dr Schneidawind and his colleagues wanted to determine exactly how CD4+ iNKT cells prevent GVHD. The group’s experiments showed that the cells inhibit the proliferation of alloreactive T cells and promote the expansion of donor-derived CD4+ FoxP3+ Tregs.

The investigators decided to take a closer look at the Tregs, evaluating their role in GVHD-related death.

To do this, the team evaluated survival in 4 groups of mice: (1) irradiated controls; (2) mice that received only bone marrow; (3) mice that received Tcon, CD4+ iNKT cells, and a graft depleted of CD4+ FoxP3+ Tregs; and (4) mice that received Tcon, CD4+ iNKT cells, and a non-depleted graft.

“Animals that received a Treg-depleted graft and were treated with CD4+ iNKT [plus Tcon] did not show a significant improvement in survival [over controls],” Dr Schneidawind said.

“In contrast, animals that received a Treg-non-depleted graft showed a significant improvement in survival [P=0.006]. So we conclude that the expansion of these Tregs is necessary to protect from GVHD lethality and that they are required in this context.”

In closing, Dr Schneidawind noted that, although human CD4+ iNKT cells are rare, they can be isolated from peripheral blood and expanded in vitro. This suggests his group’s findings might ultimately prove useful for patients.

*Information in the abstract differs from that presented.

GRAPEVINE, TEXAS—Adding specialized T cells to allogeneic bone marrow transplants can prevent graft-vs-host disease (GVHD) while preserving the graft-vs-tumor (GVT) effect, preclinical research suggests.

Donor-derived CD4+ invariant natural killer T cells (iNKT cells) helped protect mice from developing GVHD and lymphoma, thereby improving their survival.

As human CD4+ iNKT cells can be expanded in vitro, these findings may translate to the clinic, said study investigator Dominik Schneidawind, MD, of Stanford University in California.

Dr Schneidawind discussed this research at the 2014 BMT Tandem Meetings as abstract 2*, which was designated one of the meeting’s “Best Abstracts.”

Improved survival

Dr Schneidawind and his colleagues created a model of allogeneic bone marrow transplant in Balb/c (H-2Kd) mice. The mice were first irradiated with 8 Gy and then received T cell-depleted bone marrow, along with 1 x 10⁶ CD4/CD8 T cells (Tcon) from C57Bl/6 (H-2Kb) donor mice and varying doses of CD4+ iNKT cells: 1 x 10⁴ to 1 x 10⁵.

Mice that received 100,000 CD4+ iNKT cells had significantly improved survival (P=0.002)—and better weight and GVHD scores—compared to mice that received bone marrow grafts alone. But a CD4+ iNKT dose as low as 10,000 cells also conferred a significant improvement in survival (P=0.03).

“In contrast, you need roughly 500,000 to 1 million donor-derived regulatory T cells to achieve a comparable survival benefit in this model of bone marrow transplantation,” Dr Schneidawind noted.

GVT effect

Dr Schneidawind and his colleagues also evaluated the impact of CD4+ iNKT cells on the GVT effect. They used luciferase-transfected BCL1 cells to induce lymphoma development, injecting the cells into mice 1 day before transplant.

Mice that received BCL1 cells, with or without CD4+ iNKT cells, showed increasing bioluminescence imaging (BLI) signals and all died from progressive lymphoma. The mice that received BLC1 and Tcon did not show an increase in BLI signals, but they all died from GVHD.

However, the mice that received BCL1, Tcon, and CD4+ iNKT cells didn’t show any sign of lymphoma or GVHD and survived through the whole experiment (P=0.002).

The investigators conducted the same experiment with the luciferase-positive A20 cell line. And they observed similar results. Mice that received A20 cells, Tcon, and CD4+ iNKT cells showed no sign of lymphoma and had significantly improved survival (P=0.002) over animals that received A20 and Tcon.

“Interestingly, animals that received A20 cells and 50,000 CD4+ iNKT cells only, without Tcon, showed a significant decrease in BLI signal and significantly improved survival,” Dr Schneidawind noted.

“So we conclude from these experiments that CD4+ iNKT cells do not abrogate the Tcon-mediated [GVT] effect but might exert some distinct antitumor activity by themselves.”

Mechanism of GVHD prevention

Lastly, Dr Schneidawind and his colleagues wanted to determine exactly how CD4+ iNKT cells prevent GVHD. The group’s experiments showed that the cells inhibit the proliferation of alloreactive T cells and promote the expansion of donor-derived CD4+ FoxP3+ Tregs.

The investigators decided to take a closer look at the Tregs, evaluating their role in GVHD-related death.

To do this, the team evaluated survival in 4 groups of mice: (1) irradiated controls; (2) mice that received only bone marrow; (3) mice that received Tcon, CD4+ iNKT cells, and a graft depleted of CD4+ FoxP3+ Tregs; and (4) mice that received Tcon, CD4+ iNKT cells, and a non-depleted graft.

“Animals that received a Treg-depleted graft and were treated with CD4+ iNKT [plus Tcon] did not show a significant improvement in survival [over controls],” Dr Schneidawind said.

“In contrast, animals that received a Treg-non-depleted graft showed a significant improvement in survival [P=0.006]. So we conclude that the expansion of these Tregs is necessary to protect from GVHD lethality and that they are required in this context.”

In closing, Dr Schneidawind noted that, although human CD4+ iNKT cells are rare, they can be isolated from peripheral blood and expanded in vitro. This suggests his group’s findings might ultimately prove useful for patients.

*Information in the abstract differs from that presented.

GRAPEVINE, TEXAS—Adding specialized T cells to allogeneic bone marrow transplants can prevent graft-vs-host disease (GVHD) while preserving the graft-vs-tumor (GVT) effect, preclinical research suggests.

Donor-derived CD4+ invariant natural killer T cells (iNKT cells) helped protect mice from developing GVHD and lymphoma, thereby improving their survival.

As human CD4+ iNKT cells can be expanded in vitro, these findings may translate to the clinic, said study investigator Dominik Schneidawind, MD, of Stanford University in California.

Dr Schneidawind discussed this research at the 2014 BMT Tandem Meetings as abstract 2*, which was designated one of the meeting’s “Best Abstracts.”

Improved survival

Dr Schneidawind and his colleagues created a model of allogeneic bone marrow transplant in Balb/c (H-2Kd) mice. The mice were first irradiated with 8 Gy and then received T cell-depleted bone marrow, along with 1 x 10⁶ CD4/CD8 T cells (Tcon) from C57Bl/6 (H-2Kb) donor mice and varying doses of CD4+ iNKT cells: 1 x 10⁴ to 1 x 10⁵.

Mice that received 100,000 CD4+ iNKT cells had significantly improved survival (P=0.002)—and better weight and GVHD scores—compared to mice that received bone marrow grafts alone. But a CD4+ iNKT dose as low as 10,000 cells also conferred a significant improvement in survival (P=0.03).

“In contrast, you need roughly 500,000 to 1 million donor-derived regulatory T cells to achieve a comparable survival benefit in this model of bone marrow transplantation,” Dr Schneidawind noted.

GVT effect

Dr Schneidawind and his colleagues also evaluated the impact of CD4+ iNKT cells on the GVT effect. They used luciferase-transfected BCL1 cells to induce lymphoma development, injecting the cells into mice 1 day before transplant.

Mice that received BCL1 cells, with or without CD4+ iNKT cells, showed increasing bioluminescence imaging (BLI) signals and all died from progressive lymphoma. The mice that received BLC1 and Tcon did not show an increase in BLI signals, but they all died from GVHD.

However, the mice that received BCL1, Tcon, and CD4+ iNKT cells didn’t show any sign of lymphoma or GVHD and survived through the whole experiment (P=0.002).

The investigators conducted the same experiment with the luciferase-positive A20 cell line. And they observed similar results. Mice that received A20 cells, Tcon, and CD4+ iNKT cells showed no sign of lymphoma and had significantly improved survival (P=0.002) over animals that received A20 and Tcon.

“Interestingly, animals that received A20 cells and 50,000 CD4+ iNKT cells only, without Tcon, showed a significant decrease in BLI signal and significantly improved survival,” Dr Schneidawind noted.

“So we conclude from these experiments that CD4+ iNKT cells do not abrogate the Tcon-mediated [GVT] effect but might exert some distinct antitumor activity by themselves.”

Mechanism of GVHD prevention

Lastly, Dr Schneidawind and his colleagues wanted to determine exactly how CD4+ iNKT cells prevent GVHD. The group’s experiments showed that the cells inhibit the proliferation of alloreactive T cells and promote the expansion of donor-derived CD4+ FoxP3+ Tregs.

The investigators decided to take a closer look at the Tregs, evaluating their role in GVHD-related death.

To do this, the team evaluated survival in 4 groups of mice: (1) irradiated controls; (2) mice that received only bone marrow; (3) mice that received Tcon, CD4+ iNKT cells, and a graft depleted of CD4+ FoxP3+ Tregs; and (4) mice that received Tcon, CD4+ iNKT cells, and a non-depleted graft.

“Animals that received a Treg-depleted graft and were treated with CD4+ iNKT [plus Tcon] did not show a significant improvement in survival [over controls],” Dr Schneidawind said.

“In contrast, animals that received a Treg-non-depleted graft showed a significant improvement in survival [P=0.006]. So we conclude that the expansion of these Tregs is necessary to protect from GVHD lethality and that they are required in this context.”

In closing, Dr Schneidawind noted that, although human CD4+ iNKT cells are rare, they can be isolated from peripheral blood and expanded in vitro. This suggests his group’s findings might ultimately prove useful for patients.

*Information in the abstract differs from that presented.

GRAPEVINE, TEXAS—The order in which patients receive cyclophosphamide (Cy) and total body irradiation (TBI) does not affect the outcome of hematopoietic stem cell transplant (HSCT), researchers have reported.

In a large, retrospective study, the rates of relapse, survival, chronic graft-vs-host disease (GVHD), and other complications were similar whether patients received Cy-TBI or TBI-Cy.

However, receiving Cy-TBI was associated with a slight decrease in the risk of grade 2-4 acute GVHD.

Jennifer L. Holter-Chakrabarty, MD, of the University of Oklahoma in Oklahoma City, presented these findings at the 2014 BMT Tandem Meetings as abstract 13.

She noted that other researchers have investigated the impact of TBI/Cy order, but the results have not provided definitive answers.

“Mouse models show that TBI-Cy is superior, with reduced lung toxicity and increased incidence of bone marrow damage,” Dr Holter-Chakrabarty said.

“Cy-TBI, however, in a retrospective study, showed improved anti-leukemic effect, as well as increased incidence of sinusoidal obstructive syndrome. So for this reason, we wanted to look at the CIBMTR database and compare the order of cyclophosphamide and TBI.”

She and her colleagues analyzed data from 1769 HSCT recipients who were younger than 60 years of age and had been reported to the CIBMTR from 2003 to 2010. Patients had been diagnosed with acute myeloid leukemia (AML, n=945) or acute lymphoblastic leukemia (ALL, n=824) and were in their first or second remission.

They had received TBI doses of at least 1200 cGy, followed by related or unrelated bone marrow or peripheral blood stem cell grafts. Patients who had received cord blood, haploidentical, or T-cell-depleted grafts were excluded.

In all, 948 patients received Cy-TBI, and 821 received TBI-Cy. The 2 cohorts had comparable patient-, disease- and transplant-related characteristics.

The sequence of TBI and Cy did not significantly affect the rates of relapse, leukemia-free survival, or overall survival. And it had no significant impact on transplant-related complications, with the exception of acute grade 2-4 GVHD.

At 100 days, the rate of grade 2-4 acute GVHD was 39% in the Cy-TBI group and 45% in the TBI-Cy group (P=0.01). But the rates of grade 3-4 acute GVHD were 16% and 15%, respectively (P=0.62).

At 100 days, the incidence of veno-occlusive disease and sinusoidal obstructive syndrome was 4% in the Cy-TBI group and 6% in the TBI-Cy group (P=0.082). At 1 year, the incidence of interstitial pneumonia syndrome was 6% and 5%, respectively (P=0.370).

At 3 years, the relapse rate was 27% in the Cy-TBI group and 29% in the TBI-Cy group (P=0.34). Leukemia-free survival was 48% and 49%, respectively (P=0.27). And overall survival was 53% and 52%, respectively (P=0.62).

Transplant-related mortality at 3 years was 24% and 23%, respectively (P=0.67). And the rate of chronic GVHD was 45% and 47%, respectively (P=0.39).

“So, in this population, we see no difference,” Dr Holter-Chakrabarty said. “Cy-TBI or TBI-Cy—it seems to not make a difference either way in relapse, treatment-related mortality, [chronic] graft-vs-host disease, acute 3 and 4 [GVHD], and survival. However, it does give us an idea that 2-4 acute GVHD may be lower in Cy-TBI.”

GRAPEVINE, TEXAS—The order in which patients receive cyclophosphamide (Cy) and total body irradiation (TBI) does not affect the outcome of hematopoietic stem cell transplant (HSCT), researchers have reported.

In a large, retrospective study, the rates of relapse, survival, chronic graft-vs-host disease (GVHD), and other complications were similar whether patients received Cy-TBI or TBI-Cy.

However, receiving Cy-TBI was associated with a slight decrease in the risk of grade 2-4 acute GVHD.

Jennifer L. Holter-Chakrabarty, MD, of the University of Oklahoma in Oklahoma City, presented these findings at the 2014 BMT Tandem Meetings as abstract 13.

She noted that other researchers have investigated the impact of TBI/Cy order, but the results have not provided definitive answers.

“Mouse models show that TBI-Cy is superior, with reduced lung toxicity and increased incidence of bone marrow damage,” Dr Holter-Chakrabarty said.

“Cy-TBI, however, in a retrospective study, showed improved anti-leukemic effect, as well as increased incidence of sinusoidal obstructive syndrome. So for this reason, we wanted to look at the CIBMTR database and compare the order of cyclophosphamide and TBI.”

She and her colleagues analyzed data from 1769 HSCT recipients who were younger than 60 years of age and had been reported to the CIBMTR from 2003 to 2010. Patients had been diagnosed with acute myeloid leukemia (AML, n=945) or acute lymphoblastic leukemia (ALL, n=824) and were in their first or second remission.

They had received TBI doses of at least 1200 cGy, followed by related or unrelated bone marrow or peripheral blood stem cell grafts. Patients who had received cord blood, haploidentical, or T-cell-depleted grafts were excluded.

In all, 948 patients received Cy-TBI, and 821 received TBI-Cy. The 2 cohorts had comparable patient-, disease- and transplant-related characteristics.

The sequence of TBI and Cy did not significantly affect the rates of relapse, leukemia-free survival, or overall survival. And it had no significant impact on transplant-related complications, with the exception of acute grade 2-4 GVHD.

At 100 days, the rate of grade 2-4 acute GVHD was 39% in the Cy-TBI group and 45% in the TBI-Cy group (P=0.01). But the rates of grade 3-4 acute GVHD were 16% and 15%, respectively (P=0.62).

At 100 days, the incidence of veno-occlusive disease and sinusoidal obstructive syndrome was 4% in the Cy-TBI group and 6% in the TBI-Cy group (P=0.082). At 1 year, the incidence of interstitial pneumonia syndrome was 6% and 5%, respectively (P=0.370).

At 3 years, the relapse rate was 27% in the Cy-TBI group and 29% in the TBI-Cy group (P=0.34). Leukemia-free survival was 48% and 49%, respectively (P=0.27). And overall survival was 53% and 52%, respectively (P=0.62).

Transplant-related mortality at 3 years was 24% and 23%, respectively (P=0.67). And the rate of chronic GVHD was 45% and 47%, respectively (P=0.39).

“So, in this population, we see no difference,” Dr Holter-Chakrabarty said. “Cy-TBI or TBI-Cy—it seems to not make a difference either way in relapse, treatment-related mortality, [chronic] graft-vs-host disease, acute 3 and 4 [GVHD], and survival. However, it does give us an idea that 2-4 acute GVHD may be lower in Cy-TBI.”

GRAPEVINE, TEXAS—The order in which patients receive cyclophosphamide (Cy) and total body irradiation (TBI) does not affect the outcome of hematopoietic stem cell transplant (HSCT), researchers have reported.

In a large, retrospective study, the rates of relapse, survival, chronic graft-vs-host disease (GVHD), and other complications were similar whether patients received Cy-TBI or TBI-Cy.

However, receiving Cy-TBI was associated with a slight decrease in the risk of grade 2-4 acute GVHD.

Jennifer L. Holter-Chakrabarty, MD, of the University of Oklahoma in Oklahoma City, presented these findings at the 2014 BMT Tandem Meetings as abstract 13.

She noted that other researchers have investigated the impact of TBI/Cy order, but the results have not provided definitive answers.

“Mouse models show that TBI-Cy is superior, with reduced lung toxicity and increased incidence of bone marrow damage,” Dr Holter-Chakrabarty said.

“Cy-TBI, however, in a retrospective study, showed improved anti-leukemic effect, as well as increased incidence of sinusoidal obstructive syndrome. So for this reason, we wanted to look at the CIBMTR database and compare the order of cyclophosphamide and TBI.”

She and her colleagues analyzed data from 1769 HSCT recipients who were younger than 60 years of age and had been reported to the CIBMTR from 2003 to 2010. Patients had been diagnosed with acute myeloid leukemia (AML, n=945) or acute lymphoblastic leukemia (ALL, n=824) and were in their first or second remission.

They had received TBI doses of at least 1200 cGy, followed by related or unrelated bone marrow or peripheral blood stem cell grafts. Patients who had received cord blood, haploidentical, or T-cell-depleted grafts were excluded.

In all, 948 patients received Cy-TBI, and 821 received TBI-Cy. The 2 cohorts had comparable patient-, disease- and transplant-related characteristics.

The sequence of TBI and Cy did not significantly affect the rates of relapse, leukemia-free survival, or overall survival. And it had no significant impact on transplant-related complications, with the exception of acute grade 2-4 GVHD.

At 100 days, the rate of grade 2-4 acute GVHD was 39% in the Cy-TBI group and 45% in the TBI-Cy group (P=0.01). But the rates of grade 3-4 acute GVHD were 16% and 15%, respectively (P=0.62).

At 100 days, the incidence of veno-occlusive disease and sinusoidal obstructive syndrome was 4% in the Cy-TBI group and 6% in the TBI-Cy group (P=0.082). At 1 year, the incidence of interstitial pneumonia syndrome was 6% and 5%, respectively (P=0.370).

At 3 years, the relapse rate was 27% in the Cy-TBI group and 29% in the TBI-Cy group (P=0.34). Leukemia-free survival was 48% and 49%, respectively (P=0.27). And overall survival was 53% and 52%, respectively (P=0.62).

Transplant-related mortality at 3 years was 24% and 23%, respectively (P=0.67). And the rate of chronic GVHD was 45% and 47%, respectively (P=0.39).

“So, in this population, we see no difference,” Dr Holter-Chakrabarty said. “Cy-TBI or TBI-Cy—it seems to not make a difference either way in relapse, treatment-related mortality, [chronic] graft-vs-host disease, acute 3 and 4 [GVHD], and survival. However, it does give us an idea that 2-4 acute GVHD may be lower in Cy-TBI.”

GRAPEVINE, TEXAS—Administering radioimmunotherapy (RIT) prior to non-myeloablative allogeneic transplant (NMAT) can improve survival in patients with persistent disease, according to a speaker at the 2014 BMT Tandem Meetings.

Ryan Cassaday, MD, of the University of Washington in Seattle, noted that RIT-augmented NMAT can produce long-term remissions in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL) or chronic lymphocytic leukemia (CLL).

But outcomes for patients with persistent disease are “underdescribed.”

So he and his colleagues set out to describe outcomes of NMAT for patients with persistent indolent B-NHL or CLL and estimate the impact of RIT in these patients.

Treatment details

The researchers retrospectively analyzed data from 89 patients who underwent NMAT from December 1998 to April 2009 and were followed until September 2013. Eighteen of the patients had received RIT as part of a prospective study (AK Gopal et al, Blood 2011).

The remaining 71 patients did not receive RIT but met eligibility criteria for that study. Specifically, they had a CD20+ B-cell malignancy, an HLA-matched peripheral blood stem cell donor, and persistent disease at NMAT. These control subjects received fludarabine (30 mg/m² on days -7, -6, and -5) and 2 Gy of total body irradiation prior to NMAT.

Patients in the RIT group received the same treatment following RIT. On day -21, they received 250 mg/m² of rituximab before an imaging dose of ¹¹¹In-ibritumomab tiuxetan. And on day -14, they received 250 mg/m² of rituximab and 0.4 mCi/kg of ⁹⁰Y-ibritumomab tiuxetan.

Patient characteristics

In the RIT group, 10 patients had CLL/small lymphocytic lymphoma (SLL), 6 had follicular lymphoma (FL), 1 had marginal zone lymphoma (MZL), and 1 had hairy cell leukemia. As for controls, 52 had CLL/SLL, 18 had FL, and 1 had MZL.

“The majority of patients were male [74%] and a relatively young age, given the diseases being treated [median of 56 years],” Dr Cassaday said. “The majority of patients had previously received rituximab [88%], and patients were heavily pretreated [median of 4 prior therapies, range 1-12].”

There were no significant differences between the 2 treatment groups with regard to the aforementioned characteristics. However, there were some “striking differences” between the 2 groups, Dr Cassaday said, including characteristics that portend worse prognosis.

Specifically, RIT-treated patients had more bulky disease (> 5 cm) than controls (61% vs 15%, P<0.001) and more chemoresistant disease (81% vs 39%, P=0.003). And RIT patients were more likely to have HCT comorbidity index scores of 3 or higher (72% vs 37%, P=0.006), as well as pre-NMAT platelet counts less than 25k/μL (33% vs 7%, P=0.002).

RIT improves PFS, OS

The researchers conducted a multivariate analysis including the factors that differed significantly between the 2 treatment groups. And they found that only RIT was significantly associated with both progression-free survival (PFS) and overall survival (OS).

When calculating survival curves, the researchers adjusted for the imbalance in covariates between the treatment groups.

“[The adjusted survival rate] is essentially what one might expect had the RIT group had similar baseline characteristics as the control group,” Dr Cassaday explained.

Control subjects had a 3-year OS of 55%. For the RIT-treated patients, the unadjusted 3-year OS was 78% (P=0.20), and the adjusted OS was 87% (P=0.008).

The 3-year PFS was 44% for controls. For the RIT group, the unadjusted 3-year PFS was 56% (P=0.36), and the adjusted PFS was 71% (P=0.02).

The researchers also found that RIT did not increase the rate of non-relapse mortality. The unadjusted hazard ratio was 0.5 (P=0.32), and the adjusted hazard ratio was 0.4 (P=0.18).

“This analysis does have some limitations,” Dr Cassaday conceded. “Clearly, it does not replace the strength of evidence that would come from a randomized, controlled trial. And the relatively small sample size does limit our ability to look at a lot of different subgroups.”

In addition, the findings may not apply to other non-myeloablative regimens. And, due to the time frame of the study, the researchers could not account for the potential impact of newer agents.

Nevertheless, Dr Cassaday said the data suggest that RIT can improve the outcome of NMAT in patients with persistent indolent B-NHL or CLL. And a prospective, randomized study evaluating this approach is warranted.

Dr Cassaday presented this research at the 2014 BMT Tandem Meetings as abstract 75. Information in the abstract differs from that presented.

GRAPEVINE, TEXAS—Administering radioimmunotherapy (RIT) prior to non-myeloablative allogeneic transplant (NMAT) can improve survival in patients with persistent disease, according to a speaker at the 2014 BMT Tandem Meetings.

Ryan Cassaday, MD, of the University of Washington in Seattle, noted that RIT-augmented NMAT can produce long-term remissions in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL) or chronic lymphocytic leukemia (CLL).

But outcomes for patients with persistent disease are “underdescribed.”

So he and his colleagues set out to describe outcomes of NMAT for patients with persistent indolent B-NHL or CLL and estimate the impact of RIT in these patients.

Treatment details

The researchers retrospectively analyzed data from 89 patients who underwent NMAT from December 1998 to April 2009 and were followed until September 2013. Eighteen of the patients had received RIT as part of a prospective study (AK Gopal et al, Blood 2011).

The remaining 71 patients did not receive RIT but met eligibility criteria for that study. Specifically, they had a CD20+ B-cell malignancy, an HLA-matched peripheral blood stem cell donor, and persistent disease at NMAT. These control subjects received fludarabine (30 mg/m² on days -7, -6, and -5) and 2 Gy of total body irradiation prior to NMAT.

Patients in the RIT group received the same treatment following RIT. On day -21, they received 250 mg/m² of rituximab before an imaging dose of ¹¹¹In-ibritumomab tiuxetan. And on day -14, they received 250 mg/m² of rituximab and 0.4 mCi/kg of ⁹⁰Y-ibritumomab tiuxetan.

Patient characteristics

In the RIT group, 10 patients had CLL/small lymphocytic lymphoma (SLL), 6 had follicular lymphoma (FL), 1 had marginal zone lymphoma (MZL), and 1 had hairy cell leukemia. As for controls, 52 had CLL/SLL, 18 had FL, and 1 had MZL.

“The majority of patients were male [74%] and a relatively young age, given the diseases being treated [median of 56 years],” Dr Cassaday said. “The majority of patients had previously received rituximab [88%], and patients were heavily pretreated [median of 4 prior therapies, range 1-12].”

There were no significant differences between the 2 treatment groups with regard to the aforementioned characteristics. However, there were some “striking differences” between the 2 groups, Dr Cassaday said, including characteristics that portend worse prognosis.

Specifically, RIT-treated patients had more bulky disease (> 5 cm) than controls (61% vs 15%, P<0.001) and more chemoresistant disease (81% vs 39%, P=0.003). And RIT patients were more likely to have HCT comorbidity index scores of 3 or higher (72% vs 37%, P=0.006), as well as pre-NMAT platelet counts less than 25k/μL (33% vs 7%, P=0.002).

RIT improves PFS, OS

The researchers conducted a multivariate analysis including the factors that differed significantly between the 2 treatment groups. And they found that only RIT was significantly associated with both progression-free survival (PFS) and overall survival (OS).

When calculating survival curves, the researchers adjusted for the imbalance in covariates between the treatment groups.

“[The adjusted survival rate] is essentially what one might expect had the RIT group had similar baseline characteristics as the control group,” Dr Cassaday explained.

Control subjects had a 3-year OS of 55%. For the RIT-treated patients, the unadjusted 3-year OS was 78% (P=0.20), and the adjusted OS was 87% (P=0.008).

The 3-year PFS was 44% for controls. For the RIT group, the unadjusted 3-year PFS was 56% (P=0.36), and the adjusted PFS was 71% (P=0.02).

The researchers also found that RIT did not increase the rate of non-relapse mortality. The unadjusted hazard ratio was 0.5 (P=0.32), and the adjusted hazard ratio was 0.4 (P=0.18).

“This analysis does have some limitations,” Dr Cassaday conceded. “Clearly, it does not replace the strength of evidence that would come from a randomized, controlled trial. And the relatively small sample size does limit our ability to look at a lot of different subgroups.”

In addition, the findings may not apply to other non-myeloablative regimens. And, due to the time frame of the study, the researchers could not account for the potential impact of newer agents.

Nevertheless, Dr Cassaday said the data suggest that RIT can improve the outcome of NMAT in patients with persistent indolent B-NHL or CLL. And a prospective, randomized study evaluating this approach is warranted.

Dr Cassaday presented this research at the 2014 BMT Tandem Meetings as abstract 75. Information in the abstract differs from that presented.

GRAPEVINE, TEXAS—Administering radioimmunotherapy (RIT) prior to non-myeloablative allogeneic transplant (NMAT) can improve survival in patients with persistent disease, according to a speaker at the 2014 BMT Tandem Meetings.

Ryan Cassaday, MD, of the University of Washington in Seattle, noted that RIT-augmented NMAT can produce long-term remissions in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL) or chronic lymphocytic leukemia (CLL).

But outcomes for patients with persistent disease are “underdescribed.”

So he and his colleagues set out to describe outcomes of NMAT for patients with persistent indolent B-NHL or CLL and estimate the impact of RIT in these patients.

Treatment details

The researchers retrospectively analyzed data from 89 patients who underwent NMAT from December 1998 to April 2009 and were followed until September 2013. Eighteen of the patients had received RIT as part of a prospective study (AK Gopal et al, Blood 2011).

The remaining 71 patients did not receive RIT but met eligibility criteria for that study. Specifically, they had a CD20+ B-cell malignancy, an HLA-matched peripheral blood stem cell donor, and persistent disease at NMAT. These control subjects received fludarabine (30 mg/m² on days -7, -6, and -5) and 2 Gy of total body irradiation prior to NMAT.

Patients in the RIT group received the same treatment following RIT. On day -21, they received 250 mg/m² of rituximab before an imaging dose of ¹¹¹In-ibritumomab tiuxetan. And on day -14, they received 250 mg/m² of rituximab and 0.4 mCi/kg of ⁹⁰Y-ibritumomab tiuxetan.

Patient characteristics

In the RIT group, 10 patients had CLL/small lymphocytic lymphoma (SLL), 6 had follicular lymphoma (FL), 1 had marginal zone lymphoma (MZL), and 1 had hairy cell leukemia. As for controls, 52 had CLL/SLL, 18 had FL, and 1 had MZL.

“The majority of patients were male [74%] and a relatively young age, given the diseases being treated [median of 56 years],” Dr Cassaday said. “The majority of patients had previously received rituximab [88%], and patients were heavily pretreated [median of 4 prior therapies, range 1-12].”

There were no significant differences between the 2 treatment groups with regard to the aforementioned characteristics. However, there were some “striking differences” between the 2 groups, Dr Cassaday said, including characteristics that portend worse prognosis.

Specifically, RIT-treated patients had more bulky disease (> 5 cm) than controls (61% vs 15%, P<0.001) and more chemoresistant disease (81% vs 39%, P=0.003). And RIT patients were more likely to have HCT comorbidity index scores of 3 or higher (72% vs 37%, P=0.006), as well as pre-NMAT platelet counts less than 25k/μL (33% vs 7%, P=0.002).

RIT improves PFS, OS

The researchers conducted a multivariate analysis including the factors that differed significantly between the 2 treatment groups. And they found that only RIT was significantly associated with both progression-free survival (PFS) and overall survival (OS).

When calculating survival curves, the researchers adjusted for the imbalance in covariates between the treatment groups.

“[The adjusted survival rate] is essentially what one might expect had the RIT group had similar baseline characteristics as the control group,” Dr Cassaday explained.

Control subjects had a 3-year OS of 55%. For the RIT-treated patients, the unadjusted 3-year OS was 78% (P=0.20), and the adjusted OS was 87% (P=0.008).

The 3-year PFS was 44% for controls. For the RIT group, the unadjusted 3-year PFS was 56% (P=0.36), and the adjusted PFS was 71% (P=0.02).

The researchers also found that RIT did not increase the rate of non-relapse mortality. The unadjusted hazard ratio was 0.5 (P=0.32), and the adjusted hazard ratio was 0.4 (P=0.18).

“This analysis does have some limitations,” Dr Cassaday conceded. “Clearly, it does not replace the strength of evidence that would come from a randomized, controlled trial. And the relatively small sample size does limit our ability to look at a lot of different subgroups.”

In addition, the findings may not apply to other non-myeloablative regimens. And, due to the time frame of the study, the researchers could not account for the potential impact of newer agents.

Nevertheless, Dr Cassaday said the data suggest that RIT can improve the outcome of NMAT in patients with persistent indolent B-NHL or CLL. And a prospective, randomized study evaluating this approach is warranted.

Dr Cassaday presented this research at the 2014 BMT Tandem Meetings as abstract 75. Information in the abstract differs from that presented.

GRAPEVINE, TEXAS—Acute leukemia patients who undergo cord blood (CB) transplant have longer hospital stays than patients who receive other types of transplant, new research indicates.

The study also suggests the length of stay (LOS) is similar whether patients receive double or single CB grafts.

So it seems strategies are needed to decrease hospital stay after CB transplant, particularly as LOS drives the cost of care, said Karen K. Ballen, MD, of Massachusetts General Hospital in Boston.

Dr Ballen presented this research at the 2014 BMT Tandem Meetings as abstract 104.*

She and her colleagues studied patients diagnosed with acute leukemias who were transplanted at US centers and reported to the CIBMTR between 2008 and 2011.

Patients were eligible if they received an unrelated single or double CB transplant, an 8/8 matched unrelated donor (MUD) transplant with peripheral blood (PB) or bone marrow (BM), or a 7/8 MUD PB or BM graft.

In all, 1796 patients met these criteria. The researchers evaluated patients’ total hospital LOS in the first 100 days after transplant, compared LOS among graft sources, and looked for predictors of LOS in the first 100 days.

The team stratified patients according to age and conditioning regimen. Pediatric patients were classified as those aged 18 and younger, and they only received myeloablative conditioning (MAC). Adults received either MAC or reduced-intensity conditioning (RIC).

Pediatric patients

In a univariate analysis of the 368 pediatric patients, there was no significant difference in 100-day survival according to graft source (P=0.13).

However, patients who received single or double CB grafts had a significantly higher median total LOS by day 100 than patients who received 8/8 MUD BM, which was the only other graft source in this patient group (P=0.03).

Patients who received CB grafts also had significantly fewer days in which they were alive and not in the hospital (P=0.005).

“We wanted to account for patients whose length of stay was short because they actually died early after transplant,” Dr Ballen explained. “Therefore, we did an analysis of days alive and not in the hospital.”

In a multivariate analysis, pediatric patients who received CB grafts had significantly fewer days alive and out of the hospital than those who received 8/8 MUD BM (P=0.03).

Other factors associated with fewer days alive and out of the hospital were CMV positivity (P=0.01), black race (P=0.01), and a Karnofsky performance score of less than 80 (P=0.03).

Adults on MAC

In a univariate analysis of the 768 adults who received MAC, recipients of CB grafts had significantly worse 100-day survival than their peers (P<0.001), as well as a longer median LOS by day 100 (P<0.001) and fewer days alive and not in the hospital (P<0.001).

In a multivariate analysis, adults who received MAC had significantly fewer days alive and out of the hospital if they received CB grafts than if they received 8/8 MUD BM (P<0.001), 8/8 MUD PB (P<0.001), or 7/8 MUD PB (P=0.01), but not 7/8 MUD BM (P=0.49).

Other factors associated with fewer days alive and out of the hospital were black race (P=0.04), having acute lymphocytic leukemia rather than acute myeloid leukemia (P=0.01), and age 18-25 (P=0.01).

“We were a little surprised at these results—that the older patients actually spent more time alive and out of the hospital,” Dr Ballen said.

Adults on RIC

In a univariate analysis of the 660 adults who received RIC, recipients of CB grafts had significantly worse 100-day survival than their peers (P=0.017), as well as a longer median LOS by day 100 (P<0.001) and fewer days alive and not in the hospital (P<0.001).

In a multivariate analysis, adults who received RIC had significantly fewer days alive and out of the hospital if they received CB grafts than if they received 8/8 MUD PB (P<0.001) or 7/8 MUD PB (P<0.001).

No other factors were associated with the number of days these patients were alive and out of the hospital.

These results, when taken together, suggest that CB grafts are associated with longer hospital stays, independent of other factors.

“The majority of cost appears to be driven by the number of days in the hospital,” Dr Ballen noted. “So these data may be important for resource allocation, especially given the recent changes in the US healthcare system.”

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

GRAPEVINE, TEXAS—Acute leukemia patients who undergo cord blood (CB) transplant have longer hospital stays than patients who receive other types of transplant, new research indicates.

The study also suggests the length of stay (LOS) is similar whether patients receive double or single CB grafts.

So it seems strategies are needed to decrease hospital stay after CB transplant, particularly as LOS drives the cost of care, said Karen K. Ballen, MD, of Massachusetts General Hospital in Boston.

Dr Ballen presented this research at the 2014 BMT Tandem Meetings as abstract 104.*

She and her colleagues studied patients diagnosed with acute leukemias who were transplanted at US centers and reported to the CIBMTR between 2008 and 2011.

Patients were eligible if they received an unrelated single or double CB transplant, an 8/8 matched unrelated donor (MUD) transplant with peripheral blood (PB) or bone marrow (BM), or a 7/8 MUD PB or BM graft.

In all, 1796 patients met these criteria. The researchers evaluated patients’ total hospital LOS in the first 100 days after transplant, compared LOS among graft sources, and looked for predictors of LOS in the first 100 days.

The team stratified patients according to age and conditioning regimen. Pediatric patients were classified as those aged 18 and younger, and they only received myeloablative conditioning (MAC). Adults received either MAC or reduced-intensity conditioning (RIC).

Pediatric patients

In a univariate analysis of the 368 pediatric patients, there was no significant difference in 100-day survival according to graft source (P=0.13).

However, patients who received single or double CB grafts had a significantly higher median total LOS by day 100 than patients who received 8/8 MUD BM, which was the only other graft source in this patient group (P=0.03).

Patients who received CB grafts also had significantly fewer days in which they were alive and not in the hospital (P=0.005).

“We wanted to account for patients whose length of stay was short because they actually died early after transplant,” Dr Ballen explained. “Therefore, we did an analysis of days alive and not in the hospital.”

In a multivariate analysis, pediatric patients who received CB grafts had significantly fewer days alive and out of the hospital than those who received 8/8 MUD BM (P=0.03).

Other factors associated with fewer days alive and out of the hospital were CMV positivity (P=0.01), black race (P=0.01), and a Karnofsky performance score of less than 80 (P=0.03).

Adults on MAC

In a univariate analysis of the 768 adults who received MAC, recipients of CB grafts had significantly worse 100-day survival than their peers (P<0.001), as well as a longer median LOS by day 100 (P<0.001) and fewer days alive and not in the hospital (P<0.001).

In a multivariate analysis, adults who received MAC had significantly fewer days alive and out of the hospital if they received CB grafts than if they received 8/8 MUD BM (P<0.001), 8/8 MUD PB (P<0.001), or 7/8 MUD PB (P=0.01), but not 7/8 MUD BM (P=0.49).

Other factors associated with fewer days alive and out of the hospital were black race (P=0.04), having acute lymphocytic leukemia rather than acute myeloid leukemia (P=0.01), and age 18-25 (P=0.01).

“We were a little surprised at these results—that the older patients actually spent more time alive and out of the hospital,” Dr Ballen said.

Adults on RIC

In a univariate analysis of the 660 adults who received RIC, recipients of CB grafts had significantly worse 100-day survival than their peers (P=0.017), as well as a longer median LOS by day 100 (P<0.001) and fewer days alive and not in the hospital (P<0.001).

In a multivariate analysis, adults who received RIC had significantly fewer days alive and out of the hospital if they received CB grafts than if they received 8/8 MUD PB (P<0.001) or 7/8 MUD PB (P<0.001).

No other factors were associated with the number of days these patients were alive and out of the hospital.

These results, when taken together, suggest that CB grafts are associated with longer hospital stays, independent of other factors.

“The majority of cost appears to be driven by the number of days in the hospital,” Dr Ballen noted. “So these data may be important for resource allocation, especially given the recent changes in the US healthcare system.”

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

GRAPEVINE, TEXAS—Acute leukemia patients who undergo cord blood (CB) transplant have longer hospital stays than patients who receive other types of transplant, new research indicates.

The study also suggests the length of stay (LOS) is similar whether patients receive double or single CB grafts.

So it seems strategies are needed to decrease hospital stay after CB transplant, particularly as LOS drives the cost of care, said Karen K. Ballen, MD, of Massachusetts General Hospital in Boston.

Dr Ballen presented this research at the 2014 BMT Tandem Meetings as abstract 104.*

She and her colleagues studied patients diagnosed with acute leukemias who were transplanted at US centers and reported to the CIBMTR between 2008 and 2011.

Patients were eligible if they received an unrelated single or double CB transplant, an 8/8 matched unrelated donor (MUD) transplant with peripheral blood (PB) or bone marrow (BM), or a 7/8 MUD PB or BM graft.

In all, 1796 patients met these criteria. The researchers evaluated patients’ total hospital LOS in the first 100 days after transplant, compared LOS among graft sources, and looked for predictors of LOS in the first 100 days.

The team stratified patients according to age and conditioning regimen. Pediatric patients were classified as those aged 18 and younger, and they only received myeloablative conditioning (MAC). Adults received either MAC or reduced-intensity conditioning (RIC).

Pediatric patients

In a univariate analysis of the 368 pediatric patients, there was no significant difference in 100-day survival according to graft source (P=0.13).

However, patients who received single or double CB grafts had a significantly higher median total LOS by day 100 than patients who received 8/8 MUD BM, which was the only other graft source in this patient group (P=0.03).

Patients who received CB grafts also had significantly fewer days in which they were alive and not in the hospital (P=0.005).

“We wanted to account for patients whose length of stay was short because they actually died early after transplant,” Dr Ballen explained. “Therefore, we did an analysis of days alive and not in the hospital.”

In a multivariate analysis, pediatric patients who received CB grafts had significantly fewer days alive and out of the hospital than those who received 8/8 MUD BM (P=0.03).

Other factors associated with fewer days alive and out of the hospital were CMV positivity (P=0.01), black race (P=0.01), and a Karnofsky performance score of less than 80 (P=0.03).

Adults on MAC

In a univariate analysis of the 768 adults who received MAC, recipients of CB grafts had significantly worse 100-day survival than their peers (P<0.001), as well as a longer median LOS by day 100 (P<0.001) and fewer days alive and not in the hospital (P<0.001).

In a multivariate analysis, adults who received MAC had significantly fewer days alive and out of the hospital if they received CB grafts than if they received 8/8 MUD BM (P<0.001), 8/8 MUD PB (P<0.001), or 7/8 MUD PB (P=0.01), but not 7/8 MUD BM (P=0.49).

Other factors associated with fewer days alive and out of the hospital were black race (P=0.04), having acute lymphocytic leukemia rather than acute myeloid leukemia (P=0.01), and age 18-25 (P=0.01).

“We were a little surprised at these results—that the older patients actually spent more time alive and out of the hospital,” Dr Ballen said.

Adults on RIC

In a univariate analysis of the 660 adults who received RIC, recipients of CB grafts had significantly worse 100-day survival than their peers (P=0.017), as well as a longer median LOS by day 100 (P<0.001) and fewer days alive and not in the hospital (P<0.001).

In a multivariate analysis, adults who received RIC had significantly fewer days alive and out of the hospital if they received CB grafts than if they received 8/8 MUD PB (P<0.001) or 7/8 MUD PB (P<0.001).

No other factors were associated with the number of days these patients were alive and out of the hospital.

These results, when taken together, suggest that CB grafts are associated with longer hospital stays, independent of other factors.

“The majority of cost appears to be driven by the number of days in the hospital,” Dr Ballen noted. “So these data may be important for resource allocation, especially given the recent changes in the US healthcare system.”

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