SNOWMASS, COLO. – The current American College of Rheumatology gout guidelines contain a number of recommendations that may come as a surprise to rheumatologists and primary care physicians alike.

The guidelines state, for example, that urate-lowering therapy should be undertaken routinely in any patient with an established diagnosis of gout who has comorbid chronic kidney disease (CKD) that is stage 2 or worse, meaning an estimated glomerular filtration rate of 89 mL/minute per 1.73 m² or less.

The rationale is that it’s particularly important to try to prevent acute gout attacks in such patients because their renal dysfunction makes it problematic to use colchicine and NSAIDs to quell attacks. Intriguing studies suggest that lowering serum urate may actually slow progression of CKD, Dr. Michael H. Pillinger said at the Winter Rheumatology symposium sponsored by the American College of Rheumatology.

The guidelines name the other indications for urate lowering in gout patients as the presence of a tophus on clinical examination or an imaging study, a history of two or more gout attacks per year, or a history of kidney stones.

Traditionally, urate-lowering therapy has been initiated during quiescent periods, but the ACR guidelines state that it also can be started during an acute attack if effective anti-inflammatory management has been instituted.

"This goes against what I was taught," observed Dr. Pillinger, a rheumatologist and director of the crystal diseases study group at New York University.

The guidelines (Arthritis Care Res. 2012;64:1431-46 and 1447-61) emphasize the importance of a treat-to-target approach.

"The primary care physicians I talk to still don’t know this. The ACR recommends a minimum serum urate target of less than 6.0 mg/dL, but the guidelines are very clear that if 6 isn’t good enough, you keep going. You go below 5. When I see patients with tophaceous gout, my target is never 6. My target is 5 or 4. That’s what I teach my fellows," explained Dr. Pillinger, who served on an expert panel that advised the guideline-writing task force.

The ACR urate-lowering algorithm begins with either allopurinol or febuxostat (Uloric) as first-line therapy. The guideline committee, which expressly excluded cost as a consideration, offered no guidance as to which xanthine oxidase inhibitor is preferred. Dr. Pillinger noted that febuxostat is a more specific xanthine oxidase inhibitor, is simpler to dose, and is far less likely to cause hypersensitivity reactions than is allopurinol. It is also more effective, although not dramatically more so. And it is considerably more expensive.

Febuxostat is approved by the Food and Drug Administration specifically for use in patients with mild to moderate CKD. Allopurinol is not. However, the gout guidelines endorse the use of allopurinol in that setting.

When allopurinol is the initial drug, the guidelines recommend dosing it in a manner that is different from how most physicians have been using it, the rheumatologist said. The recommended starting dose is lower than has been customary: 100 mg/day, and 50 mg/day in patients with stage 4 or 5 CKD. The drug is to be titrated upward every 2-5 weeks as needed to achieve the target urate level. The maximum dose is 800 mg/day, even in patients with comorbid CKD. Although the guidelines don’t provide guidance as to the size of the stepwise dosing increases, Dr. Pillinger usually boosts the allopurinol dose by 100 mg at a time, or 50 mg in patients with CKD.

"Most patients don’t get to target at 300 mg/day. You’ve got to go higher," he said.

An important innovation in the current guidelines is the recommendation for testing for the HLA-B*5801 allele in patients of Korean, Thai, or Han Chinese ancestry who are being considered for allopurinol therapy. The presence of this allele confers a several hundred–fold increased risk of allopurinol hypersensitivity.

Probenecid is endorsed as the alternative first-line urate-lowering agent, but only if at least one xanthine oxidase inhibitor is contraindicated or not tolerated. No other agents get the nod as first-line therapy.

The guidelines state that if a patient’s serum urate is not at target despite maximum-dose therapy with a first-line xanthine oxidase inhibitor, it is not appropriate to switch to the other xanthine oxidase inhibitor. Instead, it is time to add a uricosuric agent: probenecid, losartan, or fenofibrate. If the urate level still is not at target and the patient is generally well, with few gout attacks, then that’s an acceptable result. However, if the patient has moderate tophaceous gout or chronic gouty arthropathy, it’s appropriate to place the patient on pegloticase (Krystexxa) while discontinuing all other urate-lowering agents.

The ACR guidelines stress that it is vital to always try to prevent gout attacks during initiation of urate-lowering therapy. The recommended first-line agents for prophylaxis are low-dose colchicine or a low-dose NSAID, with prednisone at a dose not to exceed 10 mg/day reserved as second-line therapy in the event the first-line agents are not tolerated or are ineffective.

Prophylaxis is supposed to continue as long as a patient has any evidence of disease activity. And once all symptoms and tophi have resolved, all measures needed to keep the serum urate below 6.0 mg/dL are to be continued indefinitely.

"For most patients," Dr. Pillinger concluded, "gout treatment is almost always forever."

He reported having received research grants from Takeda, which markets febuxostat in the United States, and Savient, which markets pegloticase.

[email protected]

SNOWMASS, COLO. – The current American College of Rheumatology gout guidelines contain a number of recommendations that may come as a surprise to rheumatologists and primary care physicians alike.

The guidelines state, for example, that urate-lowering therapy should be undertaken routinely in any patient with an established diagnosis of gout who has comorbid chronic kidney disease (CKD) that is stage 2 or worse, meaning an estimated glomerular filtration rate of 89 mL/minute per 1.73 m² or less.

The rationale is that it’s particularly important to try to prevent acute gout attacks in such patients because their renal dysfunction makes it problematic to use colchicine and NSAIDs to quell attacks. Intriguing studies suggest that lowering serum urate may actually slow progression of CKD, Dr. Michael H. Pillinger said at the Winter Rheumatology symposium sponsored by the American College of Rheumatology.

The guidelines name the other indications for urate lowering in gout patients as the presence of a tophus on clinical examination or an imaging study, a history of two or more gout attacks per year, or a history of kidney stones.

Traditionally, urate-lowering therapy has been initiated during quiescent periods, but the ACR guidelines state that it also can be started during an acute attack if effective anti-inflammatory management has been instituted.

"This goes against what I was taught," observed Dr. Pillinger, a rheumatologist and director of the crystal diseases study group at New York University.

The guidelines (Arthritis Care Res. 2012;64:1431-46 and 1447-61) emphasize the importance of a treat-to-target approach.

"The primary care physicians I talk to still don’t know this. The ACR recommends a minimum serum urate target of less than 6.0 mg/dL, but the guidelines are very clear that if 6 isn’t good enough, you keep going. You go below 5. When I see patients with tophaceous gout, my target is never 6. My target is 5 or 4. That’s what I teach my fellows," explained Dr. Pillinger, who served on an expert panel that advised the guideline-writing task force.

The ACR urate-lowering algorithm begins with either allopurinol or febuxostat (Uloric) as first-line therapy. The guideline committee, which expressly excluded cost as a consideration, offered no guidance as to which xanthine oxidase inhibitor is preferred. Dr. Pillinger noted that febuxostat is a more specific xanthine oxidase inhibitor, is simpler to dose, and is far less likely to cause hypersensitivity reactions than is allopurinol. It is also more effective, although not dramatically more so. And it is considerably more expensive.

Febuxostat is approved by the Food and Drug Administration specifically for use in patients with mild to moderate CKD. Allopurinol is not. However, the gout guidelines endorse the use of allopurinol in that setting.

When allopurinol is the initial drug, the guidelines recommend dosing it in a manner that is different from how most physicians have been using it, the rheumatologist said. The recommended starting dose is lower than has been customary: 100 mg/day, and 50 mg/day in patients with stage 4 or 5 CKD. The drug is to be titrated upward every 2-5 weeks as needed to achieve the target urate level. The maximum dose is 800 mg/day, even in patients with comorbid CKD. Although the guidelines don’t provide guidance as to the size of the stepwise dosing increases, Dr. Pillinger usually boosts the allopurinol dose by 100 mg at a time, or 50 mg in patients with CKD.

"Most patients don’t get to target at 300 mg/day. You’ve got to go higher," he said.

An important innovation in the current guidelines is the recommendation for testing for the HLA-B*5801 allele in patients of Korean, Thai, or Han Chinese ancestry who are being considered for allopurinol therapy. The presence of this allele confers a several hundred–fold increased risk of allopurinol hypersensitivity.

Probenecid is endorsed as the alternative first-line urate-lowering agent, but only if at least one xanthine oxidase inhibitor is contraindicated or not tolerated. No other agents get the nod as first-line therapy.

The guidelines state that if a patient’s serum urate is not at target despite maximum-dose therapy with a first-line xanthine oxidase inhibitor, it is not appropriate to switch to the other xanthine oxidase inhibitor. Instead, it is time to add a uricosuric agent: probenecid, losartan, or fenofibrate. If the urate level still is not at target and the patient is generally well, with few gout attacks, then that’s an acceptable result. However, if the patient has moderate tophaceous gout or chronic gouty arthropathy, it’s appropriate to place the patient on pegloticase (Krystexxa) while discontinuing all other urate-lowering agents.

The ACR guidelines stress that it is vital to always try to prevent gout attacks during initiation of urate-lowering therapy. The recommended first-line agents for prophylaxis are low-dose colchicine or a low-dose NSAID, with prednisone at a dose not to exceed 10 mg/day reserved as second-line therapy in the event the first-line agents are not tolerated or are ineffective.

Prophylaxis is supposed to continue as long as a patient has any evidence of disease activity. And once all symptoms and tophi have resolved, all measures needed to keep the serum urate below 6.0 mg/dL are to be continued indefinitely.

"For most patients," Dr. Pillinger concluded, "gout treatment is almost always forever."

He reported having received research grants from Takeda, which markets febuxostat in the United States, and Savient, which markets pegloticase.

[email protected]

SNOWMASS, COLO. – The current American College of Rheumatology gout guidelines contain a number of recommendations that may come as a surprise to rheumatologists and primary care physicians alike.

The guidelines state, for example, that urate-lowering therapy should be undertaken routinely in any patient with an established diagnosis of gout who has comorbid chronic kidney disease (CKD) that is stage 2 or worse, meaning an estimated glomerular filtration rate of 89 mL/minute per 1.73 m² or less.

The rationale is that it’s particularly important to try to prevent acute gout attacks in such patients because their renal dysfunction makes it problematic to use colchicine and NSAIDs to quell attacks. Intriguing studies suggest that lowering serum urate may actually slow progression of CKD, Dr. Michael H. Pillinger said at the Winter Rheumatology symposium sponsored by the American College of Rheumatology.

The guidelines name the other indications for urate lowering in gout patients as the presence of a tophus on clinical examination or an imaging study, a history of two or more gout attacks per year, or a history of kidney stones.

Traditionally, urate-lowering therapy has been initiated during quiescent periods, but the ACR guidelines state that it also can be started during an acute attack if effective anti-inflammatory management has been instituted.

"This goes against what I was taught," observed Dr. Pillinger, a rheumatologist and director of the crystal diseases study group at New York University.

The guidelines (Arthritis Care Res. 2012;64:1431-46 and 1447-61) emphasize the importance of a treat-to-target approach.

"The primary care physicians I talk to still don’t know this. The ACR recommends a minimum serum urate target of less than 6.0 mg/dL, but the guidelines are very clear that if 6 isn’t good enough, you keep going. You go below 5. When I see patients with tophaceous gout, my target is never 6. My target is 5 or 4. That’s what I teach my fellows," explained Dr. Pillinger, who served on an expert panel that advised the guideline-writing task force.

The ACR urate-lowering algorithm begins with either allopurinol or febuxostat (Uloric) as first-line therapy. The guideline committee, which expressly excluded cost as a consideration, offered no guidance as to which xanthine oxidase inhibitor is preferred. Dr. Pillinger noted that febuxostat is a more specific xanthine oxidase inhibitor, is simpler to dose, and is far less likely to cause hypersensitivity reactions than is allopurinol. It is also more effective, although not dramatically more so. And it is considerably more expensive.

Febuxostat is approved by the Food and Drug Administration specifically for use in patients with mild to moderate CKD. Allopurinol is not. However, the gout guidelines endorse the use of allopurinol in that setting.

When allopurinol is the initial drug, the guidelines recommend dosing it in a manner that is different from how most physicians have been using it, the rheumatologist said. The recommended starting dose is lower than has been customary: 100 mg/day, and 50 mg/day in patients with stage 4 or 5 CKD. The drug is to be titrated upward every 2-5 weeks as needed to achieve the target urate level. The maximum dose is 800 mg/day, even in patients with comorbid CKD. Although the guidelines don’t provide guidance as to the size of the stepwise dosing increases, Dr. Pillinger usually boosts the allopurinol dose by 100 mg at a time, or 50 mg in patients with CKD.

"Most patients don’t get to target at 300 mg/day. You’ve got to go higher," he said.

An important innovation in the current guidelines is the recommendation for testing for the HLA-B*5801 allele in patients of Korean, Thai, or Han Chinese ancestry who are being considered for allopurinol therapy. The presence of this allele confers a several hundred–fold increased risk of allopurinol hypersensitivity.

Probenecid is endorsed as the alternative first-line urate-lowering agent, but only if at least one xanthine oxidase inhibitor is contraindicated or not tolerated. No other agents get the nod as first-line therapy.

The guidelines state that if a patient’s serum urate is not at target despite maximum-dose therapy with a first-line xanthine oxidase inhibitor, it is not appropriate to switch to the other xanthine oxidase inhibitor. Instead, it is time to add a uricosuric agent: probenecid, losartan, or fenofibrate. If the urate level still is not at target and the patient is generally well, with few gout attacks, then that’s an acceptable result. However, if the patient has moderate tophaceous gout or chronic gouty arthropathy, it’s appropriate to place the patient on pegloticase (Krystexxa) while discontinuing all other urate-lowering agents.

The ACR guidelines stress that it is vital to always try to prevent gout attacks during initiation of urate-lowering therapy. The recommended first-line agents for prophylaxis are low-dose colchicine or a low-dose NSAID, with prednisone at a dose not to exceed 10 mg/day reserved as second-line therapy in the event the first-line agents are not tolerated or are ineffective.

Prophylaxis is supposed to continue as long as a patient has any evidence of disease activity. And once all symptoms and tophi have resolved, all measures needed to keep the serum urate below 6.0 mg/dL are to be continued indefinitely.

"For most patients," Dr. Pillinger concluded, "gout treatment is almost always forever."

He reported having received research grants from Takeda, which markets febuxostat in the United States, and Savient, which markets pegloticase.

[email protected]

SAN FRANCISCO—A group’s effort to identify optimal front-line treatment for peripheral T-cell lymphomas (PTCLs) was not as successful as researchers anticipated.

The North American PTCL Consortium set out to find a treatment that could best CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone), as studies have suggested this regimen is inadequate for patients with PTCL.

So the group organized a trial testing

a potentially more promising regimen: cyclophosphamide, etoposide, vincristine, and prednisone, alternating with pralatrexate (CEOP-P).

However, CEOP-P elicited a complete response (CR) rate comparable to rates historically seen with CHOP, and progression-free survival rates with the new regimen were “not particularly encouraging.”

Ranjana Advani, MD, of Stanford University Medical Center in California, discussed this trial’s inception, execution, and results at the 6th Annual T-cell Lymphoma Forum.

Trial inception

It all began with the first meeting of the North American PTCL Consortium, which took place at the 2006 ASH Annual Meeting. Physicians from 17 centers gathered to discuss the state of PTCL research in North America.

The group realized there were too many open studies for such a rare disease, and efforts should be more focused. However, they could not agree publicly as to which studies should get priority, so they used an anonymous survey to obtain a consensus.

Survey responses were “all over the map,” Dr Advani said. But ultimately, the consensus was that ongoing trials were not sufficient, and a new trial was necessary.

The group decided to first lend their support to ongoing trials and then launch a new study. At the fourth and fifth meetings of the North American PTCL Consortium (both in 2009), they drafted the concept of a front-line trial testing CEOP-P.

“We decided to use [CEOP] as a backbone because there were reservations about anthracyclines having a role in PTCL, and there was data . . . in patients [with B-cell lymphomas] who were not anthracycline-eligible and did reasonably well when etoposide was substituted [for hydroxydaunorubicin],” Dr Advani said.

As for for the second “P” in CEOP-P, pralatrexate was the first drug approved for patients with relapsed PTCL, which provided the rationale for evaluating it in the front-line setting.

Execution and results

The primary aim of this study was to improve the CR rate from 40% to 60% with CEOP-P followed by optional transplant. A literature review had revealed that CRs with CHOP have been in the range of 40% to 50%.

The researchers enrolled a total of 34 patients, but 1 withdrew consent. Twenty-seven patients received at least 2 cycles of CEOP-P. Of the 6 patients who received a single cycle, 4 discontinued treatment due to early disease progression, and 2 discontinued because of adverse events.

Grade 3-4 adverse events associated with CEOP-P included anemia, thrombocytopenia, febrile neutropenia, mucositis, sepsis, increased creatinine, and liver transaminases.

The researchers had used a 2-stage Simon design (alpha=0.10, 90% power) to test the null hypothesis that the CR rate would be 40% or greater.

For the first stage of 20 evaluable patients, the trial would be terminated if 8 or fewer patients experienced a CR after course 2B of chemotherapy. For the second stage, 34 patients were required, and at least 17 had to achieve a CR at the end of therapy for the regimen to be considered useful.

At the end of stage 1, 50% of the patients (10/20) had achieved a CR. Ultimately, 52% of all patients (n=17) achieved a CR.

This suggests CEOP-P is a useful regimen, according to the study design. But the primary aim of improving CR from 40% to 60% was not met.

Furthermore, the estimated 1-year and 2-year progression-free survival rates were “not particularly encouraging,” according to Dr Advani. The rates were 50% and 34%, respectively. And the estimated 1-year and 2-year overall survival rate was 64%.

“So this was a lesson in working together and getting a trial from ground zero, to up and running, to a presentation, and publication underway,” Dr Advani said.

“And even though it took in all the ingredients of what everybody thought was important . . . , it’s not a regimen which has that much promise to move to a randomized setting. And so defining the optimal front-line therapy in PTCL continues to be a challenge and an unmet need.”

Now, the North American PTCL Consortium is working on a second front-line trial testing cyclophosphamide, hydroxydaunorubicin, vincristine, etoposide, and prednisone (CHOEP) plus lenalidomide in stage II, III, and IV PTCL. The final protocol has been circulated, and the group anticipates the first patient will be enrolled by June or July of this year.

Dr Advani and her colleagues also presented results of the CEOP-P trial at the 2013 ASH Annual Meeting as abstract 3044. (Information in the abstract differs from that presented at the T-cell Lymphoma Forum.)

SAN FRANCISCO—A group’s effort to identify optimal front-line treatment for peripheral T-cell lymphomas (PTCLs) was not as successful as researchers anticipated.

The North American PTCL Consortium set out to find a treatment that could best CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone), as studies have suggested this regimen is inadequate for patients with PTCL.

So the group organized a trial testing

a potentially more promising regimen: cyclophosphamide, etoposide, vincristine, and prednisone, alternating with pralatrexate (CEOP-P).

However, CEOP-P elicited a complete response (CR) rate comparable to rates historically seen with CHOP, and progression-free survival rates with the new regimen were “not particularly encouraging.”

Ranjana Advani, MD, of Stanford University Medical Center in California, discussed this trial’s inception, execution, and results at the 6th Annual T-cell Lymphoma Forum.

Trial inception

It all began with the first meeting of the North American PTCL Consortium, which took place at the 2006 ASH Annual Meeting. Physicians from 17 centers gathered to discuss the state of PTCL research in North America.

The group realized there were too many open studies for such a rare disease, and efforts should be more focused. However, they could not agree publicly as to which studies should get priority, so they used an anonymous survey to obtain a consensus.

Survey responses were “all over the map,” Dr Advani said. But ultimately, the consensus was that ongoing trials were not sufficient, and a new trial was necessary.

The group decided to first lend their support to ongoing trials and then launch a new study. At the fourth and fifth meetings of the North American PTCL Consortium (both in 2009), they drafted the concept of a front-line trial testing CEOP-P.

“We decided to use [CEOP] as a backbone because there were reservations about anthracyclines having a role in PTCL, and there was data . . . in patients [with B-cell lymphomas] who were not anthracycline-eligible and did reasonably well when etoposide was substituted [for hydroxydaunorubicin],” Dr Advani said.

As for for the second “P” in CEOP-P, pralatrexate was the first drug approved for patients with relapsed PTCL, which provided the rationale for evaluating it in the front-line setting.

Execution and results

The primary aim of this study was to improve the CR rate from 40% to 60% with CEOP-P followed by optional transplant. A literature review had revealed that CRs with CHOP have been in the range of 40% to 50%.

The researchers enrolled a total of 34 patients, but 1 withdrew consent. Twenty-seven patients received at least 2 cycles of CEOP-P. Of the 6 patients who received a single cycle, 4 discontinued treatment due to early disease progression, and 2 discontinued because of adverse events.

Grade 3-4 adverse events associated with CEOP-P included anemia, thrombocytopenia, febrile neutropenia, mucositis, sepsis, increased creatinine, and liver transaminases.

The researchers had used a 2-stage Simon design (alpha=0.10, 90% power) to test the null hypothesis that the CR rate would be 40% or greater.

For the first stage of 20 evaluable patients, the trial would be terminated if 8 or fewer patients experienced a CR after course 2B of chemotherapy. For the second stage, 34 patients were required, and at least 17 had to achieve a CR at the end of therapy for the regimen to be considered useful.

At the end of stage 1, 50% of the patients (10/20) had achieved a CR. Ultimately, 52% of all patients (n=17) achieved a CR.

This suggests CEOP-P is a useful regimen, according to the study design. But the primary aim of improving CR from 40% to 60% was not met.

Furthermore, the estimated 1-year and 2-year progression-free survival rates were “not particularly encouraging,” according to Dr Advani. The rates were 50% and 34%, respectively. And the estimated 1-year and 2-year overall survival rate was 64%.

“So this was a lesson in working together and getting a trial from ground zero, to up and running, to a presentation, and publication underway,” Dr Advani said.

“And even though it took in all the ingredients of what everybody thought was important . . . , it’s not a regimen which has that much promise to move to a randomized setting. And so defining the optimal front-line therapy in PTCL continues to be a challenge and an unmet need.”

Now, the North American PTCL Consortium is working on a second front-line trial testing cyclophosphamide, hydroxydaunorubicin, vincristine, etoposide, and prednisone (CHOEP) plus lenalidomide in stage II, III, and IV PTCL. The final protocol has been circulated, and the group anticipates the first patient will be enrolled by June or July of this year.

Dr Advani and her colleagues also presented results of the CEOP-P trial at the 2013 ASH Annual Meeting as abstract 3044. (Information in the abstract differs from that presented at the T-cell Lymphoma Forum.)

SAN FRANCISCO—A group’s effort to identify optimal front-line treatment for peripheral T-cell lymphomas (PTCLs) was not as successful as researchers anticipated.

The North American PTCL Consortium set out to find a treatment that could best CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone), as studies have suggested this regimen is inadequate for patients with PTCL.

So the group organized a trial testing

a potentially more promising regimen: cyclophosphamide, etoposide, vincristine, and prednisone, alternating with pralatrexate (CEOP-P).

However, CEOP-P elicited a complete response (CR) rate comparable to rates historically seen with CHOP, and progression-free survival rates with the new regimen were “not particularly encouraging.”

Ranjana Advani, MD, of Stanford University Medical Center in California, discussed this trial’s inception, execution, and results at the 6th Annual T-cell Lymphoma Forum.

Trial inception

It all began with the first meeting of the North American PTCL Consortium, which took place at the 2006 ASH Annual Meeting. Physicians from 17 centers gathered to discuss the state of PTCL research in North America.

The group realized there were too many open studies for such a rare disease, and efforts should be more focused. However, they could not agree publicly as to which studies should get priority, so they used an anonymous survey to obtain a consensus.

Survey responses were “all over the map,” Dr Advani said. But ultimately, the consensus was that ongoing trials were not sufficient, and a new trial was necessary.

The group decided to first lend their support to ongoing trials and then launch a new study. At the fourth and fifth meetings of the North American PTCL Consortium (both in 2009), they drafted the concept of a front-line trial testing CEOP-P.

“We decided to use [CEOP] as a backbone because there were reservations about anthracyclines having a role in PTCL, and there was data . . . in patients [with B-cell lymphomas] who were not anthracycline-eligible and did reasonably well when etoposide was substituted [for hydroxydaunorubicin],” Dr Advani said.

As for for the second “P” in CEOP-P, pralatrexate was the first drug approved for patients with relapsed PTCL, which provided the rationale for evaluating it in the front-line setting.

Execution and results

The primary aim of this study was to improve the CR rate from 40% to 60% with CEOP-P followed by optional transplant. A literature review had revealed that CRs with CHOP have been in the range of 40% to 50%.

The researchers enrolled a total of 34 patients, but 1 withdrew consent. Twenty-seven patients received at least 2 cycles of CEOP-P. Of the 6 patients who received a single cycle, 4 discontinued treatment due to early disease progression, and 2 discontinued because of adverse events.

Grade 3-4 adverse events associated with CEOP-P included anemia, thrombocytopenia, febrile neutropenia, mucositis, sepsis, increased creatinine, and liver transaminases.

The researchers had used a 2-stage Simon design (alpha=0.10, 90% power) to test the null hypothesis that the CR rate would be 40% or greater.

For the first stage of 20 evaluable patients, the trial would be terminated if 8 or fewer patients experienced a CR after course 2B of chemotherapy. For the second stage, 34 patients were required, and at least 17 had to achieve a CR at the end of therapy for the regimen to be considered useful.

At the end of stage 1, 50% of the patients (10/20) had achieved a CR. Ultimately, 52% of all patients (n=17) achieved a CR.

This suggests CEOP-P is a useful regimen, according to the study design. But the primary aim of improving CR from 40% to 60% was not met.

Furthermore, the estimated 1-year and 2-year progression-free survival rates were “not particularly encouraging,” according to Dr Advani. The rates were 50% and 34%, respectively. And the estimated 1-year and 2-year overall survival rate was 64%.

“So this was a lesson in working together and getting a trial from ground zero, to up and running, to a presentation, and publication underway,” Dr Advani said.

“And even though it took in all the ingredients of what everybody thought was important . . . , it’s not a regimen which has that much promise to move to a randomized setting. And so defining the optimal front-line therapy in PTCL continues to be a challenge and an unmet need.”

Now, the North American PTCL Consortium is working on a second front-line trial testing cyclophosphamide, hydroxydaunorubicin, vincristine, etoposide, and prednisone (CHOEP) plus lenalidomide in stage II, III, and IV PTCL. The final protocol has been circulated, and the group anticipates the first patient will be enrolled by June or July of this year.

Dr Advani and her colleagues also presented results of the CEOP-P trial at the 2013 ASH Annual Meeting as abstract 3044. (Information in the abstract differs from that presented at the T-cell Lymphoma Forum.)

Researchers in the lab

Credit: Rhoda Baer

New research indicates that author status affects how frequently scientific papers are cited, but the size of that effect depends on a number of other factors.

Investigators found that, overall, citations increased 12% above the expected level when authors were awarded “prestigious investigator status” at the Howard Hughes Medical Institute (HHMI).

However, certain kinds of research papers benefitted more than others by this increased prestige.

“We find much more of an effect on recent papers published in a short window before the prize,” said study author Pierre Azoulay, PhD, of the MIT Sloan School of Management in Cambridge.

And the greatest gains came for papers in new areas of research and for papers published in lower-profile journals. Younger researchers who had lower profiles prior to receiving the HHMI award were more likely to see a change as well.

“The effect was much more pronounced when there was more reason to be uncertain about the quality of the science or the scientist before the prize,” Dr Azoulay noted.

This paper, titled “Matthew: Effect or Fable?,” was published in Management Science.

The “Matthew Effect” is a term coined by sociologist Robert K. Merton to describe the possibility that the work of those with high status receives greater attention than equivalent work by those who are not as well known.

Positively identifying this phenomenon in scientific paper citations is difficult, however, because it is hard to separate the status of the author from the quality of the paper. It is possible, after all, that better-known researchers are simply producing higher-quality papers, which get more attention as a result.

But Dr Azoulay and his colleagues said they’ve found a way to address this issue. They looked at papers first published before the authors became HHMI investigators, then examined the citation rates for those papers after the HHMI appointments occurred, compared to a baseline of similar papers whose authors did not receive HHMI appointments.

More specifically, each paper in the study was paired with what Dr Azoulay called a “fraternal twin,” that is, another paper published in the same journal, at the same time, with the same initial citation pattern. For good measure, the authors of the papers in this comparison group were all scientists who had received other early career awards.

In all, from 1984 through 2003, 443 scientists were named HHMI investigators. Dr Azoulay and his colleagues examined 3636 papers written by 424 of those scientists, comparing them to 3636 papers in the control group.

“You couldn’t tell [the 2 sets of papers] apart in terms of citation trajectories, up until the time of the prize,” Dr Azoulay said.

Beyond the overall 12% increase in citations, the effect was nearly twice as great for papers published in lower-profile journals.

Alternately, Dr Azoulay pointed out, “If your paper was published in Cell or Nature or Science, the HHMI [award] doesn’t add a lot.”

Researchers in the lab

Credit: Rhoda Baer

New research indicates that author status affects how frequently scientific papers are cited, but the size of that effect depends on a number of other factors.

Investigators found that, overall, citations increased 12% above the expected level when authors were awarded “prestigious investigator status” at the Howard Hughes Medical Institute (HHMI).

However, certain kinds of research papers benefitted more than others by this increased prestige.

“We find much more of an effect on recent papers published in a short window before the prize,” said study author Pierre Azoulay, PhD, of the MIT Sloan School of Management in Cambridge.

And the greatest gains came for papers in new areas of research and for papers published in lower-profile journals. Younger researchers who had lower profiles prior to receiving the HHMI award were more likely to see a change as well.

“The effect was much more pronounced when there was more reason to be uncertain about the quality of the science or the scientist before the prize,” Dr Azoulay noted.

This paper, titled “Matthew: Effect or Fable?,” was published in Management Science.

The “Matthew Effect” is a term coined by sociologist Robert K. Merton to describe the possibility that the work of those with high status receives greater attention than equivalent work by those who are not as well known.

Positively identifying this phenomenon in scientific paper citations is difficult, however, because it is hard to separate the status of the author from the quality of the paper. It is possible, after all, that better-known researchers are simply producing higher-quality papers, which get more attention as a result.

But Dr Azoulay and his colleagues said they’ve found a way to address this issue. They looked at papers first published before the authors became HHMI investigators, then examined the citation rates for those papers after the HHMI appointments occurred, compared to a baseline of similar papers whose authors did not receive HHMI appointments.

More specifically, each paper in the study was paired with what Dr Azoulay called a “fraternal twin,” that is, another paper published in the same journal, at the same time, with the same initial citation pattern. For good measure, the authors of the papers in this comparison group were all scientists who had received other early career awards.

In all, from 1984 through 2003, 443 scientists were named HHMI investigators. Dr Azoulay and his colleagues examined 3636 papers written by 424 of those scientists, comparing them to 3636 papers in the control group.

“You couldn’t tell [the 2 sets of papers] apart in terms of citation trajectories, up until the time of the prize,” Dr Azoulay said.

Beyond the overall 12% increase in citations, the effect was nearly twice as great for papers published in lower-profile journals.

Alternately, Dr Azoulay pointed out, “If your paper was published in Cell or Nature or Science, the HHMI [award] doesn’t add a lot.”

Researchers in the lab

Credit: Rhoda Baer

New research indicates that author status affects how frequently scientific papers are cited, but the size of that effect depends on a number of other factors.

Investigators found that, overall, citations increased 12% above the expected level when authors were awarded “prestigious investigator status” at the Howard Hughes Medical Institute (HHMI).

However, certain kinds of research papers benefitted more than others by this increased prestige.

“We find much more of an effect on recent papers published in a short window before the prize,” said study author Pierre Azoulay, PhD, of the MIT Sloan School of Management in Cambridge.

And the greatest gains came for papers in new areas of research and for papers published in lower-profile journals. Younger researchers who had lower profiles prior to receiving the HHMI award were more likely to see a change as well.

“The effect was much more pronounced when there was more reason to be uncertain about the quality of the science or the scientist before the prize,” Dr Azoulay noted.

This paper, titled “Matthew: Effect or Fable?,” was published in Management Science.

The “Matthew Effect” is a term coined by sociologist Robert K. Merton to describe the possibility that the work of those with high status receives greater attention than equivalent work by those who are not as well known.

Positively identifying this phenomenon in scientific paper citations is difficult, however, because it is hard to separate the status of the author from the quality of the paper. It is possible, after all, that better-known researchers are simply producing higher-quality papers, which get more attention as a result.

But Dr Azoulay and his colleagues said they’ve found a way to address this issue. They looked at papers first published before the authors became HHMI investigators, then examined the citation rates for those papers after the HHMI appointments occurred, compared to a baseline of similar papers whose authors did not receive HHMI appointments.

More specifically, each paper in the study was paired with what Dr Azoulay called a “fraternal twin,” that is, another paper published in the same journal, at the same time, with the same initial citation pattern. For good measure, the authors of the papers in this comparison group were all scientists who had received other early career awards.

In all, from 1984 through 2003, 443 scientists were named HHMI investigators. Dr Azoulay and his colleagues examined 3636 papers written by 424 of those scientists, comparing them to 3636 papers in the control group.

“You couldn’t tell [the 2 sets of papers] apart in terms of citation trajectories, up until the time of the prize,” Dr Azoulay said.

Beyond the overall 12% increase in citations, the effect was nearly twice as great for papers published in lower-profile journals.

Alternately, Dr Azoulay pointed out, “If your paper was published in Cell or Nature or Science, the HHMI [award] doesn’t add a lot.”

AML cells

Credit: Lance Liotta

Researchers have found evidence to suggest that methylation patterns in hematopoietic stem cells (HSCs) can be used to determine prognosis in patients with acute myeloid leukemia (AML).

The team discovered that patients with methylation patterns resembling those of healthy individuals lived longer than patients with substantially different patterns.

If validated in clinical trials, this finding could be used to help physicians tailor treatment according to a patient’s needs.

Ulrich Steidl, MD, PhD, of the Albert Einstein College of Medicine in New York, and his colleagues described this research in The Journal of Clinical Investigation.

The investigators knew that aberrations in HSC methylation can prevent the cells from differentiating into mature blood cells, which leads to AML.

So they speculated that comparing how closely the methylation patterns in cells from AML patients resemble the patterns found in healthy individuals’ HSCs might foretell the patients’ response to treatment.

To find out, the researchers first looked at methylation patterns in HSCs from healthy individuals. The team found that most cytosines are methylated in healthy HSCs.

And where demethylation occurs, it’s mainly limited to one particular stage of HSC differentiation—the commitment step from short-term HSC to common myeloid progenitor.

The investigators then set out to identify loci with the most significant methylation changes across differentiation stages. Their analysis revealed a set of 561 loci that distinguished between the 4 stages of HSC development they investigated.

The team next wanted to determine whether the methylation status of these loci was affected in AML. So they developed an epigenetic signature score based on loci methylation. A patient’s score increased the more his methylation pattern differed from that of a healthy individual.

The researchers tested their scoring method using data from 3 cohorts of AML patients. In each of these groups, patients with low scores had approximately twice the median survival time of patients with high scores.

Specifically, the investigators evaluated AML patients in a trial testing 2 different doses of daunorubicin (Fernandez et al, NEJM 2009).

Among patients receiving lower-dose daunorubicin, those with lower epigenetic signature scores had a median overall survival (OS) of 19 months, compared with 10.8 months for patients with higher scores (P=0.0165).

The researchers observed similar results in the patients receiving a higher dose of daunorubicin. The median OS in the group with low epigenetic signature scores was 25.4 months, compared with 13.2 months in the group with high scores (P=0.0062).

Likewise, in a third cohort of AML patients, those with a low epigenetic signature score had significantly better OS than those with a high score—a median of 28.1 months and 14.9 months, respectively (P=0.0150).

The investigators performed the same analyses using a commitment-associated gene-expression signature. And they found their epigenetic signature was more effective at predicting patient survival.

Dr Steidl and his colleagues are now studying the genes found in the aberrant epigenetic signatures to determine if they play a role in causing AML.

AML cells

Credit: Lance Liotta

Researchers have found evidence to suggest that methylation patterns in hematopoietic stem cells (HSCs) can be used to determine prognosis in patients with acute myeloid leukemia (AML).

The team discovered that patients with methylation patterns resembling those of healthy individuals lived longer than patients with substantially different patterns.

If validated in clinical trials, this finding could be used to help physicians tailor treatment according to a patient’s needs.

Ulrich Steidl, MD, PhD, of the Albert Einstein College of Medicine in New York, and his colleagues described this research in The Journal of Clinical Investigation.

The investigators knew that aberrations in HSC methylation can prevent the cells from differentiating into mature blood cells, which leads to AML.

So they speculated that comparing how closely the methylation patterns in cells from AML patients resemble the patterns found in healthy individuals’ HSCs might foretell the patients’ response to treatment.

To find out, the researchers first looked at methylation patterns in HSCs from healthy individuals. The team found that most cytosines are methylated in healthy HSCs.

And where demethylation occurs, it’s mainly limited to one particular stage of HSC differentiation—the commitment step from short-term HSC to common myeloid progenitor.

The investigators then set out to identify loci with the most significant methylation changes across differentiation stages. Their analysis revealed a set of 561 loci that distinguished between the 4 stages of HSC development they investigated.

The team next wanted to determine whether the methylation status of these loci was affected in AML. So they developed an epigenetic signature score based on loci methylation. A patient’s score increased the more his methylation pattern differed from that of a healthy individual.

The researchers tested their scoring method using data from 3 cohorts of AML patients. In each of these groups, patients with low scores had approximately twice the median survival time of patients with high scores.

Specifically, the investigators evaluated AML patients in a trial testing 2 different doses of daunorubicin (Fernandez et al, NEJM 2009).

Among patients receiving lower-dose daunorubicin, those with lower epigenetic signature scores had a median overall survival (OS) of 19 months, compared with 10.8 months for patients with higher scores (P=0.0165).

The researchers observed similar results in the patients receiving a higher dose of daunorubicin. The median OS in the group with low epigenetic signature scores was 25.4 months, compared with 13.2 months in the group with high scores (P=0.0062).

Likewise, in a third cohort of AML patients, those with a low epigenetic signature score had significantly better OS than those with a high score—a median of 28.1 months and 14.9 months, respectively (P=0.0150).

The investigators performed the same analyses using a commitment-associated gene-expression signature. And they found their epigenetic signature was more effective at predicting patient survival.

Dr Steidl and his colleagues are now studying the genes found in the aberrant epigenetic signatures to determine if they play a role in causing AML.

AML cells

Credit: Lance Liotta

Researchers have found evidence to suggest that methylation patterns in hematopoietic stem cells (HSCs) can be used to determine prognosis in patients with acute myeloid leukemia (AML).

The team discovered that patients with methylation patterns resembling those of healthy individuals lived longer than patients with substantially different patterns.

If validated in clinical trials, this finding could be used to help physicians tailor treatment according to a patient’s needs.

Ulrich Steidl, MD, PhD, of the Albert Einstein College of Medicine in New York, and his colleagues described this research in The Journal of Clinical Investigation.

The investigators knew that aberrations in HSC methylation can prevent the cells from differentiating into mature blood cells, which leads to AML.

So they speculated that comparing how closely the methylation patterns in cells from AML patients resemble the patterns found in healthy individuals’ HSCs might foretell the patients’ response to treatment.

To find out, the researchers first looked at methylation patterns in HSCs from healthy individuals. The team found that most cytosines are methylated in healthy HSCs.

And where demethylation occurs, it’s mainly limited to one particular stage of HSC differentiation—the commitment step from short-term HSC to common myeloid progenitor.

The investigators then set out to identify loci with the most significant methylation changes across differentiation stages. Their analysis revealed a set of 561 loci that distinguished between the 4 stages of HSC development they investigated.

The team next wanted to determine whether the methylation status of these loci was affected in AML. So they developed an epigenetic signature score based on loci methylation. A patient’s score increased the more his methylation pattern differed from that of a healthy individual.

The researchers tested their scoring method using data from 3 cohorts of AML patients. In each of these groups, patients with low scores had approximately twice the median survival time of patients with high scores.

Specifically, the investigators evaluated AML patients in a trial testing 2 different doses of daunorubicin (Fernandez et al, NEJM 2009).

Among patients receiving lower-dose daunorubicin, those with lower epigenetic signature scores had a median overall survival (OS) of 19 months, compared with 10.8 months for patients with higher scores (P=0.0165).

The researchers observed similar results in the patients receiving a higher dose of daunorubicin. The median OS in the group with low epigenetic signature scores was 25.4 months, compared with 13.2 months in the group with high scores (P=0.0062).

Likewise, in a third cohort of AML patients, those with a low epigenetic signature score had significantly better OS than those with a high score—a median of 28.1 months and 14.9 months, respectively (P=0.0150).

The investigators performed the same analyses using a commitment-associated gene-expression signature. And they found their epigenetic signature was more effective at predicting patient survival.

Dr Steidl and his colleagues are now studying the genes found in the aberrant epigenetic signatures to determine if they play a role in causing AML.

CliniMACS system

Credit: Miltenyi Biotec

The US Food and Drug Administration (FDA) has granted approval for a device system that can prevent graft-vs-host disease (GVHD).

The CliniMACS CD34 Reagent System is intended for use in patients with acute myeloid leukemia who are in first complete remission and undergoing stem cell transplant (SCT) from a matched, related donor.

This in vitro system enriches CD34+ hematopoietic stem cells from a donated apheresis product, while depleting other cells that can cause GVHD.

The system employs a reagent consisting of a CD34 antibody conjugated to an iron-containing nanoparticle. It enriches CD34+ cells by passing the antibody/nanoparticle-labeled cell suspension through a magnetic separation column, which is provided as part of a single-use, disposable tubing set.

Magnetically labeled CD34+ target cells are retained within the separation column, while the unlabeled cells flow through. The CD34+ cells can be recovered by removing the magnetic field and eluting the targeted CD34+ cells into a collection bag.

The FDA’s approval of this system was based on data from a phase 2 study (BMT CTN 0303) conducted by the Blood and Marrow Transplant Clinical Trials Network (Pasquini et al, JCO 2012).

The trial included 128 patients undergoing SCT from a matched, sibling donor. Forty-four patients received grafts that were T-cell depleted (TCD) using the CliniMACS system as the sole form of immune suppression. The other 84 patients received T-cell-replete grafts and pharmacologic immune suppression therapy (IST).

The 2 groups were largely similar, although more patients in the TCD arm received treatment regimens that included radiation—100% vs 50%.

Neutrophil engraftment was similar between the 2 groups. At 28 days, 96% of patients in the IST arm and 100% in the TCD arm had achieved engraftment.

Patients in the TCD arm had a significantly lower rate of chronic GVHD than those in the IST arm. The TCD patients also had a lower rate of acute GVHD, but the difference was not significant.

At 100 days, the rates of grade 2-4, acute GVHD were 39% with IST and 23% with TCD grafts (P=0.07). At 2 years, the rates of chronic GVHD were 19% with TCD grafts and 50% with IST (P<0.001).

There were no significant differences between the 2 groups with regard to graft rejection, leukemia relapse, treatment-related mortality, disease-free survival, or overall survival. However, patients in the TCD arm had a higher rate of GVHD-free survival at 2 years—41% vs 19% (P=0.006).

The CliniMACS CD34 Reagent System is manufactured by Miltenyi Biotec. For more information on the system, see the company’s website.

CliniMACS system

Credit: Miltenyi Biotec

The US Food and Drug Administration (FDA) has granted approval for a device system that can prevent graft-vs-host disease (GVHD).

The CliniMACS CD34 Reagent System is intended for use in patients with acute myeloid leukemia who are in first complete remission and undergoing stem cell transplant (SCT) from a matched, related donor.

This in vitro system enriches CD34+ hematopoietic stem cells from a donated apheresis product, while depleting other cells that can cause GVHD.

The system employs a reagent consisting of a CD34 antibody conjugated to an iron-containing nanoparticle. It enriches CD34+ cells by passing the antibody/nanoparticle-labeled cell suspension through a magnetic separation column, which is provided as part of a single-use, disposable tubing set.

Magnetically labeled CD34+ target cells are retained within the separation column, while the unlabeled cells flow through. The CD34+ cells can be recovered by removing the magnetic field and eluting the targeted CD34+ cells into a collection bag.

The FDA’s approval of this system was based on data from a phase 2 study (BMT CTN 0303) conducted by the Blood and Marrow Transplant Clinical Trials Network (Pasquini et al, JCO 2012).

The trial included 128 patients undergoing SCT from a matched, sibling donor. Forty-four patients received grafts that were T-cell depleted (TCD) using the CliniMACS system as the sole form of immune suppression. The other 84 patients received T-cell-replete grafts and pharmacologic immune suppression therapy (IST).

The 2 groups were largely similar, although more patients in the TCD arm received treatment regimens that included radiation—100% vs 50%.

Neutrophil engraftment was similar between the 2 groups. At 28 days, 96% of patients in the IST arm and 100% in the TCD arm had achieved engraftment.

Patients in the TCD arm had a significantly lower rate of chronic GVHD than those in the IST arm. The TCD patients also had a lower rate of acute GVHD, but the difference was not significant.

At 100 days, the rates of grade 2-4, acute GVHD were 39% with IST and 23% with TCD grafts (P=0.07). At 2 years, the rates of chronic GVHD were 19% with TCD grafts and 50% with IST (P<0.001).

There were no significant differences between the 2 groups with regard to graft rejection, leukemia relapse, treatment-related mortality, disease-free survival, or overall survival. However, patients in the TCD arm had a higher rate of GVHD-free survival at 2 years—41% vs 19% (P=0.006).

The CliniMACS CD34 Reagent System is manufactured by Miltenyi Biotec. For more information on the system, see the company’s website.

CliniMACS system

Credit: Miltenyi Biotec

The US Food and Drug Administration (FDA) has granted approval for a device system that can prevent graft-vs-host disease (GVHD).

The CliniMACS CD34 Reagent System is intended for use in patients with acute myeloid leukemia who are in first complete remission and undergoing stem cell transplant (SCT) from a matched, related donor.

This in vitro system enriches CD34+ hematopoietic stem cells from a donated apheresis product, while depleting other cells that can cause GVHD.

The system employs a reagent consisting of a CD34 antibody conjugated to an iron-containing nanoparticle. It enriches CD34+ cells by passing the antibody/nanoparticle-labeled cell suspension through a magnetic separation column, which is provided as part of a single-use, disposable tubing set.

Magnetically labeled CD34+ target cells are retained within the separation column, while the unlabeled cells flow through. The CD34+ cells can be recovered by removing the magnetic field and eluting the targeted CD34+ cells into a collection bag.

The FDA’s approval of this system was based on data from a phase 2 study (BMT CTN 0303) conducted by the Blood and Marrow Transplant Clinical Trials Network (Pasquini et al, JCO 2012).

The trial included 128 patients undergoing SCT from a matched, sibling donor. Forty-four patients received grafts that were T-cell depleted (TCD) using the CliniMACS system as the sole form of immune suppression. The other 84 patients received T-cell-replete grafts and pharmacologic immune suppression therapy (IST).

The 2 groups were largely similar, although more patients in the TCD arm received treatment regimens that included radiation—100% vs 50%.

Neutrophil engraftment was similar between the 2 groups. At 28 days, 96% of patients in the IST arm and 100% in the TCD arm had achieved engraftment.

Patients in the TCD arm had a significantly lower rate of chronic GVHD than those in the IST arm. The TCD patients also had a lower rate of acute GVHD, but the difference was not significant.

At 100 days, the rates of grade 2-4, acute GVHD were 39% with IST and 23% with TCD grafts (P=0.07). At 2 years, the rates of chronic GVHD were 19% with TCD grafts and 50% with IST (P<0.001).

There were no significant differences between the 2 groups with regard to graft rejection, leukemia relapse, treatment-related mortality, disease-free survival, or overall survival. However, patients in the TCD arm had a higher rate of GVHD-free survival at 2 years—41% vs 19% (P=0.006).

The CliniMACS CD34 Reagent System is manufactured by Miltenyi Biotec. For more information on the system, see the company’s website.

While better appreciated than 2 decades ago, gender-related differences remain an important issue in clinical practice. This supplement includes 8 articles that focus on the needs and considerations in providing care to women. Four articles focus on cardiometabolic diseases: acute coronary syndrome, coronary heart disease, obesity, and diabetes mellitus. Additional topics include the early management of rheumatoid arthritis and the pharmacologic management of nausea and vomiting of pregnancy.

The last 2 articles each offer the opportunity to earn 1 free CME credit: The Pharmacologic Management of Idiopathic Overactive Bladder in Primary Care and Chronic Migraine in Women. Credit is awarded for successful completion of the quizzes at the links below; these links may also be found in the Women’s Health supplement on the first page of each article.

The Pharmacologic Management of Idiopathic Overactive Bladder in Primary Care www.pceconsortium.org/oab

Chronic Migraine in Women www.pceconsortium.org/migraine

Click here to view the supplement

While better appreciated than 2 decades ago, gender-related differences remain an important issue in clinical practice. This supplement includes 8 articles that focus on the needs and considerations in providing care to women. Four articles focus on cardiometabolic diseases: acute coronary syndrome, coronary heart disease, obesity, and diabetes mellitus. Additional topics include the early management of rheumatoid arthritis and the pharmacologic management of nausea and vomiting of pregnancy.

The last 2 articles each offer the opportunity to earn 1 free CME credit: The Pharmacologic Management of Idiopathic Overactive Bladder in Primary Care and Chronic Migraine in Women. Credit is awarded for successful completion of the quizzes at the links below; these links may also be found in the Women’s Health supplement on the first page of each article.

The Pharmacologic Management of Idiopathic Overactive Bladder in Primary Care www.pceconsortium.org/oab

Chronic Migraine in Women www.pceconsortium.org/migraine

Click here to view the supplement

While better appreciated than 2 decades ago, gender-related differences remain an important issue in clinical practice. This supplement includes 8 articles that focus on the needs and considerations in providing care to women. Four articles focus on cardiometabolic diseases: acute coronary syndrome, coronary heart disease, obesity, and diabetes mellitus. Additional topics include the early management of rheumatoid arthritis and the pharmacologic management of nausea and vomiting of pregnancy.

The last 2 articles each offer the opportunity to earn 1 free CME credit: The Pharmacologic Management of Idiopathic Overactive Bladder in Primary Care and Chronic Migraine in Women. Credit is awarded for successful completion of the quizzes at the links below; these links may also be found in the Women’s Health supplement on the first page of each article.

The Pharmacologic Management of Idiopathic Overactive Bladder in Primary Care www.pceconsortium.org/oab

Chronic Migraine in Women www.pceconsortium.org/migraine

Click here to view the supplement

SNOWMASS, COLO. – Pegloticase (Krystexxa) is a gout drug that’s expensive, inconveniently administered by intravenous infusion every 2 weeks, and saddled with a substantial rate of immunogenicity, with infusion reactions that can include anaphylaxis.

So why does gout authority Dr. Michael H. Pillinger call pegloticase "a greatly underestimated and underutilized drug"? And why do the current American College of Rheumatology gout guidelines recommend pegloticase for refractory gout?

"Nothing else we have will get rid of tophi the way this drug gets rid of tophi," Dr. Pillinger explained at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

"Why do we care about that? Because tophi are erosive, they’re damaging, and also because they’re much more extensive than we think they are," said Dr. Pillinger, a rheumatologist and director of the crystal diseases study group at New York University.

Besides, the safety concern regarding this powerhouse urate-lowering drug has been resolved. The infusion reactions are readily avoidable. Pegloticase is not a drug rheumatologists should be scared of, he emphasized.

Dr. Pillinger cited an eye-opening study that demonstrated just how much larger gout patients’ total body urate burden actually is compared with what’s apparent clinically. Investigators at the University of British Columbia, Vancouver, used dual-energy CT to assess urate deposits in 20 consecutive patients with tophaceous gout and 10 controls with other arthritic conditions. Physical evaluation of the gout patients turned up 111 areas of urate deposition; dual-energy CT revealed 440 such areas. The mean total urate volume was a hefty 40.2 cm³ (Ann. Rheum. Dis. 2009;68:1609-12).

"There’s a lot more tophi under the surface," Dr. Pillinger commented.

Pegloticase is a recombinant porcine uricase that’s modified with a baboon N-terminus. It’s pegylated to reduce immunogenicity to the uricase and increase stability and half-life. Paradoxically, the drug is still quite immunogenic because many patients develop antibodies to the polyethylene glycol used in pegylation.

The drug’s urate-lowering effect is unmatched. Within 12-24 hours of the first dose, the plasma uric acid level plummets to almost nothing.

"What happens is that very, very quickly these patients are going to split into two groups. For one group this is the greatest drug in the world; their uric acid remains almost undetectable – and that’s in our sickest refractory patients. And then there’s another group that starts to fail. It’s in the neighborhood of 30%-40% of patients, so it’s a real problem. We know they’re failing because their uric acid level starts rising. They’re making antibodies and inactivating the drug every time it’s given. And they’re the ones who get bad infusion reactions," the rheumatologist explained.

The solution to using pegloticase safely is to routinely measure serum urate 1-2 days before each infusion. If the serum urate climbs to 6 mg/dL on one or two occasions, it’s time to discontinue the drug.

"For everybody else, they’re going to do really, really well," Dr. Pillinger said.

A key point emphasized in the 2012 ACR gout guidelines (Arthritis Care Res. 2012;64:1431-46; 1447-61) is that when patients go on pegloticase, all other urate-lowering therapies must be stopped as a matter of safety. Otherwise, it’s impossible to use the pre-infusion plasma urate measurement to determine if pegloticase has stopped working.

The ACR guidelines recommend pegloticase as third-line urate-lowering therapy in patients who are not at target despite maximum-dose therapy with a xanthine oxidase inhibitor plus second-line therapy with probenecid, losartan, or fenofibrate.

Dr. Pillinger reported having received research grants from Savient, which markets pegloticase, and Takeda.

[email protected]

SNOWMASS, COLO. – Pegloticase (Krystexxa) is a gout drug that’s expensive, inconveniently administered by intravenous infusion every 2 weeks, and saddled with a substantial rate of immunogenicity, with infusion reactions that can include anaphylaxis.

So why does gout authority Dr. Michael H. Pillinger call pegloticase "a greatly underestimated and underutilized drug"? And why do the current American College of Rheumatology gout guidelines recommend pegloticase for refractory gout?

"Nothing else we have will get rid of tophi the way this drug gets rid of tophi," Dr. Pillinger explained at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

"Why do we care about that? Because tophi are erosive, they’re damaging, and also because they’re much more extensive than we think they are," said Dr. Pillinger, a rheumatologist and director of the crystal diseases study group at New York University.

Besides, the safety concern regarding this powerhouse urate-lowering drug has been resolved. The infusion reactions are readily avoidable. Pegloticase is not a drug rheumatologists should be scared of, he emphasized.

Dr. Pillinger cited an eye-opening study that demonstrated just how much larger gout patients’ total body urate burden actually is compared with what’s apparent clinically. Investigators at the University of British Columbia, Vancouver, used dual-energy CT to assess urate deposits in 20 consecutive patients with tophaceous gout and 10 controls with other arthritic conditions. Physical evaluation of the gout patients turned up 111 areas of urate deposition; dual-energy CT revealed 440 such areas. The mean total urate volume was a hefty 40.2 cm³ (Ann. Rheum. Dis. 2009;68:1609-12).

"There’s a lot more tophi under the surface," Dr. Pillinger commented.

Pegloticase is a recombinant porcine uricase that’s modified with a baboon N-terminus. It’s pegylated to reduce immunogenicity to the uricase and increase stability and half-life. Paradoxically, the drug is still quite immunogenic because many patients develop antibodies to the polyethylene glycol used in pegylation.

The drug’s urate-lowering effect is unmatched. Within 12-24 hours of the first dose, the plasma uric acid level plummets to almost nothing.

"What happens is that very, very quickly these patients are going to split into two groups. For one group this is the greatest drug in the world; their uric acid remains almost undetectable – and that’s in our sickest refractory patients. And then there’s another group that starts to fail. It’s in the neighborhood of 30%-40% of patients, so it’s a real problem. We know they’re failing because their uric acid level starts rising. They’re making antibodies and inactivating the drug every time it’s given. And they’re the ones who get bad infusion reactions," the rheumatologist explained.

The solution to using pegloticase safely is to routinely measure serum urate 1-2 days before each infusion. If the serum urate climbs to 6 mg/dL on one or two occasions, it’s time to discontinue the drug.

"For everybody else, they’re going to do really, really well," Dr. Pillinger said.

A key point emphasized in the 2012 ACR gout guidelines (Arthritis Care Res. 2012;64:1431-46; 1447-61) is that when patients go on pegloticase, all other urate-lowering therapies must be stopped as a matter of safety. Otherwise, it’s impossible to use the pre-infusion plasma urate measurement to determine if pegloticase has stopped working.

The ACR guidelines recommend pegloticase as third-line urate-lowering therapy in patients who are not at target despite maximum-dose therapy with a xanthine oxidase inhibitor plus second-line therapy with probenecid, losartan, or fenofibrate.

Dr. Pillinger reported having received research grants from Savient, which markets pegloticase, and Takeda.

[email protected]

SNOWMASS, COLO. – Pegloticase (Krystexxa) is a gout drug that’s expensive, inconveniently administered by intravenous infusion every 2 weeks, and saddled with a substantial rate of immunogenicity, with infusion reactions that can include anaphylaxis.

So why does gout authority Dr. Michael H. Pillinger call pegloticase "a greatly underestimated and underutilized drug"? And why do the current American College of Rheumatology gout guidelines recommend pegloticase for refractory gout?

"Nothing else we have will get rid of tophi the way this drug gets rid of tophi," Dr. Pillinger explained at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

"Why do we care about that? Because tophi are erosive, they’re damaging, and also because they’re much more extensive than we think they are," said Dr. Pillinger, a rheumatologist and director of the crystal diseases study group at New York University.

Besides, the safety concern regarding this powerhouse urate-lowering drug has been resolved. The infusion reactions are readily avoidable. Pegloticase is not a drug rheumatologists should be scared of, he emphasized.

Dr. Pillinger cited an eye-opening study that demonstrated just how much larger gout patients’ total body urate burden actually is compared with what’s apparent clinically. Investigators at the University of British Columbia, Vancouver, used dual-energy CT to assess urate deposits in 20 consecutive patients with tophaceous gout and 10 controls with other arthritic conditions. Physical evaluation of the gout patients turned up 111 areas of urate deposition; dual-energy CT revealed 440 such areas. The mean total urate volume was a hefty 40.2 cm³ (Ann. Rheum. Dis. 2009;68:1609-12).

"There’s a lot more tophi under the surface," Dr. Pillinger commented.

Pegloticase is a recombinant porcine uricase that’s modified with a baboon N-terminus. It’s pegylated to reduce immunogenicity to the uricase and increase stability and half-life. Paradoxically, the drug is still quite immunogenic because many patients develop antibodies to the polyethylene glycol used in pegylation.

The drug’s urate-lowering effect is unmatched. Within 12-24 hours of the first dose, the plasma uric acid level plummets to almost nothing.

"What happens is that very, very quickly these patients are going to split into two groups. For one group this is the greatest drug in the world; their uric acid remains almost undetectable – and that’s in our sickest refractory patients. And then there’s another group that starts to fail. It’s in the neighborhood of 30%-40% of patients, so it’s a real problem. We know they’re failing because their uric acid level starts rising. They’re making antibodies and inactivating the drug every time it’s given. And they’re the ones who get bad infusion reactions," the rheumatologist explained.

The solution to using pegloticase safely is to routinely measure serum urate 1-2 days before each infusion. If the serum urate climbs to 6 mg/dL on one or two occasions, it’s time to discontinue the drug.

"For everybody else, they’re going to do really, really well," Dr. Pillinger said.

A key point emphasized in the 2012 ACR gout guidelines (Arthritis Care Res. 2012;64:1431-46; 1447-61) is that when patients go on pegloticase, all other urate-lowering therapies must be stopped as a matter of safety. Otherwise, it’s impossible to use the pre-infusion plasma urate measurement to determine if pegloticase has stopped working.

The ACR guidelines recommend pegloticase as third-line urate-lowering therapy in patients who are not at target despite maximum-dose therapy with a xanthine oxidase inhibitor plus second-line therapy with probenecid, losartan, or fenofibrate.

Dr. Pillinger reported having received research grants from Savient, which markets pegloticase, and Takeda.

[email protected]

Cell undergoing mitosis

(endoplasmic reticulum in

green, mitochondria in red,

and chromosomes in blue)

Wellcome Images

The dynein-binding protein Lis1 is critical for hematopoietic stem cell (HSC) function and blood formation, according to a paper published in Nature Genetics.

Investigators found that Lis1 regulates asymmetric division of HSCs, ensuring the cells correctly differentiate to provide an adequate supply of new blood cells.

The research also indicated that Lis1 plays a key role in leukemias, as leukemic stem cells rely on the protein to regulate and sustain their growth.

“[Asymmetric division] is very important for the proper generation of all the cells needed for the development and function of many normal tissues,” said study author Tannishtha Reya, PhD, of the University of California, San Diego School of Medicine.

When cells divide, Lis1 controls orientation of the mitotic spindle, an apparatus of subcellular fibers that segregates chromosomes during cell division.

“During division, the spindle is attached to a particular point on the cell membrane, which also determines the axis along which the cell will divide,” Dr Reya said. “Because proteins are not evenly distributed throughout the cell, the axis of division, in turn, determines the types and amounts of proteins that get distributed to each daughter cell.”

When the investigators deleted Lis1 from mouse HSCs, differentiation was radically altered. Asymmetric division increased and accelerated differentiation.

This led to an oversupply of specialized cells and an ever-diminishing reserve of undifferentiated stem cells, which eventually resulted in a bloodless mouse.

“What we found was that a large part of the defect in blood formation was due to a failure of stem cells to expand,” Dr Reya said.

“Instead of undergoing symmetric divisions to generate 2 stem cell daughters, they predominantly underwent asymmetric division to generate more specialized cells. As a result, the mice were unable to generate enough stem cells to sustain blood cell production.”

The investigators next looked at how leukemic stem cells in mice behaved when the Lis1 signaling pathway was blocked. And the team discovered that these cells also lost the ability to renew and propagate.

“In this sense, the effect Lis1 has on leukemic self-renewal parallels its role in normal stem cell self-renewal,” Dr Reya said.

She added that these findings shed new light on the fundamental regulators of cell growth, both in normal development and in cancer.

“Our work shows that elimination of Lis1 potently inhibits cancer growth and identifies Lis1 and other regulators of protein inheritance as a new class of molecules that could be targeted in cancer therapy,” she said.

However, it remains to be seen whether inhibiting Lis1 in cancer cells would produce unacceptable consequences in normal cells as well.

“Agents that target Lis1 might be more specific and less toxic [than chemotherapy],” Dr Reya said, “which would give them significant clinical value.”

Cell undergoing mitosis

(endoplasmic reticulum in

green, mitochondria in red,

and chromosomes in blue)

Wellcome Images

The dynein-binding protein Lis1 is critical for hematopoietic stem cell (HSC) function and blood formation, according to a paper published in Nature Genetics.

Investigators found that Lis1 regulates asymmetric division of HSCs, ensuring the cells correctly differentiate to provide an adequate supply of new blood cells.

The research also indicated that Lis1 plays a key role in leukemias, as leukemic stem cells rely on the protein to regulate and sustain their growth.

“[Asymmetric division] is very important for the proper generation of all the cells needed for the development and function of many normal tissues,” said study author Tannishtha Reya, PhD, of the University of California, San Diego School of Medicine.

When cells divide, Lis1 controls orientation of the mitotic spindle, an apparatus of subcellular fibers that segregates chromosomes during cell division.

“During division, the spindle is attached to a particular point on the cell membrane, which also determines the axis along which the cell will divide,” Dr Reya said. “Because proteins are not evenly distributed throughout the cell, the axis of division, in turn, determines the types and amounts of proteins that get distributed to each daughter cell.”

When the investigators deleted Lis1 from mouse HSCs, differentiation was radically altered. Asymmetric division increased and accelerated differentiation.

This led to an oversupply of specialized cells and an ever-diminishing reserve of undifferentiated stem cells, which eventually resulted in a bloodless mouse.

“What we found was that a large part of the defect in blood formation was due to a failure of stem cells to expand,” Dr Reya said.

“Instead of undergoing symmetric divisions to generate 2 stem cell daughters, they predominantly underwent asymmetric division to generate more specialized cells. As a result, the mice were unable to generate enough stem cells to sustain blood cell production.”

The investigators next looked at how leukemic stem cells in mice behaved when the Lis1 signaling pathway was blocked. And the team discovered that these cells also lost the ability to renew and propagate.

“In this sense, the effect Lis1 has on leukemic self-renewal parallels its role in normal stem cell self-renewal,” Dr Reya said.

She added that these findings shed new light on the fundamental regulators of cell growth, both in normal development and in cancer.

“Our work shows that elimination of Lis1 potently inhibits cancer growth and identifies Lis1 and other regulators of protein inheritance as a new class of molecules that could be targeted in cancer therapy,” she said.

However, it remains to be seen whether inhibiting Lis1 in cancer cells would produce unacceptable consequences in normal cells as well.

“Agents that target Lis1 might be more specific and less toxic [than chemotherapy],” Dr Reya said, “which would give them significant clinical value.”

Cell undergoing mitosis

(endoplasmic reticulum in

green, mitochondria in red,

and chromosomes in blue)

Wellcome Images

The dynein-binding protein Lis1 is critical for hematopoietic stem cell (HSC) function and blood formation, according to a paper published in Nature Genetics.

Investigators found that Lis1 regulates asymmetric division of HSCs, ensuring the cells correctly differentiate to provide an adequate supply of new blood cells.

The research also indicated that Lis1 plays a key role in leukemias, as leukemic stem cells rely on the protein to regulate and sustain their growth.

“[Asymmetric division] is very important for the proper generation of all the cells needed for the development and function of many normal tissues,” said study author Tannishtha Reya, PhD, of the University of California, San Diego School of Medicine.

When cells divide, Lis1 controls orientation of the mitotic spindle, an apparatus of subcellular fibers that segregates chromosomes during cell division.

“During division, the spindle is attached to a particular point on the cell membrane, which also determines the axis along which the cell will divide,” Dr Reya said. “Because proteins are not evenly distributed throughout the cell, the axis of division, in turn, determines the types and amounts of proteins that get distributed to each daughter cell.”

When the investigators deleted Lis1 from mouse HSCs, differentiation was radically altered. Asymmetric division increased and accelerated differentiation.

This led to an oversupply of specialized cells and an ever-diminishing reserve of undifferentiated stem cells, which eventually resulted in a bloodless mouse.

“What we found was that a large part of the defect in blood formation was due to a failure of stem cells to expand,” Dr Reya said.

“Instead of undergoing symmetric divisions to generate 2 stem cell daughters, they predominantly underwent asymmetric division to generate more specialized cells. As a result, the mice were unable to generate enough stem cells to sustain blood cell production.”

The investigators next looked at how leukemic stem cells in mice behaved when the Lis1 signaling pathway was blocked. And the team discovered that these cells also lost the ability to renew and propagate.

“In this sense, the effect Lis1 has on leukemic self-renewal parallels its role in normal stem cell self-renewal,” Dr Reya said.

She added that these findings shed new light on the fundamental regulators of cell growth, both in normal development and in cancer.

“Our work shows that elimination of Lis1 potently inhibits cancer growth and identifies Lis1 and other regulators of protein inheritance as a new class of molecules that could be targeted in cancer therapy,” she said.

However, it remains to be seen whether inhibiting Lis1 in cancer cells would produce unacceptable consequences in normal cells as well.

“Agents that target Lis1 might be more specific and less toxic [than chemotherapy],” Dr Reya said, “which would give them significant clinical value.”

Axel Kallies, PhD

Walter and Eliza Hall Institute

Preclinical research indicates that immune cells undergo daily, spontaneous changes that could lead to diffuse large B-cell lymphoma (DLBCL), if not for the diligent surveillance of the immune system.

Experiments in mice revealed that T cells are responsible for eliminating potentially cancerous B cells in their early stages, before they develop into DLBCL.

This immune surveillance may account for what the researchers call the “surprising rarity” of DLBCL in humans, given how often these spontaneous changes occur.

The team believes their discovery could eventually help physicians identify patients at high risk of developing DLBCL, thereby enabling preventative treatment.

Axel Kallies, PhD, of the Walter and Eliza Hall Institute of Medical Research in Victoria, Australia, and his colleagues conducted this research and recounted their findings in Nature Medicine.

The researchers knew that many DLBCL cases are characterized by deregulated expression of the oncogene BCL6 or loss of function of the tumor suppressor gene PRDM1 (also known as BLIMP1).

But mice with mutations in either gene infrequently develop lymphoma, and, if they do, the process is slow. The same is true for humans with BCL6 mutations.

To investigate this phenomenon, the team conducted experiments in mice. The results showed that T cells prevent lymphoma development caused by Blimp1 deficiency or overexpression of Bcl6. But impairing T-cell control removed this protection.

“[W]e ‘disabled’ the T cells to suppress the immune system and, to our surprise, found that lymphoma developed in a matter of weeks, where it would normally take years,” Dr Kallies said.

The researchers also found that the DLBCL-like disease the mice developed could be eliminated by polyclonal CD8+ T cells. But deletion of the B-lymphoma cells was dependent upon the T-cell receptor, co-stimulation via CD28, and expression of the Fas ligand.

These results suggest that malignant transformation of mature B cells—in mice and perhaps in humans—is only possible when T-cell-mediated tumor surveillance is disabled.

“Each and every one of us has spontaneous mutations in our immune B cells that occur as a result of their normal function,” Dr Kallies said. “It is then somewhat of a paradox that B-cell lymphoma is not more common in the population.”

“Our finding that immune surveillance by T cells enables early detection and elimination of these cancerous and pre-cancerous cells provides an answer to this puzzle and proves that immune surveillance is essential to preventing the development of this blood cancer.”

Study author David Tarlinton, PhD, also of the Walter and Eliza Hall Institute, said this research could be used to help scientists identify pre-cancerous cells in the initial stages of their development, thereby enabling early intervention for patients at risk of developing DLBCL.

“In the majority of patients, the first sign that something is wrong is finding an established tumor, which, in many cases, is difficult to treat,” he noted.

“Now that we know B-cell lymphoma is suppressed by the immune system, we could use this information to develop a diagnostic test that identifies people in early stages of this disease, before tumors develop and they progress to cancer. There are already therapies that could remove these aberrant B cells in at-risk patients, so once a test is developed, it can be rapidly moved towards clinical use.”

Axel Kallies, PhD

Walter and Eliza Hall Institute

Preclinical research indicates that immune cells undergo daily, spontaneous changes that could lead to diffuse large B-cell lymphoma (DLBCL), if not for the diligent surveillance of the immune system.

Experiments in mice revealed that T cells are responsible for eliminating potentially cancerous B cells in their early stages, before they develop into DLBCL.

This immune surveillance may account for what the researchers call the “surprising rarity” of DLBCL in humans, given how often these spontaneous changes occur.

The team believes their discovery could eventually help physicians identify patients at high risk of developing DLBCL, thereby enabling preventative treatment.

Axel Kallies, PhD, of the Walter and Eliza Hall Institute of Medical Research in Victoria, Australia, and his colleagues conducted this research and recounted their findings in Nature Medicine.

The researchers knew that many DLBCL cases are characterized by deregulated expression of the oncogene BCL6 or loss of function of the tumor suppressor gene PRDM1 (also known as BLIMP1).

But mice with mutations in either gene infrequently develop lymphoma, and, if they do, the process is slow. The same is true for humans with BCL6 mutations.

To investigate this phenomenon, the team conducted experiments in mice. The results showed that T cells prevent lymphoma development caused by Blimp1 deficiency or overexpression of Bcl6. But impairing T-cell control removed this protection.

“[W]e ‘disabled’ the T cells to suppress the immune system and, to our surprise, found that lymphoma developed in a matter of weeks, where it would normally take years,” Dr Kallies said.

The researchers also found that the DLBCL-like disease the mice developed could be eliminated by polyclonal CD8+ T cells. But deletion of the B-lymphoma cells was dependent upon the T-cell receptor, co-stimulation via CD28, and expression of the Fas ligand.

These results suggest that malignant transformation of mature B cells—in mice and perhaps in humans—is only possible when T-cell-mediated tumor surveillance is disabled.

“Each and every one of us has spontaneous mutations in our immune B cells that occur as a result of their normal function,” Dr Kallies said. “It is then somewhat of a paradox that B-cell lymphoma is not more common in the population.”

“Our finding that immune surveillance by T cells enables early detection and elimination of these cancerous and pre-cancerous cells provides an answer to this puzzle and proves that immune surveillance is essential to preventing the development of this blood cancer.”

Study author David Tarlinton, PhD, also of the Walter and Eliza Hall Institute, said this research could be used to help scientists identify pre-cancerous cells in the initial stages of their development, thereby enabling early intervention for patients at risk of developing DLBCL.

“In the majority of patients, the first sign that something is wrong is finding an established tumor, which, in many cases, is difficult to treat,” he noted.

“Now that we know B-cell lymphoma is suppressed by the immune system, we could use this information to develop a diagnostic test that identifies people in early stages of this disease, before tumors develop and they progress to cancer. There are already therapies that could remove these aberrant B cells in at-risk patients, so once a test is developed, it can be rapidly moved towards clinical use.”

Axel Kallies, PhD

Walter and Eliza Hall Institute

Preclinical research indicates that immune cells undergo daily, spontaneous changes that could lead to diffuse large B-cell lymphoma (DLBCL), if not for the diligent surveillance of the immune system.

Experiments in mice revealed that T cells are responsible for eliminating potentially cancerous B cells in their early stages, before they develop into DLBCL.

This immune surveillance may account for what the researchers call the “surprising rarity” of DLBCL in humans, given how often these spontaneous changes occur.

The team believes their discovery could eventually help physicians identify patients at high risk of developing DLBCL, thereby enabling preventative treatment.

Axel Kallies, PhD, of the Walter and Eliza Hall Institute of Medical Research in Victoria, Australia, and his colleagues conducted this research and recounted their findings in Nature Medicine.

The researchers knew that many DLBCL cases are characterized by deregulated expression of the oncogene BCL6 or loss of function of the tumor suppressor gene PRDM1 (also known as BLIMP1).

But mice with mutations in either gene infrequently develop lymphoma, and, if they do, the process is slow. The same is true for humans with BCL6 mutations.

To investigate this phenomenon, the team conducted experiments in mice. The results showed that T cells prevent lymphoma development caused by Blimp1 deficiency or overexpression of Bcl6. But impairing T-cell control removed this protection.

“[W]e ‘disabled’ the T cells to suppress the immune system and, to our surprise, found that lymphoma developed in a matter of weeks, where it would normally take years,” Dr Kallies said.

The researchers also found that the DLBCL-like disease the mice developed could be eliminated by polyclonal CD8+ T cells. But deletion of the B-lymphoma cells was dependent upon the T-cell receptor, co-stimulation via CD28, and expression of the Fas ligand.

These results suggest that malignant transformation of mature B cells—in mice and perhaps in humans—is only possible when T-cell-mediated tumor surveillance is disabled.

“Each and every one of us has spontaneous mutations in our immune B cells that occur as a result of their normal function,” Dr Kallies said. “It is then somewhat of a paradox that B-cell lymphoma is not more common in the population.”

“Our finding that immune surveillance by T cells enables early detection and elimination of these cancerous and pre-cancerous cells provides an answer to this puzzle and proves that immune surveillance is essential to preventing the development of this blood cancer.”

Study author David Tarlinton, PhD, also of the Walter and Eliza Hall Institute, said this research could be used to help scientists identify pre-cancerous cells in the initial stages of their development, thereby enabling early intervention for patients at risk of developing DLBCL.

“In the majority of patients, the first sign that something is wrong is finding an established tumor, which, in many cases, is difficult to treat,” he noted.

“Now that we know B-cell lymphoma is suppressed by the immune system, we could use this information to develop a diagnostic test that identifies people in early stages of this disease, before tumors develop and they progress to cancer. There are already therapies that could remove these aberrant B cells in at-risk patients, so once a test is developed, it can be rapidly moved towards clinical use.”