Follicular Lymphoma

 

 

Micrograph showing DLBCL

 

ProNAi Therapeutics recently announced its decision to stop development of PNT2258, a drug designed to treat cancers characterized by overexpression of BCL2.

In June, the company suspended development of PNT2258, closing enrollment in a phase 2 trial of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and a phase 2 trial of patients with Richter’s transformation.

Now, ProNAi has said it does not plan to resume development of the drug.

“[N]o further investment in PNT2258 or the underlying DNAi platform by ProNAi is contemplated, and the company subsequently has closed its research facility based in Plymouth, Michigan, which supported these programs,” the company said in a statement.

About PNT2258

PNT2258 consists of a single-stranded, 24-base DNAi oligonucleotide known as PNT100 that is encapsulated in lipid nanoparticles.

The DNAi technology platform is based on a discovery that single-stranded DNA oligonucleotides can interact with genomic DNA to interfere with oncogenes. PNT100 DNAi is designed to target a genetic regulatory region associated with BCL2.

Last March, PNT2258 was granted orphan drug designation from the US Food and Drug Administration for the treatment of DLBCL.

ProNAi initially suspended the development of PNT2258 in June, following a review of interim data from the phase 2 Wolverine trial. The company said the drug produced “modest efficacy” in this trial, but it seemed the data were not “robust enough” to justify continued development of PNT2258.

“We have decided to suspend development of PNT2258 pending further review of these data in order to determine next steps for both this asset and the DNAi platform,” Nick Glover, president and CEO of ProNAi, said at the time.

The Wolverine trial was designed to evaluate the safety and efficacy of PNT2258 monotherapy in 61 patients with relapsed/refractory DLBCL.

ProNAi reported interim safety and efficacy data as of April 25, 2016, for the first 37 subjects enrolled. The response rate was 8.1% overall (n=37) and 15.8% in the response-evaluable subgroup (n=19).

Subjects were considered response-evaluable if they met the amended eligibility criteria—a performance status of 0 to 1, 1 to 3 prior systemic treatment regimens, and receipt of at least 8 doses of PNT2258 within 35 days of starting therapy.

PNT2258 was also being evaluated in patients with Richter’s transformation in the phase 2 Brighton study. In June, ProNAi said it had enrolled 5 subjects in this study, and 4 had discontinued. No responses were observed.

“On the basis of these interim assessments, we have decided to close the Wolverine and Brighton studies to further enrollment of new subjects,” Barbara Klencke, chief development officer of ProNAi, said at the time.

PNT2258 was evaluated in 2 prior studies as well. In a phase 1 study (NCT01191775), PNT2258 was given to 22 subjects with advanced solid tumors. The drug was considered well tolerated at doses ranging from 1 mg/m² through 150 mg/m².

A pilot study of PNT2258 (NCT01733238) enrolled 13 subjects with relapsed/refractory B-cell non-Hodgkin lymphoma. Responses were observed in subjects with DLBCL and those with follicular lymphoma.

Six subjects were progression-free at 12 months, and progression-free survival extended to 2 years and beyond in 4 subjects. The majority of the adverse events were grade 1 or 2.

 

 

Micrograph showing DLBCL

 

ProNAi Therapeutics recently announced its decision to stop development of PNT2258, a drug designed to treat cancers characterized by overexpression of BCL2.

In June, the company suspended development of PNT2258, closing enrollment in a phase 2 trial of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and a phase 2 trial of patients with Richter’s transformation.

Now, ProNAi has said it does not plan to resume development of the drug.

“[N]o further investment in PNT2258 or the underlying DNAi platform by ProNAi is contemplated, and the company subsequently has closed its research facility based in Plymouth, Michigan, which supported these programs,” the company said in a statement.

About PNT2258

PNT2258 consists of a single-stranded, 24-base DNAi oligonucleotide known as PNT100 that is encapsulated in lipid nanoparticles.

The DNAi technology platform is based on a discovery that single-stranded DNA oligonucleotides can interact with genomic DNA to interfere with oncogenes. PNT100 DNAi is designed to target a genetic regulatory region associated with BCL2.

Last March, PNT2258 was granted orphan drug designation from the US Food and Drug Administration for the treatment of DLBCL.

ProNAi initially suspended the development of PNT2258 in June, following a review of interim data from the phase 2 Wolverine trial. The company said the drug produced “modest efficacy” in this trial, but it seemed the data were not “robust enough” to justify continued development of PNT2258.

“We have decided to suspend development of PNT2258 pending further review of these data in order to determine next steps for both this asset and the DNAi platform,” Nick Glover, president and CEO of ProNAi, said at the time.

The Wolverine trial was designed to evaluate the safety and efficacy of PNT2258 monotherapy in 61 patients with relapsed/refractory DLBCL.

ProNAi reported interim safety and efficacy data as of April 25, 2016, for the first 37 subjects enrolled. The response rate was 8.1% overall (n=37) and 15.8% in the response-evaluable subgroup (n=19).

Subjects were considered response-evaluable if they met the amended eligibility criteria—a performance status of 0 to 1, 1 to 3 prior systemic treatment regimens, and receipt of at least 8 doses of PNT2258 within 35 days of starting therapy.

PNT2258 was also being evaluated in patients with Richter’s transformation in the phase 2 Brighton study. In June, ProNAi said it had enrolled 5 subjects in this study, and 4 had discontinued. No responses were observed.

“On the basis of these interim assessments, we have decided to close the Wolverine and Brighton studies to further enrollment of new subjects,” Barbara Klencke, chief development officer of ProNAi, said at the time.

PNT2258 was evaluated in 2 prior studies as well. In a phase 1 study (NCT01191775), PNT2258 was given to 22 subjects with advanced solid tumors. The drug was considered well tolerated at doses ranging from 1 mg/m² through 150 mg/m².

A pilot study of PNT2258 (NCT01733238) enrolled 13 subjects with relapsed/refractory B-cell non-Hodgkin lymphoma. Responses were observed in subjects with DLBCL and those with follicular lymphoma.

Six subjects were progression-free at 12 months, and progression-free survival extended to 2 years and beyond in 4 subjects. The majority of the adverse events were grade 1 or 2.

 

 

Micrograph showing DLBCL

 

ProNAi Therapeutics recently announced its decision to stop development of PNT2258, a drug designed to treat cancers characterized by overexpression of BCL2.

In June, the company suspended development of PNT2258, closing enrollment in a phase 2 trial of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and a phase 2 trial of patients with Richter’s transformation.

Now, ProNAi has said it does not plan to resume development of the drug.

“[N]o further investment in PNT2258 or the underlying DNAi platform by ProNAi is contemplated, and the company subsequently has closed its research facility based in Plymouth, Michigan, which supported these programs,” the company said in a statement.

About PNT2258

PNT2258 consists of a single-stranded, 24-base DNAi oligonucleotide known as PNT100 that is encapsulated in lipid nanoparticles.

The DNAi technology platform is based on a discovery that single-stranded DNA oligonucleotides can interact with genomic DNA to interfere with oncogenes. PNT100 DNAi is designed to target a genetic regulatory region associated with BCL2.

Last March, PNT2258 was granted orphan drug designation from the US Food and Drug Administration for the treatment of DLBCL.

ProNAi initially suspended the development of PNT2258 in June, following a review of interim data from the phase 2 Wolverine trial. The company said the drug produced “modest efficacy” in this trial, but it seemed the data were not “robust enough” to justify continued development of PNT2258.

“We have decided to suspend development of PNT2258 pending further review of these data in order to determine next steps for both this asset and the DNAi platform,” Nick Glover, president and CEO of ProNAi, said at the time.

The Wolverine trial was designed to evaluate the safety and efficacy of PNT2258 monotherapy in 61 patients with relapsed/refractory DLBCL.

ProNAi reported interim safety and efficacy data as of April 25, 2016, for the first 37 subjects enrolled. The response rate was 8.1% overall (n=37) and 15.8% in the response-evaluable subgroup (n=19).

Subjects were considered response-evaluable if they met the amended eligibility criteria—a performance status of 0 to 1, 1 to 3 prior systemic treatment regimens, and receipt of at least 8 doses of PNT2258 within 35 days of starting therapy.

PNT2258 was also being evaluated in patients with Richter’s transformation in the phase 2 Brighton study. In June, ProNAi said it had enrolled 5 subjects in this study, and 4 had discontinued. No responses were observed.

“On the basis of these interim assessments, we have decided to close the Wolverine and Brighton studies to further enrollment of new subjects,” Barbara Klencke, chief development officer of ProNAi, said at the time.

PNT2258 was evaluated in 2 prior studies as well. In a phase 1 study (NCT01191775), PNT2258 was given to 22 subjects with advanced solid tumors. The drug was considered well tolerated at doses ranging from 1 mg/m² through 150 mg/m².

A pilot study of PNT2258 (NCT01733238) enrolled 13 subjects with relapsed/refractory B-cell non-Hodgkin lymphoma. Responses were observed in subjects with DLBCL and those with follicular lymphoma.

Six subjects were progression-free at 12 months, and progression-free survival extended to 2 years and beyond in 4 subjects. The majority of the adverse events were grade 1 or 2.

 

 

T cells

Photo courtesy of NIAID

 

The US Food and Drug Administration (FDA) has granted orphan drug designation for a CD4-directed chimeric antigen receptor (CD4CAR) T-cell therapy to treat peripheral T-cell lymphoma (PTCL).

The CD4CAR therapy, also known as ICG122, consists of properly matched allogeneic T cells engineered to express an anti-CD4 single-chain variable fragment antibody domain.

ICG122 is being developed by iCell Gene Therapeutics.

The company is planning a phase 1 trial of ICG122 in cooperation with the National Institutes of Health, Indiana Clinical and Translational Sciences Institute, Stony Brook Hospital, and the James Graham Brown Cancer Center at University of Louisville.

“CD4CAR could significantly enhance currently available treatment options for [PTCL] patients,” said Yupo Ma, MD, PhD, a professor at Stony Brook University and chairman and chief scientific officer at iCell Gene Therapeutics.

“The orphan drug designation is an important achievement as we advance our development plans for this promising treatment in T-cell hematologic cancers.”

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the drug is approved.

 

 

T cells

Photo courtesy of NIAID

 

The US Food and Drug Administration (FDA) has granted orphan drug designation for a CD4-directed chimeric antigen receptor (CD4CAR) T-cell therapy to treat peripheral T-cell lymphoma (PTCL).

The CD4CAR therapy, also known as ICG122, consists of properly matched allogeneic T cells engineered to express an anti-CD4 single-chain variable fragment antibody domain.

ICG122 is being developed by iCell Gene Therapeutics.

The company is planning a phase 1 trial of ICG122 in cooperation with the National Institutes of Health, Indiana Clinical and Translational Sciences Institute, Stony Brook Hospital, and the James Graham Brown Cancer Center at University of Louisville.

“CD4CAR could significantly enhance currently available treatment options for [PTCL] patients,” said Yupo Ma, MD, PhD, a professor at Stony Brook University and chairman and chief scientific officer at iCell Gene Therapeutics.

“The orphan drug designation is an important achievement as we advance our development plans for this promising treatment in T-cell hematologic cancers.”

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the drug is approved.

 

 

T cells

Photo courtesy of NIAID

 

The US Food and Drug Administration (FDA) has granted orphan drug designation for a CD4-directed chimeric antigen receptor (CD4CAR) T-cell therapy to treat peripheral T-cell lymphoma (PTCL).

The CD4CAR therapy, also known as ICG122, consists of properly matched allogeneic T cells engineered to express an anti-CD4 single-chain variable fragment antibody domain.

ICG122 is being developed by iCell Gene Therapeutics.

The company is planning a phase 1 trial of ICG122 in cooperation with the National Institutes of Health, Indiana Clinical and Translational Sciences Institute, Stony Brook Hospital, and the James Graham Brown Cancer Center at University of Louisville.

“CD4CAR could significantly enhance currently available treatment options for [PTCL] patients,” said Yupo Ma, MD, PhD, a professor at Stony Brook University and chairman and chief scientific officer at iCell Gene Therapeutics.

“The orphan drug designation is an important achievement as we advance our development plans for this promising treatment in T-cell hematologic cancers.”

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the drug is approved.

 

 

Lenalidomide (Revlimid)

Photo courtesy of Celgene

 

Initial results from the phase 3 REMARC study suggest that lenalidomide (Revlimid) maintenance does not prolong overall survival (OS) in patients with diffuse large B-cell lymphoma (DLBCL) who have responded to first-line treatment with R-CHOP.

Based on these results, Celgene Corporation, the company developing lenalidomide, said it does not plan to seek approval for the drug for this indication.

REMARC is a randomized, double-blind study designed to compare lenalidomide maintenance to placebo in 650 patients responding to induction therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

Patients in REMARC had received 6 to 8 cycles of the R-CHOP-14 regimen, 6 to 8 cycles of the R-CHOP-21 regimen, or 6 cycles of R-CHOP-14/R-CHOP-21 completed by 2 cycles of rituximab alone.

The primary endpoint of the study—a significant improvement in progression-free survival for patients receiving lenalidomide—was met.

However, the interim analysis of OS showed no benefit for patients in the lenalidomide arm.

Celgene said that, based on these results, the company is not planning to seek approval for lenalidomide as maintenance in this patient population.

“We are continuing to partner with LYSA [Lymphoma Study Association] to complete the analyses of the REMARC study,” said Michael Pehl, of Celgene.

“We remain committed to finishing the 4 ongoing phase 3 trials evaluating Revlimid and are confident about its potential as a treatment option across different settings in lymphoma.”

The REMARC study is part of a research program focused on non-Hodgkin lymphoma. In addition to the REMARC study, lenalidomide is also being evaluated in:

• The RELEVANCE study—in combination with rituximab in previously untreated follicular lymphoma (FL)
• The AUGMENT study—in combination with rituximab in relapsed/refractory FL and marginal zone lymphoma
• The MAGNIFY study—in combination with rituximab in relapsed/refractory FL, marginal zone lymphoma, and mantle cell lymphoma
• The ROBUST study—in combination with R-CHOP in previously untreated ABC-subtype DLBCL.

Data from RELEVANCE and AUGMENT are expected in the first and second half of 2017, respectively.

 

 

Lenalidomide (Revlimid)

Photo courtesy of Celgene

 

Initial results from the phase 3 REMARC study suggest that lenalidomide (Revlimid) maintenance does not prolong overall survival (OS) in patients with diffuse large B-cell lymphoma (DLBCL) who have responded to first-line treatment with R-CHOP.

Based on these results, Celgene Corporation, the company developing lenalidomide, said it does not plan to seek approval for the drug for this indication.

REMARC is a randomized, double-blind study designed to compare lenalidomide maintenance to placebo in 650 patients responding to induction therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

Patients in REMARC had received 6 to 8 cycles of the R-CHOP-14 regimen, 6 to 8 cycles of the R-CHOP-21 regimen, or 6 cycles of R-CHOP-14/R-CHOP-21 completed by 2 cycles of rituximab alone.

The primary endpoint of the study—a significant improvement in progression-free survival for patients receiving lenalidomide—was met.

However, the interim analysis of OS showed no benefit for patients in the lenalidomide arm.

Celgene said that, based on these results, the company is not planning to seek approval for lenalidomide as maintenance in this patient population.

“We are continuing to partner with LYSA [Lymphoma Study Association] to complete the analyses of the REMARC study,” said Michael Pehl, of Celgene.

“We remain committed to finishing the 4 ongoing phase 3 trials evaluating Revlimid and are confident about its potential as a treatment option across different settings in lymphoma.”

The REMARC study is part of a research program focused on non-Hodgkin lymphoma. In addition to the REMARC study, lenalidomide is also being evaluated in:

• The RELEVANCE study—in combination with rituximab in previously untreated follicular lymphoma (FL)
• The AUGMENT study—in combination with rituximab in relapsed/refractory FL and marginal zone lymphoma
• The MAGNIFY study—in combination with rituximab in relapsed/refractory FL, marginal zone lymphoma, and mantle cell lymphoma
• The ROBUST study—in combination with R-CHOP in previously untreated ABC-subtype DLBCL.

Data from RELEVANCE and AUGMENT are expected in the first and second half of 2017, respectively.

 

 

Lenalidomide (Revlimid)

Photo courtesy of Celgene

 

Initial results from the phase 3 REMARC study suggest that lenalidomide (Revlimid) maintenance does not prolong overall survival (OS) in patients with diffuse large B-cell lymphoma (DLBCL) who have responded to first-line treatment with R-CHOP.

Based on these results, Celgene Corporation, the company developing lenalidomide, said it does not plan to seek approval for the drug for this indication.

REMARC is a randomized, double-blind study designed to compare lenalidomide maintenance to placebo in 650 patients responding to induction therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

Patients in REMARC had received 6 to 8 cycles of the R-CHOP-14 regimen, 6 to 8 cycles of the R-CHOP-21 regimen, or 6 cycles of R-CHOP-14/R-CHOP-21 completed by 2 cycles of rituximab alone.

The primary endpoint of the study—a significant improvement in progression-free survival for patients receiving lenalidomide—was met.

However, the interim analysis of OS showed no benefit for patients in the lenalidomide arm.

Celgene said that, based on these results, the company is not planning to seek approval for lenalidomide as maintenance in this patient population.

“We are continuing to partner with LYSA [Lymphoma Study Association] to complete the analyses of the REMARC study,” said Michael Pehl, of Celgene.

“We remain committed to finishing the 4 ongoing phase 3 trials evaluating Revlimid and are confident about its potential as a treatment option across different settings in lymphoma.”

The REMARC study is part of a research program focused on non-Hodgkin lymphoma. In addition to the REMARC study, lenalidomide is also being evaluated in:

• The RELEVANCE study—in combination with rituximab in previously untreated follicular lymphoma (FL)
• The AUGMENT study—in combination with rituximab in relapsed/refractory FL and marginal zone lymphoma
• The MAGNIFY study—in combination with rituximab in relapsed/refractory FL, marginal zone lymphoma, and mantle cell lymphoma
• The ROBUST study—in combination with R-CHOP in previously untreated ABC-subtype DLBCL.

Data from RELEVANCE and AUGMENT are expected in the first and second half of 2017, respectively.

 

 

Micrograph showing DLBCL

 

Results of a phase 3 study suggest that obinutuzumab may not confer a benefit over standard therapy in patients with previously untreated diffuse large B-cell lymphoma (DLBCL).

The data showed that obinutuzumab plus CHOP chemotherapy does not improve progression-free survival (PFS) in DLBCL patients, when compared to rituximab plus CHOP.

Adverse events with both treatment regimens were consistent with those seen in previous clinical trials, according to Genentech and Biogen, the companies developing obinutuzumab.

The companies have not released any data from this trial, known as GOYA, but they said results will be presented at an upcoming medical meeting.

“Two previous studies showed [obinutuzumab] helped people with previously untreated follicular lymphoma or chronic lymphocytic leukemia live longer without their disease worsening compared to [rituximab], when each was combined with chemotherapy,” said Sandra Horning, MD, chief medical officer and head of global product development at Genentech.

“We were hopeful we could show a similar result for people with diffuse large B-cell lymphoma and once again improve on the standard of care. We will continue to analyze the GOYA data to better understand the results, and to study other investigational treatments in this disease with the goal of further helping these patients.”

The GOYA trial enrolled 1418 previously untreated patients with CD20-positive DLBCL. The patients were randomized to receive obinutuzumab at 1000 mg every 21 days or rituximab at 375 mg/m² every 21 days for 8 cycles, in addition to 6 to 8 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) every 21 days.

The primary endpoint of the study is investigator-assessed PFS, with secondary endpoints including PFS assessed by an independent review committee, response rate, overall survival, disease-free survival, and safety profile.

Obinutuzumab is an engineered monoclonal antibody designed to attach to CD20, a protein found on certain B cells. The drug is thought to work by attacking targeted cells both directly and together with the immune system.

In the US and the European Union (EU), obinutuzumab is approved for use in combination with chlorambucil to treat adults with previously untreated chronic lymphocytic leukemia.

Obinutuzumab is also approved in the US and the EU to treat patients with follicular lymphoma. The drug can be given, first in combination with bendamustine and then alone as maintenance therapy, to adults with follicular lymphoma who did not respond to a rituximab-containing regimen or whose disease returned after such treatment.

Obinutuzumab is marketed as Gazyvaro in the EU and Switzerland and Gazyva in the rest of the world.

 

 

Micrograph showing DLBCL

 

Results of a phase 3 study suggest that obinutuzumab may not confer a benefit over standard therapy in patients with previously untreated diffuse large B-cell lymphoma (DLBCL).

The data showed that obinutuzumab plus CHOP chemotherapy does not improve progression-free survival (PFS) in DLBCL patients, when compared to rituximab plus CHOP.

Adverse events with both treatment regimens were consistent with those seen in previous clinical trials, according to Genentech and Biogen, the companies developing obinutuzumab.

The companies have not released any data from this trial, known as GOYA, but they said results will be presented at an upcoming medical meeting.

“Two previous studies showed [obinutuzumab] helped people with previously untreated follicular lymphoma or chronic lymphocytic leukemia live longer without their disease worsening compared to [rituximab], when each was combined with chemotherapy,” said Sandra Horning, MD, chief medical officer and head of global product development at Genentech.

“We were hopeful we could show a similar result for people with diffuse large B-cell lymphoma and once again improve on the standard of care. We will continue to analyze the GOYA data to better understand the results, and to study other investigational treatments in this disease with the goal of further helping these patients.”

The GOYA trial enrolled 1418 previously untreated patients with CD20-positive DLBCL. The patients were randomized to receive obinutuzumab at 1000 mg every 21 days or rituximab at 375 mg/m² every 21 days for 8 cycles, in addition to 6 to 8 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) every 21 days.

The primary endpoint of the study is investigator-assessed PFS, with secondary endpoints including PFS assessed by an independent review committee, response rate, overall survival, disease-free survival, and safety profile.

Obinutuzumab is an engineered monoclonal antibody designed to attach to CD20, a protein found on certain B cells. The drug is thought to work by attacking targeted cells both directly and together with the immune system.

In the US and the European Union (EU), obinutuzumab is approved for use in combination with chlorambucil to treat adults with previously untreated chronic lymphocytic leukemia.

Obinutuzumab is also approved in the US and the EU to treat patients with follicular lymphoma. The drug can be given, first in combination with bendamustine and then alone as maintenance therapy, to adults with follicular lymphoma who did not respond to a rituximab-containing regimen or whose disease returned after such treatment.

Obinutuzumab is marketed as Gazyvaro in the EU and Switzerland and Gazyva in the rest of the world.

 

 

Micrograph showing DLBCL

 

Results of a phase 3 study suggest that obinutuzumab may not confer a benefit over standard therapy in patients with previously untreated diffuse large B-cell lymphoma (DLBCL).

The data showed that obinutuzumab plus CHOP chemotherapy does not improve progression-free survival (PFS) in DLBCL patients, when compared to rituximab plus CHOP.

Adverse events with both treatment regimens were consistent with those seen in previous clinical trials, according to Genentech and Biogen, the companies developing obinutuzumab.

The companies have not released any data from this trial, known as GOYA, but they said results will be presented at an upcoming medical meeting.

“Two previous studies showed [obinutuzumab] helped people with previously untreated follicular lymphoma or chronic lymphocytic leukemia live longer without their disease worsening compared to [rituximab], when each was combined with chemotherapy,” said Sandra Horning, MD, chief medical officer and head of global product development at Genentech.

“We were hopeful we could show a similar result for people with diffuse large B-cell lymphoma and once again improve on the standard of care. We will continue to analyze the GOYA data to better understand the results, and to study other investigational treatments in this disease with the goal of further helping these patients.”

The GOYA trial enrolled 1418 previously untreated patients with CD20-positive DLBCL. The patients were randomized to receive obinutuzumab at 1000 mg every 21 days or rituximab at 375 mg/m² every 21 days for 8 cycles, in addition to 6 to 8 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) every 21 days.

The primary endpoint of the study is investigator-assessed PFS, with secondary endpoints including PFS assessed by an independent review committee, response rate, overall survival, disease-free survival, and safety profile.

Obinutuzumab is an engineered monoclonal antibody designed to attach to CD20, a protein found on certain B cells. The drug is thought to work by attacking targeted cells both directly and together with the immune system.

In the US and the European Union (EU), obinutuzumab is approved for use in combination with chlorambucil to treat adults with previously untreated chronic lymphocytic leukemia.

Obinutuzumab is also approved in the US and the EU to treat patients with follicular lymphoma. The drug can be given, first in combination with bendamustine and then alone as maintenance therapy, to adults with follicular lymphoma who did not respond to a rituximab-containing regimen or whose disease returned after such treatment.

Obinutuzumab is marketed as Gazyvaro in the EU and Switzerland and Gazyva in the rest of the world.

 

 

Idelalisib (Zydelig)

Photo courtesy of

Gilead Sciences, Inc.

 

The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) has completed its review of the PI3Kδ inhibitor idelalisib (Zyedelig) and concluded that the drug’s benefits outweigh its risks in the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma.

However, the PRAC also confirmed that the drug increases the risk of serious infections, including Pneumocystis jirovecii pneumonia.

And the committee updated its previous recommendations to manage this risk.

The PRAC’s recommendations will now be sent to the Committee for Medicinal Products for Human Use, which will adopt the EMA’s final opinion. The final stage of the review procedure is the adoption by the European Commission of a legally binding decision applicable in all member states of the European Union (EU).

About idelalisib

In the EU, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients unsuitable for chemo-immunotherapy.

Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.

About the review

The PRAC’s review of idelalisib began after a higher rate of serious adverse events, including deaths, was seen in 3 clinical trials evaluating the addition of idelalisib to standard therapy in first-line CLL and relapsed indolent non-Hodgkin lymphoma (NHL).

Most of the deaths were related to infections such as Pneumocystis jirovecii pneumonia and cytomegalovirus infection. Other excess deaths were related mainly to respiratory events.

The NHL studies (NCT01732926 and NCT01732913) included patients with disease characteristics different from those covered by the currently approved indications for idelalisib and investigated combinations of drugs that are not currently approved in the EU—idelalisib plus rituximab for NHL and idelalisib plus bendamustine and rituximab for NHL.

The CLL trial (NCT01980888) involved patients who had not received previous treatment, some of whom had the 17p deletion or TP53 mutation. However, the trial also investigated a combination of drugs not currently approved in the EU—idelalisib plus bendamustine and rituximab.

PRAC’s recommendations

The PRAC noted that, although the aforementioned trials did not all use idelalisib as currently authorized, the risk of serious infection is considered relevant to the authorized use.

Therefore, the PRAC recommends that all patients treated with idelalisib receive antibiotics to prevent Pneumocystis jirovecii pneumonia during treatment and for up to 2 to 6 months after treatment has stopped.

Patients should also be monitored for infection and have regular blood tests for white cell counts because low counts can increase their risk of infection.

Furthermore, idelalisib should not be started in patients with a generalized infection.

At the beginning of its review, the PRAC had said idelalisib should not be started in patients with previously untreated CLL and 17p deletion or TP53 mutation.

Now, the PRAC has concluded that idelalisib can be initiated in these patients, provided they cannot take any alternative treatment and that the recommended measures to prevent infection are followed.

 

 

Idelalisib (Zydelig)

Photo courtesy of

Gilead Sciences, Inc.

 

The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) has completed its review of the PI3Kδ inhibitor idelalisib (Zyedelig) and concluded that the drug’s benefits outweigh its risks in the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma.

However, the PRAC also confirmed that the drug increases the risk of serious infections, including Pneumocystis jirovecii pneumonia.

And the committee updated its previous recommendations to manage this risk.

The PRAC’s recommendations will now be sent to the Committee for Medicinal Products for Human Use, which will adopt the EMA’s final opinion. The final stage of the review procedure is the adoption by the European Commission of a legally binding decision applicable in all member states of the European Union (EU).

About idelalisib

In the EU, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients unsuitable for chemo-immunotherapy.

Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.

About the review

The PRAC’s review of idelalisib began after a higher rate of serious adverse events, including deaths, was seen in 3 clinical trials evaluating the addition of idelalisib to standard therapy in first-line CLL and relapsed indolent non-Hodgkin lymphoma (NHL).

Most of the deaths were related to infections such as Pneumocystis jirovecii pneumonia and cytomegalovirus infection. Other excess deaths were related mainly to respiratory events.

The NHL studies (NCT01732926 and NCT01732913) included patients with disease characteristics different from those covered by the currently approved indications for idelalisib and investigated combinations of drugs that are not currently approved in the EU—idelalisib plus rituximab for NHL and idelalisib plus bendamustine and rituximab for NHL.

The CLL trial (NCT01980888) involved patients who had not received previous treatment, some of whom had the 17p deletion or TP53 mutation. However, the trial also investigated a combination of drugs not currently approved in the EU—idelalisib plus bendamustine and rituximab.

PRAC’s recommendations

The PRAC noted that, although the aforementioned trials did not all use idelalisib as currently authorized, the risk of serious infection is considered relevant to the authorized use.

Therefore, the PRAC recommends that all patients treated with idelalisib receive antibiotics to prevent Pneumocystis jirovecii pneumonia during treatment and for up to 2 to 6 months after treatment has stopped.

Patients should also be monitored for infection and have regular blood tests for white cell counts because low counts can increase their risk of infection.

Furthermore, idelalisib should not be started in patients with a generalized infection.

At the beginning of its review, the PRAC had said idelalisib should not be started in patients with previously untreated CLL and 17p deletion or TP53 mutation.

Now, the PRAC has concluded that idelalisib can be initiated in these patients, provided they cannot take any alternative treatment and that the recommended measures to prevent infection are followed.

 

 

Idelalisib (Zydelig)

Photo courtesy of

Gilead Sciences, Inc.

 

The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) has completed its review of the PI3Kδ inhibitor idelalisib (Zyedelig) and concluded that the drug’s benefits outweigh its risks in the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma.

However, the PRAC also confirmed that the drug increases the risk of serious infections, including Pneumocystis jirovecii pneumonia.

And the committee updated its previous recommendations to manage this risk.

The PRAC’s recommendations will now be sent to the Committee for Medicinal Products for Human Use, which will adopt the EMA’s final opinion. The final stage of the review procedure is the adoption by the European Commission of a legally binding decision applicable in all member states of the European Union (EU).

About idelalisib

In the EU, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients unsuitable for chemo-immunotherapy.

Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.

About the review

The PRAC’s review of idelalisib began after a higher rate of serious adverse events, including deaths, was seen in 3 clinical trials evaluating the addition of idelalisib to standard therapy in first-line CLL and relapsed indolent non-Hodgkin lymphoma (NHL).

Most of the deaths were related to infections such as Pneumocystis jirovecii pneumonia and cytomegalovirus infection. Other excess deaths were related mainly to respiratory events.

The NHL studies (NCT01732926 and NCT01732913) included patients with disease characteristics different from those covered by the currently approved indications for idelalisib and investigated combinations of drugs that are not currently approved in the EU—idelalisib plus rituximab for NHL and idelalisib plus bendamustine and rituximab for NHL.

The CLL trial (NCT01980888) involved patients who had not received previous treatment, some of whom had the 17p deletion or TP53 mutation. However, the trial also investigated a combination of drugs not currently approved in the EU—idelalisib plus bendamustine and rituximab.

PRAC’s recommendations

The PRAC noted that, although the aforementioned trials did not all use idelalisib as currently authorized, the risk of serious infection is considered relevant to the authorized use.

Therefore, the PRAC recommends that all patients treated with idelalisib receive antibiotics to prevent Pneumocystis jirovecii pneumonia during treatment and for up to 2 to 6 months after treatment has stopped.

Patients should also be monitored for infection and have regular blood tests for white cell counts because low counts can increase their risk of infection.

Furthermore, idelalisib should not be started in patients with a generalized infection.

At the beginning of its review, the PRAC had said idelalisib should not be started in patients with previously untreated CLL and 17p deletion or TP53 mutation.

Now, the PRAC has concluded that idelalisib can be initiated in these patients, provided they cannot take any alternative treatment and that the recommended measures to prevent infection are followed.

 

 

Micrograph showing FL

 

The European Commission (EC) has approved the use of obinutuzumab (Gazyvaro), an anti-CD20 monoclonal antibody, in patients with follicular lymphoma (FL).

The approval means obinutuzumab can be given, first in combination with bendamustine and then alone as maintenance therapy, to FL patients who did not respond to, progressed during, or progressed up to 6 months after treatment with rituximab or a rituximab-containing regimen.

Obinutuzumab was previously granted approval by the EC for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia and comorbidities that make them unsuitable for full-dose fludarabine-based therapy.

Obinutuzumab is being developed by Roche. The drug is marketed as Gazyvaro in the European Union and Switzerland but as Gazyva in the rest of the world.

GADOLIN trial

The EC’s approval of obinutuzumab in FL is based on results from the phase 3 GADOLIN trial. The study included 413 patients with rituximab-refractory non-Hodgkin lymphoma, including 321 patients with FL, 46 with marginal zone lymphoma, and 28 with small lymphocytic lymphoma.

The patients were randomized to receive bendamustine alone (control arm) or a combination of bendamustine and obinutuzumab followed by obinutuzumab maintenance (every 2 months for 2 years or until progression).

The primary endpoint of the study was progression-free survival (PFS), as assessed by an independent review committee (IRC). The secondary endpoints were PFS assessed by investigator review, best overall response, complete response (CR), partial response (PR), duration of response, overall survival, and safety profile.

Among patients with FL, the obinutuzumab regimen improved PFS compared to bendamustine alone, as assessed by the IRC (hazard ratio [HR]=0.48, P<0.0001). The median PFS was not reached in patients receiving the obinutuzumab regimen but was 13.8 months in those receiving bendamustine alone.

Investigator-assessed PFS was consistent with IRC-assessed PFS. Investigators said the median PFS with the obinutuzumab regimen was more than double that with bendamustine alone—29.2 months vs 13.7 months (HR=0.48, P<0.0001).

The best overall response for patients receiving the obinutuzumab regimen was 78.7% (15.5% CR, 63.2% PR), compared to 74.7% (18.7% CR, 56% PR) for those receiving bendamustine alone, as assessed by the IRC.

The median duration of response was not reached for patients receiving the obinutuzumab regimen and was 11.6 months for those receiving bendamustine alone.

The median overall survival has not yet been reached in either study arm.

The most common grade 3/4 adverse events observed in patients receiving the obinutuzumab regimen were neutropenia (33%), infusion reactions (11%), and thrombocytopenia (10%).

The most common adverse events of any grade were infusion reactions (69%), neutropenia (35%), nausea (54%), fatigue (39%), cough (26%), diarrhea (27%), constipation (19%), fever (18%), thrombocytopenia (15%), vomiting (22%), upper respiratory tract infection (13%), decreased appetite (18%), joint or muscle pain (12%), sinusitis (12%), anemia (12%), general weakness (11%), and urinary tract infection (10%).

 

 

Micrograph showing FL

 

The European Commission (EC) has approved the use of obinutuzumab (Gazyvaro), an anti-CD20 monoclonal antibody, in patients with follicular lymphoma (FL).

The approval means obinutuzumab can be given, first in combination with bendamustine and then alone as maintenance therapy, to FL patients who did not respond to, progressed during, or progressed up to 6 months after treatment with rituximab or a rituximab-containing regimen.

Obinutuzumab was previously granted approval by the EC for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia and comorbidities that make them unsuitable for full-dose fludarabine-based therapy.

Obinutuzumab is being developed by Roche. The drug is marketed as Gazyvaro in the European Union and Switzerland but as Gazyva in the rest of the world.

GADOLIN trial

The EC’s approval of obinutuzumab in FL is based on results from the phase 3 GADOLIN trial. The study included 413 patients with rituximab-refractory non-Hodgkin lymphoma, including 321 patients with FL, 46 with marginal zone lymphoma, and 28 with small lymphocytic lymphoma.

The patients were randomized to receive bendamustine alone (control arm) or a combination of bendamustine and obinutuzumab followed by obinutuzumab maintenance (every 2 months for 2 years or until progression).

The primary endpoint of the study was progression-free survival (PFS), as assessed by an independent review committee (IRC). The secondary endpoints were PFS assessed by investigator review, best overall response, complete response (CR), partial response (PR), duration of response, overall survival, and safety profile.

Among patients with FL, the obinutuzumab regimen improved PFS compared to bendamustine alone, as assessed by the IRC (hazard ratio [HR]=0.48, P<0.0001). The median PFS was not reached in patients receiving the obinutuzumab regimen but was 13.8 months in those receiving bendamustine alone.

Investigator-assessed PFS was consistent with IRC-assessed PFS. Investigators said the median PFS with the obinutuzumab regimen was more than double that with bendamustine alone—29.2 months vs 13.7 months (HR=0.48, P<0.0001).

The best overall response for patients receiving the obinutuzumab regimen was 78.7% (15.5% CR, 63.2% PR), compared to 74.7% (18.7% CR, 56% PR) for those receiving bendamustine alone, as assessed by the IRC.

The median duration of response was not reached for patients receiving the obinutuzumab regimen and was 11.6 months for those receiving bendamustine alone.

The median overall survival has not yet been reached in either study arm.

The most common grade 3/4 adverse events observed in patients receiving the obinutuzumab regimen were neutropenia (33%), infusion reactions (11%), and thrombocytopenia (10%).

The most common adverse events of any grade were infusion reactions (69%), neutropenia (35%), nausea (54%), fatigue (39%), cough (26%), diarrhea (27%), constipation (19%), fever (18%), thrombocytopenia (15%), vomiting (22%), upper respiratory tract infection (13%), decreased appetite (18%), joint or muscle pain (12%), sinusitis (12%), anemia (12%), general weakness (11%), and urinary tract infection (10%).

 

 

Micrograph showing FL

 

The European Commission (EC) has approved the use of obinutuzumab (Gazyvaro), an anti-CD20 monoclonal antibody, in patients with follicular lymphoma (FL).

The approval means obinutuzumab can be given, first in combination with bendamustine and then alone as maintenance therapy, to FL patients who did not respond to, progressed during, or progressed up to 6 months after treatment with rituximab or a rituximab-containing regimen.

Obinutuzumab was previously granted approval by the EC for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia and comorbidities that make them unsuitable for full-dose fludarabine-based therapy.

Obinutuzumab is being developed by Roche. The drug is marketed as Gazyvaro in the European Union and Switzerland but as Gazyva in the rest of the world.

GADOLIN trial

The EC’s approval of obinutuzumab in FL is based on results from the phase 3 GADOLIN trial. The study included 413 patients with rituximab-refractory non-Hodgkin lymphoma, including 321 patients with FL, 46 with marginal zone lymphoma, and 28 with small lymphocytic lymphoma.

The patients were randomized to receive bendamustine alone (control arm) or a combination of bendamustine and obinutuzumab followed by obinutuzumab maintenance (every 2 months for 2 years or until progression).

The primary endpoint of the study was progression-free survival (PFS), as assessed by an independent review committee (IRC). The secondary endpoints were PFS assessed by investigator review, best overall response, complete response (CR), partial response (PR), duration of response, overall survival, and safety profile.

Among patients with FL, the obinutuzumab regimen improved PFS compared to bendamustine alone, as assessed by the IRC (hazard ratio [HR]=0.48, P<0.0001). The median PFS was not reached in patients receiving the obinutuzumab regimen but was 13.8 months in those receiving bendamustine alone.

Investigator-assessed PFS was consistent with IRC-assessed PFS. Investigators said the median PFS with the obinutuzumab regimen was more than double that with bendamustine alone—29.2 months vs 13.7 months (HR=0.48, P<0.0001).

The best overall response for patients receiving the obinutuzumab regimen was 78.7% (15.5% CR, 63.2% PR), compared to 74.7% (18.7% CR, 56% PR) for those receiving bendamustine alone, as assessed by the IRC.

The median duration of response was not reached for patients receiving the obinutuzumab regimen and was 11.6 months for those receiving bendamustine alone.

The median overall survival has not yet been reached in either study arm.

The most common grade 3/4 adverse events observed in patients receiving the obinutuzumab regimen were neutropenia (33%), infusion reactions (11%), and thrombocytopenia (10%).

The most common adverse events of any grade were infusion reactions (69%), neutropenia (35%), nausea (54%), fatigue (39%), cough (26%), diarrhea (27%), constipation (19%), fever (18%), thrombocytopenia (15%), vomiting (22%), upper respiratory tract infection (13%), decreased appetite (18%), joint or muscle pain (12%), sinusitis (12%), anemia (12%), general weakness (11%), and urinary tract infection (10%).

Among patients with high tumor burden follicular lymphoma (FL) that responded to rituximab chemotherapy but then underwent histologic transformation, median overall survival was not reached when patients received autologous stem cell transplantation (ASCT), but was only 1.7 years otherwise, based on results of an ancillary study of a clinical trial.

In contrast, ASCT did not affect overall survival when patients progressed to untransformed FL, said Dr. Clémentine Sarkozy of Centre Hospitalier Lyon-Sud in Pierre Bénite, France, and her associates. Fully 58% of histologic transformations occurred in the first year of follow-up, highlighting “the necessity for biopsy at the first recurrence of FL,” they wrote online June 13 in the Journal of Clinical Oncology.

Histologic transformation in FL signifies progression to aggressive lymphoma. Studies of histologic transformation and subsequent overall survival in the rituximab era have been retrospective, with variable patient populations and initial management regimens, according to the investigators. Therefore, they followed 1,018 patients from the multicenter, randomized, phase III PRIMA (Primary Rituximab and Maintenance) trial, which evaluated maintenance rituximab therapy among patients with symptomatic FL who had responded to induction chemotherapy plus rituximab (J Clin Oncol. 2016 Jun. doi: 10.1200/JCO.2015.65.7163).

A total of 463 patients (45.5%) experienced disease recurrence or progression, and 194 (42%) were biopsied over a median follow-up time of 6 years. A total of 40 (20.6%) biopsies showed histologic transformation, while 154 (79.4%) had untransformed FL. Median time to recurrence was 9.6 months for patients with histologic transformation and 22.8 months for patients with untransformed FL (P = .02). Median overall survival with histologic transformation was worse than with untransformed FL (3.8 years vs. 6.4 years; hazard ratio, 3.9; 95% confidence interval, 2.2-6.9; P = .001). Furthermore, among patients who progressed within 12 months, median overall survival with histologic transformation was 2 years, compared with 6.4 years for patients with untransformed FL (P = .007).

After salvage therapy, 17 (42%) patients with histologic transformation underwent consolidation with high-dose chemotherapy and ASCT. Median overall survival for these patients was not reached, versus 1.7 years when they did not undergo ASCT. In contrast, ASCT did not improve overall survival among patients with untransformed FL. Results were similar after excluding patients with early progression and patients who were older than 65 years, the investigators reported.

Risk factors for histologic transformation in the univariate analysis included performance status, anemia, high lactate dehydrogenase level, “B” symptoms, histologic grade 3a, and high Follicular Lymphoma International Prognostic Index scores at diagnosis. However, only Eastern Cooperative Oncology Group performance status of 2 to 4 (HR, 5.6; 95% CI, 1.7-17.7), and anemia (HR, 3.7; 95% CI, 1.4-9.7) remained significant in the multivariate analysis. Neither the choice of induction regimen nor the quality of response seemed to affect the likelihood of histologic transformation, and rituximab maintenance therapy did not seem to alter response to salvage treatment or survival after histologic transformation. By necessity, the study excluded patients who did not respond to initial immunochemotherapy, which could have limited the generalizability of the findings, the investigators noted.

The study was funded by Sandoz and Takeda Pharmaceuticals. Dr. Sarkozy disclosed research funding from Sandoz and Takeda Pharmaceuticals and honoraria from Gilead Sciences. Twelve coinvestigators also disclosed ties to Takeda and a number of other pharmaceutical companies. The other seven coinvestigators had no disclosures.

Among patients with high tumor burden follicular lymphoma (FL) that responded to rituximab chemotherapy but then underwent histologic transformation, median overall survival was not reached when patients received autologous stem cell transplantation (ASCT), but was only 1.7 years otherwise, based on results of an ancillary study of a clinical trial.

In contrast, ASCT did not affect overall survival when patients progressed to untransformed FL, said Dr. Clémentine Sarkozy of Centre Hospitalier Lyon-Sud in Pierre Bénite, France, and her associates. Fully 58% of histologic transformations occurred in the first year of follow-up, highlighting “the necessity for biopsy at the first recurrence of FL,” they wrote online June 13 in the Journal of Clinical Oncology.

Histologic transformation in FL signifies progression to aggressive lymphoma. Studies of histologic transformation and subsequent overall survival in the rituximab era have been retrospective, with variable patient populations and initial management regimens, according to the investigators. Therefore, they followed 1,018 patients from the multicenter, randomized, phase III PRIMA (Primary Rituximab and Maintenance) trial, which evaluated maintenance rituximab therapy among patients with symptomatic FL who had responded to induction chemotherapy plus rituximab (J Clin Oncol. 2016 Jun. doi: 10.1200/JCO.2015.65.7163).

A total of 463 patients (45.5%) experienced disease recurrence or progression, and 194 (42%) were biopsied over a median follow-up time of 6 years. A total of 40 (20.6%) biopsies showed histologic transformation, while 154 (79.4%) had untransformed FL. Median time to recurrence was 9.6 months for patients with histologic transformation and 22.8 months for patients with untransformed FL (P = .02). Median overall survival with histologic transformation was worse than with untransformed FL (3.8 years vs. 6.4 years; hazard ratio, 3.9; 95% confidence interval, 2.2-6.9; P = .001). Furthermore, among patients who progressed within 12 months, median overall survival with histologic transformation was 2 years, compared with 6.4 years for patients with untransformed FL (P = .007).

After salvage therapy, 17 (42%) patients with histologic transformation underwent consolidation with high-dose chemotherapy and ASCT. Median overall survival for these patients was not reached, versus 1.7 years when they did not undergo ASCT. In contrast, ASCT did not improve overall survival among patients with untransformed FL. Results were similar after excluding patients with early progression and patients who were older than 65 years, the investigators reported.

Risk factors for histologic transformation in the univariate analysis included performance status, anemia, high lactate dehydrogenase level, “B” symptoms, histologic grade 3a, and high Follicular Lymphoma International Prognostic Index scores at diagnosis. However, only Eastern Cooperative Oncology Group performance status of 2 to 4 (HR, 5.6; 95% CI, 1.7-17.7), and anemia (HR, 3.7; 95% CI, 1.4-9.7) remained significant in the multivariate analysis. Neither the choice of induction regimen nor the quality of response seemed to affect the likelihood of histologic transformation, and rituximab maintenance therapy did not seem to alter response to salvage treatment or survival after histologic transformation. By necessity, the study excluded patients who did not respond to initial immunochemotherapy, which could have limited the generalizability of the findings, the investigators noted.

The study was funded by Sandoz and Takeda Pharmaceuticals. Dr. Sarkozy disclosed research funding from Sandoz and Takeda Pharmaceuticals and honoraria from Gilead Sciences. Twelve coinvestigators also disclosed ties to Takeda and a number of other pharmaceutical companies. The other seven coinvestigators had no disclosures.

Among patients with high tumor burden follicular lymphoma (FL) that responded to rituximab chemotherapy but then underwent histologic transformation, median overall survival was not reached when patients received autologous stem cell transplantation (ASCT), but was only 1.7 years otherwise, based on results of an ancillary study of a clinical trial.

In contrast, ASCT did not affect overall survival when patients progressed to untransformed FL, said Dr. Clémentine Sarkozy of Centre Hospitalier Lyon-Sud in Pierre Bénite, France, and her associates. Fully 58% of histologic transformations occurred in the first year of follow-up, highlighting “the necessity for biopsy at the first recurrence of FL,” they wrote online June 13 in the Journal of Clinical Oncology.

Histologic transformation in FL signifies progression to aggressive lymphoma. Studies of histologic transformation and subsequent overall survival in the rituximab era have been retrospective, with variable patient populations and initial management regimens, according to the investigators. Therefore, they followed 1,018 patients from the multicenter, randomized, phase III PRIMA (Primary Rituximab and Maintenance) trial, which evaluated maintenance rituximab therapy among patients with symptomatic FL who had responded to induction chemotherapy plus rituximab (J Clin Oncol. 2016 Jun. doi: 10.1200/JCO.2015.65.7163).

A total of 463 patients (45.5%) experienced disease recurrence or progression, and 194 (42%) were biopsied over a median follow-up time of 6 years. A total of 40 (20.6%) biopsies showed histologic transformation, while 154 (79.4%) had untransformed FL. Median time to recurrence was 9.6 months for patients with histologic transformation and 22.8 months for patients with untransformed FL (P = .02). Median overall survival with histologic transformation was worse than with untransformed FL (3.8 years vs. 6.4 years; hazard ratio, 3.9; 95% confidence interval, 2.2-6.9; P = .001). Furthermore, among patients who progressed within 12 months, median overall survival with histologic transformation was 2 years, compared with 6.4 years for patients with untransformed FL (P = .007).

After salvage therapy, 17 (42%) patients with histologic transformation underwent consolidation with high-dose chemotherapy and ASCT. Median overall survival for these patients was not reached, versus 1.7 years when they did not undergo ASCT. In contrast, ASCT did not improve overall survival among patients with untransformed FL. Results were similar after excluding patients with early progression and patients who were older than 65 years, the investigators reported.

Risk factors for histologic transformation in the univariate analysis included performance status, anemia, high lactate dehydrogenase level, “B” symptoms, histologic grade 3a, and high Follicular Lymphoma International Prognostic Index scores at diagnosis. However, only Eastern Cooperative Oncology Group performance status of 2 to 4 (HR, 5.6; 95% CI, 1.7-17.7), and anemia (HR, 3.7; 95% CI, 1.4-9.7) remained significant in the multivariate analysis. Neither the choice of induction regimen nor the quality of response seemed to affect the likelihood of histologic transformation, and rituximab maintenance therapy did not seem to alter response to salvage treatment or survival after histologic transformation. By necessity, the study excluded patients who did not respond to initial immunochemotherapy, which could have limited the generalizability of the findings, the investigators noted.

The study was funded by Sandoz and Takeda Pharmaceuticals. Dr. Sarkozy disclosed research funding from Sandoz and Takeda Pharmaceuticals and honoraria from Gilead Sciences. Twelve coinvestigators also disclosed ties to Takeda and a number of other pharmaceutical companies. The other seven coinvestigators had no disclosures.

Hematology News’ Editor-in-Chief Matt Kalaycio selected the following as his “top 10” picks for hematologic oncology abstracts at ASCO 2016:

Abstract 7000: Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML

Comment: When any treatment appears to improve survival, compared with 7+3 for AML, all must take notice.

Link to abstract 7000

Abstract 7001: Treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) treated with frontline nilotinib: Results from the ENESTFreedom study

Comment: About 50% of the CML patients treated with frontline nilotinib are eventually able to stop the drug and successfully stay off of it. That means more patients in treatment-free remission, compared with those initially treated with imatinib.

Link to abstract 7001

Abstract 7007: Phase Ib/2 study of venetoclax with low-dose cytarabine in treatment-naive patients age ≥ 65 with acute myelogenous leukemia

Abstract 7009: Results of a phase 1b study of venetoclax plus decitabine or azacitidine in untreated acute myeloid leukemia patients ≥ 65 years ineligible for standard induction therapy

Comment: The response rates in these older AML patients are remarkable and challenge results typically seen with 7+3 in a younger population.

Link to abstract 7007 and 7009

Abstract 7501: A prospective, multicenter, randomized study of anti-CCR4 monoclonal antibody mogamulizumab (moga) vs investigator’s choice (IC) in the treatment of patients (pts) with relapsed/refractory (R/R) adult T-cell leukemia-lymphoma (ATL)

Comment: The response rate to mogamulizumab was outstanding in the largest randomized clinical trial thus far conducted for this cancer. Although rare in the USA, ATL is more common in Asia.

Link to abstract 7501

Abstract 7507: Effect of bortezomib on complete remission (CR) rate when added to bendamustine-rituximab (BR) in previously untreated high-risk (HR) follicular lymphoma (FL): A randomized phase II trial of the ECOG-ACRIN Cancer Research Group (E2408)

Comment: This interesting observation of improved complete remission needs longer follow-up.

Link to abstract 7507

Abstract 7519: Venetoclax activity in CLL patients who have relapsed after or are refractory to ibrutinib or idelalisib

Comment: This study has implications for practice. Venetoclax elicits a 50%-60% response rate after patients with CLL progress during treatment with B-cell receptor pathway inhibitors.

Link to abstract 7519

Abstract 7521: Acalabrutinib, a second-generation bruton tyrosine kinase (Btk) inhibitor, in previously untreated chronic lymphocytic leukemia (CLL)

Comment: This next-generation variation on ibrutinib was associated with a 96% overall response rate with fewer adverse effects such as atrial fibrillation.

Link to abstract 7521

Abstract 8000: Upfront autologous stem cell transplantation (ASCT) versus novel agent-based therapy for multiple myeloma (MM): A randomized phase 3 study of the European Myeloma Network (EMN02/HO95 MM trial)

Comment: Other trials are underway to address the role of upfront ASCT for newly diagnosed multiple myeloma. While the last word on this issue has yet to be written, ASCT remains the standard of care for MM patients after induction.

Link to abstract 8000

LBA4: Phase III randomized controlled study of daratumumab, bortezomib, and dexamethasone (DVd) versus bortezomib and dexamethasone (Vd) in patients (pts) with relapsed or refractory multiple myeloma (RRMM): CASTOR study

Comment: As predicted by most, the addition of daratumumab to bortezomib-based therapy increases response rates, compared with bortezomib-based alone. Efficacy is becoming less of a concern with myeloma treatment than is economics..

Look for the full, final text of this abstract to be posted online at 7:30 AM (EDT) on Sunday, June 5.

Hematology News’ Editor-in-Chief Matt Kalaycio selected the following as his “top 10” picks for hematologic oncology abstracts at ASCO 2016:

Abstract 7000: Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML

Comment: When any treatment appears to improve survival, compared with 7+3 for AML, all must take notice.

Link to abstract 7000

Abstract 7001: Treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) treated with frontline nilotinib: Results from the ENESTFreedom study

Comment: About 50% of the CML patients treated with frontline nilotinib are eventually able to stop the drug and successfully stay off of it. That means more patients in treatment-free remission, compared with those initially treated with imatinib.

Link to abstract 7001

Abstract 7007: Phase Ib/2 study of venetoclax with low-dose cytarabine in treatment-naive patients age ≥ 65 with acute myelogenous leukemia

Abstract 7009: Results of a phase 1b study of venetoclax plus decitabine or azacitidine in untreated acute myeloid leukemia patients ≥ 65 years ineligible for standard induction therapy

Comment: The response rates in these older AML patients are remarkable and challenge results typically seen with 7+3 in a younger population.

Link to abstract 7007 and 7009

Abstract 7501: A prospective, multicenter, randomized study of anti-CCR4 monoclonal antibody mogamulizumab (moga) vs investigator’s choice (IC) in the treatment of patients (pts) with relapsed/refractory (R/R) adult T-cell leukemia-lymphoma (ATL)

Comment: The response rate to mogamulizumab was outstanding in the largest randomized clinical trial thus far conducted for this cancer. Although rare in the USA, ATL is more common in Asia.

Link to abstract 7501

Abstract 7507: Effect of bortezomib on complete remission (CR) rate when added to bendamustine-rituximab (BR) in previously untreated high-risk (HR) follicular lymphoma (FL): A randomized phase II trial of the ECOG-ACRIN Cancer Research Group (E2408)

Comment: This interesting observation of improved complete remission needs longer follow-up.

Link to abstract 7507

Abstract 7519: Venetoclax activity in CLL patients who have relapsed after or are refractory to ibrutinib or idelalisib

Comment: This study has implications for practice. Venetoclax elicits a 50%-60% response rate after patients with CLL progress during treatment with B-cell receptor pathway inhibitors.

Link to abstract 7519

Abstract 7521: Acalabrutinib, a second-generation bruton tyrosine kinase (Btk) inhibitor, in previously untreated chronic lymphocytic leukemia (CLL)

Comment: This next-generation variation on ibrutinib was associated with a 96% overall response rate with fewer adverse effects such as atrial fibrillation.

Link to abstract 7521

Abstract 8000: Upfront autologous stem cell transplantation (ASCT) versus novel agent-based therapy for multiple myeloma (MM): A randomized phase 3 study of the European Myeloma Network (EMN02/HO95 MM trial)

Comment: Other trials are underway to address the role of upfront ASCT for newly diagnosed multiple myeloma. While the last word on this issue has yet to be written, ASCT remains the standard of care for MM patients after induction.

Link to abstract 8000

LBA4: Phase III randomized controlled study of daratumumab, bortezomib, and dexamethasone (DVd) versus bortezomib and dexamethasone (Vd) in patients (pts) with relapsed or refractory multiple myeloma (RRMM): CASTOR study

Comment: As predicted by most, the addition of daratumumab to bortezomib-based therapy increases response rates, compared with bortezomib-based alone. Efficacy is becoming less of a concern with myeloma treatment than is economics..

Look for the full, final text of this abstract to be posted online at 7:30 AM (EDT) on Sunday, June 5.

Hematology News’ Editor-in-Chief Matt Kalaycio selected the following as his “top 10” picks for hematologic oncology abstracts at ASCO 2016:

Abstract 7000: Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML

Comment: When any treatment appears to improve survival, compared with 7+3 for AML, all must take notice.

Link to abstract 7000

Abstract 7001: Treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) treated with frontline nilotinib: Results from the ENESTFreedom study

Comment: About 50% of the CML patients treated with frontline nilotinib are eventually able to stop the drug and successfully stay off of it. That means more patients in treatment-free remission, compared with those initially treated with imatinib.

Link to abstract 7001

Abstract 7007: Phase Ib/2 study of venetoclax with low-dose cytarabine in treatment-naive patients age ≥ 65 with acute myelogenous leukemia

Abstract 7009: Results of a phase 1b study of venetoclax plus decitabine or azacitidine in untreated acute myeloid leukemia patients ≥ 65 years ineligible for standard induction therapy

Comment: The response rates in these older AML patients are remarkable and challenge results typically seen with 7+3 in a younger population.

Link to abstract 7007 and 7009

Abstract 7501: A prospective, multicenter, randomized study of anti-CCR4 monoclonal antibody mogamulizumab (moga) vs investigator’s choice (IC) in the treatment of patients (pts) with relapsed/refractory (R/R) adult T-cell leukemia-lymphoma (ATL)

Comment: The response rate to mogamulizumab was outstanding in the largest randomized clinical trial thus far conducted for this cancer. Although rare in the USA, ATL is more common in Asia.

Link to abstract 7501

Abstract 7507: Effect of bortezomib on complete remission (CR) rate when added to bendamustine-rituximab (BR) in previously untreated high-risk (HR) follicular lymphoma (FL): A randomized phase II trial of the ECOG-ACRIN Cancer Research Group (E2408)

Comment: This interesting observation of improved complete remission needs longer follow-up.

Link to abstract 7507

Abstract 7519: Venetoclax activity in CLL patients who have relapsed after or are refractory to ibrutinib or idelalisib

Comment: This study has implications for practice. Venetoclax elicits a 50%-60% response rate after patients with CLL progress during treatment with B-cell receptor pathway inhibitors.

Link to abstract 7519

Abstract 7521: Acalabrutinib, a second-generation bruton tyrosine kinase (Btk) inhibitor, in previously untreated chronic lymphocytic leukemia (CLL)

Comment: This next-generation variation on ibrutinib was associated with a 96% overall response rate with fewer adverse effects such as atrial fibrillation.

Link to abstract 7521

Abstract 8000: Upfront autologous stem cell transplantation (ASCT) versus novel agent-based therapy for multiple myeloma (MM): A randomized phase 3 study of the European Myeloma Network (EMN02/HO95 MM trial)

Comment: Other trials are underway to address the role of upfront ASCT for newly diagnosed multiple myeloma. While the last word on this issue has yet to be written, ASCT remains the standard of care for MM patients after induction.

Link to abstract 8000

LBA4: Phase III randomized controlled study of daratumumab, bortezomib, and dexamethasone (DVd) versus bortezomib and dexamethasone (Vd) in patients (pts) with relapsed or refractory multiple myeloma (RRMM): CASTOR study

Comment: As predicted by most, the addition of daratumumab to bortezomib-based therapy increases response rates, compared with bortezomib-based alone. Efficacy is becoming less of a concern with myeloma treatment than is economics..

Look for the full, final text of this abstract to be posted online at 7:30 AM (EDT) on Sunday, June 5.

Maintenance therapy with enzastaurin, an experimental agent directed against B-cell malignancies, did not improve disease-free survival among patients with high-risk diffuse large B-cell lymphomas following complete responses to chemotherapy with rituximab.

In a randomized, double-blind trial, after a median follow-up of 48 months, the hazard ratio for disease-free survival with enzastaurin vs. placebo, the primary endpoint, was 0.92 (P = .541), reported Dr. Michael Crump of Princess Margaret Cancer Centre in Toronto, and colleagues.

WikimediaCommons/Copyright © 2011 Michael Bonert.

“The risk of treatment failure, however defined, is likely to be different in the subpopulation of patients who achieve remission after that treatment. Furthermore, identifying the value of specific biomarkers in predicting therapeutic response to novel targeted agents may be necessary in guiding future trials within defined subgroups of patients with DLBCL,” they wrote in the study, published online May 23 in Journal of Clinical Oncology.

Enzastaurin is a selective inhibitor of the protein kinase C-beta isoform (PKC-beta) expressed in both normal and malignant B cells. It has been shown to decrease tumor proliferation and induced apoptosis in cancer cells, and has been shown to have activity against relapsed or refractory DLBCL, mantle cell lymphoma, and follicular lymphoma, the authors explained.

Dr. Crump and colleagues conducted a phase III study to determine whether enzastaurin could be effective as maintenance therapy in patients with DLBCL at high risk for relapse after having had complete responses to first-line therapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).

They enrolled 758 patients with stage II bulky DLBCL or stage III-IV disease who had three or more International Prognostic Index risk factors at diagnosis, and who had achieved either a confirmed or unconfirmed complete response after six to eight cycles of R-CHOP.

The patients were randomly assigned on a 2:1 basis to receive either oral enzastaurin 500 mg daily or placebo for 3 years, or until disease progression or unacceptable toxicity,

As noted, there was no significant difference in DFS with the active drug vs. placebo. In addition, in correlative analyses looking for biomarkers of response by cell of origin (i.e., germinal-center or non–germinal-center B cell) or by PKC-beta protein expression, the authors found no significant associations with either DFS or overall survival.

Enzastaurin was generally safe, with minor and manageable adverse events. More patients in the enzastaurin arm had episodes of QTc prolongation, but these did not require discontinuation of the drug.

Dr. Crump and coauthors disclosed consulting, advising, research funding and other relationships with various companies, including Eli Lilly. Five coauthors are Lilly employees.

Maintenance therapy with enzastaurin, an experimental agent directed against B-cell malignancies, did not improve disease-free survival among patients with high-risk diffuse large B-cell lymphomas following complete responses to chemotherapy with rituximab.

In a randomized, double-blind trial, after a median follow-up of 48 months, the hazard ratio for disease-free survival with enzastaurin vs. placebo, the primary endpoint, was 0.92 (P = .541), reported Dr. Michael Crump of Princess Margaret Cancer Centre in Toronto, and colleagues.

WikimediaCommons/Copyright © 2011 Michael Bonert.

“The risk of treatment failure, however defined, is likely to be different in the subpopulation of patients who achieve remission after that treatment. Furthermore, identifying the value of specific biomarkers in predicting therapeutic response to novel targeted agents may be necessary in guiding future trials within defined subgroups of patients with DLBCL,” they wrote in the study, published online May 23 in Journal of Clinical Oncology.

Enzastaurin is a selective inhibitor of the protein kinase C-beta isoform (PKC-beta) expressed in both normal and malignant B cells. It has been shown to decrease tumor proliferation and induced apoptosis in cancer cells, and has been shown to have activity against relapsed or refractory DLBCL, mantle cell lymphoma, and follicular lymphoma, the authors explained.

Dr. Crump and colleagues conducted a phase III study to determine whether enzastaurin could be effective as maintenance therapy in patients with DLBCL at high risk for relapse after having had complete responses to first-line therapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).

They enrolled 758 patients with stage II bulky DLBCL or stage III-IV disease who had three or more International Prognostic Index risk factors at diagnosis, and who had achieved either a confirmed or unconfirmed complete response after six to eight cycles of R-CHOP.

The patients were randomly assigned on a 2:1 basis to receive either oral enzastaurin 500 mg daily or placebo for 3 years, or until disease progression or unacceptable toxicity,

As noted, there was no significant difference in DFS with the active drug vs. placebo. In addition, in correlative analyses looking for biomarkers of response by cell of origin (i.e., germinal-center or non–germinal-center B cell) or by PKC-beta protein expression, the authors found no significant associations with either DFS or overall survival.

Enzastaurin was generally safe, with minor and manageable adverse events. More patients in the enzastaurin arm had episodes of QTc prolongation, but these did not require discontinuation of the drug.

Dr. Crump and coauthors disclosed consulting, advising, research funding and other relationships with various companies, including Eli Lilly. Five coauthors are Lilly employees.

Maintenance therapy with enzastaurin, an experimental agent directed against B-cell malignancies, did not improve disease-free survival among patients with high-risk diffuse large B-cell lymphomas following complete responses to chemotherapy with rituximab.

In a randomized, double-blind trial, after a median follow-up of 48 months, the hazard ratio for disease-free survival with enzastaurin vs. placebo, the primary endpoint, was 0.92 (P = .541), reported Dr. Michael Crump of Princess Margaret Cancer Centre in Toronto, and colleagues.

WikimediaCommons/Copyright © 2011 Michael Bonert.

“The risk of treatment failure, however defined, is likely to be different in the subpopulation of patients who achieve remission after that treatment. Furthermore, identifying the value of specific biomarkers in predicting therapeutic response to novel targeted agents may be necessary in guiding future trials within defined subgroups of patients with DLBCL,” they wrote in the study, published online May 23 in Journal of Clinical Oncology.

Enzastaurin is a selective inhibitor of the protein kinase C-beta isoform (PKC-beta) expressed in both normal and malignant B cells. It has been shown to decrease tumor proliferation and induced apoptosis in cancer cells, and has been shown to have activity against relapsed or refractory DLBCL, mantle cell lymphoma, and follicular lymphoma, the authors explained.

Dr. Crump and colleagues conducted a phase III study to determine whether enzastaurin could be effective as maintenance therapy in patients with DLBCL at high risk for relapse after having had complete responses to first-line therapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).

They enrolled 758 patients with stage II bulky DLBCL or stage III-IV disease who had three or more International Prognostic Index risk factors at diagnosis, and who had achieved either a confirmed or unconfirmed complete response after six to eight cycles of R-CHOP.

The patients were randomly assigned on a 2:1 basis to receive either oral enzastaurin 500 mg daily or placebo for 3 years, or until disease progression or unacceptable toxicity,

As noted, there was no significant difference in DFS with the active drug vs. placebo. In addition, in correlative analyses looking for biomarkers of response by cell of origin (i.e., germinal-center or non–germinal-center B cell) or by PKC-beta protein expression, the authors found no significant associations with either DFS or overall survival.

Enzastaurin was generally safe, with minor and manageable adverse events. More patients in the enzastaurin arm had episodes of QTc prolongation, but these did not require discontinuation of the drug.

Dr. Crump and coauthors disclosed consulting, advising, research funding and other relationships with various companies, including Eli Lilly. Five coauthors are Lilly employees.

 

 

Three generations of women

 

New research suggests there is a significant positive association between high levels of residential radon and the risk of hematologic malignancies in women.

The study is the first prospective, population-based study of residential radon exposure and hematologic malignancy risk.

Therefore, the researchers caution that it requires replication to better understand the association and whether it truly differs by sex.

Lauren Teras, PhD, of the American Cancer Society in Atlanta, Georgia, and her colleagues conducted this study and reported the results in Environmental Research.

Radon is a naturally occurring byproduct of the decay of radium and is a known human lung carcinogen. It is the second-leading cause of lung cancer in the US.

Modeling studies have shown that radon delivers a non-negligible dose of alpha radiation to the bone marrow and therefore could increase the risk of hematologic malignancies. However, studies investigating the link between radon and hematologic malignancies have produced inconsistent results.

For the current study, Dr Teras and her colleagues used data from the American Cancer Society Cancer Prevention Study-II Nutrition Cohort to examine the association between county-level residential radon exposure and the risk of hematologic cancer.

The analysis included 140,652 participants, including 3019 who had hematologic malignancies during 19 years of follow-up (1992 to 2011).

The researchers found that women living in counties with the highest mean radon concentration (> 148 Bq/m³) had a significantly higher risk of developing a hematologic malignancy than women living in counties with the lowest radon levels (< 74 Bq/m³).

The adjusted hazard ratio (adjusted for age, race, family history of hematologic malignancy, etc.) was 1.63 (P=0.0010).

The researchers also found evidence of a dose-response relationship, with an adjusted hazard ratio of 1.38 (P=0.001).

The team said there was evidence of a positive exposure-response relationship between radon concentration and the risk of all lymphoid malignancy subtypes in women. But the highest risk was observed for follicular lymphoma, with an adjusted hazard ratio of 2.74 (P=0.02).

On the other hand, there was a non-significant inverse association between radon and myeloid leukemias in women.

There was no association between hematologic malignancy and radon exposure among the men.

The researchers said a possible explanation for this finding is that men may have a higher baseline risk of hematologic malignancy, possibly because of more exposure to occupational or other risk factors, which would reduce the impact of any additional risk from residential radon.

In women, who have a smaller baseline risk, residential radon exposure might be a larger contributor to overall risk.

Another reason for the sex difference observed in this study may be that the women of this generation spent more time in their homes, so they had more residential exposure than men.

“The overall lifetime risk of hematological cancers in the United States is about 2%, so even a 60% relative increase would still mean a relatively small absolute risk,” Dr Teras noted.

“Nonetheless, radon is already associated with lung cancer, and if other studies confirm the link to blood cancers, we think it would warrant strengthened public health efforts to mitigate residential radon risks.”

 

 

Three generations of women

 

New research suggests there is a significant positive association between high levels of residential radon and the risk of hematologic malignancies in women.

The study is the first prospective, population-based study of residential radon exposure and hematologic malignancy risk.

Therefore, the researchers caution that it requires replication to better understand the association and whether it truly differs by sex.

Lauren Teras, PhD, of the American Cancer Society in Atlanta, Georgia, and her colleagues conducted this study and reported the results in Environmental Research.

Radon is a naturally occurring byproduct of the decay of radium and is a known human lung carcinogen. It is the second-leading cause of lung cancer in the US.

Modeling studies have shown that radon delivers a non-negligible dose of alpha radiation to the bone marrow and therefore could increase the risk of hematologic malignancies. However, studies investigating the link between radon and hematologic malignancies have produced inconsistent results.

For the current study, Dr Teras and her colleagues used data from the American Cancer Society Cancer Prevention Study-II Nutrition Cohort to examine the association between county-level residential radon exposure and the risk of hematologic cancer.

The analysis included 140,652 participants, including 3019 who had hematologic malignancies during 19 years of follow-up (1992 to 2011).

The researchers found that women living in counties with the highest mean radon concentration (> 148 Bq/m³) had a significantly higher risk of developing a hematologic malignancy than women living in counties with the lowest radon levels (< 74 Bq/m³).

The adjusted hazard ratio (adjusted for age, race, family history of hematologic malignancy, etc.) was 1.63 (P=0.0010).

The researchers also found evidence of a dose-response relationship, with an adjusted hazard ratio of 1.38 (P=0.001).

The team said there was evidence of a positive exposure-response relationship between radon concentration and the risk of all lymphoid malignancy subtypes in women. But the highest risk was observed for follicular lymphoma, with an adjusted hazard ratio of 2.74 (P=0.02).

On the other hand, there was a non-significant inverse association between radon and myeloid leukemias in women.

There was no association between hematologic malignancy and radon exposure among the men.

The researchers said a possible explanation for this finding is that men may have a higher baseline risk of hematologic malignancy, possibly because of more exposure to occupational or other risk factors, which would reduce the impact of any additional risk from residential radon.

In women, who have a smaller baseline risk, residential radon exposure might be a larger contributor to overall risk.

Another reason for the sex difference observed in this study may be that the women of this generation spent more time in their homes, so they had more residential exposure than men.

“The overall lifetime risk of hematological cancers in the United States is about 2%, so even a 60% relative increase would still mean a relatively small absolute risk,” Dr Teras noted.

“Nonetheless, radon is already associated with lung cancer, and if other studies confirm the link to blood cancers, we think it would warrant strengthened public health efforts to mitigate residential radon risks.”

 

 

Three generations of women

 

New research suggests there is a significant positive association between high levels of residential radon and the risk of hematologic malignancies in women.

The study is the first prospective, population-based study of residential radon exposure and hematologic malignancy risk.

Therefore, the researchers caution that it requires replication to better understand the association and whether it truly differs by sex.

Lauren Teras, PhD, of the American Cancer Society in Atlanta, Georgia, and her colleagues conducted this study and reported the results in Environmental Research.

Radon is a naturally occurring byproduct of the decay of radium and is a known human lung carcinogen. It is the second-leading cause of lung cancer in the US.

Modeling studies have shown that radon delivers a non-negligible dose of alpha radiation to the bone marrow and therefore could increase the risk of hematologic malignancies. However, studies investigating the link between radon and hematologic malignancies have produced inconsistent results.

For the current study, Dr Teras and her colleagues used data from the American Cancer Society Cancer Prevention Study-II Nutrition Cohort to examine the association between county-level residential radon exposure and the risk of hematologic cancer.

The analysis included 140,652 participants, including 3019 who had hematologic malignancies during 19 years of follow-up (1992 to 2011).

The researchers found that women living in counties with the highest mean radon concentration (> 148 Bq/m³) had a significantly higher risk of developing a hematologic malignancy than women living in counties with the lowest radon levels (< 74 Bq/m³).

The adjusted hazard ratio (adjusted for age, race, family history of hematologic malignancy, etc.) was 1.63 (P=0.0010).

The researchers also found evidence of a dose-response relationship, with an adjusted hazard ratio of 1.38 (P=0.001).

The team said there was evidence of a positive exposure-response relationship between radon concentration and the risk of all lymphoid malignancy subtypes in women. But the highest risk was observed for follicular lymphoma, with an adjusted hazard ratio of 2.74 (P=0.02).

On the other hand, there was a non-significant inverse association between radon and myeloid leukemias in women.

There was no association between hematologic malignancy and radon exposure among the men.

The researchers said a possible explanation for this finding is that men may have a higher baseline risk of hematologic malignancy, possibly because of more exposure to occupational or other risk factors, which would reduce the impact of any additional risk from residential radon.

In women, who have a smaller baseline risk, residential radon exposure might be a larger contributor to overall risk.

Another reason for the sex difference observed in this study may be that the women of this generation spent more time in their homes, so they had more residential exposure than men.

“The overall lifetime risk of hematological cancers in the United States is about 2%, so even a 60% relative increase would still mean a relatively small absolute risk,” Dr Teras noted.

“Nonetheless, radon is already associated with lung cancer, and if other studies confirm the link to blood cancers, we think it would warrant strengthened public health efforts to mitigate residential radon risks.”