HT Staff

Diffuse large B-cell lymphoma

HOUSTON—Preclinical data suggest the second-generation cyclin-dependent kinase (CDK) inhibitor CYC065 is active against lymphomas as well as leukemias.

Previous research showed that CYC065 can fight acute myeloid leukemia (AML) in vitro and in vivo.

New research shows that CYC065 can decrease cell viability in a range of B-cell lymphoma cell lines, and the drug synergizes with both venetoclax and cytarabine.

Sheelagh Frame, PhD, and her colleagues presented these results at the SOHO 2015 Annual Meeting (poster 213). All of the investigators involved in the research are employees of Cyclacel Ltd., the company developing CYC065.

The investigators analyzed the anticancer activity of CYC065 in a range of cell lines and found that CYC065 induced apoptosis by inhibiting the expression of CDK9-dependent oncogenic transcripts, including Mcl-1, c-Myc, Hoxa9, and Meis1.

Results in AML

Experiments in the AML-MLL cell line MOLM-13 showed that short pulses of CYC065 (6 hours), rather than continuous treatment, were sufficient to achieve maximal cytotoxicity.

CYC065 induced apoptosis, in a dose-dependent manner, in other AML cell lines as well, including EOL-1 (MLL-PTD), MV4-11 (MLL-AF4, FLT3-ITD, and trisomy chr 8), HL60 (Myc amplified), and Kasumi-1.

The investigators noted that AML cell lines with MLL rearrangements were especially sensitive to CYC065, and the reliance of AML on Mcl-1 confers sensitivity to CYC065.

They also found evidence to suggest that Bak and Bcl-xL levels may be predictive of CYC065 response in AML. Cell lines that were less sensitive to treatment had high levels of Bcl-xL and negligible levels of Bak.

B-cell lymphomas

In B-cell lymphoma cell lines, the investigators observed a dose-dependent reduction in cell viability after CYC065 treatment (8-hour pulses).

CYC065 proved most effective in cell lines without genomic alterations associated with poor prognosis (HT and U-698-M) and in cell lines with Myc rearrangements (SU-DHL-8 and WILL-1).

The drug also decreased cell viability—but to a lesser degree—in cell lines with Bcl-2 rearrangements (SU-DHL-4 and U2932) and in double-hit lymphoma cell lines (MAVER-1, RI-1, SC-1, and SU-DHL-10).

The investigators therefore theorized that combining CYC065 with a Bcl-2 inhibitor might prove more effective in these cell lines.

CYC065 in combination

CYC065 synergized with the Bcl-2 inhibitor venetoclax in all B-cell lymphoma cell lines tested. The drugs were “strongly synergistic” in U2932 and RI-1 cell lines but simply “synergistic” in SU-CHL-4 and MAVER-1 cell lines.

CYC065 also synergized with cytarabine to fight AML. The combination proved synergistic at a range of doses in the HL60 and MV4-11 cell lines.

Considering these results together, the investigators concluded that CYC065 has shown potential for treating a range of leukemias and lymphomas with unmet clinical need, including MLL-rearranged leukemia and Myc-driven lymphoma.

And the drug might prove effective in combination with standard cytotoxic agents or agents targeting apoptotic regulators.

Diffuse large B-cell lymphoma

HOUSTON—Preclinical data suggest the second-generation cyclin-dependent kinase (CDK) inhibitor CYC065 is active against lymphomas as well as leukemias.

Previous research showed that CYC065 can fight acute myeloid leukemia (AML) in vitro and in vivo.

New research shows that CYC065 can decrease cell viability in a range of B-cell lymphoma cell lines, and the drug synergizes with both venetoclax and cytarabine.

Sheelagh Frame, PhD, and her colleagues presented these results at the SOHO 2015 Annual Meeting (poster 213). All of the investigators involved in the research are employees of Cyclacel Ltd., the company developing CYC065.

The investigators analyzed the anticancer activity of CYC065 in a range of cell lines and found that CYC065 induced apoptosis by inhibiting the expression of CDK9-dependent oncogenic transcripts, including Mcl-1, c-Myc, Hoxa9, and Meis1.

Results in AML

Experiments in the AML-MLL cell line MOLM-13 showed that short pulses of CYC065 (6 hours), rather than continuous treatment, were sufficient to achieve maximal cytotoxicity.

CYC065 induced apoptosis, in a dose-dependent manner, in other AML cell lines as well, including EOL-1 (MLL-PTD), MV4-11 (MLL-AF4, FLT3-ITD, and trisomy chr 8), HL60 (Myc amplified), and Kasumi-1.

The investigators noted that AML cell lines with MLL rearrangements were especially sensitive to CYC065, and the reliance of AML on Mcl-1 confers sensitivity to CYC065.

They also found evidence to suggest that Bak and Bcl-xL levels may be predictive of CYC065 response in AML. Cell lines that were less sensitive to treatment had high levels of Bcl-xL and negligible levels of Bak.

B-cell lymphomas

In B-cell lymphoma cell lines, the investigators observed a dose-dependent reduction in cell viability after CYC065 treatment (8-hour pulses).

CYC065 proved most effective in cell lines without genomic alterations associated with poor prognosis (HT and U-698-M) and in cell lines with Myc rearrangements (SU-DHL-8 and WILL-1).

The drug also decreased cell viability—but to a lesser degree—in cell lines with Bcl-2 rearrangements (SU-DHL-4 and U2932) and in double-hit lymphoma cell lines (MAVER-1, RI-1, SC-1, and SU-DHL-10).

The investigators therefore theorized that combining CYC065 with a Bcl-2 inhibitor might prove more effective in these cell lines.

CYC065 in combination

CYC065 synergized with the Bcl-2 inhibitor venetoclax in all B-cell lymphoma cell lines tested. The drugs were “strongly synergistic” in U2932 and RI-1 cell lines but simply “synergistic” in SU-CHL-4 and MAVER-1 cell lines.

CYC065 also synergized with cytarabine to fight AML. The combination proved synergistic at a range of doses in the HL60 and MV4-11 cell lines.

Considering these results together, the investigators concluded that CYC065 has shown potential for treating a range of leukemias and lymphomas with unmet clinical need, including MLL-rearranged leukemia and Myc-driven lymphoma.

And the drug might prove effective in combination with standard cytotoxic agents or agents targeting apoptotic regulators.

Diffuse large B-cell lymphoma

HOUSTON—Preclinical data suggest the second-generation cyclin-dependent kinase (CDK) inhibitor CYC065 is active against lymphomas as well as leukemias.

Previous research showed that CYC065 can fight acute myeloid leukemia (AML) in vitro and in vivo.

New research shows that CYC065 can decrease cell viability in a range of B-cell lymphoma cell lines, and the drug synergizes with both venetoclax and cytarabine.

Sheelagh Frame, PhD, and her colleagues presented these results at the SOHO 2015 Annual Meeting (poster 213). All of the investigators involved in the research are employees of Cyclacel Ltd., the company developing CYC065.

The investigators analyzed the anticancer activity of CYC065 in a range of cell lines and found that CYC065 induced apoptosis by inhibiting the expression of CDK9-dependent oncogenic transcripts, including Mcl-1, c-Myc, Hoxa9, and Meis1.

Results in AML

Experiments in the AML-MLL cell line MOLM-13 showed that short pulses of CYC065 (6 hours), rather than continuous treatment, were sufficient to achieve maximal cytotoxicity.

CYC065 induced apoptosis, in a dose-dependent manner, in other AML cell lines as well, including EOL-1 (MLL-PTD), MV4-11 (MLL-AF4, FLT3-ITD, and trisomy chr 8), HL60 (Myc amplified), and Kasumi-1.

The investigators noted that AML cell lines with MLL rearrangements were especially sensitive to CYC065, and the reliance of AML on Mcl-1 confers sensitivity to CYC065.

They also found evidence to suggest that Bak and Bcl-xL levels may be predictive of CYC065 response in AML. Cell lines that were less sensitive to treatment had high levels of Bcl-xL and negligible levels of Bak.

B-cell lymphomas

In B-cell lymphoma cell lines, the investigators observed a dose-dependent reduction in cell viability after CYC065 treatment (8-hour pulses).

CYC065 proved most effective in cell lines without genomic alterations associated with poor prognosis (HT and U-698-M) and in cell lines with Myc rearrangements (SU-DHL-8 and WILL-1).

The drug also decreased cell viability—but to a lesser degree—in cell lines with Bcl-2 rearrangements (SU-DHL-4 and U2932) and in double-hit lymphoma cell lines (MAVER-1, RI-1, SC-1, and SU-DHL-10).

The investigators therefore theorized that combining CYC065 with a Bcl-2 inhibitor might prove more effective in these cell lines.

CYC065 in combination

CYC065 synergized with the Bcl-2 inhibitor venetoclax in all B-cell lymphoma cell lines tested. The drugs were “strongly synergistic” in U2932 and RI-1 cell lines but simply “synergistic” in SU-CHL-4 and MAVER-1 cell lines.

CYC065 also synergized with cytarabine to fight AML. The combination proved synergistic at a range of doses in the HL60 and MV4-11 cell lines.

Considering these results together, the investigators concluded that CYC065 has shown potential for treating a range of leukemias and lymphomas with unmet clinical need, including MLL-rearranged leukemia and Myc-driven lymphoma.

And the drug might prove effective in combination with standard cytotoxic agents or agents targeting apoptotic regulators.

Doctor examines child with SCD

Photo courtesy of St. Jude

Children’s Research Hospital

A quality improvement initiative may help reduce the amount of time pediatric patients with sickle cell disease (SCD) wait for pain medication when visiting the emergency department (ED) for a vaso-occlusive episode (VOE).

In a single-center study, the initiative cut patients’ average wait time from triage to the first dose of pain medication by more than 50%—from 56 minutes to 23 minutes.

The researchers described this study in Pediatrics.

The National Heart, Lung, and Blood Institute recommends that a pediatric SCD patient experiencing a VOE be triaged and treated as quickly as possible in the ED. However, previous US studies have indicated that patients often wait, on average, between 65 and 90 minutes for their first dose of pain medication.

“When a child with sickle cell disease comes to the emergency room with pain from a VOE, they likely have been in tremendous pain for hours,” said study author Patricia Kavanagh, MD, of Boston Medical Center (BMC) in Massachusetts.

“The goal of this initiative was to treat the pain episode as quickly and aggressively as possible so that these children could return to their usual activities, including school and time with family and friends.”

Implementing the initiative

From September 2010 to April 2014, a team at BMC implemented the following interventions in the pediatric ED:

1. Using a standardized, time-specific protocol that guides care when the patient is in the ED
2. Using intranasal fentanyl as a first-line pain medication, as placing intravenous lines (IVs) can be difficult in children with SCD
3. Using an online calculator to determine appropriate pain medication doses in line with what is used nationally for children in the ED
4. Providing education on this work to emergency providers and families.

The team implemented these interventions in phases. From September 2010 to May 2011 (baseline), they collected data on the timing of first and subsequent pain medications for children with SCD who presented to the ED with VOEs.

From May to November 2011 (phase 1), the team introduced intranasal fentanyl as the first-line parenteral opioid.

From December 2011 to November 2012 (phase 2), the goal was to streamline VOE care from triage to disposition decision. The team revised the VOE algorithm to recommend 2 doses of intranasal fentanyl, 2 doses of IV opioids, and then a disposition decision. Then, they introduced the pain medication calculator.

From December 2012 to April 2014 (phase 3), the team assessed the sustainability of the interventions from phase 2. The team also revised the VOE algorithm in May 2013 to initiate patient-controlled analgesics after the first dose of IV opioid for patients with severe pain.

Results

The team observed a reduction in the average time from triage to the first dose of a pain medication—either through the nose or IV—from 56 minutes at baseline to 23 minutes in phase 3. The time to the second IV pain medication dose decreased as well—from 106 minutes to 83 minutes.

There was also a reduction in the time it took for the physician to determine whether the patient would be admitted—from 163 minutes to 109 minutes—or discharged—from 271 minutes to 178 minutes.

In addition, patients who were admitted were given patient-controlled analgesics to control their pain, and the time to its initiation decreased from 216 minutes to 141 minutes.

“While future studies are necessary to determine if these results can be replicated at other hospitals, our data indicates that these initiatives could have a tremendous impact on care for kids with SCD across the country,” said James Moses, MD, of BMC.

Doctor examines child with SCD

Photo courtesy of St. Jude

Children’s Research Hospital

A quality improvement initiative may help reduce the amount of time pediatric patients with sickle cell disease (SCD) wait for pain medication when visiting the emergency department (ED) for a vaso-occlusive episode (VOE).

In a single-center study, the initiative cut patients’ average wait time from triage to the first dose of pain medication by more than 50%—from 56 minutes to 23 minutes.

The researchers described this study in Pediatrics.

The National Heart, Lung, and Blood Institute recommends that a pediatric SCD patient experiencing a VOE be triaged and treated as quickly as possible in the ED. However, previous US studies have indicated that patients often wait, on average, between 65 and 90 minutes for their first dose of pain medication.

“When a child with sickle cell disease comes to the emergency room with pain from a VOE, they likely have been in tremendous pain for hours,” said study author Patricia Kavanagh, MD, of Boston Medical Center (BMC) in Massachusetts.

“The goal of this initiative was to treat the pain episode as quickly and aggressively as possible so that these children could return to their usual activities, including school and time with family and friends.”

Implementing the initiative

From September 2010 to April 2014, a team at BMC implemented the following interventions in the pediatric ED:

1. Using a standardized, time-specific protocol that guides care when the patient is in the ED
2. Using intranasal fentanyl as a first-line pain medication, as placing intravenous lines (IVs) can be difficult in children with SCD
3. Using an online calculator to determine appropriate pain medication doses in line with what is used nationally for children in the ED
4. Providing education on this work to emergency providers and families.

The team implemented these interventions in phases. From September 2010 to May 2011 (baseline), they collected data on the timing of first and subsequent pain medications for children with SCD who presented to the ED with VOEs.

From May to November 2011 (phase 1), the team introduced intranasal fentanyl as the first-line parenteral opioid.

From December 2011 to November 2012 (phase 2), the goal was to streamline VOE care from triage to disposition decision. The team revised the VOE algorithm to recommend 2 doses of intranasal fentanyl, 2 doses of IV opioids, and then a disposition decision. Then, they introduced the pain medication calculator.

From December 2012 to April 2014 (phase 3), the team assessed the sustainability of the interventions from phase 2. The team also revised the VOE algorithm in May 2013 to initiate patient-controlled analgesics after the first dose of IV opioid for patients with severe pain.

Results

The team observed a reduction in the average time from triage to the first dose of a pain medication—either through the nose or IV—from 56 minutes at baseline to 23 minutes in phase 3. The time to the second IV pain medication dose decreased as well—from 106 minutes to 83 minutes.

There was also a reduction in the time it took for the physician to determine whether the patient would be admitted—from 163 minutes to 109 minutes—or discharged—from 271 minutes to 178 minutes.

In addition, patients who were admitted were given patient-controlled analgesics to control their pain, and the time to its initiation decreased from 216 minutes to 141 minutes.

“While future studies are necessary to determine if these results can be replicated at other hospitals, our data indicates that these initiatives could have a tremendous impact on care for kids with SCD across the country,” said James Moses, MD, of BMC.

Doctor examines child with SCD

Photo courtesy of St. Jude

Children’s Research Hospital

A quality improvement initiative may help reduce the amount of time pediatric patients with sickle cell disease (SCD) wait for pain medication when visiting the emergency department (ED) for a vaso-occlusive episode (VOE).

In a single-center study, the initiative cut patients’ average wait time from triage to the first dose of pain medication by more than 50%—from 56 minutes to 23 minutes.

The researchers described this study in Pediatrics.

The National Heart, Lung, and Blood Institute recommends that a pediatric SCD patient experiencing a VOE be triaged and treated as quickly as possible in the ED. However, previous US studies have indicated that patients often wait, on average, between 65 and 90 minutes for their first dose of pain medication.

“When a child with sickle cell disease comes to the emergency room with pain from a VOE, they likely have been in tremendous pain for hours,” said study author Patricia Kavanagh, MD, of Boston Medical Center (BMC) in Massachusetts.

“The goal of this initiative was to treat the pain episode as quickly and aggressively as possible so that these children could return to their usual activities, including school and time with family and friends.”

Implementing the initiative

From September 2010 to April 2014, a team at BMC implemented the following interventions in the pediatric ED:

1. Using a standardized, time-specific protocol that guides care when the patient is in the ED
2. Using intranasal fentanyl as a first-line pain medication, as placing intravenous lines (IVs) can be difficult in children with SCD
3. Using an online calculator to determine appropriate pain medication doses in line with what is used nationally for children in the ED
4. Providing education on this work to emergency providers and families.

The team implemented these interventions in phases. From September 2010 to May 2011 (baseline), they collected data on the timing of first and subsequent pain medications for children with SCD who presented to the ED with VOEs.

From May to November 2011 (phase 1), the team introduced intranasal fentanyl as the first-line parenteral opioid.

From December 2011 to November 2012 (phase 2), the goal was to streamline VOE care from triage to disposition decision. The team revised the VOE algorithm to recommend 2 doses of intranasal fentanyl, 2 doses of IV opioids, and then a disposition decision. Then, they introduced the pain medication calculator.

From December 2012 to April 2014 (phase 3), the team assessed the sustainability of the interventions from phase 2. The team also revised the VOE algorithm in May 2013 to initiate patient-controlled analgesics after the first dose of IV opioid for patients with severe pain.

Results

The team observed a reduction in the average time from triage to the first dose of a pain medication—either through the nose or IV—from 56 minutes at baseline to 23 minutes in phase 3. The time to the second IV pain medication dose decreased as well—from 106 minutes to 83 minutes.

There was also a reduction in the time it took for the physician to determine whether the patient would be admitted—from 163 minutes to 109 minutes—or discharged—from 271 minutes to 178 minutes.

In addition, patients who were admitted were given patient-controlled analgesics to control their pain, and the time to its initiation decreased from 216 minutes to 141 minutes.

“While future studies are necessary to determine if these results can be replicated at other hospitals, our data indicates that these initiatives could have a tremendous impact on care for kids with SCD across the country,” said James Moses, MD, of BMC.

Red blood cells

The US Food and Drug Administration (FDA) has granted fast track designation to a gene therapy product being developed to treat hemophilia B.

The product, DTX101, is designed to deliver factor IX gene expression in a durable fashion to prevent the long-term complications of hemophilia B.

Preclinical studies have indicated that DTX101 has the potential to be a well-tolerated, effective therapy for hemophilia B, according to Dimension Therapeutics, Inc., the company developing DTX101.

The company said it expects to initiate a multicenter, phase 1/2 study to evaluate DTX101 in adults with moderate/severe to severe hemophilia B by the end of this year.

DTX101 also has orphan designation from the FDA.

About fast track designation

The FDA’s fast track program is designed to facilitate and expedite the development and review of new drugs intended to treat serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the drug may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings with the FDA to discuss the drug’s development plan and ensure collection of the appropriate data needed to support drug approval. And the designation allows for more frequent written communication from the FDA about things such as the design of proposed clinical trials and the use of biomarkers.

Red blood cells

The US Food and Drug Administration (FDA) has granted fast track designation to a gene therapy product being developed to treat hemophilia B.

The product, DTX101, is designed to deliver factor IX gene expression in a durable fashion to prevent the long-term complications of hemophilia B.

Preclinical studies have indicated that DTX101 has the potential to be a well-tolerated, effective therapy for hemophilia B, according to Dimension Therapeutics, Inc., the company developing DTX101.

The company said it expects to initiate a multicenter, phase 1/2 study to evaluate DTX101 in adults with moderate/severe to severe hemophilia B by the end of this year.

DTX101 also has orphan designation from the FDA.

About fast track designation

The FDA’s fast track program is designed to facilitate and expedite the development and review of new drugs intended to treat serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the drug may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings with the FDA to discuss the drug’s development plan and ensure collection of the appropriate data needed to support drug approval. And the designation allows for more frequent written communication from the FDA about things such as the design of proposed clinical trials and the use of biomarkers.

Red blood cells

The US Food and Drug Administration (FDA) has granted fast track designation to a gene therapy product being developed to treat hemophilia B.

The product, DTX101, is designed to deliver factor IX gene expression in a durable fashion to prevent the long-term complications of hemophilia B.

Preclinical studies have indicated that DTX101 has the potential to be a well-tolerated, effective therapy for hemophilia B, according to Dimension Therapeutics, Inc., the company developing DTX101.

The company said it expects to initiate a multicenter, phase 1/2 study to evaluate DTX101 in adults with moderate/severe to severe hemophilia B by the end of this year.

DTX101 also has orphan designation from the FDA.

About fast track designation

The FDA’s fast track program is designed to facilitate and expedite the development and review of new drugs intended to treat serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the drug may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings with the FDA to discuss the drug’s development plan and ensure collection of the appropriate data needed to support drug approval. And the designation allows for more frequent written communication from the FDA about things such as the design of proposed clinical trials and the use of biomarkers.

Micrograph showing

multiple myeloma

The US Food and Drug Administration (FDA) has granted priority review for 4 drugs intended to treat multiple myeloma (MM): elotuzumab (Empliciti), daratumumab, ixazomib (MLN9708), and carfilzomib (Kyprolis).

The FDA grants priority review to investigational therapies that, if approved, may offer significant improvements in the treatment, prevention, or diagnosis of a serious condition.

The designation shortens the review period from 10 months to 6 months.

Carfilzomib

Carfilzomib, an injectable proteasome inhibitor, is currently under review for use in combination with dexamethasone to treat patients with relapsed MM who have received at least 1 prior therapy.

Carfilzomib is already FDA-approved for use in combination with lenalidomide and dexamethasone to treat patients with relapsed MM who have received 1 to 3 prior lines of therapy.

Carfilzomib also has accelerated approval from the FDA as monotherapy for MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent (IMiD), and have demonstrated disease progression on or within 60 days of completing their last treatment.

The new regulatory submission for carfilzomib is based on data from the phase 3 ENDEAVOR trial, which were presented at ASCO 2015. In this trial, relapsed MM patients who received carfilzomib and low-dose dexamethasone had significantly longer progression-free survival (PFS) than patients who received bortezomib and low-dose dexamethasone.

Carfilzomib is under development by Onyx Pharmaceuticals, Inc., an Amgen subsidiary.

Ixazomib

Ixazomib, an oral proteasome inhibitor, is under review for the treatment of relapsed and/or refractory MM. Ixazomib has orphan drug designation from the FDA for this patient population.

The regulatory submission for ixazomib is primarily based on results of the first interim analysis of the phase 3 TOURMALINE-MM1 trial.

In this trial, patients with relapsed and/or refractory MM who received ixazomib plus lenalidomide and dexamethasone had superior PFS to patients who received placebo plus lenalidomide and dexamethasone, according to Takeda Pharmaceutical Company Limited, the company developing ixazomib. Detailed data from this study have not yet been released.

Ixazomib is currently under investigation in 3 other phase 3 trials of MM patients:

• TOURMALINE-MM2, investigating ixazomib vs placebo, both in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM
• TOURMALINE-MM3, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM following induction therapy and autologous stem cell transplant
• TOURMALINE-MM4, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM who have not undergone autologous stem cell transplant.

Daratumumab

Daratumumab, an investigational human anti-CD38 monoclonal antibody, is under review as monotherapy for MM patients who are refractory to both a proteasome inhibitor and an IMiD, or who have received 3 or more prior lines of therapy, including a proteasome inhibitor and an IMiD.

Daratumumab already has fast track, breakthrough therapy, and orphan drug designations from the FDA.

The regulatory submission for daratumumab is primarily supported by data from the phase 2 MMY2002 (SIRIUS) monotherapy study, which were presented at ASCO 2015. Results from this study indicated that daratumumab can produce responses in heavily pretreated MM patients.

Additional data from 4 other studies, including the phase 1/2 GEN501 monotherapy study, which was recently published in NEJM, also support the submission.

Daratumumab is under development by Janssen Research & Development, LLC.

Elotuzumab

Elotuzumab, a signaling lymphocyte activation molecule (SLAMF7)-directed immunostimulatory antibody, is under review for use in combination with lenalidomide and dexamethasone to treat MM patients who have received at least 1 prior treatment.

The FDA has already granted elotuzumab breakthrough therapy and orphan drug designations.

The regulatory submission for elotuzumab is primarily supported by data from the ELOQUENT-2 trial, which were presented at ASCO 2015. In this phase 3 study, researchers evaluated elotuzumab in combination with lenalidomide and dexamethasone, compared to lenalidomide and dexamethasone alone.

The submission is also supported by data from the CA204-009 trial, which were presented at EHA 2015. In this phase 2 study, researchers evaluated elotuzumab in combination with bortezomib and dexamethasone compared to bortezomib and dexamethasone alone.

Results from both trials suggested that adding elotuzumab to combination treatment can prolong PFS in MM patients.

Bristol-Myers Squibb and AbbVie are co-developing elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities.

Micrograph showing

multiple myeloma

The US Food and Drug Administration (FDA) has granted priority review for 4 drugs intended to treat multiple myeloma (MM): elotuzumab (Empliciti), daratumumab, ixazomib (MLN9708), and carfilzomib (Kyprolis).

The FDA grants priority review to investigational therapies that, if approved, may offer significant improvements in the treatment, prevention, or diagnosis of a serious condition.

The designation shortens the review period from 10 months to 6 months.

Carfilzomib

Carfilzomib, an injectable proteasome inhibitor, is currently under review for use in combination with dexamethasone to treat patients with relapsed MM who have received at least 1 prior therapy.

Carfilzomib is already FDA-approved for use in combination with lenalidomide and dexamethasone to treat patients with relapsed MM who have received 1 to 3 prior lines of therapy.

Carfilzomib also has accelerated approval from the FDA as monotherapy for MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent (IMiD), and have demonstrated disease progression on or within 60 days of completing their last treatment.

The new regulatory submission for carfilzomib is based on data from the phase 3 ENDEAVOR trial, which were presented at ASCO 2015. In this trial, relapsed MM patients who received carfilzomib and low-dose dexamethasone had significantly longer progression-free survival (PFS) than patients who received bortezomib and low-dose dexamethasone.

Carfilzomib is under development by Onyx Pharmaceuticals, Inc., an Amgen subsidiary.

Ixazomib

Ixazomib, an oral proteasome inhibitor, is under review for the treatment of relapsed and/or refractory MM. Ixazomib has orphan drug designation from the FDA for this patient population.

The regulatory submission for ixazomib is primarily based on results of the first interim analysis of the phase 3 TOURMALINE-MM1 trial.

In this trial, patients with relapsed and/or refractory MM who received ixazomib plus lenalidomide and dexamethasone had superior PFS to patients who received placebo plus lenalidomide and dexamethasone, according to Takeda Pharmaceutical Company Limited, the company developing ixazomib. Detailed data from this study have not yet been released.

Ixazomib is currently under investigation in 3 other phase 3 trials of MM patients:

• TOURMALINE-MM2, investigating ixazomib vs placebo, both in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM
• TOURMALINE-MM3, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM following induction therapy and autologous stem cell transplant
• TOURMALINE-MM4, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM who have not undergone autologous stem cell transplant.

Daratumumab

Daratumumab, an investigational human anti-CD38 monoclonal antibody, is under review as monotherapy for MM patients who are refractory to both a proteasome inhibitor and an IMiD, or who have received 3 or more prior lines of therapy, including a proteasome inhibitor and an IMiD.

Daratumumab already has fast track, breakthrough therapy, and orphan drug designations from the FDA.

The regulatory submission for daratumumab is primarily supported by data from the phase 2 MMY2002 (SIRIUS) monotherapy study, which were presented at ASCO 2015. Results from this study indicated that daratumumab can produce responses in heavily pretreated MM patients.

Additional data from 4 other studies, including the phase 1/2 GEN501 monotherapy study, which was recently published in NEJM, also support the submission.

Daratumumab is under development by Janssen Research & Development, LLC.

Elotuzumab

Elotuzumab, a signaling lymphocyte activation molecule (SLAMF7)-directed immunostimulatory antibody, is under review for use in combination with lenalidomide and dexamethasone to treat MM patients who have received at least 1 prior treatment.

The FDA has already granted elotuzumab breakthrough therapy and orphan drug designations.

The regulatory submission for elotuzumab is primarily supported by data from the ELOQUENT-2 trial, which were presented at ASCO 2015. In this phase 3 study, researchers evaluated elotuzumab in combination with lenalidomide and dexamethasone, compared to lenalidomide and dexamethasone alone.

The submission is also supported by data from the CA204-009 trial, which were presented at EHA 2015. In this phase 2 study, researchers evaluated elotuzumab in combination with bortezomib and dexamethasone compared to bortezomib and dexamethasone alone.

Results from both trials suggested that adding elotuzumab to combination treatment can prolong PFS in MM patients.

Bristol-Myers Squibb and AbbVie are co-developing elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities.

Micrograph showing

multiple myeloma

The US Food and Drug Administration (FDA) has granted priority review for 4 drugs intended to treat multiple myeloma (MM): elotuzumab (Empliciti), daratumumab, ixazomib (MLN9708), and carfilzomib (Kyprolis).

The FDA grants priority review to investigational therapies that, if approved, may offer significant improvements in the treatment, prevention, or diagnosis of a serious condition.

The designation shortens the review period from 10 months to 6 months.

Carfilzomib

Carfilzomib, an injectable proteasome inhibitor, is currently under review for use in combination with dexamethasone to treat patients with relapsed MM who have received at least 1 prior therapy.

Carfilzomib is already FDA-approved for use in combination with lenalidomide and dexamethasone to treat patients with relapsed MM who have received 1 to 3 prior lines of therapy.

Carfilzomib also has accelerated approval from the FDA as monotherapy for MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent (IMiD), and have demonstrated disease progression on or within 60 days of completing their last treatment.

The new regulatory submission for carfilzomib is based on data from the phase 3 ENDEAVOR trial, which were presented at ASCO 2015. In this trial, relapsed MM patients who received carfilzomib and low-dose dexamethasone had significantly longer progression-free survival (PFS) than patients who received bortezomib and low-dose dexamethasone.

Carfilzomib is under development by Onyx Pharmaceuticals, Inc., an Amgen subsidiary.

Ixazomib

Ixazomib, an oral proteasome inhibitor, is under review for the treatment of relapsed and/or refractory MM. Ixazomib has orphan drug designation from the FDA for this patient population.

The regulatory submission for ixazomib is primarily based on results of the first interim analysis of the phase 3 TOURMALINE-MM1 trial.

In this trial, patients with relapsed and/or refractory MM who received ixazomib plus lenalidomide and dexamethasone had superior PFS to patients who received placebo plus lenalidomide and dexamethasone, according to Takeda Pharmaceutical Company Limited, the company developing ixazomib. Detailed data from this study have not yet been released.

Ixazomib is currently under investigation in 3 other phase 3 trials of MM patients:

• TOURMALINE-MM2, investigating ixazomib vs placebo, both in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM
• TOURMALINE-MM3, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM following induction therapy and autologous stem cell transplant
• TOURMALINE-MM4, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM who have not undergone autologous stem cell transplant.

Daratumumab

Daratumumab, an investigational human anti-CD38 monoclonal antibody, is under review as monotherapy for MM patients who are refractory to both a proteasome inhibitor and an IMiD, or who have received 3 or more prior lines of therapy, including a proteasome inhibitor and an IMiD.

Daratumumab already has fast track, breakthrough therapy, and orphan drug designations from the FDA.

The regulatory submission for daratumumab is primarily supported by data from the phase 2 MMY2002 (SIRIUS) monotherapy study, which were presented at ASCO 2015. Results from this study indicated that daratumumab can produce responses in heavily pretreated MM patients.

Additional data from 4 other studies, including the phase 1/2 GEN501 monotherapy study, which was recently published in NEJM, also support the submission.

Daratumumab is under development by Janssen Research & Development, LLC.

Elotuzumab

Elotuzumab, a signaling lymphocyte activation molecule (SLAMF7)-directed immunostimulatory antibody, is under review for use in combination with lenalidomide and dexamethasone to treat MM patients who have received at least 1 prior treatment.

The FDA has already granted elotuzumab breakthrough therapy and orphan drug designations.

The regulatory submission for elotuzumab is primarily supported by data from the ELOQUENT-2 trial, which were presented at ASCO 2015. In this phase 3 study, researchers evaluated elotuzumab in combination with lenalidomide and dexamethasone, compared to lenalidomide and dexamethasone alone.

The submission is also supported by data from the CA204-009 trial, which were presented at EHA 2015. In this phase 2 study, researchers evaluated elotuzumab in combination with bortezomib and dexamethasone compared to bortezomib and dexamethasone alone.

Results from both trials suggested that adding elotuzumab to combination treatment can prolong PFS in MM patients.

Bristol-Myers Squibb and AbbVie are co-developing elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities.

Road traffic

A French study has revealed an increased incidence of acute myeloid leukemia (AML) among children living close to heavily used roads.

The incidence of AML was 30% higher among children who lived within 150 m of heavily used roads and where the combined length of road sections

within this radius exceeded 260 m.

The researchers believe the association between AML and road proximity may be driven by traffic-related benzene exposure.

Previous research has shown an increased risk of leukemia among adults with a history of occupational exposure to benzene.

The current study did not suggest an increased risk of acute lymphoblastic leukemia (ALL) among children living closed to heavily used roads.

Jacqueline Clavel, MD, PhD, of INSERM in Paris, France, and her colleagues reported these findings in the American Journal of Epidemiology.

The team analyzed 2760 cases of leukemia diagnosed in children younger than 15 years of age in metropolitan France between 2002 and 2007, including 418 cases of AML and 2275 cases of ALL.

The researchers compared these cases to a contemporary sample of 30,000 control children representative of the metropolitan population.

The data showed that neither distance from the nearest major road(s) nor the length of major roads within 150 m of a child’s residence was associated with ALL.

However, there was an association for AML. For children whose home was less than 150 m from the nearest major road(s), the odds ratio (OR) was 1.2.

When the total length of major road(s) within 150 m from the child’s residence was 257-308 m (second tertile) or 309 m or greater (third tertile), the OR was 1.3. When the total length of major roads was 1-256 m (first tertile), the OR was 0.90.

The researchers noted that traffic-related nitrogen dioxide concentration was not associated with ALL or AML. But their data indicated that benzene concentration was associated with AML.

To assess this potential association, the team studied the Île-de-France region of Paris, the most urbanized region, for which the mean annual concentration of benzene, mainly from road traffic, was estimated in the vicinity of each residence.

The median estimated benzene concentration for controls living in the Île-de-France region was 1.3 μg/m³ (range, 0.3 to 8.5 μg/m³). And the length of major roads within 150 m of a child’s residence was positively and significantly correlated with log benzene concentration (r=0.3, P<0.001).

So it followed that exposure to an estimated benzene concentration greater than the median was associated with AML (OR=1.6).

The researchers also used a composite variable based on the estimated benzene concentration and the length of major roads around a child’s residence.

The association with AML was largest among children with at least 309 m of major roads within 150 m of their residence and estimated benzene concentrations of 1.3 μg/m³ or greater (OR=2.2).

The researchers said these results support a role for traffic-related benzene exposure in the etiology of childhood AML.

Road traffic

A French study has revealed an increased incidence of acute myeloid leukemia (AML) among children living close to heavily used roads.

The incidence of AML was 30% higher among children who lived within 150 m of heavily used roads and where the combined length of road sections

within this radius exceeded 260 m.

The researchers believe the association between AML and road proximity may be driven by traffic-related benzene exposure.

Previous research has shown an increased risk of leukemia among adults with a history of occupational exposure to benzene.

The current study did not suggest an increased risk of acute lymphoblastic leukemia (ALL) among children living closed to heavily used roads.

Jacqueline Clavel, MD, PhD, of INSERM in Paris, France, and her colleagues reported these findings in the American Journal of Epidemiology.

The team analyzed 2760 cases of leukemia diagnosed in children younger than 15 years of age in metropolitan France between 2002 and 2007, including 418 cases of AML and 2275 cases of ALL.

The researchers compared these cases to a contemporary sample of 30,000 control children representative of the metropolitan population.

The data showed that neither distance from the nearest major road(s) nor the length of major roads within 150 m of a child’s residence was associated with ALL.

However, there was an association for AML. For children whose home was less than 150 m from the nearest major road(s), the odds ratio (OR) was 1.2.

When the total length of major road(s) within 150 m from the child’s residence was 257-308 m (second tertile) or 309 m or greater (third tertile), the OR was 1.3. When the total length of major roads was 1-256 m (first tertile), the OR was 0.90.

The researchers noted that traffic-related nitrogen dioxide concentration was not associated with ALL or AML. But their data indicated that benzene concentration was associated with AML.

To assess this potential association, the team studied the Île-de-France region of Paris, the most urbanized region, for which the mean annual concentration of benzene, mainly from road traffic, was estimated in the vicinity of each residence.

The median estimated benzene concentration for controls living in the Île-de-France region was 1.3 μg/m³ (range, 0.3 to 8.5 μg/m³). And the length of major roads within 150 m of a child’s residence was positively and significantly correlated with log benzene concentration (r=0.3, P<0.001).

So it followed that exposure to an estimated benzene concentration greater than the median was associated with AML (OR=1.6).

The researchers also used a composite variable based on the estimated benzene concentration and the length of major roads around a child’s residence.

The association with AML was largest among children with at least 309 m of major roads within 150 m of their residence and estimated benzene concentrations of 1.3 μg/m³ or greater (OR=2.2).

The researchers said these results support a role for traffic-related benzene exposure in the etiology of childhood AML.

Road traffic

A French study has revealed an increased incidence of acute myeloid leukemia (AML) among children living close to heavily used roads.

The incidence of AML was 30% higher among children who lived within 150 m of heavily used roads and where the combined length of road sections

within this radius exceeded 260 m.

The researchers believe the association between AML and road proximity may be driven by traffic-related benzene exposure.

Previous research has shown an increased risk of leukemia among adults with a history of occupational exposure to benzene.

The current study did not suggest an increased risk of acute lymphoblastic leukemia (ALL) among children living closed to heavily used roads.

Jacqueline Clavel, MD, PhD, of INSERM in Paris, France, and her colleagues reported these findings in the American Journal of Epidemiology.

The team analyzed 2760 cases of leukemia diagnosed in children younger than 15 years of age in metropolitan France between 2002 and 2007, including 418 cases of AML and 2275 cases of ALL.

The researchers compared these cases to a contemporary sample of 30,000 control children representative of the metropolitan population.

The data showed that neither distance from the nearest major road(s) nor the length of major roads within 150 m of a child’s residence was associated with ALL.

However, there was an association for AML. For children whose home was less than 150 m from the nearest major road(s), the odds ratio (OR) was 1.2.

When the total length of major road(s) within 150 m from the child’s residence was 257-308 m (second tertile) or 309 m or greater (third tertile), the OR was 1.3. When the total length of major roads was 1-256 m (first tertile), the OR was 0.90.

The researchers noted that traffic-related nitrogen dioxide concentration was not associated with ALL or AML. But their data indicated that benzene concentration was associated with AML.

To assess this potential association, the team studied the Île-de-France region of Paris, the most urbanized region, for which the mean annual concentration of benzene, mainly from road traffic, was estimated in the vicinity of each residence.

The median estimated benzene concentration for controls living in the Île-de-France region was 1.3 μg/m³ (range, 0.3 to 8.5 μg/m³). And the length of major roads within 150 m of a child’s residence was positively and significantly correlated with log benzene concentration (r=0.3, P<0.001).

So it followed that exposure to an estimated benzene concentration greater than the median was associated with AML (OR=1.6).

The researchers also used a composite variable based on the estimated benzene concentration and the length of major roads around a child’s residence.

The association with AML was largest among children with at least 309 m of major roads within 150 m of their residence and estimated benzene concentrations of 1.3 μg/m³ or greater (OR=2.2).

The researchers said these results support a role for traffic-related benzene exposure in the etiology of childhood AML.

Transplant preparation

Photo by Chad McNeeley

Chemotherapy-free allogeneic transplant can cure sickle cell disease (SCD) in adults, according to researchers.

In a phase 1/2 trial, the treatment normalized hemoglobin concentrations, reduced SCD-related complications, and improved cardiopulmonary function in 12 of 13 patients.

The single graft failure was due to noncompliance with post-transplant treatment.

There were no deaths and no cases of graft-vs-host disease. However, most patients did experience some form of transplant-related toxicity.

These transplants were performed at the University of Illinois Hospital & Health Sciences System in Chicago. But the chemotherapy-free transplant regimen was developed—and initially tested—at the National Institutes of Health in Bethesda, Maryland.

Physicians there have treated 30 patients with the regimen. An account of that work was published in JAMA last year.

The current study has been published in Biology of Blood & Marrow Transplantation.

“Adults with sickle cell disease can be cured without chemotherapy—the main barrier that has stood in the way for them for so long,” said study author Damiano Rondelli, MD, of the University of Illinois Hospital & Health Sciences System.

“Our data provide more support that this therapy is safe and effective and prevents patients from living shortened lives, condemned to pain and progressive complications.”

Treatment and outcome

The study included 13 patients, ages 17 to 40, who were transplanted between November 2011 and June 2014. Prior to transplant, patients received alemtuzumab and total-body irradiation (300 cGy).

They then received peripheral blood stem cells from matched related donors. All donors were a 10/10 human leukocyte antigen match, but 2 donors had different blood types than the recipients. After transplant, the patients received sirolimus.

All 13 patients initially engrafted, but 1 patient experienced secondary graft failure due to noncompliance with sirolimus.

At a median follow-up of 22 months (range, 12-44), all 13 patients are alive, and 12 have maintained a stable mixed donor/recipient chimerism.

At 1 year after transplant, the 12 patients with stable donor chimerism had significant improvements from baseline in hemoglobin, reticulocyte percentage, lactate dehydrogenase concentration, and cardiopulmonary function.

One of these patients required readmission to the hospital for vaso-occlusive crisis. Before transplant, this patient experienced about 12 crises a year.

No other SCD-related complications have occurred. And 4 patients have been able to stop taking sirolimus without transplant rejection or other complications.

Nine of the engrafted patients completed quality of life assessments before transplant and at 1 year after the procedure. They reported improvements in pain, general health, vitality, and social functioning.

“[W]ith this chemotherapy-free transplant, we are curing adults with sickle cell disease, and we see that their quality of life improves vastly within just 1 month of the transplant,” Dr Rondelli said. “They are able to go back to school, go back to work, and can experience life without pain.”

Toxicity

Four patients did not experience any transplant-related toxicity. And there were no cases of acute or chronic graft-vs-host disease.

One patient developed gram-negative rods in her hip prosthesis after transplant, 1 patient experienced delayed hemolytic transfusion reaction after exchange transfusion, 1 patient developed viral pharyngitis, and 1 patient developed Coxsackie B.

One patient developed a urinary tract infection due to extended spectrum beta-lactamase, Clostridium difficile colitis, and Mycoplasma pneumoniae.

Two patients had grade 2 mucositis, one of whom also developed line-associated deep vein thrombosis and cytomegalovirus (CMV) reactivation. Two other patients had CMV reactivation as well, one of whom also had methicillin-resistant Staphylococcus aureus pneumonia.

All 3 patients with CMV reactivation were successfully treated with valgancyclovir and did not develop CMV disease.

Six patients had arthralgias attributed to sirolimus, and 2 of them required dose reductions.

One patient developed chest pain and a decline in carbon monoxide diffusion capacity by 30% that was attributed to sirolimus. The patient was switched to cyclosporine but developed posterior reversible encephalopathy syndrome and was then put on mycophenolate mofetil.

The patient has since maintained stable donor chimerism, and the carbon monoxide diffusing capacity has increased to near-baseline value.

Transplant preparation

Photo by Chad McNeeley

Chemotherapy-free allogeneic transplant can cure sickle cell disease (SCD) in adults, according to researchers.

In a phase 1/2 trial, the treatment normalized hemoglobin concentrations, reduced SCD-related complications, and improved cardiopulmonary function in 12 of 13 patients.

The single graft failure was due to noncompliance with post-transplant treatment.

There were no deaths and no cases of graft-vs-host disease. However, most patients did experience some form of transplant-related toxicity.

These transplants were performed at the University of Illinois Hospital & Health Sciences System in Chicago. But the chemotherapy-free transplant regimen was developed—and initially tested—at the National Institutes of Health in Bethesda, Maryland.

Physicians there have treated 30 patients with the regimen. An account of that work was published in JAMA last year.

The current study has been published in Biology of Blood & Marrow Transplantation.

“Adults with sickle cell disease can be cured without chemotherapy—the main barrier that has stood in the way for them for so long,” said study author Damiano Rondelli, MD, of the University of Illinois Hospital & Health Sciences System.

“Our data provide more support that this therapy is safe and effective and prevents patients from living shortened lives, condemned to pain and progressive complications.”

Treatment and outcome

The study included 13 patients, ages 17 to 40, who were transplanted between November 2011 and June 2014. Prior to transplant, patients received alemtuzumab and total-body irradiation (300 cGy).

They then received peripheral blood stem cells from matched related donors. All donors were a 10/10 human leukocyte antigen match, but 2 donors had different blood types than the recipients. After transplant, the patients received sirolimus.

All 13 patients initially engrafted, but 1 patient experienced secondary graft failure due to noncompliance with sirolimus.

At a median follow-up of 22 months (range, 12-44), all 13 patients are alive, and 12 have maintained a stable mixed donor/recipient chimerism.

At 1 year after transplant, the 12 patients with stable donor chimerism had significant improvements from baseline in hemoglobin, reticulocyte percentage, lactate dehydrogenase concentration, and cardiopulmonary function.

One of these patients required readmission to the hospital for vaso-occlusive crisis. Before transplant, this patient experienced about 12 crises a year.

No other SCD-related complications have occurred. And 4 patients have been able to stop taking sirolimus without transplant rejection or other complications.

Nine of the engrafted patients completed quality of life assessments before transplant and at 1 year after the procedure. They reported improvements in pain, general health, vitality, and social functioning.

“[W]ith this chemotherapy-free transplant, we are curing adults with sickle cell disease, and we see that their quality of life improves vastly within just 1 month of the transplant,” Dr Rondelli said. “They are able to go back to school, go back to work, and can experience life without pain.”

Toxicity

Four patients did not experience any transplant-related toxicity. And there were no cases of acute or chronic graft-vs-host disease.

One patient developed gram-negative rods in her hip prosthesis after transplant, 1 patient experienced delayed hemolytic transfusion reaction after exchange transfusion, 1 patient developed viral pharyngitis, and 1 patient developed Coxsackie B.

One patient developed a urinary tract infection due to extended spectrum beta-lactamase, Clostridium difficile colitis, and Mycoplasma pneumoniae.

Two patients had grade 2 mucositis, one of whom also developed line-associated deep vein thrombosis and cytomegalovirus (CMV) reactivation. Two other patients had CMV reactivation as well, one of whom also had methicillin-resistant Staphylococcus aureus pneumonia.

All 3 patients with CMV reactivation were successfully treated with valgancyclovir and did not develop CMV disease.

Six patients had arthralgias attributed to sirolimus, and 2 of them required dose reductions.

One patient developed chest pain and a decline in carbon monoxide diffusion capacity by 30% that was attributed to sirolimus. The patient was switched to cyclosporine but developed posterior reversible encephalopathy syndrome and was then put on mycophenolate mofetil.

The patient has since maintained stable donor chimerism, and the carbon monoxide diffusing capacity has increased to near-baseline value.

Transplant preparation

Photo by Chad McNeeley

Chemotherapy-free allogeneic transplant can cure sickle cell disease (SCD) in adults, according to researchers.

In a phase 1/2 trial, the treatment normalized hemoglobin concentrations, reduced SCD-related complications, and improved cardiopulmonary function in 12 of 13 patients.

The single graft failure was due to noncompliance with post-transplant treatment.

There were no deaths and no cases of graft-vs-host disease. However, most patients did experience some form of transplant-related toxicity.

These transplants were performed at the University of Illinois Hospital & Health Sciences System in Chicago. But the chemotherapy-free transplant regimen was developed—and initially tested—at the National Institutes of Health in Bethesda, Maryland.

Physicians there have treated 30 patients with the regimen. An account of that work was published in JAMA last year.

The current study has been published in Biology of Blood & Marrow Transplantation.

“Adults with sickle cell disease can be cured without chemotherapy—the main barrier that has stood in the way for them for so long,” said study author Damiano Rondelli, MD, of the University of Illinois Hospital & Health Sciences System.

“Our data provide more support that this therapy is safe and effective and prevents patients from living shortened lives, condemned to pain and progressive complications.”

Treatment and outcome

The study included 13 patients, ages 17 to 40, who were transplanted between November 2011 and June 2014. Prior to transplant, patients received alemtuzumab and total-body irradiation (300 cGy).

They then received peripheral blood stem cells from matched related donors. All donors were a 10/10 human leukocyte antigen match, but 2 donors had different blood types than the recipients. After transplant, the patients received sirolimus.

All 13 patients initially engrafted, but 1 patient experienced secondary graft failure due to noncompliance with sirolimus.

At a median follow-up of 22 months (range, 12-44), all 13 patients are alive, and 12 have maintained a stable mixed donor/recipient chimerism.

At 1 year after transplant, the 12 patients with stable donor chimerism had significant improvements from baseline in hemoglobin, reticulocyte percentage, lactate dehydrogenase concentration, and cardiopulmonary function.

One of these patients required readmission to the hospital for vaso-occlusive crisis. Before transplant, this patient experienced about 12 crises a year.

No other SCD-related complications have occurred. And 4 patients have been able to stop taking sirolimus without transplant rejection or other complications.

Nine of the engrafted patients completed quality of life assessments before transplant and at 1 year after the procedure. They reported improvements in pain, general health, vitality, and social functioning.

“[W]ith this chemotherapy-free transplant, we are curing adults with sickle cell disease, and we see that their quality of life improves vastly within just 1 month of the transplant,” Dr Rondelli said. “They are able to go back to school, go back to work, and can experience life without pain.”

Toxicity

Four patients did not experience any transplant-related toxicity. And there were no cases of acute or chronic graft-vs-host disease.

One patient developed gram-negative rods in her hip prosthesis after transplant, 1 patient experienced delayed hemolytic transfusion reaction after exchange transfusion, 1 patient developed viral pharyngitis, and 1 patient developed Coxsackie B.

One patient developed a urinary tract infection due to extended spectrum beta-lactamase, Clostridium difficile colitis, and Mycoplasma pneumoniae.

Two patients had grade 2 mucositis, one of whom also developed line-associated deep vein thrombosis and cytomegalovirus (CMV) reactivation. Two other patients had CMV reactivation as well, one of whom also had methicillin-resistant Staphylococcus aureus pneumonia.

All 3 patients with CMV reactivation were successfully treated with valgancyclovir and did not develop CMV disease.

Six patients had arthralgias attributed to sirolimus, and 2 of them required dose reductions.

One patient developed chest pain and a decline in carbon monoxide diffusion capacity by 30% that was attributed to sirolimus. The patient was switched to cyclosporine but developed posterior reversible encephalopathy syndrome and was then put on mycophenolate mofetil.

The patient has since maintained stable donor chimerism, and the carbon monoxide diffusing capacity has increased to near-baseline value.

Drug production

Photo courtesy of the FDA

Despite recent progress in the fight against cancers, these diseases continue to exert “an immense toll” in the US, according to the AACR Cancer Progress Report 2015.

The report highlights the recent approval by the US Food and Drug Administration (FDA) of several anticancer therapies, a vaccine, and 2 diagnostic aids.

But the report also includes data suggesting that cancer cases, and costs related to cancer care, are on the rise.

The report states that, between Aug. 1, 2014, and July 31, 2015, the FDA approved 9 anticancer therapies, either for the first time or for new indications.

During the same period, the FDA approved a new cancer vaccine, a new cancer screening test, and a new use for a previously approved imaging agent.

Despite these advances, cancers continue to exert personal and economic tolls, according to the report.

It states that cancer is the number 1 cause of disease-related death among US children. And more than 589,000 people in the US are projected to die from cancer in 2015.

The number of new cancer cases in the US is predicted to rise from 1.7 million in 2015 to 2.4 million in 2035.

In addition, estimates suggest the direct medical costs of cancer care in the US in 2010 were nearly $125 billion, and these costs are predicted to rise to $156 billion in 2020.

These data underscore the need for more research to develop new approaches to cancer prevention and treatment, according to the report.

Its authors call for Congress and the administration to provide the National Institutes of Health, National Cancer Institute, and FDA with annual funding increases.

“We have made spectacular progress against cancer, which has saved the lives of millions of individuals in the United States and around the world,” said Margaret Foti, PhD, MD, chief executive officer of the AACR.

“However, without increased federal funding for cancer research, we will not be able to realize the promise of recent discoveries and technological advances.”

Drug production

Photo courtesy of the FDA

Despite recent progress in the fight against cancers, these diseases continue to exert “an immense toll” in the US, according to the AACR Cancer Progress Report 2015.

The report highlights the recent approval by the US Food and Drug Administration (FDA) of several anticancer therapies, a vaccine, and 2 diagnostic aids.

But the report also includes data suggesting that cancer cases, and costs related to cancer care, are on the rise.

The report states that, between Aug. 1, 2014, and July 31, 2015, the FDA approved 9 anticancer therapies, either for the first time or for new indications.

During the same period, the FDA approved a new cancer vaccine, a new cancer screening test, and a new use for a previously approved imaging agent.

Despite these advances, cancers continue to exert personal and economic tolls, according to the report.

It states that cancer is the number 1 cause of disease-related death among US children. And more than 589,000 people in the US are projected to die from cancer in 2015.

The number of new cancer cases in the US is predicted to rise from 1.7 million in 2015 to 2.4 million in 2035.

In addition, estimates suggest the direct medical costs of cancer care in the US in 2010 were nearly $125 billion, and these costs are predicted to rise to $156 billion in 2020.

These data underscore the need for more research to develop new approaches to cancer prevention and treatment, according to the report.

Its authors call for Congress and the administration to provide the National Institutes of Health, National Cancer Institute, and FDA with annual funding increases.

“We have made spectacular progress against cancer, which has saved the lives of millions of individuals in the United States and around the world,” said Margaret Foti, PhD, MD, chief executive officer of the AACR.

“However, without increased federal funding for cancer research, we will not be able to realize the promise of recent discoveries and technological advances.”

Drug production

Photo courtesy of the FDA

Despite recent progress in the fight against cancers, these diseases continue to exert “an immense toll” in the US, according to the AACR Cancer Progress Report 2015.

The report highlights the recent approval by the US Food and Drug Administration (FDA) of several anticancer therapies, a vaccine, and 2 diagnostic aids.

But the report also includes data suggesting that cancer cases, and costs related to cancer care, are on the rise.

The report states that, between Aug. 1, 2014, and July 31, 2015, the FDA approved 9 anticancer therapies, either for the first time or for new indications.

During the same period, the FDA approved a new cancer vaccine, a new cancer screening test, and a new use for a previously approved imaging agent.

Despite these advances, cancers continue to exert personal and economic tolls, according to the report.

It states that cancer is the number 1 cause of disease-related death among US children. And more than 589,000 people in the US are projected to die from cancer in 2015.

The number of new cancer cases in the US is predicted to rise from 1.7 million in 2015 to 2.4 million in 2035.

In addition, estimates suggest the direct medical costs of cancer care in the US in 2010 were nearly $125 billion, and these costs are predicted to rise to $156 billion in 2020.

These data underscore the need for more research to develop new approaches to cancer prevention and treatment, according to the report.

Its authors call for Congress and the administration to provide the National Institutes of Health, National Cancer Institute, and FDA with annual funding increases.

“We have made spectacular progress against cancer, which has saved the lives of millions of individuals in the United States and around the world,” said Margaret Foti, PhD, MD, chief executive officer of the AACR.

“However, without increased federal funding for cancer research, we will not be able to realize the promise of recent discoveries and technological advances.”

B-cell receptors forming

clusters on the cell surface

Image courtesy of V.

Altounian/Science Signaling

New research has provided a clearer picture of the B-cell surface, unearthing new insights regarding antigen receptors.

Mature B cells have 2 classes of antigen receptors on their surface, immunoglobulin M (IgM) and immunoglobulin D (IgD).

Using multiple imaging techniques, researchers studied the spatial relationship of these receptor types in B cells from cell lines, mice, and human blood.

The team described this work in Science Signaling.

Receptors on the surface of resting T cells are thought to reside in preformed clusters known as protein islands, but whether these islands exist on B cells has been unclear.

Palash Maity, PhD, of the University of Freiburg in Germany, and colleagues found these islands do exist on B cells, but their structure changes upon B-cell activation.

Using 2-color direct stochastical optical reconstruction microscopy (dSTORM), the researchers found that IgM and IgD reside on the plasma membrane of resting B cells in separate protein islands of approximately 150 and 240 nanometers, respectively.

The team also observed this class-specific compartmentalization of the antigen receptors using transmission electron microscopy (TEM) and Fab-based proximity-ligation assay (Fab-PLA).

However, the researchers noted a change during B-cell activation. Upon activation, the IgM and IgD protein islands broke up into smaller islands, allowing the 2 types to intermingle, although they did not make direct contact.

The researchers said it is not clear whether this increased affinity between the receptor types is a result of a direct interaction or is mediated by an adaptor protein. The function of the association between the receptors is not clear, either.

But the team believes that one possibility is that, upon B-cell activation, the IgM and IgD protein islands form nanosynapses that allow the islands to exchange proteins and lipids with one another.

The researchers hope these new insights into the nanoscale organization of antigen receptors will support the design of more efficient vaccines or better treatments for B-cell tumors, in which membrane organization is often altered.

B-cell receptors forming

clusters on the cell surface

Image courtesy of V.

Altounian/Science Signaling

New research has provided a clearer picture of the B-cell surface, unearthing new insights regarding antigen receptors.

Mature B cells have 2 classes of antigen receptors on their surface, immunoglobulin M (IgM) and immunoglobulin D (IgD).

Using multiple imaging techniques, researchers studied the spatial relationship of these receptor types in B cells from cell lines, mice, and human blood.

The team described this work in Science Signaling.

Receptors on the surface of resting T cells are thought to reside in preformed clusters known as protein islands, but whether these islands exist on B cells has been unclear.

Palash Maity, PhD, of the University of Freiburg in Germany, and colleagues found these islands do exist on B cells, but their structure changes upon B-cell activation.

Using 2-color direct stochastical optical reconstruction microscopy (dSTORM), the researchers found that IgM and IgD reside on the plasma membrane of resting B cells in separate protein islands of approximately 150 and 240 nanometers, respectively.

The team also observed this class-specific compartmentalization of the antigen receptors using transmission electron microscopy (TEM) and Fab-based proximity-ligation assay (Fab-PLA).

However, the researchers noted a change during B-cell activation. Upon activation, the IgM and IgD protein islands broke up into smaller islands, allowing the 2 types to intermingle, although they did not make direct contact.

The researchers said it is not clear whether this increased affinity between the receptor types is a result of a direct interaction or is mediated by an adaptor protein. The function of the association between the receptors is not clear, either.

But the team believes that one possibility is that, upon B-cell activation, the IgM and IgD protein islands form nanosynapses that allow the islands to exchange proteins and lipids with one another.

The researchers hope these new insights into the nanoscale organization of antigen receptors will support the design of more efficient vaccines or better treatments for B-cell tumors, in which membrane organization is often altered.

B-cell receptors forming

clusters on the cell surface

Image courtesy of V.

Altounian/Science Signaling

New research has provided a clearer picture of the B-cell surface, unearthing new insights regarding antigen receptors.

Mature B cells have 2 classes of antigen receptors on their surface, immunoglobulin M (IgM) and immunoglobulin D (IgD).

Using multiple imaging techniques, researchers studied the spatial relationship of these receptor types in B cells from cell lines, mice, and human blood.

The team described this work in Science Signaling.

Receptors on the surface of resting T cells are thought to reside in preformed clusters known as protein islands, but whether these islands exist on B cells has been unclear.

Palash Maity, PhD, of the University of Freiburg in Germany, and colleagues found these islands do exist on B cells, but their structure changes upon B-cell activation.

Using 2-color direct stochastical optical reconstruction microscopy (dSTORM), the researchers found that IgM and IgD reside on the plasma membrane of resting B cells in separate protein islands of approximately 150 and 240 nanometers, respectively.

The team also observed this class-specific compartmentalization of the antigen receptors using transmission electron microscopy (TEM) and Fab-based proximity-ligation assay (Fab-PLA).

However, the researchers noted a change during B-cell activation. Upon activation, the IgM and IgD protein islands broke up into smaller islands, allowing the 2 types to intermingle, although they did not make direct contact.

The researchers said it is not clear whether this increased affinity between the receptor types is a result of a direct interaction or is mediated by an adaptor protein. The function of the association between the receptors is not clear, either.

But the team believes that one possibility is that, upon B-cell activation, the IgM and IgD protein islands form nanosynapses that allow the islands to exchange proteins and lipids with one another.

The researchers hope these new insights into the nanoscale organization of antigen receptors will support the design of more efficient vaccines or better treatments for B-cell tumors, in which membrane organization is often altered.

Neutrophil engulfing bacteria

Image by Volker Brinkmann

Preclinical research suggests that usingantibiotics to deplete the body’s microbiome may prevent acute sickle cell crisis in patients with sickle cell disease (SCD) and could potentially offer the first effective strategy for warding off the disease’s long-term complications, such as organ failure.

The work, published in Nature, may also have implications for other inflammatory blood-vessel disorders, including septic shock.

The study was led by Paul Frenette, MD, of Albert Einstein College of Medicine in Bronx, New York. In 2002, Dr Frenette and his colleagues reported that SCD vessel blockages occur when sickled red cells bind to neutrophils that have adhered to the vessel walls.

“This earlier work indicated that not all neutrophils are the same,” Dr Frenette said. “Some appear to be inert, while others appear overly active in promoting inflammation, which is useful for attacking microbes but causes neutrophils to capture sickled red cells inside vessels.”

“So in the current study, we investigated whether the age of the neutrophils might be influencing whether they become active and pro-inflammatory.”

Neutrophils and SCD

The researchers began by transfusing whole blood into mice and then analyzing young neutrophils (harvested 10 minutes post-transfusion) and aged neutrophils (harvested 6 hours post-transfusion). The neutrophils became more active as they aged, suggesting that neutrophils receive external signals telling them to age.

The investigators were able to trace these “aging” signals to the body’s microbiome. They found the microbiome produces chemicals that cross the intestinal barrier and enter the bloodstream, where they generate the aged, overly active subset of neutrophils that contribute to SCD.

“Since the body’s microbiota seem to ‘educate’ neutrophils to age, we realized that purging those microbes through use of antibiotics might help against SCD,” Dr Frenette said.

To find out, he and his colleagues conducted experiments in a mouse model of SCD. These mice possessed 5 times as many aged neutrophils as healthy control mice.

When the researchers depleted the microbiota of SCD mice using antibiotics, they observed a striking reduction in neutrophils but not in other white blood cells (such as monocytes, T cells, and B cells).

Moreover, giving antibiotics to SCD mice appeared to prevent sickle cell crisis. Interactions between neutrophils and red cells were markedly reduced in microbiota-depleted SCD mice, resulting in improved local blood flow and greatly improved survival in the mice.

“What was most surprising and exciting to us was the effect of antibiotics on chronic tissue damage,” Dr Frenette said.

“We found that the spleen enlargement of SCD mice was significantly reduced in the microbiota-depleted animals, and liver analysis revealed major reductions in liver damage, including inflammation, scarring, and tissue death. This is the first time that anything has been found to have an impact on the organ damage that can be so devastating in SCD.”

Septic shock

The investigators then studied septic shock, another serious blood disorder in which activated, pro-inflammatory neutrophils play a role.

To induce septic shock, the team gave control and microbiota-depleted mice a dose of a bacterial toxin that would normally be lethal.

The control mice had the neutrophil aggregates and clumping of neutrophil DNA that contribute to death from septic shock, but the microbiota-depleted mice were largely free of neutrophil complications and survived.

“Remarkably, we could prevent microbiota-depleted mice from surviving septic shock if we infused them with aged neutrophils but not if we infused the same number of young neutrophils,” Dr Frenette said. “So depleting the microbiota may help against inflammatory blood diseases in addition to SCD.”

SCD patient samples

Finally, the researchers investigated whether their findings in mice might be relevant to humans with SCD.

The team obtained blood samples from 9 healthy children and 34 patients with SCD. Eleven patients were taking penicillin daily to ward off infections, as is recommended for children with SCD who are 5 years of age or younger. The other 23 patients with SCD had been off penicillin for at least 2 months.

Consistent with the findings in mice, children with SCD who were not taking penicillin had many more circulating aged neutrophils than the healthy children.

The investigators then compared neutrophil levels in the 2 groups of children with SCD—those taking penicillin and those not on the drug—and found a much lower number of aged neutrophils in the blood of those who were taking penicillin.

“Daily penicillin for patients with SCD younger than 5 works really well in preventing infections,” Dr Frenette said. “Our study suggests that penicillin and other antibiotics could play an even broader role in potentially benefiting older patients.”

“[W]e hope to carry out a clinical trial to determine whether antibiotics can help patients with SCD by preventing the sickle cell crisis and long-term organ damage associated with the disease.”

Neutrophil engulfing bacteria

Image by Volker Brinkmann

Preclinical research suggests that usingantibiotics to deplete the body’s microbiome may prevent acute sickle cell crisis in patients with sickle cell disease (SCD) and could potentially offer the first effective strategy for warding off the disease’s long-term complications, such as organ failure.

The work, published in Nature, may also have implications for other inflammatory blood-vessel disorders, including septic shock.

The study was led by Paul Frenette, MD, of Albert Einstein College of Medicine in Bronx, New York. In 2002, Dr Frenette and his colleagues reported that SCD vessel blockages occur when sickled red cells bind to neutrophils that have adhered to the vessel walls.

“This earlier work indicated that not all neutrophils are the same,” Dr Frenette said. “Some appear to be inert, while others appear overly active in promoting inflammation, which is useful for attacking microbes but causes neutrophils to capture sickled red cells inside vessels.”

“So in the current study, we investigated whether the age of the neutrophils might be influencing whether they become active and pro-inflammatory.”

Neutrophils and SCD

The researchers began by transfusing whole blood into mice and then analyzing young neutrophils (harvested 10 minutes post-transfusion) and aged neutrophils (harvested 6 hours post-transfusion). The neutrophils became more active as they aged, suggesting that neutrophils receive external signals telling them to age.

The investigators were able to trace these “aging” signals to the body’s microbiome. They found the microbiome produces chemicals that cross the intestinal barrier and enter the bloodstream, where they generate the aged, overly active subset of neutrophils that contribute to SCD.

“Since the body’s microbiota seem to ‘educate’ neutrophils to age, we realized that purging those microbes through use of antibiotics might help against SCD,” Dr Frenette said.

To find out, he and his colleagues conducted experiments in a mouse model of SCD. These mice possessed 5 times as many aged neutrophils as healthy control mice.

When the researchers depleted the microbiota of SCD mice using antibiotics, they observed a striking reduction in neutrophils but not in other white blood cells (such as monocytes, T cells, and B cells).

Moreover, giving antibiotics to SCD mice appeared to prevent sickle cell crisis. Interactions between neutrophils and red cells were markedly reduced in microbiota-depleted SCD mice, resulting in improved local blood flow and greatly improved survival in the mice.

“What was most surprising and exciting to us was the effect of antibiotics on chronic tissue damage,” Dr Frenette said.

“We found that the spleen enlargement of SCD mice was significantly reduced in the microbiota-depleted animals, and liver analysis revealed major reductions in liver damage, including inflammation, scarring, and tissue death. This is the first time that anything has been found to have an impact on the organ damage that can be so devastating in SCD.”

Septic shock

The investigators then studied septic shock, another serious blood disorder in which activated, pro-inflammatory neutrophils play a role.

To induce septic shock, the team gave control and microbiota-depleted mice a dose of a bacterial toxin that would normally be lethal.

The control mice had the neutrophil aggregates and clumping of neutrophil DNA that contribute to death from septic shock, but the microbiota-depleted mice were largely free of neutrophil complications and survived.

“Remarkably, we could prevent microbiota-depleted mice from surviving septic shock if we infused them with aged neutrophils but not if we infused the same number of young neutrophils,” Dr Frenette said. “So depleting the microbiota may help against inflammatory blood diseases in addition to SCD.”

SCD patient samples

Finally, the researchers investigated whether their findings in mice might be relevant to humans with SCD.

The team obtained blood samples from 9 healthy children and 34 patients with SCD. Eleven patients were taking penicillin daily to ward off infections, as is recommended for children with SCD who are 5 years of age or younger. The other 23 patients with SCD had been off penicillin for at least 2 months.

Consistent with the findings in mice, children with SCD who were not taking penicillin had many more circulating aged neutrophils than the healthy children.

The investigators then compared neutrophil levels in the 2 groups of children with SCD—those taking penicillin and those not on the drug—and found a much lower number of aged neutrophils in the blood of those who were taking penicillin.

“Daily penicillin for patients with SCD younger than 5 works really well in preventing infections,” Dr Frenette said. “Our study suggests that penicillin and other antibiotics could play an even broader role in potentially benefiting older patients.”

“[W]e hope to carry out a clinical trial to determine whether antibiotics can help patients with SCD by preventing the sickle cell crisis and long-term organ damage associated with the disease.”

Neutrophil engulfing bacteria

Image by Volker Brinkmann

Preclinical research suggests that usingantibiotics to deplete the body’s microbiome may prevent acute sickle cell crisis in patients with sickle cell disease (SCD) and could potentially offer the first effective strategy for warding off the disease’s long-term complications, such as organ failure.

The work, published in Nature, may also have implications for other inflammatory blood-vessel disorders, including septic shock.

The study was led by Paul Frenette, MD, of Albert Einstein College of Medicine in Bronx, New York. In 2002, Dr Frenette and his colleagues reported that SCD vessel blockages occur when sickled red cells bind to neutrophils that have adhered to the vessel walls.

“This earlier work indicated that not all neutrophils are the same,” Dr Frenette said. “Some appear to be inert, while others appear overly active in promoting inflammation, which is useful for attacking microbes but causes neutrophils to capture sickled red cells inside vessels.”

“So in the current study, we investigated whether the age of the neutrophils might be influencing whether they become active and pro-inflammatory.”

Neutrophils and SCD

The researchers began by transfusing whole blood into mice and then analyzing young neutrophils (harvested 10 minutes post-transfusion) and aged neutrophils (harvested 6 hours post-transfusion). The neutrophils became more active as they aged, suggesting that neutrophils receive external signals telling them to age.

The investigators were able to trace these “aging” signals to the body’s microbiome. They found the microbiome produces chemicals that cross the intestinal barrier and enter the bloodstream, where they generate the aged, overly active subset of neutrophils that contribute to SCD.

“Since the body’s microbiota seem to ‘educate’ neutrophils to age, we realized that purging those microbes through use of antibiotics might help against SCD,” Dr Frenette said.

To find out, he and his colleagues conducted experiments in a mouse model of SCD. These mice possessed 5 times as many aged neutrophils as healthy control mice.

When the researchers depleted the microbiota of SCD mice using antibiotics, they observed a striking reduction in neutrophils but not in other white blood cells (such as monocytes, T cells, and B cells).

Moreover, giving antibiotics to SCD mice appeared to prevent sickle cell crisis. Interactions between neutrophils and red cells were markedly reduced in microbiota-depleted SCD mice, resulting in improved local blood flow and greatly improved survival in the mice.

“What was most surprising and exciting to us was the effect of antibiotics on chronic tissue damage,” Dr Frenette said.

“We found that the spleen enlargement of SCD mice was significantly reduced in the microbiota-depleted animals, and liver analysis revealed major reductions in liver damage, including inflammation, scarring, and tissue death. This is the first time that anything has been found to have an impact on the organ damage that can be so devastating in SCD.”

Septic shock

The investigators then studied septic shock, another serious blood disorder in which activated, pro-inflammatory neutrophils play a role.

To induce septic shock, the team gave control and microbiota-depleted mice a dose of a bacterial toxin that would normally be lethal.

The control mice had the neutrophil aggregates and clumping of neutrophil DNA that contribute to death from septic shock, but the microbiota-depleted mice were largely free of neutrophil complications and survived.

“Remarkably, we could prevent microbiota-depleted mice from surviving septic shock if we infused them with aged neutrophils but not if we infused the same number of young neutrophils,” Dr Frenette said. “So depleting the microbiota may help against inflammatory blood diseases in addition to SCD.”

SCD patient samples

Finally, the researchers investigated whether their findings in mice might be relevant to humans with SCD.

The team obtained blood samples from 9 healthy children and 34 patients with SCD. Eleven patients were taking penicillin daily to ward off infections, as is recommended for children with SCD who are 5 years of age or younger. The other 23 patients with SCD had been off penicillin for at least 2 months.

Consistent with the findings in mice, children with SCD who were not taking penicillin had many more circulating aged neutrophils than the healthy children.

The investigators then compared neutrophil levels in the 2 groups of children with SCD—those taking penicillin and those not on the drug—and found a much lower number of aged neutrophils in the blood of those who were taking penicillin.

“Daily penicillin for patients with SCD younger than 5 works really well in preventing infections,” Dr Frenette said. “Our study suggests that penicillin and other antibiotics could play an even broader role in potentially benefiting older patients.”

“[W]e hope to carry out a clinical trial to determine whether antibiotics can help patients with SCD by preventing the sickle cell crisis and long-term organ damage associated with the disease.”

US dollars

Photo by Petr Kratochvil

Results of a small survey suggest patients with multiple myeloma (MM) are vulnerable to “financial toxicity,” due to costly treatments, even if they have health insurance and well-paying jobs.

All of the 100 patients surveyed had health insurance and a median household income above the US average.

Yet 46% of respondents said they tapped into their savings to pay for treatment, and 21% borrowed money to pay for care.

Seventeen percent of patients reported delays in treatment due to costs, and 11% said excessive costs caused them to stop treatment altogether.

Results of this survey appear in The Lancet Haematology.

Risk of financial toxicity

Financial toxicity is described as the burden of out-of-pocket costs that can affect patients’ wellbeing and become an adverse effect of treatment.

Previous studies have suggested that patients frequently employ coping mechanisms to help defray out-of-pocket costs, some of which compromise treatment adherence. Financial toxicity may also negatively impact quality of life, and some reports suggest it may contribute to increased mortality.

“While advances in multiple myeloma therapy have contributed to significant improvements in patient outcomes, the clinical gains have come with rising costs,” said Scott Huntington, MD, of Yale University in New Haven, Connecticut.

Costs of newly approved drugs for hematologic malignancies have increased 10-fold in the past 15 years, with many agents costing $10,000 or more a month.

“And today . . . , most patients are on a new drug, compared to a decade ago when less than 5% were,” Dr Huntington said. “So we’re not talking about a select group of patients faced with this burden. Many are facing the financial challenges of treatment.”

Survey population

To investigate the effects of treatment costs in MM, Dr Huntington and his colleagues surveyed 100 patients treated at the Abramson Cancer Center in Philadelphia, Pennsylvania. The median age of the patients was 64, and 53% were female.

The researchers used the COST (Comprehensive Score for Financial Toxicity) questionnaire and other survey questions. The COST tool measures various aspects of financial circumstances, such as income, education, marital status, ability to work, and overall opinions about additional expenses and a person’s current financial situation.

All survey respondents were insured, and all of the patients with Medicare fee-for-service coverage (39%) had additional supplemental insurance to assist with out-of-pocket costs.

The respondents also had a median household income and education level above the national average. The median annual household income

was reported between $60,000 and $79,999, and 70% of respondents reported having some college education.

At the time of the survey, 62% of respondents were receiving first-line (35%) or second-line (27%) treatment. All patients were receiving or had received at least 1 novel drug for MM.

Seventy-five percent of patients had received both lenalidomide and bortezomib since their diagnosis, and 58% had undergone an autologous stem cell transplant. Forty-four percent of patients had received 3 to 4 treatment regimens, and 25% had received 5 or more.

Survey results

Of the 100 patients surveyed, 59% said MM treatment costs were higher than expected, and 71% indicated at least minor financial burden. Fifty-five percent of patients said they had to reduce spending on basic goods since their diagnosis, and 64% said they had to reduce spending on leisure activities.

Thirty-six percent of respondents reported applying for financial assistance to pay for treatment, including 18% who reported incomes over $100,000. Forty-six percent of respondents said they used their savings to pay for treatment, and 21% borrowed money.

The high cost of MM therapy prompted treatment delays for 17% of patients, caused 12% of patients to fill only part of a prescription, and made 11% of patients stop treatment altogether.

Adding to the financial burden, more than half of respondents said they had to reduce their hours at work or quit their job after being diagnosed with MM.

The researchers said these results suggest a need to “acknowledge the untenable rise in treatment costs and its impact on patients.” And “strengthened collaboration” between patients and healthcare stakeholders is needed to promote reforms that lead to more affordable cancer care.

US dollars

Photo by Petr Kratochvil

Results of a small survey suggest patients with multiple myeloma (MM) are vulnerable to “financial toxicity,” due to costly treatments, even if they have health insurance and well-paying jobs.

All of the 100 patients surveyed had health insurance and a median household income above the US average.

Yet 46% of respondents said they tapped into their savings to pay for treatment, and 21% borrowed money to pay for care.

Seventeen percent of patients reported delays in treatment due to costs, and 11% said excessive costs caused them to stop treatment altogether.

Results of this survey appear in The Lancet Haematology.

Risk of financial toxicity

Financial toxicity is described as the burden of out-of-pocket costs that can affect patients’ wellbeing and become an adverse effect of treatment.

Previous studies have suggested that patients frequently employ coping mechanisms to help defray out-of-pocket costs, some of which compromise treatment adherence. Financial toxicity may also negatively impact quality of life, and some reports suggest it may contribute to increased mortality.

“While advances in multiple myeloma therapy have contributed to significant improvements in patient outcomes, the clinical gains have come with rising costs,” said Scott Huntington, MD, of Yale University in New Haven, Connecticut.

Costs of newly approved drugs for hematologic malignancies have increased 10-fold in the past 15 years, with many agents costing $10,000 or more a month.

“And today . . . , most patients are on a new drug, compared to a decade ago when less than 5% were,” Dr Huntington said. “So we’re not talking about a select group of patients faced with this burden. Many are facing the financial challenges of treatment.”

Survey population

To investigate the effects of treatment costs in MM, Dr Huntington and his colleagues surveyed 100 patients treated at the Abramson Cancer Center in Philadelphia, Pennsylvania. The median age of the patients was 64, and 53% were female.

The researchers used the COST (Comprehensive Score for Financial Toxicity) questionnaire and other survey questions. The COST tool measures various aspects of financial circumstances, such as income, education, marital status, ability to work, and overall opinions about additional expenses and a person’s current financial situation.

All survey respondents were insured, and all of the patients with Medicare fee-for-service coverage (39%) had additional supplemental insurance to assist with out-of-pocket costs.

The respondents also had a median household income and education level above the national average. The median annual household income

was reported between $60,000 and $79,999, and 70% of respondents reported having some college education.

At the time of the survey, 62% of respondents were receiving first-line (35%) or second-line (27%) treatment. All patients were receiving or had received at least 1 novel drug for MM.

Seventy-five percent of patients had received both lenalidomide and bortezomib since their diagnosis, and 58% had undergone an autologous stem cell transplant. Forty-four percent of patients had received 3 to 4 treatment regimens, and 25% had received 5 or more.

Survey results

Of the 100 patients surveyed, 59% said MM treatment costs were higher than expected, and 71% indicated at least minor financial burden. Fifty-five percent of patients said they had to reduce spending on basic goods since their diagnosis, and 64% said they had to reduce spending on leisure activities.

Thirty-six percent of respondents reported applying for financial assistance to pay for treatment, including 18% who reported incomes over $100,000. Forty-six percent of respondents said they used their savings to pay for treatment, and 21% borrowed money.

The high cost of MM therapy prompted treatment delays for 17% of patients, caused 12% of patients to fill only part of a prescription, and made 11% of patients stop treatment altogether.

Adding to the financial burden, more than half of respondents said they had to reduce their hours at work or quit their job after being diagnosed with MM.

The researchers said these results suggest a need to “acknowledge the untenable rise in treatment costs and its impact on patients.” And “strengthened collaboration” between patients and healthcare stakeholders is needed to promote reforms that lead to more affordable cancer care.

US dollars

Photo by Petr Kratochvil

Results of a small survey suggest patients with multiple myeloma (MM) are vulnerable to “financial toxicity,” due to costly treatments, even if they have health insurance and well-paying jobs.

All of the 100 patients surveyed had health insurance and a median household income above the US average.

Yet 46% of respondents said they tapped into their savings to pay for treatment, and 21% borrowed money to pay for care.

Seventeen percent of patients reported delays in treatment due to costs, and 11% said excessive costs caused them to stop treatment altogether.

Results of this survey appear in The Lancet Haematology.

Risk of financial toxicity

Financial toxicity is described as the burden of out-of-pocket costs that can affect patients’ wellbeing and become an adverse effect of treatment.

Previous studies have suggested that patients frequently employ coping mechanisms to help defray out-of-pocket costs, some of which compromise treatment adherence. Financial toxicity may also negatively impact quality of life, and some reports suggest it may contribute to increased mortality.

“While advances in multiple myeloma therapy have contributed to significant improvements in patient outcomes, the clinical gains have come with rising costs,” said Scott Huntington, MD, of Yale University in New Haven, Connecticut.

Costs of newly approved drugs for hematologic malignancies have increased 10-fold in the past 15 years, with many agents costing $10,000 or more a month.

“And today . . . , most patients are on a new drug, compared to a decade ago when less than 5% were,” Dr Huntington said. “So we’re not talking about a select group of patients faced with this burden. Many are facing the financial challenges of treatment.”

Survey population

To investigate the effects of treatment costs in MM, Dr Huntington and his colleagues surveyed 100 patients treated at the Abramson Cancer Center in Philadelphia, Pennsylvania. The median age of the patients was 64, and 53% were female.

The researchers used the COST (Comprehensive Score for Financial Toxicity) questionnaire and other survey questions. The COST tool measures various aspects of financial circumstances, such as income, education, marital status, ability to work, and overall opinions about additional expenses and a person’s current financial situation.

All survey respondents were insured, and all of the patients with Medicare fee-for-service coverage (39%) had additional supplemental insurance to assist with out-of-pocket costs.

The respondents also had a median household income and education level above the national average. The median annual household income

was reported between $60,000 and $79,999, and 70% of respondents reported having some college education.

At the time of the survey, 62% of respondents were receiving first-line (35%) or second-line (27%) treatment. All patients were receiving or had received at least 1 novel drug for MM.

Seventy-five percent of patients had received both lenalidomide and bortezomib since their diagnosis, and 58% had undergone an autologous stem cell transplant. Forty-four percent of patients had received 3 to 4 treatment regimens, and 25% had received 5 or more.

Survey results

Of the 100 patients surveyed, 59% said MM treatment costs were higher than expected, and 71% indicated at least minor financial burden. Fifty-five percent of patients said they had to reduce spending on basic goods since their diagnosis, and 64% said they had to reduce spending on leisure activities.

Thirty-six percent of respondents reported applying for financial assistance to pay for treatment, including 18% who reported incomes over $100,000. Forty-six percent of respondents said they used their savings to pay for treatment, and 21% borrowed money.

The high cost of MM therapy prompted treatment delays for 17% of patients, caused 12% of patients to fill only part of a prescription, and made 11% of patients stop treatment altogether.

Adding to the financial burden, more than half of respondents said they had to reduce their hours at work or quit their job after being diagnosed with MM.

The researchers said these results suggest a need to “acknowledge the untenable rise in treatment costs and its impact on patients.” And “strengthened collaboration” between patients and healthcare stakeholders is needed to promote reforms that lead to more affordable cancer care.