Lymphoma & Plasma Cell Disorders

 

 

Lobby view at ASCO 2014

©ASCO/Rodney White

 

CHICAGO—The novel, oral selective inhibitor of nuclear transport known as selinexor (KPT-330) can safely be given as monotherapy to patients with heavily pretreated non-Hodgkin lymphoma (NHL), according to a presentation at the 2014 ASCO Annual Meeting.

“Selinexor has favorable pharmacokinetic and pharmacodynamic characteristics,” said presenter Martin Gutierrez, MD, of the John Theurer Cancer Center at Hackensack University Medical Center in New Jersey.

Selinexor is a slowly reversible, selective inhibitor of nuclear transport that inhibits XPO1, which is elevated in NHL, chronic lymphocytic leukemia (CLL), and other malignances.

“It shows single-agent anti-tumor activity across all NHL types, with durable cancer control of more than 9 months [and] marked activity across germ cell B (GCB), non-germ cell B, and double-hit diffuse large B-cell lymphoma (DLBCL),” Dr Gutierrez said.

He provided an update of the ongoing phase 1 dose-escalation study at the meeting as abstract 8518.

The study now includes 51 patients, half of whom have NHL. Their median age is 60 years.

The patients received selinexor across 8 dose levels, ranging from 3 mg/m² to 60 mg/m². Dosing at 60 mg/m² twice weekly is ongoing, and the maximum-tolerated dose has not been reached.

Among the 43 evaluable patients, the disease control rate was 74%, the overall response rate was 28%, and the complete response rate was 5%.

“All patients who had their disease controlled had a reduction in lymph nodes and some degree of activity across all dose levels,” Dr Gutierrez said. “GCB and non-GCB patients responded similarly.”

The length of response was up to 632 days in the DLBCL group.

Most adverse events were gastrointestinal in nature, and most of them were grade 1 or 2. The most common adverse events were nausea, anorexia, and fatigue.

The investigators found a higher incidence of side effects in the first treatment cycle. The dosing schedule was interrupted and reduced to maintain steady state levels.

“The results suggest that an intermittent dosing schedule optimally induces a steady state with maximal induction of XPO1 mRNA,” Dr Gutierrez said.

There were 3 dose-limiting toxicities, including 1 multiple myeloma patient with grade 4 thrombocytopenia, 1 follicular lymphoma patient with grade 4 thrombocytopenia, and 1 CLL patient with grade 2 fatigue.

ASCO discussant Owen O’Connor, MD, from Columbia University Medical Center in New York, commented, “These clinical data are interesting with a provocative target. I applaud the investigators for doing a trial across a diversity of B- and T-cell lymphomas . . . . The results suggest a potential effect in a rare subset of lymphoma patients that have little treatment options.”

Frontline trials of selinexor are planned, including patients with Richter transformation and follicular lymphoma.

Selinexor recently received orphan drug status from the US Food and Drug Administration for the treatment of DLBCL.

 

 

Lobby view at ASCO 2014

©ASCO/Rodney White

 

CHICAGO—The novel, oral selective inhibitor of nuclear transport known as selinexor (KPT-330) can safely be given as monotherapy to patients with heavily pretreated non-Hodgkin lymphoma (NHL), according to a presentation at the 2014 ASCO Annual Meeting.

“Selinexor has favorable pharmacokinetic and pharmacodynamic characteristics,” said presenter Martin Gutierrez, MD, of the John Theurer Cancer Center at Hackensack University Medical Center in New Jersey.

Selinexor is a slowly reversible, selective inhibitor of nuclear transport that inhibits XPO1, which is elevated in NHL, chronic lymphocytic leukemia (CLL), and other malignances.

“It shows single-agent anti-tumor activity across all NHL types, with durable cancer control of more than 9 months [and] marked activity across germ cell B (GCB), non-germ cell B, and double-hit diffuse large B-cell lymphoma (DLBCL),” Dr Gutierrez said.

He provided an update of the ongoing phase 1 dose-escalation study at the meeting as abstract 8518.

The study now includes 51 patients, half of whom have NHL. Their median age is 60 years.

The patients received selinexor across 8 dose levels, ranging from 3 mg/m² to 60 mg/m². Dosing at 60 mg/m² twice weekly is ongoing, and the maximum-tolerated dose has not been reached.

Among the 43 evaluable patients, the disease control rate was 74%, the overall response rate was 28%, and the complete response rate was 5%.

“All patients who had their disease controlled had a reduction in lymph nodes and some degree of activity across all dose levels,” Dr Gutierrez said. “GCB and non-GCB patients responded similarly.”

The length of response was up to 632 days in the DLBCL group.

Most adverse events were gastrointestinal in nature, and most of them were grade 1 or 2. The most common adverse events were nausea, anorexia, and fatigue.

The investigators found a higher incidence of side effects in the first treatment cycle. The dosing schedule was interrupted and reduced to maintain steady state levels.

“The results suggest that an intermittent dosing schedule optimally induces a steady state with maximal induction of XPO1 mRNA,” Dr Gutierrez said.

There were 3 dose-limiting toxicities, including 1 multiple myeloma patient with grade 4 thrombocytopenia, 1 follicular lymphoma patient with grade 4 thrombocytopenia, and 1 CLL patient with grade 2 fatigue.

ASCO discussant Owen O’Connor, MD, from Columbia University Medical Center in New York, commented, “These clinical data are interesting with a provocative target. I applaud the investigators for doing a trial across a diversity of B- and T-cell lymphomas . . . . The results suggest a potential effect in a rare subset of lymphoma patients that have little treatment options.”

Frontline trials of selinexor are planned, including patients with Richter transformation and follicular lymphoma.

Selinexor recently received orphan drug status from the US Food and Drug Administration for the treatment of DLBCL.

 

 

Lobby view at ASCO 2014

©ASCO/Rodney White

 

CHICAGO—The novel, oral selective inhibitor of nuclear transport known as selinexor (KPT-330) can safely be given as monotherapy to patients with heavily pretreated non-Hodgkin lymphoma (NHL), according to a presentation at the 2014 ASCO Annual Meeting.

“Selinexor has favorable pharmacokinetic and pharmacodynamic characteristics,” said presenter Martin Gutierrez, MD, of the John Theurer Cancer Center at Hackensack University Medical Center in New Jersey.

Selinexor is a slowly reversible, selective inhibitor of nuclear transport that inhibits XPO1, which is elevated in NHL, chronic lymphocytic leukemia (CLL), and other malignances.

“It shows single-agent anti-tumor activity across all NHL types, with durable cancer control of more than 9 months [and] marked activity across germ cell B (GCB), non-germ cell B, and double-hit diffuse large B-cell lymphoma (DLBCL),” Dr Gutierrez said.

He provided an update of the ongoing phase 1 dose-escalation study at the meeting as abstract 8518.

The study now includes 51 patients, half of whom have NHL. Their median age is 60 years.

The patients received selinexor across 8 dose levels, ranging from 3 mg/m² to 60 mg/m². Dosing at 60 mg/m² twice weekly is ongoing, and the maximum-tolerated dose has not been reached.

Among the 43 evaluable patients, the disease control rate was 74%, the overall response rate was 28%, and the complete response rate was 5%.

“All patients who had their disease controlled had a reduction in lymph nodes and some degree of activity across all dose levels,” Dr Gutierrez said. “GCB and non-GCB patients responded similarly.”

The length of response was up to 632 days in the DLBCL group.

Most adverse events were gastrointestinal in nature, and most of them were grade 1 or 2. The most common adverse events were nausea, anorexia, and fatigue.

The investigators found a higher incidence of side effects in the first treatment cycle. The dosing schedule was interrupted and reduced to maintain steady state levels.

“The results suggest that an intermittent dosing schedule optimally induces a steady state with maximal induction of XPO1 mRNA,” Dr Gutierrez said.

There were 3 dose-limiting toxicities, including 1 multiple myeloma patient with grade 4 thrombocytopenia, 1 follicular lymphoma patient with grade 4 thrombocytopenia, and 1 CLL patient with grade 2 fatigue.

ASCO discussant Owen O’Connor, MD, from Columbia University Medical Center in New York, commented, “These clinical data are interesting with a provocative target. I applaud the investigators for doing a trial across a diversity of B- and T-cell lymphomas . . . . The results suggest a potential effect in a rare subset of lymphoma patients that have little treatment options.”

Frontline trials of selinexor are planned, including patients with Richter transformation and follicular lymphoma.

Selinexor recently received orphan drug status from the US Food and Drug Administration for the treatment of DLBCL.

Tumor cells producing p53

Credit: A.T. Tikhonenko

A novel sequencing technique has allowed researchers to identify direct targets of p53, providing new insight into this gene’s anticancer activity.

The research, published in eLife, revealed nearly 200 genes that were directly regulated by p53, and many of these had never been identified before.

The study’s authors said this work lays the foundation for investigations into which of these genes are necessary for p53’s cancer-killing effects and how cancer cells evade these genes.

The researchers noted that all cancers must deal with p53’s antitumor effects. Generally, there are 2 ways they do this: by mutating p53 directly or by producing the protein MDM2, which inhibits p53 function. With the current study, the team explored the second strategy.

“MDM2 inhibitors, which are through phase 1 human trials, effectively activate p53 but manage to kill only about 1 in 20 tumors,” said study author Joaquín Espinosa, PhD, of the University of Colorado in Boulder.

“The question is why. What else is happening in these cancer cells that allow them to evade p53?”

According to the researchers, the answer is in the downstream effects of p53. The gene sets in motion a cascade of events that lead to cancer cell destruction. But it has been unclear exactly which other genes are directly activated by p53.

To identify genetic targets of p53, Dr Espinosa and his colleagues used a technique called Global Run-On Sequencing (GRO-Seq). Unlike other methods, GRO-Seq measures new RNA being created, not overall RNA levels.

“Many teams around the world have been getting cancer cells, treating them with MDM2 inhibitors, and waiting hours and hours to see what genes turn on, and then, only imprecisely,” Dr Espinosa said. “GRO-Seq lets us do it in minutes, and the discoveries are massive.”

The technique generates a large quantity of data because it requires counting tens of thousands of RNA molecules before and after p53 activation. So this research required designing algorithms to sort through the data, as well as a computational biologist driving a supercomputer.

But the researchers were able to pinpoint new genes directly regulated by p53. And they believe this could aid the future development of cancer-fighting strategies.

Tumor cells producing p53

Credit: A.T. Tikhonenko

A novel sequencing technique has allowed researchers to identify direct targets of p53, providing new insight into this gene’s anticancer activity.

The research, published in eLife, revealed nearly 200 genes that were directly regulated by p53, and many of these had never been identified before.

The study’s authors said this work lays the foundation for investigations into which of these genes are necessary for p53’s cancer-killing effects and how cancer cells evade these genes.

The researchers noted that all cancers must deal with p53’s antitumor effects. Generally, there are 2 ways they do this: by mutating p53 directly or by producing the protein MDM2, which inhibits p53 function. With the current study, the team explored the second strategy.

“MDM2 inhibitors, which are through phase 1 human trials, effectively activate p53 but manage to kill only about 1 in 20 tumors,” said study author Joaquín Espinosa, PhD, of the University of Colorado in Boulder.

“The question is why. What else is happening in these cancer cells that allow them to evade p53?”

According to the researchers, the answer is in the downstream effects of p53. The gene sets in motion a cascade of events that lead to cancer cell destruction. But it has been unclear exactly which other genes are directly activated by p53.

To identify genetic targets of p53, Dr Espinosa and his colleagues used a technique called Global Run-On Sequencing (GRO-Seq). Unlike other methods, GRO-Seq measures new RNA being created, not overall RNA levels.

“Many teams around the world have been getting cancer cells, treating them with MDM2 inhibitors, and waiting hours and hours to see what genes turn on, and then, only imprecisely,” Dr Espinosa said. “GRO-Seq lets us do it in minutes, and the discoveries are massive.”

The technique generates a large quantity of data because it requires counting tens of thousands of RNA molecules before and after p53 activation. So this research required designing algorithms to sort through the data, as well as a computational biologist driving a supercomputer.

But the researchers were able to pinpoint new genes directly regulated by p53. And they believe this could aid the future development of cancer-fighting strategies.

Tumor cells producing p53

Credit: A.T. Tikhonenko

A novel sequencing technique has allowed researchers to identify direct targets of p53, providing new insight into this gene’s anticancer activity.

The research, published in eLife, revealed nearly 200 genes that were directly regulated by p53, and many of these had never been identified before.

The study’s authors said this work lays the foundation for investigations into which of these genes are necessary for p53’s cancer-killing effects and how cancer cells evade these genes.

The researchers noted that all cancers must deal with p53’s antitumor effects. Generally, there are 2 ways they do this: by mutating p53 directly or by producing the protein MDM2, which inhibits p53 function. With the current study, the team explored the second strategy.

“MDM2 inhibitors, which are through phase 1 human trials, effectively activate p53 but manage to kill only about 1 in 20 tumors,” said study author Joaquín Espinosa, PhD, of the University of Colorado in Boulder.

“The question is why. What else is happening in these cancer cells that allow them to evade p53?”

According to the researchers, the answer is in the downstream effects of p53. The gene sets in motion a cascade of events that lead to cancer cell destruction. But it has been unclear exactly which other genes are directly activated by p53.

To identify genetic targets of p53, Dr Espinosa and his colleagues used a technique called Global Run-On Sequencing (GRO-Seq). Unlike other methods, GRO-Seq measures new RNA being created, not overall RNA levels.

“Many teams around the world have been getting cancer cells, treating them with MDM2 inhibitors, and waiting hours and hours to see what genes turn on, and then, only imprecisely,” Dr Espinosa said. “GRO-Seq lets us do it in minutes, and the discoveries are massive.”

The technique generates a large quantity of data because it requires counting tens of thousands of RNA molecules before and after p53 activation. So this research required designing algorithms to sort through the data, as well as a computational biologist driving a supercomputer.

But the researchers were able to pinpoint new genes directly regulated by p53. And they believe this could aid the future development of cancer-fighting strategies.

MRI scanner

Results of a new study indicate that MRI and mammography can detect invasive breast tumors at very early stages in female survivors of Hodgkin lymphoma (HL).

Researchers said the findings underscore the need for at-risk childhood HL survivors and their physicians to be aware of screening guidelines.

The guidelines recommend survivors undergo breast MRI screening beginning at age 25 or 8 years after they received chest radiation, whichever is later.

“Female survivors of childhood HL who had chest radiation should speak with their family doctor about after-care assessment and breast cancer screening,” said David Hodgson, MD, of Princess Margaret Cancer Centre in Toronto, Canada.

“We estimate that 75% of women who are at high risk because of prior radiotherapy to the chest are not being screened. So my hope is that this new evidence will encourage these survivors to discuss early screening with their doctors.”

Dr Hodgson and his colleagues reported this evidence in Cancer.

The researchers evaluated the results of breast MRI and mammography screening among 96 female survivors of childhood HL who had been treated with chest radiotherapy.

The median patient age at first screening was 30 years, and the median number of MRI screening rounds was 3. Ten breast cancers—half of them invasive tumors—were diagnosed in 9 women during 363 person-years follow up.

The median age at breast cancer diagnosis was 39 years (range, 24 to 43 years), and the median latency period between HL diagnosis and age at breast cancer diagnoses was 21 years (range, 12 to 27 years).

“This illustrates the young age at which these cancers can occur,” Dr Hodgson said. “For some of these women, if they had been screened starting at age 40 or 50, like average-risk women, it would have been too late.”

MRI alone detected tumors with 80% sensitivity and 93.5% specificity. Mammography alone detected tumors with 70% sensitivity and 95% specificity. And both modalities combined detected tumors with 100% sensitivity and 88.6% specificity. All invasive tumors were detected by MRI.

In other words, of the 10 breast tumors, 5 were visible on both MRI and mammogram, 3 were visible only on MRI, and 2 were detected via mammogram alone (but were non-invasive). The median size of invasive tumors size was 8 mm (range, 3-15 mm), and none had spread to the lymph nodes.

The researchers noted that these results are substantially better than prior studies using only mammographic screening in young patients.

Dr Hodgson also pointed out that, because MRI screening is so much more sensitive to small changes in the appearance of the breast tissue than mammography, up to a third of patients may be called back for further testing of suspicious findings. But many of these are benign or not clinically significant and, therefore, require no treatment.

MRI scanner

Results of a new study indicate that MRI and mammography can detect invasive breast tumors at very early stages in female survivors of Hodgkin lymphoma (HL).

Researchers said the findings underscore the need for at-risk childhood HL survivors and their physicians to be aware of screening guidelines.

The guidelines recommend survivors undergo breast MRI screening beginning at age 25 or 8 years after they received chest radiation, whichever is later.

“Female survivors of childhood HL who had chest radiation should speak with their family doctor about after-care assessment and breast cancer screening,” said David Hodgson, MD, of Princess Margaret Cancer Centre in Toronto, Canada.

“We estimate that 75% of women who are at high risk because of prior radiotherapy to the chest are not being screened. So my hope is that this new evidence will encourage these survivors to discuss early screening with their doctors.”

Dr Hodgson and his colleagues reported this evidence in Cancer.

The researchers evaluated the results of breast MRI and mammography screening among 96 female survivors of childhood HL who had been treated with chest radiotherapy.

The median patient age at first screening was 30 years, and the median number of MRI screening rounds was 3. Ten breast cancers—half of them invasive tumors—were diagnosed in 9 women during 363 person-years follow up.

The median age at breast cancer diagnosis was 39 years (range, 24 to 43 years), and the median latency period between HL diagnosis and age at breast cancer diagnoses was 21 years (range, 12 to 27 years).

“This illustrates the young age at which these cancers can occur,” Dr Hodgson said. “For some of these women, if they had been screened starting at age 40 or 50, like average-risk women, it would have been too late.”

MRI alone detected tumors with 80% sensitivity and 93.5% specificity. Mammography alone detected tumors with 70% sensitivity and 95% specificity. And both modalities combined detected tumors with 100% sensitivity and 88.6% specificity. All invasive tumors were detected by MRI.

In other words, of the 10 breast tumors, 5 were visible on both MRI and mammogram, 3 were visible only on MRI, and 2 were detected via mammogram alone (but were non-invasive). The median size of invasive tumors size was 8 mm (range, 3-15 mm), and none had spread to the lymph nodes.

The researchers noted that these results are substantially better than prior studies using only mammographic screening in young patients.

Dr Hodgson also pointed out that, because MRI screening is so much more sensitive to small changes in the appearance of the breast tissue than mammography, up to a third of patients may be called back for further testing of suspicious findings. But many of these are benign or not clinically significant and, therefore, require no treatment.

MRI scanner

Results of a new study indicate that MRI and mammography can detect invasive breast tumors at very early stages in female survivors of Hodgkin lymphoma (HL).

Researchers said the findings underscore the need for at-risk childhood HL survivors and their physicians to be aware of screening guidelines.

The guidelines recommend survivors undergo breast MRI screening beginning at age 25 or 8 years after they received chest radiation, whichever is later.

“Female survivors of childhood HL who had chest radiation should speak with their family doctor about after-care assessment and breast cancer screening,” said David Hodgson, MD, of Princess Margaret Cancer Centre in Toronto, Canada.

“We estimate that 75% of women who are at high risk because of prior radiotherapy to the chest are not being screened. So my hope is that this new evidence will encourage these survivors to discuss early screening with their doctors.”

Dr Hodgson and his colleagues reported this evidence in Cancer.

The researchers evaluated the results of breast MRI and mammography screening among 96 female survivors of childhood HL who had been treated with chest radiotherapy.

The median patient age at first screening was 30 years, and the median number of MRI screening rounds was 3. Ten breast cancers—half of them invasive tumors—were diagnosed in 9 women during 363 person-years follow up.

The median age at breast cancer diagnosis was 39 years (range, 24 to 43 years), and the median latency period between HL diagnosis and age at breast cancer diagnoses was 21 years (range, 12 to 27 years).

“This illustrates the young age at which these cancers can occur,” Dr Hodgson said. “For some of these women, if they had been screened starting at age 40 or 50, like average-risk women, it would have been too late.”

MRI alone detected tumors with 80% sensitivity and 93.5% specificity. Mammography alone detected tumors with 70% sensitivity and 95% specificity. And both modalities combined detected tumors with 100% sensitivity and 88.6% specificity. All invasive tumors were detected by MRI.

In other words, of the 10 breast tumors, 5 were visible on both MRI and mammogram, 3 were visible only on MRI, and 2 were detected via mammogram alone (but were non-invasive). The median size of invasive tumors size was 8 mm (range, 3-15 mm), and none had spread to the lymph nodes.

The researchers noted that these results are substantially better than prior studies using only mammographic screening in young patients.

Dr Hodgson also pointed out that, because MRI screening is so much more sensitive to small changes in the appearance of the breast tissue than mammography, up to a third of patients may be called back for further testing of suspicious findings. But many of these are benign or not clinically significant and, therefore, require no treatment.

Lab mouse

Researchers say they’ve found a way to target myeloid-derived suppressor cells (MDSCs) while sparing other immune cells.

In preclinical experiments, the team showed they could deplete MDSCs—and shrink tumors—using peptide antibodies.

These “peptibodies” wiped out MDSCs in the blood, spleen, and tumor cells of mice without binding to other white blood cells or dendritic cells.

The researchers described this work in Nature Medicine.

“We’ve known about [MDSCs] blocking immune response for a decade but haven’t been able to shut them down for lack of an identified target,” said the paper’s senior author, Larry Kwak, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“This is the first demonstration of a molecule on these cells that allows us to make an antibody—in this case, a peptide—to bind to them and get rid of them. It’s a brand new immunotherapy target.”

Dr Kwak and his colleagues began this research by applying a peptide phage library to MDSCs, which allowed for a mass screening of candidate peptides that bind to the surface of MDSCs. This revealed 2 peptides, labeled G3 and H6, that bound only to MDSCs.

The researchers fused the 2 peptides to a portion of mouse immune globulin to generate experimental peptibodies called pep-G3 and pep-H6. Both peptibodies bound to both types of MDSCs—monocytic and granulocytic cells.

Dr Kwak and his colleagues then tested the peptibodies in 2 mouse models of thymic tumors, as well as models of melanoma and lymphoma. The team compared pep-G3 and pep-H6 to a control peptibody and an antibody against Gr-1.

Both pep-G3 and pep-H6 depleted monocytic and granulocytic MDSCs in the blood and spleens of all mice. But the Gr-1 antibody only worked against granulocytic MDSCs.

To see whether MDSC depletion would impede tumor growth, the researchers administered the peptibodies to mice with thymic tumors every other day for 2 weeks.

Mice treated with either pep-G3 or pep-H6 had tumors that were about half the size and weight of those in mice treated with the control peptibody or the Gr-1 antibody.

Lastly, the researchers analyzed surface proteins on the MDSCs and found that S100A9 and S100A8 are the likely binding targets for pep-G3 and pep-H6.

Dr Kwak and his colleagues said they are now working to extend these findings to human MDSCs.

Lab mouse

Researchers say they’ve found a way to target myeloid-derived suppressor cells (MDSCs) while sparing other immune cells.

In preclinical experiments, the team showed they could deplete MDSCs—and shrink tumors—using peptide antibodies.

These “peptibodies” wiped out MDSCs in the blood, spleen, and tumor cells of mice without binding to other white blood cells or dendritic cells.

The researchers described this work in Nature Medicine.

“We’ve known about [MDSCs] blocking immune response for a decade but haven’t been able to shut them down for lack of an identified target,” said the paper’s senior author, Larry Kwak, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“This is the first demonstration of a molecule on these cells that allows us to make an antibody—in this case, a peptide—to bind to them and get rid of them. It’s a brand new immunotherapy target.”

Dr Kwak and his colleagues began this research by applying a peptide phage library to MDSCs, which allowed for a mass screening of candidate peptides that bind to the surface of MDSCs. This revealed 2 peptides, labeled G3 and H6, that bound only to MDSCs.

The researchers fused the 2 peptides to a portion of mouse immune globulin to generate experimental peptibodies called pep-G3 and pep-H6. Both peptibodies bound to both types of MDSCs—monocytic and granulocytic cells.

Dr Kwak and his colleagues then tested the peptibodies in 2 mouse models of thymic tumors, as well as models of melanoma and lymphoma. The team compared pep-G3 and pep-H6 to a control peptibody and an antibody against Gr-1.

Both pep-G3 and pep-H6 depleted monocytic and granulocytic MDSCs in the blood and spleens of all mice. But the Gr-1 antibody only worked against granulocytic MDSCs.

To see whether MDSC depletion would impede tumor growth, the researchers administered the peptibodies to mice with thymic tumors every other day for 2 weeks.

Mice treated with either pep-G3 or pep-H6 had tumors that were about half the size and weight of those in mice treated with the control peptibody or the Gr-1 antibody.

Lastly, the researchers analyzed surface proteins on the MDSCs and found that S100A9 and S100A8 are the likely binding targets for pep-G3 and pep-H6.

Dr Kwak and his colleagues said they are now working to extend these findings to human MDSCs.

Lab mouse

Researchers say they’ve found a way to target myeloid-derived suppressor cells (MDSCs) while sparing other immune cells.

In preclinical experiments, the team showed they could deplete MDSCs—and shrink tumors—using peptide antibodies.

These “peptibodies” wiped out MDSCs in the blood, spleen, and tumor cells of mice without binding to other white blood cells or dendritic cells.

The researchers described this work in Nature Medicine.

“We’ve known about [MDSCs] blocking immune response for a decade but haven’t been able to shut them down for lack of an identified target,” said the paper’s senior author, Larry Kwak, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“This is the first demonstration of a molecule on these cells that allows us to make an antibody—in this case, a peptide—to bind to them and get rid of them. It’s a brand new immunotherapy target.”

Dr Kwak and his colleagues began this research by applying a peptide phage library to MDSCs, which allowed for a mass screening of candidate peptides that bind to the surface of MDSCs. This revealed 2 peptides, labeled G3 and H6, that bound only to MDSCs.

The researchers fused the 2 peptides to a portion of mouse immune globulin to generate experimental peptibodies called pep-G3 and pep-H6. Both peptibodies bound to both types of MDSCs—monocytic and granulocytic cells.

Dr Kwak and his colleagues then tested the peptibodies in 2 mouse models of thymic tumors, as well as models of melanoma and lymphoma. The team compared pep-G3 and pep-H6 to a control peptibody and an antibody against Gr-1.

Both pep-G3 and pep-H6 depleted monocytic and granulocytic MDSCs in the blood and spleens of all mice. But the Gr-1 antibody only worked against granulocytic MDSCs.

To see whether MDSC depletion would impede tumor growth, the researchers administered the peptibodies to mice with thymic tumors every other day for 2 weeks.

Mice treated with either pep-G3 or pep-H6 had tumors that were about half the size and weight of those in mice treated with the control peptibody or the Gr-1 antibody.

Lastly, the researchers analyzed surface proteins on the MDSCs and found that S100A9 and S100A8 are the likely binding targets for pep-G3 and pep-H6.

Dr Kwak and his colleagues said they are now working to extend these findings to human MDSCs.

Researchers in the lab

Credit: Rhoda Baer

Researchers say they have identified a source of drug resistance in chronic lymphocytic leukemia (CLL).

In a letter to The New England Journal of Medicine, the team described how a mutation in Bruton’s tyrosine kinase (BTK) triggers resistance to ibrutinib, a drug that treats CLL by inhibiting BTK.

The researchers discovered this point mutation in a CLL patient enrolled in a clinical trial. The patient initially responded well to ibrutinib but stopped responding after almost 20 months.

“In a way, we are repeating, at a faster pace, the story of Gleevec [imatinib],” said study author Y. Lynn Wang, MD, PhD, of the University of Chicago in Illinois.

“That story began with development of an effective drug with few side effects, but, in many patients, the leukemia eventually found a way around it after long-term use. So researchers developed second-line drugs to overcome resistance.”

The ibrutinib study began in 2010 at Weill Cornell Medical College in New York, one of several sites for a phase 1 trial of ibrutinib. The researchers recruited 16 patients with CLL whose disease had progressed or relapsed despite multiple treatments.

Dr Wang arranged to track the progress of each patient’s leukemic cells before and during treatment and to correlate any cellular or molecular changes with each patient’s disease activity.

One of the 16 patients in the trial seemed to be unusual. This 61-year-old woman was diagnosed in 2000 at age 49. She had unsuccessfully received several different treatments before entering the study.

Within 18 months of starting ibrutinib, she showed significant improvement. At about 20 months, however, she started to decline, developing a respiratory infection that did not improve with treatment. By 21 months, it was clear she was having a relapse. The clinical team increased her dose, with no discernable effect.

Dr Wang’s team quickly began analyzing her blood samples, looking for changes that occurred between the period when she was responding well to ibrutinib and after she began to relapse.

Because complete gene sequencing would be time consuming, Dr Wang asked a graduate student working on the project, Menu Setty from Memorial Sloan-Kettering in New York, to first focus on 3 proteins that were likely candidates. One of the candidates was BTK.

And sure enough, Setty discovered a tiny but consistent change in BTK in about 90% of post-relapse cells. It was a thymidine-to-adenine mutation at nucleotide 1634 of the BTK complementary DNA, leading to a substitution of serine for cysteine at residue 481 (C481S).

When the researchers later analyzed the entire set of the patient’s genes, they found no other genetic changes that correlated with the patient’s clinical course. BTK made perfect sense as the cause for drug resistance, the researchers noted, as it’s the primary target of ibrutinib binding, and it plays a central role in rapid cell proliferation.

Dr Wang and her colleagues used structural and biochemical measures to confirm that the C481S mutation made CLL cells resistant to ibrutinib. The studies indicated that ibrutinib was 500 times less likely to bind to mutant BTK.

In an attempt to save the patient, the researchers tested alternative kinase inhibitors against the patient’s leukemic cells in the lab.

They found some kinase inhibitors remained effective against ibrutinib-resistant cells. (These studies are described in a separate manuscript that has been submitted for publication.) Unfortunately, despite this effort, the patient passed away a few weeks later, due to sepsis.

The researchers noted that the C481S mutation is one of several mechanisms that underlie resistance to ibrutinib, but this research highlights the mutation’s role in disease development and drug resistance.

Understanding the molecular and cellular mechanisms of resistance is the first step toward monitoring, early detection, and development of novel strategies to overcome drug resistance.

Researchers in the lab

Credit: Rhoda Baer

Researchers say they have identified a source of drug resistance in chronic lymphocytic leukemia (CLL).

In a letter to The New England Journal of Medicine, the team described how a mutation in Bruton’s tyrosine kinase (BTK) triggers resistance to ibrutinib, a drug that treats CLL by inhibiting BTK.

The researchers discovered this point mutation in a CLL patient enrolled in a clinical trial. The patient initially responded well to ibrutinib but stopped responding after almost 20 months.

“In a way, we are repeating, at a faster pace, the story of Gleevec [imatinib],” said study author Y. Lynn Wang, MD, PhD, of the University of Chicago in Illinois.

“That story began with development of an effective drug with few side effects, but, in many patients, the leukemia eventually found a way around it after long-term use. So researchers developed second-line drugs to overcome resistance.”

The ibrutinib study began in 2010 at Weill Cornell Medical College in New York, one of several sites for a phase 1 trial of ibrutinib. The researchers recruited 16 patients with CLL whose disease had progressed or relapsed despite multiple treatments.

Dr Wang arranged to track the progress of each patient’s leukemic cells before and during treatment and to correlate any cellular or molecular changes with each patient’s disease activity.

One of the 16 patients in the trial seemed to be unusual. This 61-year-old woman was diagnosed in 2000 at age 49. She had unsuccessfully received several different treatments before entering the study.

Within 18 months of starting ibrutinib, she showed significant improvement. At about 20 months, however, she started to decline, developing a respiratory infection that did not improve with treatment. By 21 months, it was clear she was having a relapse. The clinical team increased her dose, with no discernable effect.

Dr Wang’s team quickly began analyzing her blood samples, looking for changes that occurred between the period when she was responding well to ibrutinib and after she began to relapse.

Because complete gene sequencing would be time consuming, Dr Wang asked a graduate student working on the project, Menu Setty from Memorial Sloan-Kettering in New York, to first focus on 3 proteins that were likely candidates. One of the candidates was BTK.

And sure enough, Setty discovered a tiny but consistent change in BTK in about 90% of post-relapse cells. It was a thymidine-to-adenine mutation at nucleotide 1634 of the BTK complementary DNA, leading to a substitution of serine for cysteine at residue 481 (C481S).

When the researchers later analyzed the entire set of the patient’s genes, they found no other genetic changes that correlated with the patient’s clinical course. BTK made perfect sense as the cause for drug resistance, the researchers noted, as it’s the primary target of ibrutinib binding, and it plays a central role in rapid cell proliferation.

Dr Wang and her colleagues used structural and biochemical measures to confirm that the C481S mutation made CLL cells resistant to ibrutinib. The studies indicated that ibrutinib was 500 times less likely to bind to mutant BTK.

In an attempt to save the patient, the researchers tested alternative kinase inhibitors against the patient’s leukemic cells in the lab.

They found some kinase inhibitors remained effective against ibrutinib-resistant cells. (These studies are described in a separate manuscript that has been submitted for publication.) Unfortunately, despite this effort, the patient passed away a few weeks later, due to sepsis.

The researchers noted that the C481S mutation is one of several mechanisms that underlie resistance to ibrutinib, but this research highlights the mutation’s role in disease development and drug resistance.

Understanding the molecular and cellular mechanisms of resistance is the first step toward monitoring, early detection, and development of novel strategies to overcome drug resistance.

Researchers in the lab

Credit: Rhoda Baer

Researchers say they have identified a source of drug resistance in chronic lymphocytic leukemia (CLL).

In a letter to The New England Journal of Medicine, the team described how a mutation in Bruton’s tyrosine kinase (BTK) triggers resistance to ibrutinib, a drug that treats CLL by inhibiting BTK.

The researchers discovered this point mutation in a CLL patient enrolled in a clinical trial. The patient initially responded well to ibrutinib but stopped responding after almost 20 months.

“In a way, we are repeating, at a faster pace, the story of Gleevec [imatinib],” said study author Y. Lynn Wang, MD, PhD, of the University of Chicago in Illinois.

“That story began with development of an effective drug with few side effects, but, in many patients, the leukemia eventually found a way around it after long-term use. So researchers developed second-line drugs to overcome resistance.”

The ibrutinib study began in 2010 at Weill Cornell Medical College in New York, one of several sites for a phase 1 trial of ibrutinib. The researchers recruited 16 patients with CLL whose disease had progressed or relapsed despite multiple treatments.

Dr Wang arranged to track the progress of each patient’s leukemic cells before and during treatment and to correlate any cellular or molecular changes with each patient’s disease activity.

One of the 16 patients in the trial seemed to be unusual. This 61-year-old woman was diagnosed in 2000 at age 49. She had unsuccessfully received several different treatments before entering the study.

Within 18 months of starting ibrutinib, she showed significant improvement. At about 20 months, however, she started to decline, developing a respiratory infection that did not improve with treatment. By 21 months, it was clear she was having a relapse. The clinical team increased her dose, with no discernable effect.

Dr Wang’s team quickly began analyzing her blood samples, looking for changes that occurred between the period when she was responding well to ibrutinib and after she began to relapse.

Because complete gene sequencing would be time consuming, Dr Wang asked a graduate student working on the project, Menu Setty from Memorial Sloan-Kettering in New York, to first focus on 3 proteins that were likely candidates. One of the candidates was BTK.

And sure enough, Setty discovered a tiny but consistent change in BTK in about 90% of post-relapse cells. It was a thymidine-to-adenine mutation at nucleotide 1634 of the BTK complementary DNA, leading to a substitution of serine for cysteine at residue 481 (C481S).

When the researchers later analyzed the entire set of the patient’s genes, they found no other genetic changes that correlated with the patient’s clinical course. BTK made perfect sense as the cause for drug resistance, the researchers noted, as it’s the primary target of ibrutinib binding, and it plays a central role in rapid cell proliferation.

Dr Wang and her colleagues used structural and biochemical measures to confirm that the C481S mutation made CLL cells resistant to ibrutinib. The studies indicated that ibrutinib was 500 times less likely to bind to mutant BTK.

In an attempt to save the patient, the researchers tested alternative kinase inhibitors against the patient’s leukemic cells in the lab.

They found some kinase inhibitors remained effective against ibrutinib-resistant cells. (These studies are described in a separate manuscript that has been submitted for publication.) Unfortunately, despite this effort, the patient passed away a few weeks later, due to sepsis.

The researchers noted that the C481S mutation is one of several mechanisms that underlie resistance to ibrutinib, but this research highlights the mutation’s role in disease development and drug resistance.

Understanding the molecular and cellular mechanisms of resistance is the first step toward monitoring, early detection, and development of novel strategies to overcome drug resistance.

Cancer patient receives therapy

Credit: Rhoda Baer

Results of a large study suggest certain malignanices are more concentrated in areas with high levels of poverty, while other cancer types arise more often in wealthy regions.

The research, conducted using data from nearly 3 million US cancer cases, also indicated that areas with higher poverty levels tended to have a lower cancer incidence but higher mortality rate than areas with lower poverty levels.

Researchers reported these findings in the journal Cancer.

Francis Boscoe, PhD, of the New York State Cancer Registry in Albany, and his colleagues conducted this research to evaluate the role of socioeconomics in cancer incidence and mortality.

So the team compared individuals living in areas with the highest poverty levels to those living in areas with the lowest poverty levels.

The researchers collected information on nearly 3 million cancer cases diagnosed between 2005 and 2009 in16 states, plus Los Angeles (an area covering 42% of the US population). Cases were divided into 1 of 4 groupings based on the poverty rate of the residential census tract at the time of diagnosis.

For all malignancies combined, there was a negligible association between cancer incidence and poverty. However, 32 of 39 cancer types showed a significant association with poverty.

Fourteen cancers were positively associated with poverty, and 18 were negatively associated. Myeloma, Hodgkin lymphoma, and non-Hodgkin lymphoma (NHL) were among the negatively associated malignancies.

The cancers most significantly associated with higher poverty levels were Kaposi sarcoma and cancers of the larynx, cervix, penis, and liver. The cancers most significantly associated with lower poverty levels were melanoma, thyroid cancer, other non-epithelial skin cancers, and testis cancer.

Overall, male malignancy rates were more sensitive to poverty level than female rates. And, in general, the race-specific cancer incidence rates differed, but the poverty gradients were similar.

For example, there was a roughly 20-fold difference in rates of melanoma between white and black individuals, but the relationship between poverty and incidence remained regardless of race.

This was not true for NHL, however. Among black individuals, the incidence of NHL increased as the poverty level increased. But among white individuals, the incidence of NHL decreased as the poverty level increased.

The researchers pointed out that—for all cancer sites, races, and sexes combined—the difference in risk between the greatest and lowest poverty category was less than 2%.

“At first glance, the effects seem to cancel one another out,” Dr Boscoe said. “But the cancers more associated with poverty have lower incidence and higher mortality, and those associated with wealth have higher incidence and lower mortality. When it comes to cancer, the poor are more likely to die of the disease, while the affluent are more likely to die with the disease.”

Dr Boscoe noted that recent gains in technology have made it much easier to link patient addresses with neighborhood characteristics, therefore making it possible to incorporate socioeconomic status into cancer surveillance.

“Our hope is that our paper will illustrate the value and necessity of doing this routinely in the future,” he concluded.

Cancer patient receives therapy

Credit: Rhoda Baer

Results of a large study suggest certain malignanices are more concentrated in areas with high levels of poverty, while other cancer types arise more often in wealthy regions.

The research, conducted using data from nearly 3 million US cancer cases, also indicated that areas with higher poverty levels tended to have a lower cancer incidence but higher mortality rate than areas with lower poverty levels.

Researchers reported these findings in the journal Cancer.

Francis Boscoe, PhD, of the New York State Cancer Registry in Albany, and his colleagues conducted this research to evaluate the role of socioeconomics in cancer incidence and mortality.

So the team compared individuals living in areas with the highest poverty levels to those living in areas with the lowest poverty levels.

The researchers collected information on nearly 3 million cancer cases diagnosed between 2005 and 2009 in16 states, plus Los Angeles (an area covering 42% of the US population). Cases were divided into 1 of 4 groupings based on the poverty rate of the residential census tract at the time of diagnosis.

For all malignancies combined, there was a negligible association between cancer incidence and poverty. However, 32 of 39 cancer types showed a significant association with poverty.

Fourteen cancers were positively associated with poverty, and 18 were negatively associated. Myeloma, Hodgkin lymphoma, and non-Hodgkin lymphoma (NHL) were among the negatively associated malignancies.

The cancers most significantly associated with higher poverty levels were Kaposi sarcoma and cancers of the larynx, cervix, penis, and liver. The cancers most significantly associated with lower poverty levels were melanoma, thyroid cancer, other non-epithelial skin cancers, and testis cancer.

Overall, male malignancy rates were more sensitive to poverty level than female rates. And, in general, the race-specific cancer incidence rates differed, but the poverty gradients were similar.

For example, there was a roughly 20-fold difference in rates of melanoma between white and black individuals, but the relationship between poverty and incidence remained regardless of race.

This was not true for NHL, however. Among black individuals, the incidence of NHL increased as the poverty level increased. But among white individuals, the incidence of NHL decreased as the poverty level increased.

The researchers pointed out that—for all cancer sites, races, and sexes combined—the difference in risk between the greatest and lowest poverty category was less than 2%.

“At first glance, the effects seem to cancel one another out,” Dr Boscoe said. “But the cancers more associated with poverty have lower incidence and higher mortality, and those associated with wealth have higher incidence and lower mortality. When it comes to cancer, the poor are more likely to die of the disease, while the affluent are more likely to die with the disease.”

Dr Boscoe noted that recent gains in technology have made it much easier to link patient addresses with neighborhood characteristics, therefore making it possible to incorporate socioeconomic status into cancer surveillance.

“Our hope is that our paper will illustrate the value and necessity of doing this routinely in the future,” he concluded.

Cancer patient receives therapy

Credit: Rhoda Baer

Results of a large study suggest certain malignanices are more concentrated in areas with high levels of poverty, while other cancer types arise more often in wealthy regions.

The research, conducted using data from nearly 3 million US cancer cases, also indicated that areas with higher poverty levels tended to have a lower cancer incidence but higher mortality rate than areas with lower poverty levels.

Researchers reported these findings in the journal Cancer.

Francis Boscoe, PhD, of the New York State Cancer Registry in Albany, and his colleagues conducted this research to evaluate the role of socioeconomics in cancer incidence and mortality.

So the team compared individuals living in areas with the highest poverty levels to those living in areas with the lowest poverty levels.

The researchers collected information on nearly 3 million cancer cases diagnosed between 2005 and 2009 in16 states, plus Los Angeles (an area covering 42% of the US population). Cases were divided into 1 of 4 groupings based on the poverty rate of the residential census tract at the time of diagnosis.

For all malignancies combined, there was a negligible association between cancer incidence and poverty. However, 32 of 39 cancer types showed a significant association with poverty.

Fourteen cancers were positively associated with poverty, and 18 were negatively associated. Myeloma, Hodgkin lymphoma, and non-Hodgkin lymphoma (NHL) were among the negatively associated malignancies.

The cancers most significantly associated with higher poverty levels were Kaposi sarcoma and cancers of the larynx, cervix, penis, and liver. The cancers most significantly associated with lower poverty levels were melanoma, thyroid cancer, other non-epithelial skin cancers, and testis cancer.

Overall, male malignancy rates were more sensitive to poverty level than female rates. And, in general, the race-specific cancer incidence rates differed, but the poverty gradients were similar.

For example, there was a roughly 20-fold difference in rates of melanoma between white and black individuals, but the relationship between poverty and incidence remained regardless of race.

This was not true for NHL, however. Among black individuals, the incidence of NHL increased as the poverty level increased. But among white individuals, the incidence of NHL decreased as the poverty level increased.

The researchers pointed out that—for all cancer sites, races, and sexes combined—the difference in risk between the greatest and lowest poverty category was less than 2%.

“At first glance, the effects seem to cancel one another out,” Dr Boscoe said. “But the cancers more associated with poverty have lower incidence and higher mortality, and those associated with wealth have higher incidence and lower mortality. When it comes to cancer, the poor are more likely to die of the disease, while the affluent are more likely to die with the disease.”

Dr Boscoe noted that recent gains in technology have made it much easier to link patient addresses with neighborhood characteristics, therefore making it possible to incorporate socioeconomic status into cancer surveillance.

“Our hope is that our paper will illustrate the value and necessity of doing this routinely in the future,” he concluded.

Monoclonal antibodies

Credit: Linda Bartlett

The European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion for ofatumumab (Arzerra), a monoclonal antibody targeting CD20.

The CHMP is recommending that ofatumumab receive conditional approval for use in combination with chlorambucil or bendamustine to treat patients with chronic lymphocytic leukemia (CLL) who have not received prior therapy and are not eligible for fludarabine-based therapy.

The European Commission (EC) will take the CHMP’s opinion into account when deciding whether to approve ofatumumab for this indication.

Ofatumumab already has conditional approval in the Europe Union to treat CLL patients who are refractory to fludarabine and alemtuzumab.

Ofatumumab received conditional approval because the drug’s benefits appear to outweigh the risks it poses. The drug will not receive full

approval until the companies developing ofatumumab, GlaxoSmithKline and Genmab, submit results of additional research to the EC.

The CHMP’s recommendation for expanded approval is based on results from 2 trials in patients with CLL who were ineligible for fludarabine-based treatment.

The first is a phase 2 study (OMB115991) in which researchers evaluated the efficacy of ofatumumab in combination with bendamustine. The second is the phase 3 COMPLEMENT 1 study (OMB110911), a randomized trial in which researchers compared ofatumumab and chlorambucil in combination to chlorambucil alone.

Phase 2 study

Results from this single-arm study were presented at the 2013 International Workshop on CLL. Researchers enrolled 97 patients with CLL, 44 of whom were previously untreated and 53 who had relapsed. The median ages were 62.5 and 68 years, respectively.

Treatment began with acetaminophen, an antihistamine, and a glucocorticoid. Patients then received ofatumumab at 300 mg on day 1 and 1000 mg on day 8 of cycle 1. For cycles 2 through 6, they received 1000 mg on day 1 every 28 days.

Patients received bendamustine on days 1 and 2, every 28 days for up to 6 cycles. The initial dose was 90 mg/m² for the untreated patients and 70 mg/m² for relapsed patients.

However, patients required a dose reduction due to toxicity. The previously untreated patients were reduced to 60 mg/m², and the relapsed patients were reduced to 50 mg/m².

The overall response rate was 95% in the previously untreated group and 74% in the relapsed group. Complete responses occurred in 43% and 11%, respectively.

CT results showed the overall response rate was 82% in the previously untreated group and 70% in the relapsed group. Complete responses occurred in 27% and 9%, respectively. The median time to response was 0.95 months for both groups.

Grade 3 or higher adverse events occurred in 25% of patients in the previously untreated group and 38% of those in the relapsed group.

This included infusion reactions (11% and 8%, respectively), neutropenia (16% and 29%, respectively), infections (11% and 15%, respectively), rash (2% of previously untreated patients), febrile neutropenia (4% of relapsed patients), and thrombocytopenia (4% of relapsed patients).

There were no deaths in the previously untreated group, but 4 patients died in the relapsed group. Two of these deaths may have been related to study treatment. One patient died of pneumonia and hemolytic anemia 15 days after the last dose of treatment, and 1 patient died of sepsis 4 days after the last dose of  treatment.

Phase 3 study

Data from the COMPLEMENT 1 study were presented at ASH 2013. Researchers compared ofatumumab plus chlorambucil to chlorambucil alone in 447 previously untreated patients with CLL who were ineligible for fludarabine-based therapy.

Patients had a median age of 69 years (range, 35 to 92). Seventy-two percent had 2 or more comorbidities, and 48% had a creatinine clearance of less than 70 mL/min.

Patients in the ofatumumab arm received the drug at 300 mg in cycle 1 on day 1, 1000 mg in cycle 1 on day 8, and 1000 mg administered on day 1 of all subsequent 28-day cycles.

In both arms, patients received chlorambucil at a dose of 10 mg/m² orally on days 1 to 7, every 28 days. Prior to each infusion of ofatumumab, patients received acetaminophen, an antihistamine, and a glucocorticoid.

The overall response rate was 82% in the ofatumumab-chlorambucil group and 69% in the chlorambucil-alone group (P=0.001). Complete response rates were 12% and 1%, respectively.

At a median follow-up of 29 months, the median overall survival was not reached for either treatment arm. However, ofatumumab-treated patients had longer progression-free survival than patients who received chlorambucil alone—22.4 months and 13.1 months, respectively (P<0.001).

Grade 3 or higher adverse events occurred in 50% of ofatumumab-treated patients and 43% of patients who received chlorambucil alone. The most common event was neutropenia, which occurred in 26% and 14% of patients, respectively.

Grade 3 or higher infections occurred in 15% of ofatumumab-treated patients and 14% of patients who received chlorambucil alone. The most common was pneumonia, which occurred in 4% and 3%, respectively.

In the entire cohort, grade 3 or higher infusion-related events occurred in 10% of patients, but there were no fatal infusion reactions. Two percent of subjects in both arms died during treatment.

Monoclonal antibodies

Credit: Linda Bartlett

The European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion for ofatumumab (Arzerra), a monoclonal antibody targeting CD20.

The CHMP is recommending that ofatumumab receive conditional approval for use in combination with chlorambucil or bendamustine to treat patients with chronic lymphocytic leukemia (CLL) who have not received prior therapy and are not eligible for fludarabine-based therapy.

The European Commission (EC) will take the CHMP’s opinion into account when deciding whether to approve ofatumumab for this indication.

Ofatumumab already has conditional approval in the Europe Union to treat CLL patients who are refractory to fludarabine and alemtuzumab.

Ofatumumab received conditional approval because the drug’s benefits appear to outweigh the risks it poses. The drug will not receive full

approval until the companies developing ofatumumab, GlaxoSmithKline and Genmab, submit results of additional research to the EC.

The CHMP’s recommendation for expanded approval is based on results from 2 trials in patients with CLL who were ineligible for fludarabine-based treatment.

The first is a phase 2 study (OMB115991) in which researchers evaluated the efficacy of ofatumumab in combination with bendamustine. The second is the phase 3 COMPLEMENT 1 study (OMB110911), a randomized trial in which researchers compared ofatumumab and chlorambucil in combination to chlorambucil alone.

Phase 2 study

Results from this single-arm study were presented at the 2013 International Workshop on CLL. Researchers enrolled 97 patients with CLL, 44 of whom were previously untreated and 53 who had relapsed. The median ages were 62.5 and 68 years, respectively.

Treatment began with acetaminophen, an antihistamine, and a glucocorticoid. Patients then received ofatumumab at 300 mg on day 1 and 1000 mg on day 8 of cycle 1. For cycles 2 through 6, they received 1000 mg on day 1 every 28 days.

Patients received bendamustine on days 1 and 2, every 28 days for up to 6 cycles. The initial dose was 90 mg/m² for the untreated patients and 70 mg/m² for relapsed patients.

However, patients required a dose reduction due to toxicity. The previously untreated patients were reduced to 60 mg/m², and the relapsed patients were reduced to 50 mg/m².

The overall response rate was 95% in the previously untreated group and 74% in the relapsed group. Complete responses occurred in 43% and 11%, respectively.

CT results showed the overall response rate was 82% in the previously untreated group and 70% in the relapsed group. Complete responses occurred in 27% and 9%, respectively. The median time to response was 0.95 months for both groups.

Grade 3 or higher adverse events occurred in 25% of patients in the previously untreated group and 38% of those in the relapsed group.

This included infusion reactions (11% and 8%, respectively), neutropenia (16% and 29%, respectively), infections (11% and 15%, respectively), rash (2% of previously untreated patients), febrile neutropenia (4% of relapsed patients), and thrombocytopenia (4% of relapsed patients).

There were no deaths in the previously untreated group, but 4 patients died in the relapsed group. Two of these deaths may have been related to study treatment. One patient died of pneumonia and hemolytic anemia 15 days after the last dose of treatment, and 1 patient died of sepsis 4 days after the last dose of  treatment.

Phase 3 study

Data from the COMPLEMENT 1 study were presented at ASH 2013. Researchers compared ofatumumab plus chlorambucil to chlorambucil alone in 447 previously untreated patients with CLL who were ineligible for fludarabine-based therapy.

Patients had a median age of 69 years (range, 35 to 92). Seventy-two percent had 2 or more comorbidities, and 48% had a creatinine clearance of less than 70 mL/min.

Patients in the ofatumumab arm received the drug at 300 mg in cycle 1 on day 1, 1000 mg in cycle 1 on day 8, and 1000 mg administered on day 1 of all subsequent 28-day cycles.

In both arms, patients received chlorambucil at a dose of 10 mg/m² orally on days 1 to 7, every 28 days. Prior to each infusion of ofatumumab, patients received acetaminophen, an antihistamine, and a glucocorticoid.

The overall response rate was 82% in the ofatumumab-chlorambucil group and 69% in the chlorambucil-alone group (P=0.001). Complete response rates were 12% and 1%, respectively.

At a median follow-up of 29 months, the median overall survival was not reached for either treatment arm. However, ofatumumab-treated patients had longer progression-free survival than patients who received chlorambucil alone—22.4 months and 13.1 months, respectively (P<0.001).

Grade 3 or higher adverse events occurred in 50% of ofatumumab-treated patients and 43% of patients who received chlorambucil alone. The most common event was neutropenia, which occurred in 26% and 14% of patients, respectively.

Grade 3 or higher infections occurred in 15% of ofatumumab-treated patients and 14% of patients who received chlorambucil alone. The most common was pneumonia, which occurred in 4% and 3%, respectively.

In the entire cohort, grade 3 or higher infusion-related events occurred in 10% of patients, but there were no fatal infusion reactions. Two percent of subjects in both arms died during treatment.

Monoclonal antibodies

Credit: Linda Bartlett

The European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion for ofatumumab (Arzerra), a monoclonal antibody targeting CD20.

The CHMP is recommending that ofatumumab receive conditional approval for use in combination with chlorambucil or bendamustine to treat patients with chronic lymphocytic leukemia (CLL) who have not received prior therapy and are not eligible for fludarabine-based therapy.

The European Commission (EC) will take the CHMP’s opinion into account when deciding whether to approve ofatumumab for this indication.

Ofatumumab already has conditional approval in the Europe Union to treat CLL patients who are refractory to fludarabine and alemtuzumab.

Ofatumumab received conditional approval because the drug’s benefits appear to outweigh the risks it poses. The drug will not receive full

approval until the companies developing ofatumumab, GlaxoSmithKline and Genmab, submit results of additional research to the EC.

The CHMP’s recommendation for expanded approval is based on results from 2 trials in patients with CLL who were ineligible for fludarabine-based treatment.

The first is a phase 2 study (OMB115991) in which researchers evaluated the efficacy of ofatumumab in combination with bendamustine. The second is the phase 3 COMPLEMENT 1 study (OMB110911), a randomized trial in which researchers compared ofatumumab and chlorambucil in combination to chlorambucil alone.

Phase 2 study

Results from this single-arm study were presented at the 2013 International Workshop on CLL. Researchers enrolled 97 patients with CLL, 44 of whom were previously untreated and 53 who had relapsed. The median ages were 62.5 and 68 years, respectively.

Treatment began with acetaminophen, an antihistamine, and a glucocorticoid. Patients then received ofatumumab at 300 mg on day 1 and 1000 mg on day 8 of cycle 1. For cycles 2 through 6, they received 1000 mg on day 1 every 28 days.

Patients received bendamustine on days 1 and 2, every 28 days for up to 6 cycles. The initial dose was 90 mg/m² for the untreated patients and 70 mg/m² for relapsed patients.

However, patients required a dose reduction due to toxicity. The previously untreated patients were reduced to 60 mg/m², and the relapsed patients were reduced to 50 mg/m².

The overall response rate was 95% in the previously untreated group and 74% in the relapsed group. Complete responses occurred in 43% and 11%, respectively.

CT results showed the overall response rate was 82% in the previously untreated group and 70% in the relapsed group. Complete responses occurred in 27% and 9%, respectively. The median time to response was 0.95 months for both groups.

Grade 3 or higher adverse events occurred in 25% of patients in the previously untreated group and 38% of those in the relapsed group.

This included infusion reactions (11% and 8%, respectively), neutropenia (16% and 29%, respectively), infections (11% and 15%, respectively), rash (2% of previously untreated patients), febrile neutropenia (4% of relapsed patients), and thrombocytopenia (4% of relapsed patients).

There were no deaths in the previously untreated group, but 4 patients died in the relapsed group. Two of these deaths may have been related to study treatment. One patient died of pneumonia and hemolytic anemia 15 days after the last dose of treatment, and 1 patient died of sepsis 4 days after the last dose of  treatment.

Phase 3 study

Data from the COMPLEMENT 1 study were presented at ASH 2013. Researchers compared ofatumumab plus chlorambucil to chlorambucil alone in 447 previously untreated patients with CLL who were ineligible for fludarabine-based therapy.

Patients had a median age of 69 years (range, 35 to 92). Seventy-two percent had 2 or more comorbidities, and 48% had a creatinine clearance of less than 70 mL/min.

Patients in the ofatumumab arm received the drug at 300 mg in cycle 1 on day 1, 1000 mg in cycle 1 on day 8, and 1000 mg administered on day 1 of all subsequent 28-day cycles.

In both arms, patients received chlorambucil at a dose of 10 mg/m² orally on days 1 to 7, every 28 days. Prior to each infusion of ofatumumab, patients received acetaminophen, an antihistamine, and a glucocorticoid.

The overall response rate was 82% in the ofatumumab-chlorambucil group and 69% in the chlorambucil-alone group (P=0.001). Complete response rates were 12% and 1%, respectively.

At a median follow-up of 29 months, the median overall survival was not reached for either treatment arm. However, ofatumumab-treated patients had longer progression-free survival than patients who received chlorambucil alone—22.4 months and 13.1 months, respectively (P<0.001).

Grade 3 or higher adverse events occurred in 50% of ofatumumab-treated patients and 43% of patients who received chlorambucil alone. The most common event was neutropenia, which occurred in 26% and 14% of patients, respectively.

Grade 3 or higher infections occurred in 15% of ofatumumab-treated patients and 14% of patients who received chlorambucil alone. The most common was pneumonia, which occurred in 4% and 3%, respectively.

In the entire cohort, grade 3 or higher infusion-related events occurred in 10% of patients, but there were no fatal infusion reactions. Two percent of subjects in both arms died during treatment.

At the 2014 National Comprehensive Cancer Network annual conference in Hollywood, Florida, Dr Andrew D Zelenetz, chair of the NCCN Non-Hodgkin Lymphomas Guidelines panel, presented guideline updates for non-Hodgkin lymphomas.

Click on the PDF icon at the top of this introduction to read the full article.

At the 2014 National Comprehensive Cancer Network annual conference in Hollywood, Florida, Dr Andrew D Zelenetz, chair of the NCCN Non-Hodgkin Lymphomas Guidelines panel, presented guideline updates for non-Hodgkin lymphomas.

Click on the PDF icon at the top of this introduction to read the full article.

At the 2014 National Comprehensive Cancer Network annual conference in Hollywood, Florida, Dr Andrew D Zelenetz, chair of the NCCN Non-Hodgkin Lymphomas Guidelines panel, presented guideline updates for non-Hodgkin lymphomas.

Click on the PDF icon at the top of this introduction to read the full article.