Who is tired of the same old stuff when it comes to acne? Innovation in therapy has been stagnant with a flurry of “me too” reformulated fixed combinations. The only true advance has been in drug delivery, with new vehicles allowing for the solubilization of established drugs such as dapsone or the combination of incompatible actives such as benzoyl peroxide and a retinoid. Before we can welcome new drugs with open arms, we must first expand the construct of acne pathophysiology to identify more appropriate targets for said new drugs. In a recent article published online in the Journal of the American Academy of Dermatology in June, Metiko et al highlight this sentiment. Generations of dermatologists were taught the 3- to 4-step process (depending on the teacher) through which an acne lesion forms: (1) follicular epidermal hyperproliferation, (2) Propionibacterium acnes colonization, and (3) inflammation. However, the molecular underpinnings of this theory have been challenged for more than a decade, with research highlighting the presence of preclinical inflammation, most recently found to be mediated by IL-1ß through a specific inflammasome pathway, NLRP3 (NOD-like receptor family, pyrin domain containing 3). Maybe we are missing a bridge between this stellar basic science and the clinical dermatologist who contends that the pesky microcomedone is the acne instigator. This short but sweet letter once again calls this antiquated prose into question in a highly visible clinical dermatology journal.

In thinking of new pathways and targets, Gupta et al published an article online in Archives of Dermatological Research on May 19 on the role of peroxisome proliferator-activated receptors (PPARs) and PPAR agonists in the treatment of multiple dermatologic diseases. For our purposes, I will highlight the section on acne and will start at the end: More research is needed. Peroxisome proliferator-activated receptors are nuclear hormone receptors that regulate gene expression, cell growth and differentiation, apoptosis, inflammatory responses, and tumorigenesis after binding with specific ligands. With respect to acne specifically, PPARs influence 2 of the pathophysiologic factors—sebum production and inflammation—due to their effect on lipid deposition in the sebocytes and inhibition of proinflammatory gene expression and downregulation of inflammatory cytokines. It appears that activation or inhibition of specific PPAR subtypes can either increase or decrease sebum production or be pro- or anti-inflammatory. The tough part is which receptors to activate and which to inhibit. This review related to an interesting clinical study that evaluated oral zileuton 600 mg administered 4 times daily for 3 months for acne. Zileuton inhibits leukotriene B4 production, which, as it turns out, is a natural ligand for PPARα. The idea here is that this blockade would be anti-inflammatory and indirectly inhibit the sebum production via PPARα suppression. The pilot study was reported as successful, with a decrease in the papulopustular acne severity index in a time-dependent manner in subjects evaluated.

What’s the issue?

So, what’s the point of this long-winded, double-paper review? We need to expand our acne horizons. We need new bench-to-bedside approaches. Which is your favorite target?

We want to know your views! Tell us what you think.

Who is tired of the same old stuff when it comes to acne? Innovation in therapy has been stagnant with a flurry of “me too” reformulated fixed combinations. The only true advance has been in drug delivery, with new vehicles allowing for the solubilization of established drugs such as dapsone or the combination of incompatible actives such as benzoyl peroxide and a retinoid. Before we can welcome new drugs with open arms, we must first expand the construct of acne pathophysiology to identify more appropriate targets for said new drugs. In a recent article published online in the Journal of the American Academy of Dermatology in June, Metiko et al highlight this sentiment. Generations of dermatologists were taught the 3- to 4-step process (depending on the teacher) through which an acne lesion forms: (1) follicular epidermal hyperproliferation, (2) Propionibacterium acnes colonization, and (3) inflammation. However, the molecular underpinnings of this theory have been challenged for more than a decade, with research highlighting the presence of preclinical inflammation, most recently found to be mediated by IL-1ß through a specific inflammasome pathway, NLRP3 (NOD-like receptor family, pyrin domain containing 3). Maybe we are missing a bridge between this stellar basic science and the clinical dermatologist who contends that the pesky microcomedone is the acne instigator. This short but sweet letter once again calls this antiquated prose into question in a highly visible clinical dermatology journal.

In thinking of new pathways and targets, Gupta et al published an article online in Archives of Dermatological Research on May 19 on the role of peroxisome proliferator-activated receptors (PPARs) and PPAR agonists in the treatment of multiple dermatologic diseases. For our purposes, I will highlight the section on acne and will start at the end: More research is needed. Peroxisome proliferator-activated receptors are nuclear hormone receptors that regulate gene expression, cell growth and differentiation, apoptosis, inflammatory responses, and tumorigenesis after binding with specific ligands. With respect to acne specifically, PPARs influence 2 of the pathophysiologic factors—sebum production and inflammation—due to their effect on lipid deposition in the sebocytes and inhibition of proinflammatory gene expression and downregulation of inflammatory cytokines. It appears that activation or inhibition of specific PPAR subtypes can either increase or decrease sebum production or be pro- or anti-inflammatory. The tough part is which receptors to activate and which to inhibit. This review related to an interesting clinical study that evaluated oral zileuton 600 mg administered 4 times daily for 3 months for acne. Zileuton inhibits leukotriene B4 production, which, as it turns out, is a natural ligand for PPARα. The idea here is that this blockade would be anti-inflammatory and indirectly inhibit the sebum production via PPARα suppression. The pilot study was reported as successful, with a decrease in the papulopustular acne severity index in a time-dependent manner in subjects evaluated.

What’s the issue?

So, what’s the point of this long-winded, double-paper review? We need to expand our acne horizons. We need new bench-to-bedside approaches. Which is your favorite target?

We want to know your views! Tell us what you think.

Who is tired of the same old stuff when it comes to acne? Innovation in therapy has been stagnant with a flurry of “me too” reformulated fixed combinations. The only true advance has been in drug delivery, with new vehicles allowing for the solubilization of established drugs such as dapsone or the combination of incompatible actives such as benzoyl peroxide and a retinoid. Before we can welcome new drugs with open arms, we must first expand the construct of acne pathophysiology to identify more appropriate targets for said new drugs. In a recent article published online in the Journal of the American Academy of Dermatology in June, Metiko et al highlight this sentiment. Generations of dermatologists were taught the 3- to 4-step process (depending on the teacher) through which an acne lesion forms: (1) follicular epidermal hyperproliferation, (2) Propionibacterium acnes colonization, and (3) inflammation. However, the molecular underpinnings of this theory have been challenged for more than a decade, with research highlighting the presence of preclinical inflammation, most recently found to be mediated by IL-1ß through a specific inflammasome pathway, NLRP3 (NOD-like receptor family, pyrin domain containing 3). Maybe we are missing a bridge between this stellar basic science and the clinical dermatologist who contends that the pesky microcomedone is the acne instigator. This short but sweet letter once again calls this antiquated prose into question in a highly visible clinical dermatology journal.

In thinking of new pathways and targets, Gupta et al published an article online in Archives of Dermatological Research on May 19 on the role of peroxisome proliferator-activated receptors (PPARs) and PPAR agonists in the treatment of multiple dermatologic diseases. For our purposes, I will highlight the section on acne and will start at the end: More research is needed. Peroxisome proliferator-activated receptors are nuclear hormone receptors that regulate gene expression, cell growth and differentiation, apoptosis, inflammatory responses, and tumorigenesis after binding with specific ligands. With respect to acne specifically, PPARs influence 2 of the pathophysiologic factors—sebum production and inflammation—due to their effect on lipid deposition in the sebocytes and inhibition of proinflammatory gene expression and downregulation of inflammatory cytokines. It appears that activation or inhibition of specific PPAR subtypes can either increase or decrease sebum production or be pro- or anti-inflammatory. The tough part is which receptors to activate and which to inhibit. This review related to an interesting clinical study that evaluated oral zileuton 600 mg administered 4 times daily for 3 months for acne. Zileuton inhibits leukotriene B4 production, which, as it turns out, is a natural ligand for PPARα. The idea here is that this blockade would be anti-inflammatory and indirectly inhibit the sebum production via PPARα suppression. The pilot study was reported as successful, with a decrease in the papulopustular acne severity index in a time-dependent manner in subjects evaluated.

What’s the issue?

So, what’s the point of this long-winded, double-paper review? We need to expand our acne horizons. We need new bench-to-bedside approaches. Which is your favorite target?

We want to know your views! Tell us what you think.

 

 

Blood samples

Photo by Graham Colm

 

GLASGOW—A non-invasive prenatal test (NIPT) used to identify chromosomal fetal disorders can detect maternal cancers before symptoms appear, a new study has shown.

Testing revealed chromosomal abnormalities in 3 women that bore a resemblance to abnormalities observed in cancers. And additional testing confirmed the women had cancer—Hodgkin lymphoma (HL), follicular lymphoma (FL), and ovarian carcinoma.

This research was presented at the European Human Genetics Conference 2015 and published simultaneously in JAMA Oncology.

Nathalie Brison, PhD, of University Hospitals Leuven in Belgium, and her colleagues conducted this research with the goal of improving the NIPT test. They wanted to overcome some of the technical problems that can cause the test to produce false-negative or false-positive results.

“Even though it is very reliable, we believed that we could make it even better, and, in doing so, we could also find other chromosomal abnormalities apart from the traditional trisomy syndromes—Down’s [trisomy 21], Edward’s [trisomy 18], and Patau [trisomy 13],” Dr Brison said.

“Using the new, adapted test in over 6000 pregnancies, and looking at other chromosomes, we identified 3 different genomic abnormalities in 3 women that could not be linked to either the maternal or fetal genomic profile. We realized that the abnormalities bore a resemblance to those found in cancer and referred the women to the oncology unit.”

Further examination, including whole-body MRI scanning and pathological and genetic investigations, revealed the presence of 3 different early stage cancers in the women: ovarian carcinoma, FL, and HL.

The researchers said that, without NIPT, these cancers likely would not have been detected until the women developed symptoms.

“Considering the bad prognosis of some cancers when detected later, and given that we know that it is both possible and safe to treat the disease during pregnancy, this is an important added advantage of NIPT,” said study author Joris Vermeesch, PhD, also of University Hospitals Leuven.

“During pregnancy, cancer-related symptoms may well be masked. Fatigue, nausea, abdominal pain, and vaginal blood loss are easily interpretable as a normal part of being pregnant. NIPT offers an opportunity for the accurate screening of high-risk women for cancer, allowing us to overcome the challenge of early diagnosis in pregnant women.”

Two of the 3 women diagnosed with cancer were treated. The woman with ovarian cancer was treated after delivery.

The woman with HL was treated during pregnancy and ultimately gave birth to a healthy girl. The woman with FL has indolent disease and may not require treatment for years, according to the researchers.

Follow-up investigations in the treated women showed that NIPT had the additional advantage of allowing for treatment monitoring. The researchers were able to see that chromosomal profiles became normal during and after chemotherapy.

Because NIPT involves looking at chromosomes other than 13, 18, and 21, the women taking part in this study were informed about the possibility of incidental findings.

“However, our study feeds into the ethical debate about whether or not to report incidental findings to patients and also has implications for the current political discussions concerning reimbursement and funding of NIPT by national healthcare systems,” Dr Vermeesch said.

The results also suggest that NIPT might enable the detection of pre-symptomatic cancers in the general population.

“We now know that it is possible to offer the accurate detection of chromosomally imbalanced cancers to the general population via minimally invasive screening methods,” Dr Brison said. “The normalization of the NIPT profile in these patients following treatment indicates that we can also measure response to treatment as early as after the first administration of chemotherapy.”

“Of course, larger-scale studies will be required to validate these results further, but we are confident that we have made an important step towards the possibility of wide-scale, effective, non-invasive cancer screening capable of detecting disease at an early stage.”

 

 

Blood samples

Photo by Graham Colm

 

GLASGOW—A non-invasive prenatal test (NIPT) used to identify chromosomal fetal disorders can detect maternal cancers before symptoms appear, a new study has shown.

Testing revealed chromosomal abnormalities in 3 women that bore a resemblance to abnormalities observed in cancers. And additional testing confirmed the women had cancer—Hodgkin lymphoma (HL), follicular lymphoma (FL), and ovarian carcinoma.

This research was presented at the European Human Genetics Conference 2015 and published simultaneously in JAMA Oncology.

Nathalie Brison, PhD, of University Hospitals Leuven in Belgium, and her colleagues conducted this research with the goal of improving the NIPT test. They wanted to overcome some of the technical problems that can cause the test to produce false-negative or false-positive results.

“Even though it is very reliable, we believed that we could make it even better, and, in doing so, we could also find other chromosomal abnormalities apart from the traditional trisomy syndromes—Down’s [trisomy 21], Edward’s [trisomy 18], and Patau [trisomy 13],” Dr Brison said.

“Using the new, adapted test in over 6000 pregnancies, and looking at other chromosomes, we identified 3 different genomic abnormalities in 3 women that could not be linked to either the maternal or fetal genomic profile. We realized that the abnormalities bore a resemblance to those found in cancer and referred the women to the oncology unit.”

Further examination, including whole-body MRI scanning and pathological and genetic investigations, revealed the presence of 3 different early stage cancers in the women: ovarian carcinoma, FL, and HL.

The researchers said that, without NIPT, these cancers likely would not have been detected until the women developed symptoms.

“Considering the bad prognosis of some cancers when detected later, and given that we know that it is both possible and safe to treat the disease during pregnancy, this is an important added advantage of NIPT,” said study author Joris Vermeesch, PhD, also of University Hospitals Leuven.

“During pregnancy, cancer-related symptoms may well be masked. Fatigue, nausea, abdominal pain, and vaginal blood loss are easily interpretable as a normal part of being pregnant. NIPT offers an opportunity for the accurate screening of high-risk women for cancer, allowing us to overcome the challenge of early diagnosis in pregnant women.”

Two of the 3 women diagnosed with cancer were treated. The woman with ovarian cancer was treated after delivery.

The woman with HL was treated during pregnancy and ultimately gave birth to a healthy girl. The woman with FL has indolent disease and may not require treatment for years, according to the researchers.

Follow-up investigations in the treated women showed that NIPT had the additional advantage of allowing for treatment monitoring. The researchers were able to see that chromosomal profiles became normal during and after chemotherapy.

Because NIPT involves looking at chromosomes other than 13, 18, and 21, the women taking part in this study were informed about the possibility of incidental findings.

“However, our study feeds into the ethical debate about whether or not to report incidental findings to patients and also has implications for the current political discussions concerning reimbursement and funding of NIPT by national healthcare systems,” Dr Vermeesch said.

The results also suggest that NIPT might enable the detection of pre-symptomatic cancers in the general population.

“We now know that it is possible to offer the accurate detection of chromosomally imbalanced cancers to the general population via minimally invasive screening methods,” Dr Brison said. “The normalization of the NIPT profile in these patients following treatment indicates that we can also measure response to treatment as early as after the first administration of chemotherapy.”

“Of course, larger-scale studies will be required to validate these results further, but we are confident that we have made an important step towards the possibility of wide-scale, effective, non-invasive cancer screening capable of detecting disease at an early stage.”

 

 

Blood samples

Photo by Graham Colm

 

GLASGOW—A non-invasive prenatal test (NIPT) used to identify chromosomal fetal disorders can detect maternal cancers before symptoms appear, a new study has shown.

Testing revealed chromosomal abnormalities in 3 women that bore a resemblance to abnormalities observed in cancers. And additional testing confirmed the women had cancer—Hodgkin lymphoma (HL), follicular lymphoma (FL), and ovarian carcinoma.

This research was presented at the European Human Genetics Conference 2015 and published simultaneously in JAMA Oncology.

Nathalie Brison, PhD, of University Hospitals Leuven in Belgium, and her colleagues conducted this research with the goal of improving the NIPT test. They wanted to overcome some of the technical problems that can cause the test to produce false-negative or false-positive results.

“Even though it is very reliable, we believed that we could make it even better, and, in doing so, we could also find other chromosomal abnormalities apart from the traditional trisomy syndromes—Down’s [trisomy 21], Edward’s [trisomy 18], and Patau [trisomy 13],” Dr Brison said.

“Using the new, adapted test in over 6000 pregnancies, and looking at other chromosomes, we identified 3 different genomic abnormalities in 3 women that could not be linked to either the maternal or fetal genomic profile. We realized that the abnormalities bore a resemblance to those found in cancer and referred the women to the oncology unit.”

Further examination, including whole-body MRI scanning and pathological and genetic investigations, revealed the presence of 3 different early stage cancers in the women: ovarian carcinoma, FL, and HL.

The researchers said that, without NIPT, these cancers likely would not have been detected until the women developed symptoms.

“Considering the bad prognosis of some cancers when detected later, and given that we know that it is both possible and safe to treat the disease during pregnancy, this is an important added advantage of NIPT,” said study author Joris Vermeesch, PhD, also of University Hospitals Leuven.

“During pregnancy, cancer-related symptoms may well be masked. Fatigue, nausea, abdominal pain, and vaginal blood loss are easily interpretable as a normal part of being pregnant. NIPT offers an opportunity for the accurate screening of high-risk women for cancer, allowing us to overcome the challenge of early diagnosis in pregnant women.”

Two of the 3 women diagnosed with cancer were treated. The woman with ovarian cancer was treated after delivery.

The woman with HL was treated during pregnancy and ultimately gave birth to a healthy girl. The woman with FL has indolent disease and may not require treatment for years, according to the researchers.

Follow-up investigations in the treated women showed that NIPT had the additional advantage of allowing for treatment monitoring. The researchers were able to see that chromosomal profiles became normal during and after chemotherapy.

Because NIPT involves looking at chromosomes other than 13, 18, and 21, the women taking part in this study were informed about the possibility of incidental findings.

“However, our study feeds into the ethical debate about whether or not to report incidental findings to patients and also has implications for the current political discussions concerning reimbursement and funding of NIPT by national healthcare systems,” Dr Vermeesch said.

The results also suggest that NIPT might enable the detection of pre-symptomatic cancers in the general population.

“We now know that it is possible to offer the accurate detection of chromosomally imbalanced cancers to the general population via minimally invasive screening methods,” Dr Brison said. “The normalization of the NIPT profile in these patients following treatment indicates that we can also measure response to treatment as early as after the first administration of chemotherapy.”

“Of course, larger-scale studies will be required to validate these results further, but we are confident that we have made an important step towards the possibility of wide-scale, effective, non-invasive cancer screening capable of detecting disease at an early stage.”

Malaria-infected cell bursting

Image by Peter H. Seeberger

A study published in PLOS Pathogens suggests the different metabolic states of reticulocytes and erythrocytes provide different growth conditions for the malaria parasites Plasmodium vivax and Plasmodium falciparum.

As P vivax grows exclusively in reticulocytes, and P falciparum grows primarily in erythrocytes, the research suggests drugs that work against one species might fail to be effective against the other.

Andrew Waters, PhD, of the University of Glasgow in the UK, and his colleagues set out to determine whether the 2 classes of host red blood cells offer different resources for parasite survival and whether these resources could influence antimalarial drug efficacy.

To do that, the team analyzed the metabolites present in reticulocytes and erythrocytes. They found that reticulocytes contain elevated levels of many metabolites that could potentially be scavenged by the invading and growing malaria parasite.

And there was a marked overlap in metabolic pathways observed in the reticulocyte and those predicted in the parasite. The researchers thought these common pathways might be uniquely dispensable to Plasmodium during its growth in reticulocytes but essential—and therefore a good drug target—for growth in erythrocytes.

To test this hypothesis, the team disrupted some of the overlapping pathways in P berghei, a species that causes malaria in mice and, similar to P vivax, has a strong preference for growth in reticulocytes.

They found the mutant P berghei strains could grow in mouse reticulocytes (utilizing the host’s metabolic products).

The researchers also compared the sensitivity of P berghei and P falciparum to a drug known to target one of the overlapping pathways, the pyrimidine biosynthesis inhibitor 5-fluoroorotate (5FOA).

They found that P berghei was considerably less sensitive to 5FOA than P falciparum. The IC₅₀ value of 5FOA in vitro was almost 90-fold higher in P berghei than in P falciparum.

This was presumably because P berghei was able to scavenge the metabolites from their reticulocyte host environment, but no such external sources were available in the erythrocyte host cells invaded by P falciparum.

The researchers said their results indicate that reticulocytes provide a highly enriched host cell environment for Plasmodium parasites, and the availability of the reticulocyte metabolome might reduce or block the efficacy of antimalarial drugs that target parasite metabolism.

Malaria-infected cell bursting

Image by Peter H. Seeberger

A study published in PLOS Pathogens suggests the different metabolic states of reticulocytes and erythrocytes provide different growth conditions for the malaria parasites Plasmodium vivax and Plasmodium falciparum.

As P vivax grows exclusively in reticulocytes, and P falciparum grows primarily in erythrocytes, the research suggests drugs that work against one species might fail to be effective against the other.

Andrew Waters, PhD, of the University of Glasgow in the UK, and his colleagues set out to determine whether the 2 classes of host red blood cells offer different resources for parasite survival and whether these resources could influence antimalarial drug efficacy.

To do that, the team analyzed the metabolites present in reticulocytes and erythrocytes. They found that reticulocytes contain elevated levels of many metabolites that could potentially be scavenged by the invading and growing malaria parasite.

And there was a marked overlap in metabolic pathways observed in the reticulocyte and those predicted in the parasite. The researchers thought these common pathways might be uniquely dispensable to Plasmodium during its growth in reticulocytes but essential—and therefore a good drug target—for growth in erythrocytes.

To test this hypothesis, the team disrupted some of the overlapping pathways in P berghei, a species that causes malaria in mice and, similar to P vivax, has a strong preference for growth in reticulocytes.

They found the mutant P berghei strains could grow in mouse reticulocytes (utilizing the host’s metabolic products).

The researchers also compared the sensitivity of P berghei and P falciparum to a drug known to target one of the overlapping pathways, the pyrimidine biosynthesis inhibitor 5-fluoroorotate (5FOA).

They found that P berghei was considerably less sensitive to 5FOA than P falciparum. The IC₅₀ value of 5FOA in vitro was almost 90-fold higher in P berghei than in P falciparum.

This was presumably because P berghei was able to scavenge the metabolites from their reticulocyte host environment, but no such external sources were available in the erythrocyte host cells invaded by P falciparum.

The researchers said their results indicate that reticulocytes provide a highly enriched host cell environment for Plasmodium parasites, and the availability of the reticulocyte metabolome might reduce or block the efficacy of antimalarial drugs that target parasite metabolism.

Malaria-infected cell bursting

Image by Peter H. Seeberger

A study published in PLOS Pathogens suggests the different metabolic states of reticulocytes and erythrocytes provide different growth conditions for the malaria parasites Plasmodium vivax and Plasmodium falciparum.

As P vivax grows exclusively in reticulocytes, and P falciparum grows primarily in erythrocytes, the research suggests drugs that work against one species might fail to be effective against the other.

Andrew Waters, PhD, of the University of Glasgow in the UK, and his colleagues set out to determine whether the 2 classes of host red blood cells offer different resources for parasite survival and whether these resources could influence antimalarial drug efficacy.

To do that, the team analyzed the metabolites present in reticulocytes and erythrocytes. They found that reticulocytes contain elevated levels of many metabolites that could potentially be scavenged by the invading and growing malaria parasite.

And there was a marked overlap in metabolic pathways observed in the reticulocyte and those predicted in the parasite. The researchers thought these common pathways might be uniquely dispensable to Plasmodium during its growth in reticulocytes but essential—and therefore a good drug target—for growth in erythrocytes.

To test this hypothesis, the team disrupted some of the overlapping pathways in P berghei, a species that causes malaria in mice and, similar to P vivax, has a strong preference for growth in reticulocytes.

They found the mutant P berghei strains could grow in mouse reticulocytes (utilizing the host’s metabolic products).

The researchers also compared the sensitivity of P berghei and P falciparum to a drug known to target one of the overlapping pathways, the pyrimidine biosynthesis inhibitor 5-fluoroorotate (5FOA).

They found that P berghei was considerably less sensitive to 5FOA than P falciparum. The IC₅₀ value of 5FOA in vitro was almost 90-fold higher in P berghei than in P falciparum.

This was presumably because P berghei was able to scavenge the metabolites from their reticulocyte host environment, but no such external sources were available in the erythrocyte host cells invaded by P falciparum.

The researchers said their results indicate that reticulocytes provide a highly enriched host cell environment for Plasmodium parasites, and the availability of the reticulocyte metabolome might reduce or block the efficacy of antimalarial drugs that target parasite metabolism.

INDIANAPOLIS – About 50% of women with multiple sclerosis are postmenopausal, but objective data about the impact of menopause on the course of multiple sclerosis are lacking.

“We don’t know anything about the impact of menopause on the MS course; there is wide variability in patient-reported outcomes, but nothing written about comorbidities or symptom management,” Dr. Riley Bove, a neurologist at Brigham and Women’s Hospital, Boston, said at the annual meeting of the Consortium of Multiple Sclerosis Centers. “We’ve been working on this. A lot of it is unknown.”

She described menopause is “an opportunity for providers to tackle symptoms and improve well-being and discuss meaningful quality of life and priorities with patients. It can be a good time to talk about these things.”

In a study that Dr. Bove conducted with the online patient-powered research platform PatientsLikeMe, female MS patients were asked to describe the impact of menopause on their disease. Among the themes that emerged were an occasional perimenopausal onset of MS (“menopause and MS symptoms were pretty much simultaneous,” one 58-year-old respondent said); the effect of hot flashes on MS symptoms (“I confused the two, especially hot flashes,” said a 53-year-old woman); and worsening of MS-related disability after menopause, particularly surgical (“Before I stopped taking birth control pills I was working and able to walk and house clean , etc.,” a 53-year-old respondent said. “I had the surgery, and I started to progress toward being completely wheelchair bound.”)

When it comes to solid recommendations for how to manage MS symptoms that overlap with menopause, “we’re in an evidence-free zone,” Dr. Bove said. “Symptoms in MS are kind of like dominoes: You have difficulty sleeping and then your day is off, fatigue is up and your mood is off, and everything can spiral. In the clinic, perimenopausal women often say things like, ‘I feel like I’m falling apart’ or ‘something has to give’ or ‘I need a change.’ ”

Common overlapping symptoms include vasomotor manifestations such as hot flashes, cold flashes, vascular instability, and rapid heartbeat. “The leading mechanistic explanation for the vasomotor symptoms is that abrupt hormone deprivation will result in the loss of negative feedback over hypothalamic NA [noradrenaline] synthesis,” Dr. Bove explained. “The proximity of the hypothalamic thermoregulatory center to luteinizing hormone–releasing hormone-producing areas may also be involved.”

Sleep disturbances and insomnia in menopausal MS patients can impact fatigue and mood. Also, hot flashes can directly exacerbate the MS symptoms, fluctuating over the day or the week.

According to recommendations from the North American Menopause Society, estradiol is the most effective therapy for treating vasomotor symptoms. Other options include selective serotonin reuptake inhibitors (SSRIs) and selective noradrenergic reuptake inhibitors (SNRIs). “Probably the best studied SNRI is venlafaxine,” Dr. Bove said. “It seems to have modest effects on sleep quality and insomnia perimenopausally, as well as on hot flashes.”

Other alternatives include clonidine and gabapentin.

“If a patient wants to use [hormone therapy] for menopausal symptoms, it has to be an individualized approach,” Dr. Bove said. “You have to communicate with the primary care physician to understand what else is going on in this woman’s medical history. The current recommendations are to treat the symptoms with as low a dose as possible for as short a duration as possible. Our MS patients are also at risk for neurodegeneration, for brain volume loss, for cognitive decline, and for worsening function over time.”

With respect to cognition, observational studies have demonstrated that during a certain window of opportunity – defined as within 5 years of the last menstrual period – hormone therapy (HT) may have protective effects against Alzheimer’s disease and against cognitive decline in general. “Beyond this window of time, perhaps due to estrogen receptor down regulation, HT can be harmful, with an increased risk of stroke and dementia reported later on,” she said.

Against this, the Women’s Health Initiative Memory Study (WHIMS) looked at unopposed estrogen, and estrogen and progestin combination, compared with placebo. It found that in women who initiated HT at the age of 65 or older faced an increased risk of dementia from any cause, and of cognitive decline. “This study really put the kibosh on HT as a form of neuroprotection,” Dr. Bove said. “But perhaps it’s unfair to the many patients who are at risk for cognitive decline and neurodegeneration, because the WHIMS did not find an increased risk of adverse cognitive events in women in whom HT was started perimenopausally. Longitudinal, placebo-controlled trials of the effects of HT within the window of opportunity are required to either prove or refute the observational studies that already exist that suggest HT may be neuroprotective. This is an important point to discuss with patients.”

The impact of perimenopausal sleep disturbance on MS symptoms also is unknown. A practical approach to managing sleep disturbance in perimenopausal MS patients is to identify and assess the triggers. “If the bladder symptoms are the major trigger versus mood disturbances such as depression and anxiety, the intervention will be different,” she said. “Consider counseling and/or consultation with a sleep specialist.” Some patients may benefit from pharmacologic treatment to “get them over the hump and get them sleeping better for a little while, versus longer term management if they have a life history of insomnia,” she said. “If the problem is sleep management, you’ll need a drug with a longer half-life. Consider other comorbidities such as anxiety and restless leg syndrome.” Classes of medications to consider include benzodiazepines, nonbenzodiazepines, tricyclic antidepressants, SSRIs and SNRIs.

Mood symptoms commonly overlap in menopausal patients with MS, especially those related to depression and anxiety. “They may be underdiagnosed and undertreated,” Dr. Bove said. “It’s been shown that depression influences the perceived severity of other MS symptoms. Depression is a strong predictor of cognitive and sexual dysfunction, so our perimenopausal MS women have a vulnerability to more severe mood symptoms.” Managing mood symptoms “needs to be multifaceted” and may include psychotherapy to optimize coping abilities, antidepressants, support groups, fatigue and sleep optimization, and social work “to see how employment or financial stressors may be playing a role in a person’s mood.”

In addition, menopausal women may report changes in attention, executive function, multitasking, word finding difficulties, and memory problems, especially in the first year after the final menstrual period. “It’s known that about half of MS patients experience some degree of cognitive impairment,” she said. “Neurocognitive testing may help to identify particular areas of dysfunction that would be amenable to some kind of cognitive rehabilitation.”

Bladder symptoms also can impact postmenopausal patients, especially increasing bladder irritability and incontinence (stress and urge). In MS, “the baseline bladder dysfunction may be magnified,” Dr. Bove said. “If you’re trying to tease out whether the postmenopausal bladder symptoms are from menopause or MS, the MS relapses tend to have more urgency, frequency, and urge incontinence, and the presentation will be more acute. Urodynamic testing can be used to tease this out. The big lifestyle piece that urologists like to hone in on is that people in America drink too much fluid. A practical guideline is that after 3 p.m. just drink for thirst; don’t worry that everything will fall apart if you don’t get your eight glasses of water per day in. If you’re not thirsty, you probably don’t need it.”

While postmenopausal women face an increased risk for osteoporosis, that risk is magnified for MS patients because of the cumulative effect of steroid use – particularly for those who were diagnosed in the pre–disease-modifying-therapy era – being sedentary, and being deconditioned. “Other MS issues such as balance, vision problems, strength or cognitive impairments may all impact gait and compound the risk of falls,” Dr. Bove said. “Osteoporosis prevention and screening should be encouraged in these patients.”

Dr. Bove concluded her presentation by noting that in general, women with disabilities are less likely to be up to date on Pap tests, mammograms, and other important preventive screening tests. “The magnitude of disparities is greater for women with complex limitations,” she said. “Women with MS may have a lower cancer risk, but a larger tumor size at diagnosis.” For example, “is this because the patient is uncomfortable getting on an exam table to get a Pap smear, or is the physician not thinking about other aspects of the person’s life because the focus is on the MS?”

Dr. Bove disclosed that she has received funding from the National Multiple Sclerosis Society, the National Institutes of Health, and from the Harvard Clinical Investigator Training Program.

[email protected]

On Twitter @dougbrunk

INDIANAPOLIS – About 50% of women with multiple sclerosis are postmenopausal, but objective data about the impact of menopause on the course of multiple sclerosis are lacking.

“We don’t know anything about the impact of menopause on the MS course; there is wide variability in patient-reported outcomes, but nothing written about comorbidities or symptom management,” Dr. Riley Bove, a neurologist at Brigham and Women’s Hospital, Boston, said at the annual meeting of the Consortium of Multiple Sclerosis Centers. “We’ve been working on this. A lot of it is unknown.”

She described menopause is “an opportunity for providers to tackle symptoms and improve well-being and discuss meaningful quality of life and priorities with patients. It can be a good time to talk about these things.”

In a study that Dr. Bove conducted with the online patient-powered research platform PatientsLikeMe, female MS patients were asked to describe the impact of menopause on their disease. Among the themes that emerged were an occasional perimenopausal onset of MS (“menopause and MS symptoms were pretty much simultaneous,” one 58-year-old respondent said); the effect of hot flashes on MS symptoms (“I confused the two, especially hot flashes,” said a 53-year-old woman); and worsening of MS-related disability after menopause, particularly surgical (“Before I stopped taking birth control pills I was working and able to walk and house clean , etc.,” a 53-year-old respondent said. “I had the surgery, and I started to progress toward being completely wheelchair bound.”)

When it comes to solid recommendations for how to manage MS symptoms that overlap with menopause, “we’re in an evidence-free zone,” Dr. Bove said. “Symptoms in MS are kind of like dominoes: You have difficulty sleeping and then your day is off, fatigue is up and your mood is off, and everything can spiral. In the clinic, perimenopausal women often say things like, ‘I feel like I’m falling apart’ or ‘something has to give’ or ‘I need a change.’ ”

Common overlapping symptoms include vasomotor manifestations such as hot flashes, cold flashes, vascular instability, and rapid heartbeat. “The leading mechanistic explanation for the vasomotor symptoms is that abrupt hormone deprivation will result in the loss of negative feedback over hypothalamic NA [noradrenaline] synthesis,” Dr. Bove explained. “The proximity of the hypothalamic thermoregulatory center to luteinizing hormone–releasing hormone-producing areas may also be involved.”

Sleep disturbances and insomnia in menopausal MS patients can impact fatigue and mood. Also, hot flashes can directly exacerbate the MS symptoms, fluctuating over the day or the week.

According to recommendations from the North American Menopause Society, estradiol is the most effective therapy for treating vasomotor symptoms. Other options include selective serotonin reuptake inhibitors (SSRIs) and selective noradrenergic reuptake inhibitors (SNRIs). “Probably the best studied SNRI is venlafaxine,” Dr. Bove said. “It seems to have modest effects on sleep quality and insomnia perimenopausally, as well as on hot flashes.”

Other alternatives include clonidine and gabapentin.

“If a patient wants to use [hormone therapy] for menopausal symptoms, it has to be an individualized approach,” Dr. Bove said. “You have to communicate with the primary care physician to understand what else is going on in this woman’s medical history. The current recommendations are to treat the symptoms with as low a dose as possible for as short a duration as possible. Our MS patients are also at risk for neurodegeneration, for brain volume loss, for cognitive decline, and for worsening function over time.”

With respect to cognition, observational studies have demonstrated that during a certain window of opportunity – defined as within 5 years of the last menstrual period – hormone therapy (HT) may have protective effects against Alzheimer’s disease and against cognitive decline in general. “Beyond this window of time, perhaps due to estrogen receptor down regulation, HT can be harmful, with an increased risk of stroke and dementia reported later on,” she said.

Against this, the Women’s Health Initiative Memory Study (WHIMS) looked at unopposed estrogen, and estrogen and progestin combination, compared with placebo. It found that in women who initiated HT at the age of 65 or older faced an increased risk of dementia from any cause, and of cognitive decline. “This study really put the kibosh on HT as a form of neuroprotection,” Dr. Bove said. “But perhaps it’s unfair to the many patients who are at risk for cognitive decline and neurodegeneration, because the WHIMS did not find an increased risk of adverse cognitive events in women in whom HT was started perimenopausally. Longitudinal, placebo-controlled trials of the effects of HT within the window of opportunity are required to either prove or refute the observational studies that already exist that suggest HT may be neuroprotective. This is an important point to discuss with patients.”

The impact of perimenopausal sleep disturbance on MS symptoms also is unknown. A practical approach to managing sleep disturbance in perimenopausal MS patients is to identify and assess the triggers. “If the bladder symptoms are the major trigger versus mood disturbances such as depression and anxiety, the intervention will be different,” she said. “Consider counseling and/or consultation with a sleep specialist.” Some patients may benefit from pharmacologic treatment to “get them over the hump and get them sleeping better for a little while, versus longer term management if they have a life history of insomnia,” she said. “If the problem is sleep management, you’ll need a drug with a longer half-life. Consider other comorbidities such as anxiety and restless leg syndrome.” Classes of medications to consider include benzodiazepines, nonbenzodiazepines, tricyclic antidepressants, SSRIs and SNRIs.

Mood symptoms commonly overlap in menopausal patients with MS, especially those related to depression and anxiety. “They may be underdiagnosed and undertreated,” Dr. Bove said. “It’s been shown that depression influences the perceived severity of other MS symptoms. Depression is a strong predictor of cognitive and sexual dysfunction, so our perimenopausal MS women have a vulnerability to more severe mood symptoms.” Managing mood symptoms “needs to be multifaceted” and may include psychotherapy to optimize coping abilities, antidepressants, support groups, fatigue and sleep optimization, and social work “to see how employment or financial stressors may be playing a role in a person’s mood.”

In addition, menopausal women may report changes in attention, executive function, multitasking, word finding difficulties, and memory problems, especially in the first year after the final menstrual period. “It’s known that about half of MS patients experience some degree of cognitive impairment,” she said. “Neurocognitive testing may help to identify particular areas of dysfunction that would be amenable to some kind of cognitive rehabilitation.”

Bladder symptoms also can impact postmenopausal patients, especially increasing bladder irritability and incontinence (stress and urge). In MS, “the baseline bladder dysfunction may be magnified,” Dr. Bove said. “If you’re trying to tease out whether the postmenopausal bladder symptoms are from menopause or MS, the MS relapses tend to have more urgency, frequency, and urge incontinence, and the presentation will be more acute. Urodynamic testing can be used to tease this out. The big lifestyle piece that urologists like to hone in on is that people in America drink too much fluid. A practical guideline is that after 3 p.m. just drink for thirst; don’t worry that everything will fall apart if you don’t get your eight glasses of water per day in. If you’re not thirsty, you probably don’t need it.”

While postmenopausal women face an increased risk for osteoporosis, that risk is magnified for MS patients because of the cumulative effect of steroid use – particularly for those who were diagnosed in the pre–disease-modifying-therapy era – being sedentary, and being deconditioned. “Other MS issues such as balance, vision problems, strength or cognitive impairments may all impact gait and compound the risk of falls,” Dr. Bove said. “Osteoporosis prevention and screening should be encouraged in these patients.”

Dr. Bove concluded her presentation by noting that in general, women with disabilities are less likely to be up to date on Pap tests, mammograms, and other important preventive screening tests. “The magnitude of disparities is greater for women with complex limitations,” she said. “Women with MS may have a lower cancer risk, but a larger tumor size at diagnosis.” For example, “is this because the patient is uncomfortable getting on an exam table to get a Pap smear, or is the physician not thinking about other aspects of the person’s life because the focus is on the MS?”

Dr. Bove disclosed that she has received funding from the National Multiple Sclerosis Society, the National Institutes of Health, and from the Harvard Clinical Investigator Training Program.

[email protected]

On Twitter @dougbrunk

INDIANAPOLIS – About 50% of women with multiple sclerosis are postmenopausal, but objective data about the impact of menopause on the course of multiple sclerosis are lacking.

“We don’t know anything about the impact of menopause on the MS course; there is wide variability in patient-reported outcomes, but nothing written about comorbidities or symptom management,” Dr. Riley Bove, a neurologist at Brigham and Women’s Hospital, Boston, said at the annual meeting of the Consortium of Multiple Sclerosis Centers. “We’ve been working on this. A lot of it is unknown.”

She described menopause is “an opportunity for providers to tackle symptoms and improve well-being and discuss meaningful quality of life and priorities with patients. It can be a good time to talk about these things.”

In a study that Dr. Bove conducted with the online patient-powered research platform PatientsLikeMe, female MS patients were asked to describe the impact of menopause on their disease. Among the themes that emerged were an occasional perimenopausal onset of MS (“menopause and MS symptoms were pretty much simultaneous,” one 58-year-old respondent said); the effect of hot flashes on MS symptoms (“I confused the two, especially hot flashes,” said a 53-year-old woman); and worsening of MS-related disability after menopause, particularly surgical (“Before I stopped taking birth control pills I was working and able to walk and house clean , etc.,” a 53-year-old respondent said. “I had the surgery, and I started to progress toward being completely wheelchair bound.”)

When it comes to solid recommendations for how to manage MS symptoms that overlap with menopause, “we’re in an evidence-free zone,” Dr. Bove said. “Symptoms in MS are kind of like dominoes: You have difficulty sleeping and then your day is off, fatigue is up and your mood is off, and everything can spiral. In the clinic, perimenopausal women often say things like, ‘I feel like I’m falling apart’ or ‘something has to give’ or ‘I need a change.’ ”

Common overlapping symptoms include vasomotor manifestations such as hot flashes, cold flashes, vascular instability, and rapid heartbeat. “The leading mechanistic explanation for the vasomotor symptoms is that abrupt hormone deprivation will result in the loss of negative feedback over hypothalamic NA [noradrenaline] synthesis,” Dr. Bove explained. “The proximity of the hypothalamic thermoregulatory center to luteinizing hormone–releasing hormone-producing areas may also be involved.”

Sleep disturbances and insomnia in menopausal MS patients can impact fatigue and mood. Also, hot flashes can directly exacerbate the MS symptoms, fluctuating over the day or the week.

According to recommendations from the North American Menopause Society, estradiol is the most effective therapy for treating vasomotor symptoms. Other options include selective serotonin reuptake inhibitors (SSRIs) and selective noradrenergic reuptake inhibitors (SNRIs). “Probably the best studied SNRI is venlafaxine,” Dr. Bove said. “It seems to have modest effects on sleep quality and insomnia perimenopausally, as well as on hot flashes.”

Other alternatives include clonidine and gabapentin.

“If a patient wants to use [hormone therapy] for menopausal symptoms, it has to be an individualized approach,” Dr. Bove said. “You have to communicate with the primary care physician to understand what else is going on in this woman’s medical history. The current recommendations are to treat the symptoms with as low a dose as possible for as short a duration as possible. Our MS patients are also at risk for neurodegeneration, for brain volume loss, for cognitive decline, and for worsening function over time.”

With respect to cognition, observational studies have demonstrated that during a certain window of opportunity – defined as within 5 years of the last menstrual period – hormone therapy (HT) may have protective effects against Alzheimer’s disease and against cognitive decline in general. “Beyond this window of time, perhaps due to estrogen receptor down regulation, HT can be harmful, with an increased risk of stroke and dementia reported later on,” she said.

Against this, the Women’s Health Initiative Memory Study (WHIMS) looked at unopposed estrogen, and estrogen and progestin combination, compared with placebo. It found that in women who initiated HT at the age of 65 or older faced an increased risk of dementia from any cause, and of cognitive decline. “This study really put the kibosh on HT as a form of neuroprotection,” Dr. Bove said. “But perhaps it’s unfair to the many patients who are at risk for cognitive decline and neurodegeneration, because the WHIMS did not find an increased risk of adverse cognitive events in women in whom HT was started perimenopausally. Longitudinal, placebo-controlled trials of the effects of HT within the window of opportunity are required to either prove or refute the observational studies that already exist that suggest HT may be neuroprotective. This is an important point to discuss with patients.”

The impact of perimenopausal sleep disturbance on MS symptoms also is unknown. A practical approach to managing sleep disturbance in perimenopausal MS patients is to identify and assess the triggers. “If the bladder symptoms are the major trigger versus mood disturbances such as depression and anxiety, the intervention will be different,” she said. “Consider counseling and/or consultation with a sleep specialist.” Some patients may benefit from pharmacologic treatment to “get them over the hump and get them sleeping better for a little while, versus longer term management if they have a life history of insomnia,” she said. “If the problem is sleep management, you’ll need a drug with a longer half-life. Consider other comorbidities such as anxiety and restless leg syndrome.” Classes of medications to consider include benzodiazepines, nonbenzodiazepines, tricyclic antidepressants, SSRIs and SNRIs.

Mood symptoms commonly overlap in menopausal patients with MS, especially those related to depression and anxiety. “They may be underdiagnosed and undertreated,” Dr. Bove said. “It’s been shown that depression influences the perceived severity of other MS symptoms. Depression is a strong predictor of cognitive and sexual dysfunction, so our perimenopausal MS women have a vulnerability to more severe mood symptoms.” Managing mood symptoms “needs to be multifaceted” and may include psychotherapy to optimize coping abilities, antidepressants, support groups, fatigue and sleep optimization, and social work “to see how employment or financial stressors may be playing a role in a person’s mood.”

In addition, menopausal women may report changes in attention, executive function, multitasking, word finding difficulties, and memory problems, especially in the first year after the final menstrual period. “It’s known that about half of MS patients experience some degree of cognitive impairment,” she said. “Neurocognitive testing may help to identify particular areas of dysfunction that would be amenable to some kind of cognitive rehabilitation.”

Bladder symptoms also can impact postmenopausal patients, especially increasing bladder irritability and incontinence (stress and urge). In MS, “the baseline bladder dysfunction may be magnified,” Dr. Bove said. “If you’re trying to tease out whether the postmenopausal bladder symptoms are from menopause or MS, the MS relapses tend to have more urgency, frequency, and urge incontinence, and the presentation will be more acute. Urodynamic testing can be used to tease this out. The big lifestyle piece that urologists like to hone in on is that people in America drink too much fluid. A practical guideline is that after 3 p.m. just drink for thirst; don’t worry that everything will fall apart if you don’t get your eight glasses of water per day in. If you’re not thirsty, you probably don’t need it.”

While postmenopausal women face an increased risk for osteoporosis, that risk is magnified for MS patients because of the cumulative effect of steroid use – particularly for those who were diagnosed in the pre–disease-modifying-therapy era – being sedentary, and being deconditioned. “Other MS issues such as balance, vision problems, strength or cognitive impairments may all impact gait and compound the risk of falls,” Dr. Bove said. “Osteoporosis prevention and screening should be encouraged in these patients.”

Dr. Bove concluded her presentation by noting that in general, women with disabilities are less likely to be up to date on Pap tests, mammograms, and other important preventive screening tests. “The magnitude of disparities is greater for women with complex limitations,” she said. “Women with MS may have a lower cancer risk, but a larger tumor size at diagnosis.” For example, “is this because the patient is uncomfortable getting on an exam table to get a Pap smear, or is the physician not thinking about other aspects of the person’s life because the focus is on the MS?”

Dr. Bove disclosed that she has received funding from the National Multiple Sclerosis Society, the National Institutes of Health, and from the Harvard Clinical Investigator Training Program.

[email protected]

On Twitter @dougbrunk

Staff member giving directions

to an attendee at ASCO 2015

© ASCO/Zach Boyden-Holmes

CHICAGO—A BCL-2 inhibitor that has shown activity in patients with chronic and acute leukemias could be a feasible treatment option for multiple myeloma (MM) too, according to research presented at the 2015 ASCO Annual Meeting.

In a pair of phase 1 studies, the drug, venetoclax, prompted responses in certain patients with relapsed or refractory MM, both when given alone and in combination with bortezomib and dexamethasone.

As monotherapy, venetoclax induced complete responses (CRs) in 2 patients with t(11;14), but the overall response rate (ORR) was low, and most patients discontinued treatment, largely due to progression.

Venetoclax in combination with bortezomib and dexamethasone prompted a response in nearly half of the patients studied, but more than half discontinued treatment. The combination produced a high ORR in patients who were bortezomib-naïve and bortezomib-sensitive, but there was no response among bortezomib-refractory patients.

“Multiple myeloma remains a high area of unmet medical need, and additional research to identify new therapies is important,” said investigator Cyrille Touzeau, MD, of the University of Nantes in France.

“The response rates shown in these studies suggest potential of venetoclax in this patient population and warrant further evaluation.”

Dr Touzeau and his colleagues presented these studies at ASCO as abstracts 8580 and 8576. Both studies were funded by AbbVie, the company developing venetoclax.

Venetoclax in combination

In a phase 1b study (abstract 8580*), the researchers evaluated venetoclax in combination with bortezomib and dexamethasone in 38 patients with relapsed or refractory MM.

The patients’ median age was 65 (range, 38-79). Five patients were t(11;14)-positive, 3 were t(4;14)-positive, 9 had del17p, and 19 had del13q. They had received a median of 5 prior lines of therapy (range, 1-15). Ten patients were bortezomib-refractory, 21 were lenalidomide-refractory, and 8 patients were refractory to both drugs.

The patients received venetoclax at doses ranging from 50 mg to 600 mg daily (with a 1-week lead-in period for the 50 mg cohort). On cycles 1-8, patients received dexamethasone (20 mg) and bortezomib (1.3 mg/m²) with venetoclax on days 1, 4, 8, and 11. They received dexamethasone (20 mg) with venetoclax on days 2, 5, 9, and 12.

On cycles 9-11, patients received dexamethasone (20 mg) and bortezomib (1.3 mg/m²) with venetoclax on days 1, 8, 15, and 22. Patients received venetoclax monotherapy for cycles 12 and beyond. They also received prophylaxis for tumor lysis syndrome.

Twenty-five patients (66%) discontinued treatment, 19 due to disease progression (including 4 deaths), 2 due to adverse events (AEs), 3 due to patient decision, and 1 due to withdrawn consent.

The ORR was 47% among the 36 evaluable patients, 83% for bortezomib-naïve patients (5/6), 60% for bortezomib-sensitive patients (12/20), and 0% for bortezomib-refractory patients (0/10).

Two patients had a stringent CR, 1 had a CR, 4 had a very good partial response, 10 had a partial response, and 2 had a minimal response. Six patients had stable disease, and 9 progressed.

The most common AEs—occurring in at least 20% of patients—were constipation (37%), diarrhea (32%), insomnia (32%), thrombocytopenia (29%), peripheral neuropathy (26%), asthenia (26%), dyspnea (26%), peripheral edema (24%), and anemia (21%).

Grade 3/4 AEs—occurring in at least 10% of patients—were thrombocytopenia (21%), anemia (13%), and dyspnea (11%). Serious AEs—each occurring in 5% of patients—were cardiac failure, pyrexia, sepsis, respiratory failure, pneumonia, and embolism.

Venetoclax as monotherapy

In a phase 1 study (abstract 8576*), researchers evaluated venetoclax as monotherapy in 29 patients with relapsed or refractory MM. Eleven patients were t(11;14)-positive, 2 were t(4;14)-positive, 4 had del17p, and 14 had del13q.

The patients’ median age was 66 (range, 42-79), and they had received a median of 6 prior therapies (range, 1-13). Fifteen patients were bortezomib-refractory, 12 were refractory to lenalidomide, and 10 patients were refractory to both drugs.

After a 2-week lead-in period, patients received venetoclax daily on a 21-day cycle, ranging from 300 mg to 1200 mg on a 3+3 design. They also received prophylaxis for tumor lysis syndrome. Patients who progressed during treatment were allowed to receive dexamethasone as well and continue the study.

Twenty-three patients (79%) discontinued treatment, 18 due to disease progression, 4 due to AEs, and 1 due to patient decision.

The ORR was 7% (n=2). Both patients achieved a CR, and both were t(11;14)-positive. One of the patients is in the 600 mg cohort and is still responding to treatment. The duration of response, thus far, is 2.1 months.

The other patient with a CR is in the 900 mg dose cohort. This patient is still responding as well, and the response duration, thus far, is 2.8 months.

Common AEs—occurring in at least 20% of patients—were diarrhea (41%), nausea (41%),  fatigue (24%), vomiting (21%), asthenia (21%), and neutropenia (21%).

Grade 3/4 AEs—occurring in at least 10% of patients—were thrombocytopenia (24%), neutropenia (14%), and anemia (10%). Serious AEs—each occurring in 7% of patients—were pyrexia, malignant neoplasm progression, and cough.

Two patients had dose-limiting toxicities at the 600 mg dose of venetoclax. However, the researchers said the maximum tolerated dose was not reached, and the recommended phase 2 dose is 1200 mg.

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

Staff member giving directions

to an attendee at ASCO 2015

© ASCO/Zach Boyden-Holmes

CHICAGO—A BCL-2 inhibitor that has shown activity in patients with chronic and acute leukemias could be a feasible treatment option for multiple myeloma (MM) too, according to research presented at the 2015 ASCO Annual Meeting.

In a pair of phase 1 studies, the drug, venetoclax, prompted responses in certain patients with relapsed or refractory MM, both when given alone and in combination with bortezomib and dexamethasone.

As monotherapy, venetoclax induced complete responses (CRs) in 2 patients with t(11;14), but the overall response rate (ORR) was low, and most patients discontinued treatment, largely due to progression.

Venetoclax in combination with bortezomib and dexamethasone prompted a response in nearly half of the patients studied, but more than half discontinued treatment. The combination produced a high ORR in patients who were bortezomib-naïve and bortezomib-sensitive, but there was no response among bortezomib-refractory patients.

“Multiple myeloma remains a high area of unmet medical need, and additional research to identify new therapies is important,” said investigator Cyrille Touzeau, MD, of the University of Nantes in France.

“The response rates shown in these studies suggest potential of venetoclax in this patient population and warrant further evaluation.”

Dr Touzeau and his colleagues presented these studies at ASCO as abstracts 8580 and 8576. Both studies were funded by AbbVie, the company developing venetoclax.

Venetoclax in combination

In a phase 1b study (abstract 8580*), the researchers evaluated venetoclax in combination with bortezomib and dexamethasone in 38 patients with relapsed or refractory MM.

The patients’ median age was 65 (range, 38-79). Five patients were t(11;14)-positive, 3 were t(4;14)-positive, 9 had del17p, and 19 had del13q. They had received a median of 5 prior lines of therapy (range, 1-15). Ten patients were bortezomib-refractory, 21 were lenalidomide-refractory, and 8 patients were refractory to both drugs.

The patients received venetoclax at doses ranging from 50 mg to 600 mg daily (with a 1-week lead-in period for the 50 mg cohort). On cycles 1-8, patients received dexamethasone (20 mg) and bortezomib (1.3 mg/m²) with venetoclax on days 1, 4, 8, and 11. They received dexamethasone (20 mg) with venetoclax on days 2, 5, 9, and 12.

On cycles 9-11, patients received dexamethasone (20 mg) and bortezomib (1.3 mg/m²) with venetoclax on days 1, 8, 15, and 22. Patients received venetoclax monotherapy for cycles 12 and beyond. They also received prophylaxis for tumor lysis syndrome.

Twenty-five patients (66%) discontinued treatment, 19 due to disease progression (including 4 deaths), 2 due to adverse events (AEs), 3 due to patient decision, and 1 due to withdrawn consent.

The ORR was 47% among the 36 evaluable patients, 83% for bortezomib-naïve patients (5/6), 60% for bortezomib-sensitive patients (12/20), and 0% for bortezomib-refractory patients (0/10).

Two patients had a stringent CR, 1 had a CR, 4 had a very good partial response, 10 had a partial response, and 2 had a minimal response. Six patients had stable disease, and 9 progressed.

The most common AEs—occurring in at least 20% of patients—were constipation (37%), diarrhea (32%), insomnia (32%), thrombocytopenia (29%), peripheral neuropathy (26%), asthenia (26%), dyspnea (26%), peripheral edema (24%), and anemia (21%).

Grade 3/4 AEs—occurring in at least 10% of patients—were thrombocytopenia (21%), anemia (13%), and dyspnea (11%). Serious AEs—each occurring in 5% of patients—were cardiac failure, pyrexia, sepsis, respiratory failure, pneumonia, and embolism.

Venetoclax as monotherapy

In a phase 1 study (abstract 8576*), researchers evaluated venetoclax as monotherapy in 29 patients with relapsed or refractory MM. Eleven patients were t(11;14)-positive, 2 were t(4;14)-positive, 4 had del17p, and 14 had del13q.

The patients’ median age was 66 (range, 42-79), and they had received a median of 6 prior therapies (range, 1-13). Fifteen patients were bortezomib-refractory, 12 were refractory to lenalidomide, and 10 patients were refractory to both drugs.

After a 2-week lead-in period, patients received venetoclax daily on a 21-day cycle, ranging from 300 mg to 1200 mg on a 3+3 design. They also received prophylaxis for tumor lysis syndrome. Patients who progressed during treatment were allowed to receive dexamethasone as well and continue the study.

Twenty-three patients (79%) discontinued treatment, 18 due to disease progression, 4 due to AEs, and 1 due to patient decision.

The ORR was 7% (n=2). Both patients achieved a CR, and both were t(11;14)-positive. One of the patients is in the 600 mg cohort and is still responding to treatment. The duration of response, thus far, is 2.1 months.

The other patient with a CR is in the 900 mg dose cohort. This patient is still responding as well, and the response duration, thus far, is 2.8 months.

Common AEs—occurring in at least 20% of patients—were diarrhea (41%), nausea (41%),  fatigue (24%), vomiting (21%), asthenia (21%), and neutropenia (21%).

Grade 3/4 AEs—occurring in at least 10% of patients—were thrombocytopenia (24%), neutropenia (14%), and anemia (10%). Serious AEs—each occurring in 7% of patients—were pyrexia, malignant neoplasm progression, and cough.

Two patients had dose-limiting toxicities at the 600 mg dose of venetoclax. However, the researchers said the maximum tolerated dose was not reached, and the recommended phase 2 dose is 1200 mg.

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

Staff member giving directions

to an attendee at ASCO 2015

© ASCO/Zach Boyden-Holmes

CHICAGO—A BCL-2 inhibitor that has shown activity in patients with chronic and acute leukemias could be a feasible treatment option for multiple myeloma (MM) too, according to research presented at the 2015 ASCO Annual Meeting.

In a pair of phase 1 studies, the drug, venetoclax, prompted responses in certain patients with relapsed or refractory MM, both when given alone and in combination with bortezomib and dexamethasone.

As monotherapy, venetoclax induced complete responses (CRs) in 2 patients with t(11;14), but the overall response rate (ORR) was low, and most patients discontinued treatment, largely due to progression.

Venetoclax in combination with bortezomib and dexamethasone prompted a response in nearly half of the patients studied, but more than half discontinued treatment. The combination produced a high ORR in patients who were bortezomib-naïve and bortezomib-sensitive, but there was no response among bortezomib-refractory patients.

“Multiple myeloma remains a high area of unmet medical need, and additional research to identify new therapies is important,” said investigator Cyrille Touzeau, MD, of the University of Nantes in France.

“The response rates shown in these studies suggest potential of venetoclax in this patient population and warrant further evaluation.”

Dr Touzeau and his colleagues presented these studies at ASCO as abstracts 8580 and 8576. Both studies were funded by AbbVie, the company developing venetoclax.

Venetoclax in combination

In a phase 1b study (abstract 8580*), the researchers evaluated venetoclax in combination with bortezomib and dexamethasone in 38 patients with relapsed or refractory MM.

The patients’ median age was 65 (range, 38-79). Five patients were t(11;14)-positive, 3 were t(4;14)-positive, 9 had del17p, and 19 had del13q. They had received a median of 5 prior lines of therapy (range, 1-15). Ten patients were bortezomib-refractory, 21 were lenalidomide-refractory, and 8 patients were refractory to both drugs.

The patients received venetoclax at doses ranging from 50 mg to 600 mg daily (with a 1-week lead-in period for the 50 mg cohort). On cycles 1-8, patients received dexamethasone (20 mg) and bortezomib (1.3 mg/m²) with venetoclax on days 1, 4, 8, and 11. They received dexamethasone (20 mg) with venetoclax on days 2, 5, 9, and 12.

On cycles 9-11, patients received dexamethasone (20 mg) and bortezomib (1.3 mg/m²) with venetoclax on days 1, 8, 15, and 22. Patients received venetoclax monotherapy for cycles 12 and beyond. They also received prophylaxis for tumor lysis syndrome.

Twenty-five patients (66%) discontinued treatment, 19 due to disease progression (including 4 deaths), 2 due to adverse events (AEs), 3 due to patient decision, and 1 due to withdrawn consent.

The ORR was 47% among the 36 evaluable patients, 83% for bortezomib-naïve patients (5/6), 60% for bortezomib-sensitive patients (12/20), and 0% for bortezomib-refractory patients (0/10).

Two patients had a stringent CR, 1 had a CR, 4 had a very good partial response, 10 had a partial response, and 2 had a minimal response. Six patients had stable disease, and 9 progressed.

The most common AEs—occurring in at least 20% of patients—were constipation (37%), diarrhea (32%), insomnia (32%), thrombocytopenia (29%), peripheral neuropathy (26%), asthenia (26%), dyspnea (26%), peripheral edema (24%), and anemia (21%).

Grade 3/4 AEs—occurring in at least 10% of patients—were thrombocytopenia (21%), anemia (13%), and dyspnea (11%). Serious AEs—each occurring in 5% of patients—were cardiac failure, pyrexia, sepsis, respiratory failure, pneumonia, and embolism.

Venetoclax as monotherapy

In a phase 1 study (abstract 8576*), researchers evaluated venetoclax as monotherapy in 29 patients with relapsed or refractory MM. Eleven patients were t(11;14)-positive, 2 were t(4;14)-positive, 4 had del17p, and 14 had del13q.

The patients’ median age was 66 (range, 42-79), and they had received a median of 6 prior therapies (range, 1-13). Fifteen patients were bortezomib-refractory, 12 were refractory to lenalidomide, and 10 patients were refractory to both drugs.

After a 2-week lead-in period, patients received venetoclax daily on a 21-day cycle, ranging from 300 mg to 1200 mg on a 3+3 design. They also received prophylaxis for tumor lysis syndrome. Patients who progressed during treatment were allowed to receive dexamethasone as well and continue the study.

Twenty-three patients (79%) discontinued treatment, 18 due to disease progression, 4 due to AEs, and 1 due to patient decision.

The ORR was 7% (n=2). Both patients achieved a CR, and both were t(11;14)-positive. One of the patients is in the 600 mg cohort and is still responding to treatment. The duration of response, thus far, is 2.1 months.

The other patient with a CR is in the 900 mg dose cohort. This patient is still responding as well, and the response duration, thus far, is 2.8 months.

Common AEs—occurring in at least 20% of patients—were diarrhea (41%), nausea (41%),  fatigue (24%), vomiting (21%), asthenia (21%), and neutropenia (21%).

Grade 3/4 AEs—occurring in at least 10% of patients—were thrombocytopenia (24%), neutropenia (14%), and anemia (10%). Serious AEs—each occurring in 7% of patients—were pyrexia, malignant neoplasm progression, and cough.

Two patients had dose-limiting toxicities at the 600 mg dose of venetoclax. However, the researchers said the maximum tolerated dose was not reached, and the recommended phase 2 dose is 1200 mg.

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

Audience during a session at

the 2015 ASCO Annual Meeting

© ASCO/Max Gersh

CHICAGO—A CD19-targeted chimeric antigen receptor (CAR) T-cell therapy can provide durable complete responses (CRs) or a bridge to allogeneic transplant in adults with relapsed or refractory acute lymphoblastic leukemia (ALL), updated results of a phase 1 study suggest.

The therapy, JCAR015, produced a CR rate of 87%, and 33% of these patients went on to transplant.

The median duration of response or relapse-free survival was 5.3 months. The median overall survival was 8.5 months.

Nearly a quarter of patients developed severe cytokine release syndrome (CRS), and nearly 30% experienced neurological toxicities. But researchers said these effects were largely treatable and reversible.

This study was temporarily placed on clinical hold last year, after 2 patients died from complications related to CRS. But the hold was soon lifted and enrollment and dosing criteria were changed in an attempt to prevent severe CRS.

Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center in New York, presented updated results of this trial (NCT01044069) at the 2015 ASCO Annual Meeting (abstract 7010*). The study is sponsored by Memorial Sloan Kettering, but funding has also been provided by Juno Therapeutics, the company developing JCAR015.

Results from this trial have previously been reported in Science Translational Medicine (Davila et al 2014; Brentjens et al 2013), at AACR 2014, and at ASH 2014.

At ASCO, Dr Park presented results in 39 patients with relapsed/refractory, CD19⁺ ALL. All of them were evaluable for toxicity assessment, and 38 were evaluable for response with at least 1 month of follow-up.

There were 29 males, and the patients’ median age was 45 (range, 22-74). Thirty-three percent had Ph⁺ ALL, and 11% had the T315I mutation.

Forty-nine percent of patients had received 2 prior therapies, 23% had received 3, and 28% had received 4 or more. Thirty-six percent of patients had a prior allogeneic hematopoietic stem cell transplant (HSCT).

For this study, patients first underwent leukapheresis. While their T cells were being manufactured, they were allowed to receive salvage chemotherapy. Patients underwent repeat bone marrow biopsy to assess their disease status immediately prior to T-cell infusion.

Fifty-four percent of patients (n=21) had morphologic disease (>5% blasts in the bone marrow, median 52%) immediately prior to JCAR015 infusion, and the remaining patients (n=18) had minimal residual disease (MRD).

Two days after conditioning with cyclophosphamide, patients received an infusion of 1-3 x 10⁶ CAR T cells/kg. At day 28, the researchers assessed patients’ disease with a repeat bone marrow biopsy.

Treatment results

The median follow-up was 5.6 months (1 to >38 months). Six patients had more than a year of follow-up.

The CR rate was 87% (33/38), and 81% of evaluable patients (26/32) were MRD-negative. The median time to CR was 23 days, and the median duration of response or relapse-free survival was 5.3 months.

“We examined the CR rates by different subgroup,” Dr Park noted. “We looked at whether patients had a pre-T-cell disease burden: morphologic disease vs minimal residual disease, whether they had an allogeneic bone marrow transplant prior to CAR T-cell infusion, their Ph⁺ status, age at infusion, and prior lines of therapy. And there was no [significant] difference between these groups for CRs and MRD-negative CR rate.”

At the time of presentation, 14 patients were disease-free, 10 of whom had not gone on to HSCT. In all, 11 patients went on to allogeneic HSCT.

Fourteen patients relapsed during follow-up, 3 after HSCT. Two of these patients had CD19-negative bone marrow blasts.

The median overall survival was 8.5 months in all patients and 10.8 months in patients who were MRD-negative. The median overall survival was 9.9 months in patients who underwent allogeneic HSCT and 8.5 months in patients who did not.

Dr Park said key adverse events were CRS—clinically manifested by fever, hypotension, and respiratory insufficiency—and neurological changes such as delirium, global encephalopathy, aphasia, and seizures.

Twenty-three percent of patients (n=9) developed severe CRS, 28% (n=11) had grade 3/4 neurotoxicity, and 8% (n=3) had grade 5 toxicity. The patients with grade 5 toxicities died of ventricular arrhythmia, sepsis, and an unknown cause (although this patient suffered a seizure).

The severity of CRS correlated with disease burden, and CRS was managed with an IL-6R inhibitor (n=4), a steroid (n=2), or both (n=9). Neurological symptoms were reversible and could occur independently of CRS, Dr Park said.

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

Audience during a session at

the 2015 ASCO Annual Meeting

© ASCO/Max Gersh

CHICAGO—A CD19-targeted chimeric antigen receptor (CAR) T-cell therapy can provide durable complete responses (CRs) or a bridge to allogeneic transplant in adults with relapsed or refractory acute lymphoblastic leukemia (ALL), updated results of a phase 1 study suggest.

The therapy, JCAR015, produced a CR rate of 87%, and 33% of these patients went on to transplant.

The median duration of response or relapse-free survival was 5.3 months. The median overall survival was 8.5 months.

Nearly a quarter of patients developed severe cytokine release syndrome (CRS), and nearly 30% experienced neurological toxicities. But researchers said these effects were largely treatable and reversible.

This study was temporarily placed on clinical hold last year, after 2 patients died from complications related to CRS. But the hold was soon lifted and enrollment and dosing criteria were changed in an attempt to prevent severe CRS.

Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center in New York, presented updated results of this trial (NCT01044069) at the 2015 ASCO Annual Meeting (abstract 7010*). The study is sponsored by Memorial Sloan Kettering, but funding has also been provided by Juno Therapeutics, the company developing JCAR015.

Results from this trial have previously been reported in Science Translational Medicine (Davila et al 2014; Brentjens et al 2013), at AACR 2014, and at ASH 2014.

At ASCO, Dr Park presented results in 39 patients with relapsed/refractory, CD19⁺ ALL. All of them were evaluable for toxicity assessment, and 38 were evaluable for response with at least 1 month of follow-up.

There were 29 males, and the patients’ median age was 45 (range, 22-74). Thirty-three percent had Ph⁺ ALL, and 11% had the T315I mutation.

Forty-nine percent of patients had received 2 prior therapies, 23% had received 3, and 28% had received 4 or more. Thirty-six percent of patients had a prior allogeneic hematopoietic stem cell transplant (HSCT).

For this study, patients first underwent leukapheresis. While their T cells were being manufactured, they were allowed to receive salvage chemotherapy. Patients underwent repeat bone marrow biopsy to assess their disease status immediately prior to T-cell infusion.

Fifty-four percent of patients (n=21) had morphologic disease (>5% blasts in the bone marrow, median 52%) immediately prior to JCAR015 infusion, and the remaining patients (n=18) had minimal residual disease (MRD).

Two days after conditioning with cyclophosphamide, patients received an infusion of 1-3 x 10⁶ CAR T cells/kg. At day 28, the researchers assessed patients’ disease with a repeat bone marrow biopsy.

Treatment results

The median follow-up was 5.6 months (1 to >38 months). Six patients had more than a year of follow-up.

The CR rate was 87% (33/38), and 81% of evaluable patients (26/32) were MRD-negative. The median time to CR was 23 days, and the median duration of response or relapse-free survival was 5.3 months.

“We examined the CR rates by different subgroup,” Dr Park noted. “We looked at whether patients had a pre-T-cell disease burden: morphologic disease vs minimal residual disease, whether they had an allogeneic bone marrow transplant prior to CAR T-cell infusion, their Ph⁺ status, age at infusion, and prior lines of therapy. And there was no [significant] difference between these groups for CRs and MRD-negative CR rate.”

At the time of presentation, 14 patients were disease-free, 10 of whom had not gone on to HSCT. In all, 11 patients went on to allogeneic HSCT.

Fourteen patients relapsed during follow-up, 3 after HSCT. Two of these patients had CD19-negative bone marrow blasts.

The median overall survival was 8.5 months in all patients and 10.8 months in patients who were MRD-negative. The median overall survival was 9.9 months in patients who underwent allogeneic HSCT and 8.5 months in patients who did not.

Dr Park said key adverse events were CRS—clinically manifested by fever, hypotension, and respiratory insufficiency—and neurological changes such as delirium, global encephalopathy, aphasia, and seizures.

Twenty-three percent of patients (n=9) developed severe CRS, 28% (n=11) had grade 3/4 neurotoxicity, and 8% (n=3) had grade 5 toxicity. The patients with grade 5 toxicities died of ventricular arrhythmia, sepsis, and an unknown cause (although this patient suffered a seizure).

The severity of CRS correlated with disease burden, and CRS was managed with an IL-6R inhibitor (n=4), a steroid (n=2), or both (n=9). Neurological symptoms were reversible and could occur independently of CRS, Dr Park said.

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

Audience during a session at

the 2015 ASCO Annual Meeting

© ASCO/Max Gersh

CHICAGO—A CD19-targeted chimeric antigen receptor (CAR) T-cell therapy can provide durable complete responses (CRs) or a bridge to allogeneic transplant in adults with relapsed or refractory acute lymphoblastic leukemia (ALL), updated results of a phase 1 study suggest.

The therapy, JCAR015, produced a CR rate of 87%, and 33% of these patients went on to transplant.

The median duration of response or relapse-free survival was 5.3 months. The median overall survival was 8.5 months.

Nearly a quarter of patients developed severe cytokine release syndrome (CRS), and nearly 30% experienced neurological toxicities. But researchers said these effects were largely treatable and reversible.

This study was temporarily placed on clinical hold last year, after 2 patients died from complications related to CRS. But the hold was soon lifted and enrollment and dosing criteria were changed in an attempt to prevent severe CRS.

Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center in New York, presented updated results of this trial (NCT01044069) at the 2015 ASCO Annual Meeting (abstract 7010*). The study is sponsored by Memorial Sloan Kettering, but funding has also been provided by Juno Therapeutics, the company developing JCAR015.

Results from this trial have previously been reported in Science Translational Medicine (Davila et al 2014; Brentjens et al 2013), at AACR 2014, and at ASH 2014.

At ASCO, Dr Park presented results in 39 patients with relapsed/refractory, CD19⁺ ALL. All of them were evaluable for toxicity assessment, and 38 were evaluable for response with at least 1 month of follow-up.

There were 29 males, and the patients’ median age was 45 (range, 22-74). Thirty-three percent had Ph⁺ ALL, and 11% had the T315I mutation.

Forty-nine percent of patients had received 2 prior therapies, 23% had received 3, and 28% had received 4 or more. Thirty-six percent of patients had a prior allogeneic hematopoietic stem cell transplant (HSCT).

For this study, patients first underwent leukapheresis. While their T cells were being manufactured, they were allowed to receive salvage chemotherapy. Patients underwent repeat bone marrow biopsy to assess their disease status immediately prior to T-cell infusion.

Fifty-four percent of patients (n=21) had morphologic disease (>5% blasts in the bone marrow, median 52%) immediately prior to JCAR015 infusion, and the remaining patients (n=18) had minimal residual disease (MRD).

Two days after conditioning with cyclophosphamide, patients received an infusion of 1-3 x 10⁶ CAR T cells/kg. At day 28, the researchers assessed patients’ disease with a repeat bone marrow biopsy.

Treatment results

The median follow-up was 5.6 months (1 to >38 months). Six patients had more than a year of follow-up.

The CR rate was 87% (33/38), and 81% of evaluable patients (26/32) were MRD-negative. The median time to CR was 23 days, and the median duration of response or relapse-free survival was 5.3 months.

“We examined the CR rates by different subgroup,” Dr Park noted. “We looked at whether patients had a pre-T-cell disease burden: morphologic disease vs minimal residual disease, whether they had an allogeneic bone marrow transplant prior to CAR T-cell infusion, their Ph⁺ status, age at infusion, and prior lines of therapy. And there was no [significant] difference between these groups for CRs and MRD-negative CR rate.”

At the time of presentation, 14 patients were disease-free, 10 of whom had not gone on to HSCT. In all, 11 patients went on to allogeneic HSCT.

Fourteen patients relapsed during follow-up, 3 after HSCT. Two of these patients had CD19-negative bone marrow blasts.

The median overall survival was 8.5 months in all patients and 10.8 months in patients who were MRD-negative. The median overall survival was 9.9 months in patients who underwent allogeneic HSCT and 8.5 months in patients who did not.

Dr Park said key adverse events were CRS—clinically manifested by fever, hypotension, and respiratory insufficiency—and neurological changes such as delirium, global encephalopathy, aphasia, and seizures.

Twenty-three percent of patients (n=9) developed severe CRS, 28% (n=11) had grade 3/4 neurotoxicity, and 8% (n=3) had grade 5 toxicity. The patients with grade 5 toxicities died of ventricular arrhythmia, sepsis, and an unknown cause (although this patient suffered a seizure).

The severity of CRS correlated with disease burden, and CRS was managed with an IL-6R inhibitor (n=4), a steroid (n=2), or both (n=9). Neurological symptoms were reversible and could occur independently of CRS, Dr Park said.

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

“An apple a day keeps the doctor away,” and coffee each day keeps the melanoma away. A recent analysis of data by Loftfield et al from a food frequency questionnaire published online on January 20 in the Journal of the National Cancer Institute demonstrated that caffeinated coffee intake was inversely associated with melanoma. Specifically, consuming 4 or more cups of caffeinated coffee each day was found to decrease the risk for melanoma by 20%.

The authors’ reference groups were derived from a National Institutes of Health–AARP prospective cohort diet and health study that commenced in 1995 to 1996 and concluded on December 31, 2006. They observed that the lower risk for melanoma was only associated with caffeinated coffee. Unexpectedly, they also observed that caffeinated coffee drinking only decreased the risk for melanoma but not melanoma in situ.

There is scientific evidence that coffee has a role in decreasing UVB-induced carcinogenesis. Caffeine (both orally and topically) inhibits UVB-induced carcinogenesis by absorbing UV radiation. Also, 5-O-caffeoylquinic acid (the major chlorogenic acid in coffee) and its metabolite caffeic acid inhibit cyclooxygenase 2 expression, which is overexpressed in human melanoma cells and in response to UVB exposure. In addition to caffeine, coffee also contains several bioactive compounds: diterpenes, polyphenols, and trigonelline. Topical diterpenes inhibit inflammation in epidermal cells. During coffee roasting, trigonelline generates nicotinic acid and nicotinamide, both of which are protective against UVB-induced skin carcinogenesis in mice and UVB-induced immunosuppression in both humans and mice.

What’s the issue?

According to an article in The Washington Post, the “apple” adage originated in the 1860s; the original phrase was “Eat an apple on going to bed, and you’ll keep the doctor from earning his bread,” which evolved to “An apple a day, no doctor to pay,” then “An apple a day sends the doctor away” before the current version was first used in 1922. As one who enjoys having a cup of caffeinated coffee next to my computer in the office or at home, I can easily welcome the prospect of a few additional cups each day to prevent melanoma. And, as advocates for a possible benefit to our patients’ better health, should we should provide complimentary caffeinated coffee in our office waiting rooms to encourage our dermatology patients to decrease their risk for developing melanoma?

We want to know your views! Tell us what you think.

“An apple a day keeps the doctor away,” and coffee each day keeps the melanoma away. A recent analysis of data by Loftfield et al from a food frequency questionnaire published online on January 20 in the Journal of the National Cancer Institute demonstrated that caffeinated coffee intake was inversely associated with melanoma. Specifically, consuming 4 or more cups of caffeinated coffee each day was found to decrease the risk for melanoma by 20%.

The authors’ reference groups were derived from a National Institutes of Health–AARP prospective cohort diet and health study that commenced in 1995 to 1996 and concluded on December 31, 2006. They observed that the lower risk for melanoma was only associated with caffeinated coffee. Unexpectedly, they also observed that caffeinated coffee drinking only decreased the risk for melanoma but not melanoma in situ.

There is scientific evidence that coffee has a role in decreasing UVB-induced carcinogenesis. Caffeine (both orally and topically) inhibits UVB-induced carcinogenesis by absorbing UV radiation. Also, 5-O-caffeoylquinic acid (the major chlorogenic acid in coffee) and its metabolite caffeic acid inhibit cyclooxygenase 2 expression, which is overexpressed in human melanoma cells and in response to UVB exposure. In addition to caffeine, coffee also contains several bioactive compounds: diterpenes, polyphenols, and trigonelline. Topical diterpenes inhibit inflammation in epidermal cells. During coffee roasting, trigonelline generates nicotinic acid and nicotinamide, both of which are protective against UVB-induced skin carcinogenesis in mice and UVB-induced immunosuppression in both humans and mice.

What’s the issue?

According to an article in The Washington Post, the “apple” adage originated in the 1860s; the original phrase was “Eat an apple on going to bed, and you’ll keep the doctor from earning his bread,” which evolved to “An apple a day, no doctor to pay,” then “An apple a day sends the doctor away” before the current version was first used in 1922. As one who enjoys having a cup of caffeinated coffee next to my computer in the office or at home, I can easily welcome the prospect of a few additional cups each day to prevent melanoma. And, as advocates for a possible benefit to our patients’ better health, should we should provide complimentary caffeinated coffee in our office waiting rooms to encourage our dermatology patients to decrease their risk for developing melanoma?

We want to know your views! Tell us what you think.

“An apple a day keeps the doctor away,” and coffee each day keeps the melanoma away. A recent analysis of data by Loftfield et al from a food frequency questionnaire published online on January 20 in the Journal of the National Cancer Institute demonstrated that caffeinated coffee intake was inversely associated with melanoma. Specifically, consuming 4 or more cups of caffeinated coffee each day was found to decrease the risk for melanoma by 20%.

The authors’ reference groups were derived from a National Institutes of Health–AARP prospective cohort diet and health study that commenced in 1995 to 1996 and concluded on December 31, 2006. They observed that the lower risk for melanoma was only associated with caffeinated coffee. Unexpectedly, they also observed that caffeinated coffee drinking only decreased the risk for melanoma but not melanoma in situ.

There is scientific evidence that coffee has a role in decreasing UVB-induced carcinogenesis. Caffeine (both orally and topically) inhibits UVB-induced carcinogenesis by absorbing UV radiation. Also, 5-O-caffeoylquinic acid (the major chlorogenic acid in coffee) and its metabolite caffeic acid inhibit cyclooxygenase 2 expression, which is overexpressed in human melanoma cells and in response to UVB exposure. In addition to caffeine, coffee also contains several bioactive compounds: diterpenes, polyphenols, and trigonelline. Topical diterpenes inhibit inflammation in epidermal cells. During coffee roasting, trigonelline generates nicotinic acid and nicotinamide, both of which are protective against UVB-induced skin carcinogenesis in mice and UVB-induced immunosuppression in both humans and mice.

What’s the issue?

According to an article in The Washington Post, the “apple” adage originated in the 1860s; the original phrase was “Eat an apple on going to bed, and you’ll keep the doctor from earning his bread,” which evolved to “An apple a day, no doctor to pay,” then “An apple a day sends the doctor away” before the current version was first used in 1922. As one who enjoys having a cup of caffeinated coffee next to my computer in the office or at home, I can easily welcome the prospect of a few additional cups each day to prevent melanoma. And, as advocates for a possible benefit to our patients’ better health, should we should provide complimentary caffeinated coffee in our office waiting rooms to encourage our dermatology patients to decrease their risk for developing melanoma?

We want to know your views! Tell us what you think.

As the obesity epidemic continues to rage unabated and diabetes takes its toll on nerves, I am seeing an increase in diabetic foot ulcers.

Traditionally, we have used topical therapies and dressings and pressure relief through accommodative footwear. This usually produces moderate to no effect in many of my patients. Perhaps this is because we are not monitoring in the clinic every other day, or patients are having a difficult time adhering to the complex wound care regimens we prescribe.

Then along came MIST, a proprietary, noncontact ultrasound device delivering low-frequency/low-intensity ultrasound waves via atomized sterile saline. Researchers at our institution have published data suggesting the efficacy of this treatment.

You’ll notice these data are far from new. Sorry to be late to the party, but what is new is my own case series of patients who have done astoundingly well with this therapy.

MIST Therapy heals by activating fibroblasts, reducing bacterial count, and disrupting that pernicious biofilm. The recommended regimen is three treatments per week, with treatments lasting 3-20 minutes depending on wound size. Larger wounds get longer treatments. Many centers are using this therapy exclusively when more than minimal debridement is required.

The MIST Therapy website suggests that this therapy is associated with a $2,600 cost savings over standard of care (estimated to be $10,300). In March 2013, the American Medical Association approved a CPT I code (97610) for MIST Therapy, which became effective in 2014.

Perhaps this code has resulted in more widespread use. However, my wound care colleagues said they have been using this for years prior to the code being issued, and reimbursement has not been a problem.

What I have noticed is how clean and healthy the wounds look very early in the treatment cycle. If you are not adding this therapy to your program for addressing foot ulcers, you need to. Ask your local wound care center about it, and apologize (for me) for being so late to the party.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author and do not necessarily represent the views and opinions of the Mayo Clinic. The opinions expressed in this article should not be used to diagnose or treat any medical condition, nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician. Dr. Ebbert has no relevant disclosures.

As the obesity epidemic continues to rage unabated and diabetes takes its toll on nerves, I am seeing an increase in diabetic foot ulcers.

Traditionally, we have used topical therapies and dressings and pressure relief through accommodative footwear. This usually produces moderate to no effect in many of my patients. Perhaps this is because we are not monitoring in the clinic every other day, or patients are having a difficult time adhering to the complex wound care regimens we prescribe.

Then along came MIST, a proprietary, noncontact ultrasound device delivering low-frequency/low-intensity ultrasound waves via atomized sterile saline. Researchers at our institution have published data suggesting the efficacy of this treatment.

You’ll notice these data are far from new. Sorry to be late to the party, but what is new is my own case series of patients who have done astoundingly well with this therapy.

MIST Therapy heals by activating fibroblasts, reducing bacterial count, and disrupting that pernicious biofilm. The recommended regimen is three treatments per week, with treatments lasting 3-20 minutes depending on wound size. Larger wounds get longer treatments. Many centers are using this therapy exclusively when more than minimal debridement is required.

The MIST Therapy website suggests that this therapy is associated with a $2,600 cost savings over standard of care (estimated to be $10,300). In March 2013, the American Medical Association approved a CPT I code (97610) for MIST Therapy, which became effective in 2014.

Perhaps this code has resulted in more widespread use. However, my wound care colleagues said they have been using this for years prior to the code being issued, and reimbursement has not been a problem.

What I have noticed is how clean and healthy the wounds look very early in the treatment cycle. If you are not adding this therapy to your program for addressing foot ulcers, you need to. Ask your local wound care center about it, and apologize (for me) for being so late to the party.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author and do not necessarily represent the views and opinions of the Mayo Clinic. The opinions expressed in this article should not be used to diagnose or treat any medical condition, nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician. Dr. Ebbert has no relevant disclosures.

As the obesity epidemic continues to rage unabated and diabetes takes its toll on nerves, I am seeing an increase in diabetic foot ulcers.

Traditionally, we have used topical therapies and dressings and pressure relief through accommodative footwear. This usually produces moderate to no effect in many of my patients. Perhaps this is because we are not monitoring in the clinic every other day, or patients are having a difficult time adhering to the complex wound care regimens we prescribe.

Then along came MIST, a proprietary, noncontact ultrasound device delivering low-frequency/low-intensity ultrasound waves via atomized sterile saline. Researchers at our institution have published data suggesting the efficacy of this treatment.

You’ll notice these data are far from new. Sorry to be late to the party, but what is new is my own case series of patients who have done astoundingly well with this therapy.

MIST Therapy heals by activating fibroblasts, reducing bacterial count, and disrupting that pernicious biofilm. The recommended regimen is three treatments per week, with treatments lasting 3-20 minutes depending on wound size. Larger wounds get longer treatments. Many centers are using this therapy exclusively when more than minimal debridement is required.

The MIST Therapy website suggests that this therapy is associated with a $2,600 cost savings over standard of care (estimated to be $10,300). In March 2013, the American Medical Association approved a CPT I code (97610) for MIST Therapy, which became effective in 2014.

Perhaps this code has resulted in more widespread use. However, my wound care colleagues said they have been using this for years prior to the code being issued, and reimbursement has not been a problem.

What I have noticed is how clean and healthy the wounds look very early in the treatment cycle. If you are not adding this therapy to your program for addressing foot ulcers, you need to. Ask your local wound care center about it, and apologize (for me) for being so late to the party.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author and do not necessarily represent the views and opinions of the Mayo Clinic. The opinions expressed in this article should not be used to diagnose or treat any medical condition, nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician. Dr. Ebbert has no relevant disclosures.