Steven Treon, MD, PhD
Photo courtesy of DFCI

NEW YORK—Whole-genome sequencing has changed the entire approach to drug development for Waldenström’s macroglobulinemia (WM), according to a speaker at Lymphoma & Myeloma 2016.

The strategy has changed from a hand-me-down one, relying on drugs developed first for other diseases, to a rational plan designed specifically to treat WM patients. 

“We would wait for our colleagues in the myeloma world or lymphoma world, CLL world, anywhere we could find them, to help us with the development of drugs,” said Steven Treon, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts. 

“And, sometimes, this resulted in delays of many, many years before those therapeutics could be vetted out and eventually be handed down to the Waldenström investigators.”

At Lymphoma & Myeloma 2016, Dr Treon described the current therapy of WM and the impact of the discovery of MYD88 and CXCR4 on drug development and treatment choices in WM.

Rituximab-based therapy

WM is a disease that strongly expresses CD20, even though it’s a lymphoplasmacytic disease. So rituximab, given alone and in combination, has been, to date, the most common approach to treating WM.

As a single agent, rituximab produces a response in 25% to 40% of WM patients, but these are very seldom deep responses, Dr Treon noted.

So investigators combined rituximab with cyclophosphamide, nucleoside analogues, proteasome inhibitors, and bendamustine, which increased the overall response rate and depth of response. 

This translated into improvement in time to progression, which is now 4 to 5 years with these combination therapies.

“Now, the problem is, when you borrow things from other people, you sometimes end up with problems you didn’t anticipate,” Dr Treon said. 

One of the unanticipated side effects with rituximab in WM patients is the IgM flare, which occurs in 40% to 60% of WM patients. 

Rituximab can also cause hypogammaglobulinema, leading to infections, and results in a high intolerance rate, which tends to occur a few cycles into induction or maintenance therapy. 

“In some cases,” Dr Treon advised, “a switch to ofatumumab, a fully human CD20 molecule, overcomes this intolerance.”

Nucleoside analogues, which used to be the mainstay of WM, have a high rate of transformation into a more aggressive lymphoma or acute myeloid leukemia.

Immunomodulatory drugs, particularly thalidomide, cause peripheral neuropathy greater than grade 2 in 60% of patients.

And a greater incidence of peripheral neuropathy is also observed with proteasome inhibitors, particularly bortezomib, in WM patients than in myeloma or mantle cell lymphoma patients.

“So this was at least the impetus for why we needed to develop novel approaches to treating this disease,” Dr Treon said.

MYD88 mutations

With whole-genome sequencing, investigators discovered that mutations in the MYD88 gene were highly prevalent in WM patients.

About 93% to 95% of WM patients have the L265P MYD88 mutation, and about 2% have the non-L265P MYD88 mutation. 

MYD88 has prognostic significance in WM. Mutated MYD88 confers a better prognosis than unmutated MYD88.

MYD88 may also be important in predicting who will respond to drugs like ibrutinib.

CXCR4 mutations

Mutations in CXCR4 are the second most common mutation in WM. 

Between 30% and 40% of WM patients have the WHIM-like CXCR4 C-tail mutations, which traffic the Waldenström’s cells to the bone marrow.

This mutation promotes drug resistance, including resistance to ibrutinib because of the enhanced AKT/ERK signaling. 

Ibrutinib therapy 

With this in mind, investigators set out to evaluate the potential of using a BTK inhibitor in relapsed/refractory WM patients and at the same time observe the genomics that might predict for response and resistance. 

They enrolled 63 patients in the multicenter study. Patients had a median of 2 prior therapies (range, 1–9), and 60% had bone marrow involvement.

Patients received single-agent ibrutinib at a dose of 420 mg orally each day until disease progression or the development of unacceptable toxic side effects.

“By the time they came back 4 weeks later to be evaluated, many of them were already in a response,” Dr Treon said. “And what we saw, in fact, was almost immediate improvement in hemoglobin, something that we didn’t see with many of our trials before that.” 

The best IgM response reduced levels from 3520 to 880 mg/dL (P<0.001) for the entire cohort. 

The best hemoglobin response increased hemoglobin levels 3 points, from 10.5 to 13.8 g/dL (P<0.001).

The progression-free survival at 2 years was 69% and overall survival was 95%. 

At 37 months, most patients who achieve a response experience a durable, ongoing response, according to an update presented at the IX International Workshop on Waldenstrom’s Macroglobulinemia. 

And toxicities were “very much in line with what our colleagues have seen in other disease groups,” Dr Treon stated. 

Response to ibrutinib by mutation status

The overall response rate was 90% for all patients, but there were differences according to mutation status. 

Patients with no MYD88 mutation and no CXCR4 mutation had absolutely no major response.

Patients with a MYD88 mutation responded at an overall rate of 100% and had a major response rate of 91.7% if they did not have a CXCR4 mutation as well. 

If they also had a CXCR4^WHIM mutation, the overall response rate was lower, at 85.7%, and the major response rate was 61.9%. 

“It’s still something to be incredibly excited about—61.9% single-agent activity,” Dr Treon said.

Patients with a CXCR4 mutation also respond more slowly than those without the mutation.

This investigator-sponsored study led to the approval of ibrutinib in WM in the US as well as in Europe and Canada.

“And the point to make about this is that investigators can bring their data to the FDA, the EMA, even Canada, and it can make a difference,” Dr Treon said. 

“We don’t always have to have company-sponsored registration studies to be able to make these kinds of advances.” 

Ibrutinib in rituximab-refractory patients

A multicenter, phase 3 study of ibrutinib in rituximab-refractory patients was “almost a photocopy of our study,” Dr Treon said.

The main difference was that the patients were even sicker, having failed a median of 4 prior therapies.

Patients experienced rapid improvements in hemoglobin and IgM levels and had an overall response rate of 90%.

Patients with a CXCR4 mutation also tended to lag in terms of pace of hemoglobin improvement and reduction in IgM.

The study was just accepted for publication in Lancet Oncology.

IRAK inhibition

Investigators were puzzled by the paucity of complete responses with ibrutinib, and they found the IRAK pathway remained turned on in patients treated with ibrutinib.

So they took cells of patients treated for 6 months with ibrutinib and co-cultured them with ibrutinib and an IRAK inhibitor. They observed the induction of apoptosis.

Based on this finding, the investigators are manufacturing a very potent IRAK1 inhibitor (JH-X-119), which, when combined with ibrutinib, synergistically increases tumor-cell killing.

“And so one of the strategies we have going forward,” Dr Treon said, “is the ability to advance ibrutinib therapy in MYD88-mutated tumors by the addition of the IRAK inhibitor.”  

Resistance to ibrutinib 

Investigators have found multiple mutations in the C481 site in individual WM patients, which is where ibrutinib binds. 

These mutations represent a minority of the clone, but they exert almost a fully clonal signature. The few patients with these mutations also have a CXCR4 mutation. 

C481 mutations shift the signaling of cells in the presence of ibrutinib toward ERK, which is a very powerful survival pathway.

So investigators are examining whether an ERK inhibitor combined with ibrutinib can elicit synergistic killing of BTK-resistant cells.

Investigators have also been synthesizing potent HCK inhibitors, which might overcome BTK mutations by shutting down the ability to activate Bruton’s tyrosine kinase. 

Other drugs being developed for WM include:

• Combinations with a proteasome inhibitor, such as ixazomib, dexamethasone, and rituximab
• Agents that target MYD88 signaling, such as the BTK inhibitors acalabrutinib and BGB-3111
  
• Agents that block CXCR4 receptor signaling, such as ulocuplomab
• The BCL2 inhibitor venetoclax
• The CD38-targeted agent daratumumab.

Current treatment strategies

Knowing a patient’s MYD88 and CXCR4 mutation status provides an opportunity to take a rational approach to treating individuals with WM, Dr Treon said.

For patients with mutated MYD88 and no CXCR4 mutation:

• If patients do not have bulky disease or contraindications, ibrutinib may be used if available.
• If patients have bulky disease, a combination of bendamustine and rituximab may be used. 
• If patients have amyloidosis, a combination of bortezomib, dexamethasone, and rituximab is possible.
• If patients have IgM peripheral neuropathy, then rituximab with or without an alkylator is recommended.

For patients with mutated MYD88 and mutated CXCR4, the same treatments can be used as for patients with mutated MYD88 and unmutated CXCR4 with the same restrictions. 

To achieve an immediate response for patients with a CXCR4 mutation, an alternative therapy to ibrutinib—such as the bendamustine, dexamethasone, rituximab combination—may be the best choice, because CXCR4-mutated individuals have a slower response to ibrutinib. 

The problem arises with the MYD88-wild-type patients, because their survival is poorer than the MYD88-mutated patients.

“We still don’t know what’s wrong with these individuals,” Dr Treon said. “We don’t have any idea about what their basic genomic problems are.”

Bendamustine- or bortezomib-based therapy is effective in this population and can be considered. 

In terms of salvage therapy, “the only thing to keep in mind is that if something worked the first time and you got at least a 2-year response with it, you can go back and consider it,” Dr Treon said.

Steven Treon, MD, PhD
Photo courtesy of DFCI

NEW YORK—Whole-genome sequencing has changed the entire approach to drug development for Waldenström’s macroglobulinemia (WM), according to a speaker at Lymphoma & Myeloma 2016.

The strategy has changed from a hand-me-down one, relying on drugs developed first for other diseases, to a rational plan designed specifically to treat WM patients. 

“We would wait for our colleagues in the myeloma world or lymphoma world, CLL world, anywhere we could find them, to help us with the development of drugs,” said Steven Treon, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts. 

“And, sometimes, this resulted in delays of many, many years before those therapeutics could be vetted out and eventually be handed down to the Waldenström investigators.”

At Lymphoma & Myeloma 2016, Dr Treon described the current therapy of WM and the impact of the discovery of MYD88 and CXCR4 on drug development and treatment choices in WM.

Rituximab-based therapy

WM is a disease that strongly expresses CD20, even though it’s a lymphoplasmacytic disease. So rituximab, given alone and in combination, has been, to date, the most common approach to treating WM.

As a single agent, rituximab produces a response in 25% to 40% of WM patients, but these are very seldom deep responses, Dr Treon noted.

So investigators combined rituximab with cyclophosphamide, nucleoside analogues, proteasome inhibitors, and bendamustine, which increased the overall response rate and depth of response. 

This translated into improvement in time to progression, which is now 4 to 5 years with these combination therapies.

“Now, the problem is, when you borrow things from other people, you sometimes end up with problems you didn’t anticipate,” Dr Treon said. 

One of the unanticipated side effects with rituximab in WM patients is the IgM flare, which occurs in 40% to 60% of WM patients. 

Rituximab can also cause hypogammaglobulinema, leading to infections, and results in a high intolerance rate, which tends to occur a few cycles into induction or maintenance therapy. 

“In some cases,” Dr Treon advised, “a switch to ofatumumab, a fully human CD20 molecule, overcomes this intolerance.”

Nucleoside analogues, which used to be the mainstay of WM, have a high rate of transformation into a more aggressive lymphoma or acute myeloid leukemia.

Immunomodulatory drugs, particularly thalidomide, cause peripheral neuropathy greater than grade 2 in 60% of patients.

And a greater incidence of peripheral neuropathy is also observed with proteasome inhibitors, particularly bortezomib, in WM patients than in myeloma or mantle cell lymphoma patients.

“So this was at least the impetus for why we needed to develop novel approaches to treating this disease,” Dr Treon said.

MYD88 mutations

With whole-genome sequencing, investigators discovered that mutations in the MYD88 gene were highly prevalent in WM patients.

About 93% to 95% of WM patients have the L265P MYD88 mutation, and about 2% have the non-L265P MYD88 mutation. 

MYD88 has prognostic significance in WM. Mutated MYD88 confers a better prognosis than unmutated MYD88.

MYD88 may also be important in predicting who will respond to drugs like ibrutinib.

CXCR4 mutations

Mutations in CXCR4 are the second most common mutation in WM. 

Between 30% and 40% of WM patients have the WHIM-like CXCR4 C-tail mutations, which traffic the Waldenström’s cells to the bone marrow.

This mutation promotes drug resistance, including resistance to ibrutinib because of the enhanced AKT/ERK signaling. 

Ibrutinib therapy 

With this in mind, investigators set out to evaluate the potential of using a BTK inhibitor in relapsed/refractory WM patients and at the same time observe the genomics that might predict for response and resistance. 

They enrolled 63 patients in the multicenter study. Patients had a median of 2 prior therapies (range, 1–9), and 60% had bone marrow involvement.

Patients received single-agent ibrutinib at a dose of 420 mg orally each day until disease progression or the development of unacceptable toxic side effects.

“By the time they came back 4 weeks later to be evaluated, many of them were already in a response,” Dr Treon said. “And what we saw, in fact, was almost immediate improvement in hemoglobin, something that we didn’t see with many of our trials before that.” 

The best IgM response reduced levels from 3520 to 880 mg/dL (P<0.001) for the entire cohort. 

The best hemoglobin response increased hemoglobin levels 3 points, from 10.5 to 13.8 g/dL (P<0.001).

The progression-free survival at 2 years was 69% and overall survival was 95%. 

At 37 months, most patients who achieve a response experience a durable, ongoing response, according to an update presented at the IX International Workshop on Waldenstrom’s Macroglobulinemia. 

And toxicities were “very much in line with what our colleagues have seen in other disease groups,” Dr Treon stated. 

Response to ibrutinib by mutation status

The overall response rate was 90% for all patients, but there were differences according to mutation status. 

Patients with no MYD88 mutation and no CXCR4 mutation had absolutely no major response.

Patients with a MYD88 mutation responded at an overall rate of 100% and had a major response rate of 91.7% if they did not have a CXCR4 mutation as well. 

If they also had a CXCR4^WHIM mutation, the overall response rate was lower, at 85.7%, and the major response rate was 61.9%. 

“It’s still something to be incredibly excited about—61.9% single-agent activity,” Dr Treon said.

Patients with a CXCR4 mutation also respond more slowly than those without the mutation.

This investigator-sponsored study led to the approval of ibrutinib in WM in the US as well as in Europe and Canada.

“And the point to make about this is that investigators can bring their data to the FDA, the EMA, even Canada, and it can make a difference,” Dr Treon said. 

“We don’t always have to have company-sponsored registration studies to be able to make these kinds of advances.” 

Ibrutinib in rituximab-refractory patients

A multicenter, phase 3 study of ibrutinib in rituximab-refractory patients was “almost a photocopy of our study,” Dr Treon said.

The main difference was that the patients were even sicker, having failed a median of 4 prior therapies.

Patients experienced rapid improvements in hemoglobin and IgM levels and had an overall response rate of 90%.

Patients with a CXCR4 mutation also tended to lag in terms of pace of hemoglobin improvement and reduction in IgM.

The study was just accepted for publication in Lancet Oncology.

IRAK inhibition

Investigators were puzzled by the paucity of complete responses with ibrutinib, and they found the IRAK pathway remained turned on in patients treated with ibrutinib.

So they took cells of patients treated for 6 months with ibrutinib and co-cultured them with ibrutinib and an IRAK inhibitor. They observed the induction of apoptosis.

Based on this finding, the investigators are manufacturing a very potent IRAK1 inhibitor (JH-X-119), which, when combined with ibrutinib, synergistically increases tumor-cell killing.

“And so one of the strategies we have going forward,” Dr Treon said, “is the ability to advance ibrutinib therapy in MYD88-mutated tumors by the addition of the IRAK inhibitor.”  

Resistance to ibrutinib 

Investigators have found multiple mutations in the C481 site in individual WM patients, which is where ibrutinib binds. 

These mutations represent a minority of the clone, but they exert almost a fully clonal signature. The few patients with these mutations also have a CXCR4 mutation. 

C481 mutations shift the signaling of cells in the presence of ibrutinib toward ERK, which is a very powerful survival pathway.

So investigators are examining whether an ERK inhibitor combined with ibrutinib can elicit synergistic killing of BTK-resistant cells.

Investigators have also been synthesizing potent HCK inhibitors, which might overcome BTK mutations by shutting down the ability to activate Bruton’s tyrosine kinase. 

Other drugs being developed for WM include:

• Combinations with a proteasome inhibitor, such as ixazomib, dexamethasone, and rituximab
• Agents that target MYD88 signaling, such as the BTK inhibitors acalabrutinib and BGB-3111
  
• Agents that block CXCR4 receptor signaling, such as ulocuplomab
• The BCL2 inhibitor venetoclax
• The CD38-targeted agent daratumumab.

Current treatment strategies

Knowing a patient’s MYD88 and CXCR4 mutation status provides an opportunity to take a rational approach to treating individuals with WM, Dr Treon said.

For patients with mutated MYD88 and no CXCR4 mutation:

• If patients do not have bulky disease or contraindications, ibrutinib may be used if available.
• If patients have bulky disease, a combination of bendamustine and rituximab may be used. 
• If patients have amyloidosis, a combination of bortezomib, dexamethasone, and rituximab is possible.
• If patients have IgM peripheral neuropathy, then rituximab with or without an alkylator is recommended.

For patients with mutated MYD88 and mutated CXCR4, the same treatments can be used as for patients with mutated MYD88 and unmutated CXCR4 with the same restrictions. 

To achieve an immediate response for patients with a CXCR4 mutation, an alternative therapy to ibrutinib—such as the bendamustine, dexamethasone, rituximab combination—may be the best choice, because CXCR4-mutated individuals have a slower response to ibrutinib. 

The problem arises with the MYD88-wild-type patients, because their survival is poorer than the MYD88-mutated patients.

“We still don’t know what’s wrong with these individuals,” Dr Treon said. “We don’t have any idea about what their basic genomic problems are.”

Bendamustine- or bortezomib-based therapy is effective in this population and can be considered. 

In terms of salvage therapy, “the only thing to keep in mind is that if something worked the first time and you got at least a 2-year response with it, you can go back and consider it,” Dr Treon said.

Steven Treon, MD, PhD
Photo courtesy of DFCI

NEW YORK—Whole-genome sequencing has changed the entire approach to drug development for Waldenström’s macroglobulinemia (WM), according to a speaker at Lymphoma & Myeloma 2016.

The strategy has changed from a hand-me-down one, relying on drugs developed first for other diseases, to a rational plan designed specifically to treat WM patients. 

“We would wait for our colleagues in the myeloma world or lymphoma world, CLL world, anywhere we could find them, to help us with the development of drugs,” said Steven Treon, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts. 

“And, sometimes, this resulted in delays of many, many years before those therapeutics could be vetted out and eventually be handed down to the Waldenström investigators.”

At Lymphoma & Myeloma 2016, Dr Treon described the current therapy of WM and the impact of the discovery of MYD88 and CXCR4 on drug development and treatment choices in WM.

Rituximab-based therapy

WM is a disease that strongly expresses CD20, even though it’s a lymphoplasmacytic disease. So rituximab, given alone and in combination, has been, to date, the most common approach to treating WM.

As a single agent, rituximab produces a response in 25% to 40% of WM patients, but these are very seldom deep responses, Dr Treon noted.

So investigators combined rituximab with cyclophosphamide, nucleoside analogues, proteasome inhibitors, and bendamustine, which increased the overall response rate and depth of response. 

This translated into improvement in time to progression, which is now 4 to 5 years with these combination therapies.

“Now, the problem is, when you borrow things from other people, you sometimes end up with problems you didn’t anticipate,” Dr Treon said. 

One of the unanticipated side effects with rituximab in WM patients is the IgM flare, which occurs in 40% to 60% of WM patients. 

Rituximab can also cause hypogammaglobulinema, leading to infections, and results in a high intolerance rate, which tends to occur a few cycles into induction or maintenance therapy. 

“In some cases,” Dr Treon advised, “a switch to ofatumumab, a fully human CD20 molecule, overcomes this intolerance.”

Nucleoside analogues, which used to be the mainstay of WM, have a high rate of transformation into a more aggressive lymphoma or acute myeloid leukemia.

Immunomodulatory drugs, particularly thalidomide, cause peripheral neuropathy greater than grade 2 in 60% of patients.

And a greater incidence of peripheral neuropathy is also observed with proteasome inhibitors, particularly bortezomib, in WM patients than in myeloma or mantle cell lymphoma patients.

“So this was at least the impetus for why we needed to develop novel approaches to treating this disease,” Dr Treon said.

MYD88 mutations

With whole-genome sequencing, investigators discovered that mutations in the MYD88 gene were highly prevalent in WM patients.

About 93% to 95% of WM patients have the L265P MYD88 mutation, and about 2% have the non-L265P MYD88 mutation. 

MYD88 has prognostic significance in WM. Mutated MYD88 confers a better prognosis than unmutated MYD88.

MYD88 may also be important in predicting who will respond to drugs like ibrutinib.

CXCR4 mutations

Mutations in CXCR4 are the second most common mutation in WM. 

Between 30% and 40% of WM patients have the WHIM-like CXCR4 C-tail mutations, which traffic the Waldenström’s cells to the bone marrow.

This mutation promotes drug resistance, including resistance to ibrutinib because of the enhanced AKT/ERK signaling. 

Ibrutinib therapy 

With this in mind, investigators set out to evaluate the potential of using a BTK inhibitor in relapsed/refractory WM patients and at the same time observe the genomics that might predict for response and resistance. 

They enrolled 63 patients in the multicenter study. Patients had a median of 2 prior therapies (range, 1–9), and 60% had bone marrow involvement.

Patients received single-agent ibrutinib at a dose of 420 mg orally each day until disease progression or the development of unacceptable toxic side effects.

“By the time they came back 4 weeks later to be evaluated, many of them were already in a response,” Dr Treon said. “And what we saw, in fact, was almost immediate improvement in hemoglobin, something that we didn’t see with many of our trials before that.” 

The best IgM response reduced levels from 3520 to 880 mg/dL (P<0.001) for the entire cohort. 

The best hemoglobin response increased hemoglobin levels 3 points, from 10.5 to 13.8 g/dL (P<0.001).

The progression-free survival at 2 years was 69% and overall survival was 95%. 

At 37 months, most patients who achieve a response experience a durable, ongoing response, according to an update presented at the IX International Workshop on Waldenstrom’s Macroglobulinemia. 

And toxicities were “very much in line with what our colleagues have seen in other disease groups,” Dr Treon stated. 

Response to ibrutinib by mutation status

The overall response rate was 90% for all patients, but there were differences according to mutation status. 

Patients with no MYD88 mutation and no CXCR4 mutation had absolutely no major response.

Patients with a MYD88 mutation responded at an overall rate of 100% and had a major response rate of 91.7% if they did not have a CXCR4 mutation as well. 

If they also had a CXCR4^WHIM mutation, the overall response rate was lower, at 85.7%, and the major response rate was 61.9%. 

“It’s still something to be incredibly excited about—61.9% single-agent activity,” Dr Treon said.

Patients with a CXCR4 mutation also respond more slowly than those without the mutation.

This investigator-sponsored study led to the approval of ibrutinib in WM in the US as well as in Europe and Canada.

“And the point to make about this is that investigators can bring their data to the FDA, the EMA, even Canada, and it can make a difference,” Dr Treon said. 

“We don’t always have to have company-sponsored registration studies to be able to make these kinds of advances.” 

Ibrutinib in rituximab-refractory patients

A multicenter, phase 3 study of ibrutinib in rituximab-refractory patients was “almost a photocopy of our study,” Dr Treon said.

The main difference was that the patients were even sicker, having failed a median of 4 prior therapies.

Patients experienced rapid improvements in hemoglobin and IgM levels and had an overall response rate of 90%.

Patients with a CXCR4 mutation also tended to lag in terms of pace of hemoglobin improvement and reduction in IgM.

The study was just accepted for publication in Lancet Oncology.

IRAK inhibition

Investigators were puzzled by the paucity of complete responses with ibrutinib, and they found the IRAK pathway remained turned on in patients treated with ibrutinib.

So they took cells of patients treated for 6 months with ibrutinib and co-cultured them with ibrutinib and an IRAK inhibitor. They observed the induction of apoptosis.

Based on this finding, the investigators are manufacturing a very potent IRAK1 inhibitor (JH-X-119), which, when combined with ibrutinib, synergistically increases tumor-cell killing.

“And so one of the strategies we have going forward,” Dr Treon said, “is the ability to advance ibrutinib therapy in MYD88-mutated tumors by the addition of the IRAK inhibitor.”  

Resistance to ibrutinib 

Investigators have found multiple mutations in the C481 site in individual WM patients, which is where ibrutinib binds. 

These mutations represent a minority of the clone, but they exert almost a fully clonal signature. The few patients with these mutations also have a CXCR4 mutation. 

C481 mutations shift the signaling of cells in the presence of ibrutinib toward ERK, which is a very powerful survival pathway.

So investigators are examining whether an ERK inhibitor combined with ibrutinib can elicit synergistic killing of BTK-resistant cells.

Investigators have also been synthesizing potent HCK inhibitors, which might overcome BTK mutations by shutting down the ability to activate Bruton’s tyrosine kinase. 

Other drugs being developed for WM include:

• Combinations with a proteasome inhibitor, such as ixazomib, dexamethasone, and rituximab
• Agents that target MYD88 signaling, such as the BTK inhibitors acalabrutinib and BGB-3111
  
• Agents that block CXCR4 receptor signaling, such as ulocuplomab
• The BCL2 inhibitor venetoclax
• The CD38-targeted agent daratumumab.

Current treatment strategies

Knowing a patient’s MYD88 and CXCR4 mutation status provides an opportunity to take a rational approach to treating individuals with WM, Dr Treon said.

For patients with mutated MYD88 and no CXCR4 mutation:

• If patients do not have bulky disease or contraindications, ibrutinib may be used if available.
• If patients have bulky disease, a combination of bendamustine and rituximab may be used. 
• If patients have amyloidosis, a combination of bortezomib, dexamethasone, and rituximab is possible.
• If patients have IgM peripheral neuropathy, then rituximab with or without an alkylator is recommended.

For patients with mutated MYD88 and mutated CXCR4, the same treatments can be used as for patients with mutated MYD88 and unmutated CXCR4 with the same restrictions. 

To achieve an immediate response for patients with a CXCR4 mutation, an alternative therapy to ibrutinib—such as the bendamustine, dexamethasone, rituximab combination—may be the best choice, because CXCR4-mutated individuals have a slower response to ibrutinib. 

The problem arises with the MYD88-wild-type patients, because their survival is poorer than the MYD88-mutated patients.

“We still don’t know what’s wrong with these individuals,” Dr Treon said. “We don’t have any idea about what their basic genomic problems are.”

Bendamustine- or bortezomib-based therapy is effective in this population and can be considered. 

In terms of salvage therapy, “the only thing to keep in mind is that if something worked the first time and you got at least a 2-year response with it, you can go back and consider it,” Dr Treon said.

ORTHO VISION Max

Photo courtesy of

PR Newswire and

Ortho Clinical Diagnostics

The US Food and Drug Administration has granted 510(k) clearance for ORTHO VISION® Max, a fully automated blood analyzer for high-volume transfusion medicine laboratories.

Ortho Clinical Diagnostics developed ORTHO VISION Max for labs conducting more than 50 types and screens per day.

ORTHO VISION Max is now commercially available in the US as well as Europe and Japan.

The launch of ORTHO VISION® Max follows the 2015 release of the ORTHO VISION® Analyzer, an instrument designed for small- to mid-sized transfusion labs.

Together, the analyzers form the ORTHO VISION® platform. According to Ortho Clinical Diagnostics, the platform automates more tests than ever before and takes less time to perform those tests.

The platform supports complex immunohematology testing such as serial dilutions for titration studies, reflex tests, and selected cell antibody identification.

The ORTHO VISION platform also has scheduling intelligence, which allows a transfusion medicine department to process routine samples and STAT orders as they are received, rather than waiting for a complete batch before running the instrument.

The platform offers dynamic workflow and lab standardization across instrumentation, technology, procedures, and training. These features are intended to help blood bank labs keep pace with growing industry pressure to increase productivity while remaining operationally efficient.

“Labs are continuously pushed to accomplish more with fewer resources, including staff, and Ortho can now ease those pressures in labs of every size and makeup,” said Robert Yates, chief operating officer of Ortho Clinical Diagnostics.

“Whether they perform 15 tests per day or 150, the ORTHO VISION platform helps labs better manage their contribution to the overall critical care path.”

ORTHO VISION Max

Photo courtesy of

PR Newswire and

Ortho Clinical Diagnostics

The US Food and Drug Administration has granted 510(k) clearance for ORTHO VISION® Max, a fully automated blood analyzer for high-volume transfusion medicine laboratories.

Ortho Clinical Diagnostics developed ORTHO VISION Max for labs conducting more than 50 types and screens per day.

ORTHO VISION Max is now commercially available in the US as well as Europe and Japan.

The launch of ORTHO VISION® Max follows the 2015 release of the ORTHO VISION® Analyzer, an instrument designed for small- to mid-sized transfusion labs.

Together, the analyzers form the ORTHO VISION® platform. According to Ortho Clinical Diagnostics, the platform automates more tests than ever before and takes less time to perform those tests.

The platform supports complex immunohematology testing such as serial dilutions for titration studies, reflex tests, and selected cell antibody identification.

The ORTHO VISION platform also has scheduling intelligence, which allows a transfusion medicine department to process routine samples and STAT orders as they are received, rather than waiting for a complete batch before running the instrument.

The platform offers dynamic workflow and lab standardization across instrumentation, technology, procedures, and training. These features are intended to help blood bank labs keep pace with growing industry pressure to increase productivity while remaining operationally efficient.

“Labs are continuously pushed to accomplish more with fewer resources, including staff, and Ortho can now ease those pressures in labs of every size and makeup,” said Robert Yates, chief operating officer of Ortho Clinical Diagnostics.

“Whether they perform 15 tests per day or 150, the ORTHO VISION platform helps labs better manage their contribution to the overall critical care path.”

ORTHO VISION Max

Photo courtesy of

PR Newswire and

Ortho Clinical Diagnostics

The US Food and Drug Administration has granted 510(k) clearance for ORTHO VISION® Max, a fully automated blood analyzer for high-volume transfusion medicine laboratories.

Ortho Clinical Diagnostics developed ORTHO VISION Max for labs conducting more than 50 types and screens per day.

ORTHO VISION Max is now commercially available in the US as well as Europe and Japan.

The launch of ORTHO VISION® Max follows the 2015 release of the ORTHO VISION® Analyzer, an instrument designed for small- to mid-sized transfusion labs.

Together, the analyzers form the ORTHO VISION® platform. According to Ortho Clinical Diagnostics, the platform automates more tests than ever before and takes less time to perform those tests.

The platform supports complex immunohematology testing such as serial dilutions for titration studies, reflex tests, and selected cell antibody identification.

The ORTHO VISION platform also has scheduling intelligence, which allows a transfusion medicine department to process routine samples and STAT orders as they are received, rather than waiting for a complete batch before running the instrument.

The platform offers dynamic workflow and lab standardization across instrumentation, technology, procedures, and training. These features are intended to help blood bank labs keep pace with growing industry pressure to increase productivity while remaining operationally efficient.

“Labs are continuously pushed to accomplish more with fewer resources, including staff, and Ortho can now ease those pressures in labs of every size and makeup,” said Robert Yates, chief operating officer of Ortho Clinical Diagnostics.

“Whether they perform 15 tests per day or 150, the ORTHO VISION platform helps labs better manage their contribution to the overall critical care path.”

Blood for transfusion

Photo by Elise Amendola

Results of a large, international study suggest the risk of death after transfusion is not significantly affected by the age of blood transfused.

The median storage duration for the fresher blood used in this study was 11 days, and the median storage duration for older blood was 23 days.

The rate of death was 9.1% for the patients who received fresher blood and 8.8% for patients who received older blood (P=0.38).

Researchers reported these and other results from this study in NEJM.

“It’s been a contentious issue, but our study finally puts an end to the question about whether stored blood could be harmful and fresher blood would be better,” said study author Nancy Heddle, of McMaster University in Hamilton, Ontario, Canada.

“Our study provides strong evidence that transfusion of fresh blood does not improve patient outcomes, and this should reassure clinicians that fresher is not better.”

For this study, Heddle and her colleagues enrolled 31,497 adult patients treated at hospitals in Australia, Canada, Israel, and the US. However, 6761 patients did not meet all the enrollment criteria and were excluded after randomization.

A and O blood types

The researchers’ primary analysis included only patients with type A or O blood. Of these 20,858 patients, 6936 were assigned to receive blood stored for a shorter period, and 13,922 were assigned to receive blood stored for a longer period.

The mean storage duration was 13.0 ± 7.6 days in the short-term group and 23.6 ± 8.9 days in the long-term group. The median storage duration was 11 days (range, 8-16) and 23 days (range, 16-31), respectively.

The rate of death was 9.1% (n=634) in the short-term storage group and 8.7% (n=1213) in the long-term storage group. The odds ratio was 1.05 (95% CI, 0.95 to 1.16; P=0.34).

All blood types

The researchers also analyzed patients with any blood type. Of the 24,736 patients studied, 8215 were assigned to receive blood stored for a shorter period, and 16,521 were assigned to receive blood stored for a longer period.

The mean storage duration was 13.4 ± 7.7 days in the short-term group and 23.6 ± 8.9 days in the long-term group. The median storage duration was 11 days (range, 8-17) and 23 days (range, 16-31), respectively.

The rate of death was 9.1% (n=750) in the short-term storage group and 8.8% (n=1446) in the long-term storage group. The odds ratio was 1.04 (95% CI, 0.95 to 1.14; P=0.38).

The researchers said the overall results were similar to those observed in 3 pre-specified high-risk subgroups—patients undergoing cardiovascular surgery, individuals admitted to intensive care, and patients with cancer.

“Advances in blood storage now allow blood to be stored up to 42 days before transfusion, and the usual practice is to use up the blood that has been in storage the longest,” said study author John Eikelboom, MD, also of McMaster University.

“But because there are biochemical, structural, and functional changes in the blood during storage, there had been concerns about the use of ‘older’ blood. This study reassures us that aging is not bad—even for blood.”

The findings of this study are in line with the recently released AABB recommendations on blood transfusion.

Blood for transfusion

Photo by Elise Amendola

Results of a large, international study suggest the risk of death after transfusion is not significantly affected by the age of blood transfused.

The median storage duration for the fresher blood used in this study was 11 days, and the median storage duration for older blood was 23 days.

The rate of death was 9.1% for the patients who received fresher blood and 8.8% for patients who received older blood (P=0.38).

Researchers reported these and other results from this study in NEJM.

“It’s been a contentious issue, but our study finally puts an end to the question about whether stored blood could be harmful and fresher blood would be better,” said study author Nancy Heddle, of McMaster University in Hamilton, Ontario, Canada.

“Our study provides strong evidence that transfusion of fresh blood does not improve patient outcomes, and this should reassure clinicians that fresher is not better.”

For this study, Heddle and her colleagues enrolled 31,497 adult patients treated at hospitals in Australia, Canada, Israel, and the US. However, 6761 patients did not meet all the enrollment criteria and were excluded after randomization.

A and O blood types

The researchers’ primary analysis included only patients with type A or O blood. Of these 20,858 patients, 6936 were assigned to receive blood stored for a shorter period, and 13,922 were assigned to receive blood stored for a longer period.

The mean storage duration was 13.0 ± 7.6 days in the short-term group and 23.6 ± 8.9 days in the long-term group. The median storage duration was 11 days (range, 8-16) and 23 days (range, 16-31), respectively.

The rate of death was 9.1% (n=634) in the short-term storage group and 8.7% (n=1213) in the long-term storage group. The odds ratio was 1.05 (95% CI, 0.95 to 1.16; P=0.34).

All blood types

The researchers also analyzed patients with any blood type. Of the 24,736 patients studied, 8215 were assigned to receive blood stored for a shorter period, and 16,521 were assigned to receive blood stored for a longer period.

The mean storage duration was 13.4 ± 7.7 days in the short-term group and 23.6 ± 8.9 days in the long-term group. The median storage duration was 11 days (range, 8-17) and 23 days (range, 16-31), respectively.

The rate of death was 9.1% (n=750) in the short-term storage group and 8.8% (n=1446) in the long-term storage group. The odds ratio was 1.04 (95% CI, 0.95 to 1.14; P=0.38).

The researchers said the overall results were similar to those observed in 3 pre-specified high-risk subgroups—patients undergoing cardiovascular surgery, individuals admitted to intensive care, and patients with cancer.

“Advances in blood storage now allow blood to be stored up to 42 days before transfusion, and the usual practice is to use up the blood that has been in storage the longest,” said study author John Eikelboom, MD, also of McMaster University.

“But because there are biochemical, structural, and functional changes in the blood during storage, there had been concerns about the use of ‘older’ blood. This study reassures us that aging is not bad—even for blood.”

The findings of this study are in line with the recently released AABB recommendations on blood transfusion.

Blood for transfusion

Photo by Elise Amendola

Results of a large, international study suggest the risk of death after transfusion is not significantly affected by the age of blood transfused.

The median storage duration for the fresher blood used in this study was 11 days, and the median storage duration for older blood was 23 days.

The rate of death was 9.1% for the patients who received fresher blood and 8.8% for patients who received older blood (P=0.38).

Researchers reported these and other results from this study in NEJM.

“It’s been a contentious issue, but our study finally puts an end to the question about whether stored blood could be harmful and fresher blood would be better,” said study author Nancy Heddle, of McMaster University in Hamilton, Ontario, Canada.

“Our study provides strong evidence that transfusion of fresh blood does not improve patient outcomes, and this should reassure clinicians that fresher is not better.”

For this study, Heddle and her colleagues enrolled 31,497 adult patients treated at hospitals in Australia, Canada, Israel, and the US. However, 6761 patients did not meet all the enrollment criteria and were excluded after randomization.

A and O blood types

The researchers’ primary analysis included only patients with type A or O blood. Of these 20,858 patients, 6936 were assigned to receive blood stored for a shorter period, and 13,922 were assigned to receive blood stored for a longer period.

The mean storage duration was 13.0 ± 7.6 days in the short-term group and 23.6 ± 8.9 days in the long-term group. The median storage duration was 11 days (range, 8-16) and 23 days (range, 16-31), respectively.

The rate of death was 9.1% (n=634) in the short-term storage group and 8.7% (n=1213) in the long-term storage group. The odds ratio was 1.05 (95% CI, 0.95 to 1.16; P=0.34).

All blood types

The researchers also analyzed patients with any blood type. Of the 24,736 patients studied, 8215 were assigned to receive blood stored for a shorter period, and 16,521 were assigned to receive blood stored for a longer period.

The mean storage duration was 13.4 ± 7.7 days in the short-term group and 23.6 ± 8.9 days in the long-term group. The median storage duration was 11 days (range, 8-17) and 23 days (range, 16-31), respectively.

The rate of death was 9.1% (n=750) in the short-term storage group and 8.8% (n=1446) in the long-term storage group. The odds ratio was 1.04 (95% CI, 0.95 to 1.14; P=0.38).

The researchers said the overall results were similar to those observed in 3 pre-specified high-risk subgroups—patients undergoing cardiovascular surgery, individuals admitted to intensive care, and patients with cancer.

“Advances in blood storage now allow blood to be stored up to 42 days before transfusion, and the usual practice is to use up the blood that has been in storage the longest,” said study author John Eikelboom, MD, also of McMaster University.

“But because there are biochemical, structural, and functional changes in the blood during storage, there had been concerns about the use of ‘older’ blood. This study reassures us that aging is not bad—even for blood.”

The findings of this study are in line with the recently released AABB recommendations on blood transfusion.

Burkitt lymphoma

Image by Ed Uthman

A new compound has shown promise for treating hematologic malignancies and other cancers, according to preclinical research published in Nature.

The compound, known as S63845, targets the BCL2 family protein MCL1.

Investigators said their research on S63845 provides the first clear evidence that inhibiting MCL1 is effective in targeting several cancer types, including leukemia, lymphoma, and multiple myeloma (MM).

“MCL1 is important for many cancers because it is a pro-survival protein that allows the cancerous cells to evade the process of programmed cell death that normally removes cancer cells from the body,” said study author Guillaume Lessene, PhD, of the Walter and Eliza Hall Institute in Melbourne, Australia.

“Extensive studies performed in a variety of cancer models have shown that S63845 potently targets cancer cells dependent on MCL1 for their survival.”

About S63845

Dr Lessene and his colleagues said S63845 binds with high affinity to the BH3-binding groove of MCL1. And the compound kills MCL1-dependent cancer cells by activating the BAX/BAK-dependent mitochondrial apoptotic pathway.

In solid tumors, S63845 often wasn’t effective enough on its own. However, when the compound was combined with various kinase inhibitors, it induced a “potent cytotoxic response” in breast cancer, lung cancer, and melanoma cells.

In hematologic malignancies, S63845 proved effective when given alone.

Myeloma

The investigators said 17 of 25 MM cell lines tested were highly sensitive to S63845 (IC₅₀ < 0.1 μ M), 6 cell lines were moderately sensitive (0.1 μ M < IC₅₀ < 1 μ M), and 2 cell lines were insensitive (IC₅₀ > 1 μ M).

The team also administered S63845 (at 25 mg/kg) to mice with MM. Seven of 8 mice had complete regression at 100 days after treatment.

Lymphoma

The investigators tested S63845 in 11 cell lines representative of human lymphomas. Five were highly sensitive to the compound (IC₅₀ < 0.1 μ M), 3 were moderately sensitive (0.1 μ M < IC₅₀ < 1 μ M), and 3 were insensitive (IC₅₀ > 1 μ M).

The team also tested S63845 in 7 c-MYC-driven human Burkitt lymphoma cell lines and found the compound exhibited “potent cytotoxic activity” in all of them.

The investigators then tested S63845 in a c-MYC-driven mouse lymphoma model. They noted that both tumor cells and normal tissues express mouse MCL1 protein in this model.

Treatment with S63845 (25 mg/kg) for 5 consecutive days cured 70% of these mice, and the investigators said there were no evident side effects in normal tissues.

Leukemia

The investigators tested S63845 in 5 chronic myeloid leukemia cell lines, and none of them were sensitive to the compound.

However, the team also tested S63845 in 8 acute myeloid leukemia (AML) cell lines, and all of them were sensitive to the compound (IC₅₀ 4–233 nM).

When S63845 was given to mice with AML (25 mg/kg), 6 of the 8 mice achieved complete remission after 80 days.

The investigators also tested S63845 in 25 freshly derived samples from patients with AML. The team said these samples displayed a wide range of responses to S63845.

The most sensitive samples required 100- to 1000-fold less drug (to induce apoptosis) than the resistant samples or normal CD34+ progenitor cells.

Development/funding

S63845 was discovered through a collaboration between 2 pharmaceutical companies—Servier, which is headquartered in France, and Vernalis (R&D), which is based in the UK.

“[C]linical development of a MCL1 inhibitor should be launched in the near future,” said Olivier Geneste, director of oncology research at Servier.

The current research was supported through a collaboration with Servier and through funding from the National Health and Medical Research Council of Australia, the Leukemia and Lymphoma Society, Cancer Council Victoria, the Kay Kendall Leukemia Fund, Victorian Cancer Agency, Australian Cancer Research Foundation, the Victorian Government Operational Infrastructure Scheme, and the estate of Anthony Redstone.

Burkitt lymphoma

Image by Ed Uthman

A new compound has shown promise for treating hematologic malignancies and other cancers, according to preclinical research published in Nature.

The compound, known as S63845, targets the BCL2 family protein MCL1.

Investigators said their research on S63845 provides the first clear evidence that inhibiting MCL1 is effective in targeting several cancer types, including leukemia, lymphoma, and multiple myeloma (MM).

“MCL1 is important for many cancers because it is a pro-survival protein that allows the cancerous cells to evade the process of programmed cell death that normally removes cancer cells from the body,” said study author Guillaume Lessene, PhD, of the Walter and Eliza Hall Institute in Melbourne, Australia.

“Extensive studies performed in a variety of cancer models have shown that S63845 potently targets cancer cells dependent on MCL1 for their survival.”

About S63845

Dr Lessene and his colleagues said S63845 binds with high affinity to the BH3-binding groove of MCL1. And the compound kills MCL1-dependent cancer cells by activating the BAX/BAK-dependent mitochondrial apoptotic pathway.

In solid tumors, S63845 often wasn’t effective enough on its own. However, when the compound was combined with various kinase inhibitors, it induced a “potent cytotoxic response” in breast cancer, lung cancer, and melanoma cells.

In hematologic malignancies, S63845 proved effective when given alone.

Myeloma

The investigators said 17 of 25 MM cell lines tested were highly sensitive to S63845 (IC₅₀ < 0.1 μ M), 6 cell lines were moderately sensitive (0.1 μ M < IC₅₀ < 1 μ M), and 2 cell lines were insensitive (IC₅₀ > 1 μ M).

The team also administered S63845 (at 25 mg/kg) to mice with MM. Seven of 8 mice had complete regression at 100 days after treatment.

Lymphoma

The investigators tested S63845 in 11 cell lines representative of human lymphomas. Five were highly sensitive to the compound (IC₅₀ < 0.1 μ M), 3 were moderately sensitive (0.1 μ M < IC₅₀ < 1 μ M), and 3 were insensitive (IC₅₀ > 1 μ M).

The team also tested S63845 in 7 c-MYC-driven human Burkitt lymphoma cell lines and found the compound exhibited “potent cytotoxic activity” in all of them.

The investigators then tested S63845 in a c-MYC-driven mouse lymphoma model. They noted that both tumor cells and normal tissues express mouse MCL1 protein in this model.

Treatment with S63845 (25 mg/kg) for 5 consecutive days cured 70% of these mice, and the investigators said there were no evident side effects in normal tissues.

Leukemia

The investigators tested S63845 in 5 chronic myeloid leukemia cell lines, and none of them were sensitive to the compound.

However, the team also tested S63845 in 8 acute myeloid leukemia (AML) cell lines, and all of them were sensitive to the compound (IC₅₀ 4–233 nM).

When S63845 was given to mice with AML (25 mg/kg), 6 of the 8 mice achieved complete remission after 80 days.

The investigators also tested S63845 in 25 freshly derived samples from patients with AML. The team said these samples displayed a wide range of responses to S63845.

The most sensitive samples required 100- to 1000-fold less drug (to induce apoptosis) than the resistant samples or normal CD34+ progenitor cells.

Development/funding

S63845 was discovered through a collaboration between 2 pharmaceutical companies—Servier, which is headquartered in France, and Vernalis (R&D), which is based in the UK.

“[C]linical development of a MCL1 inhibitor should be launched in the near future,” said Olivier Geneste, director of oncology research at Servier.

The current research was supported through a collaboration with Servier and through funding from the National Health and Medical Research Council of Australia, the Leukemia and Lymphoma Society, Cancer Council Victoria, the Kay Kendall Leukemia Fund, Victorian Cancer Agency, Australian Cancer Research Foundation, the Victorian Government Operational Infrastructure Scheme, and the estate of Anthony Redstone.

Burkitt lymphoma

Image by Ed Uthman

A new compound has shown promise for treating hematologic malignancies and other cancers, according to preclinical research published in Nature.

The compound, known as S63845, targets the BCL2 family protein MCL1.

Investigators said their research on S63845 provides the first clear evidence that inhibiting MCL1 is effective in targeting several cancer types, including leukemia, lymphoma, and multiple myeloma (MM).

“MCL1 is important for many cancers because it is a pro-survival protein that allows the cancerous cells to evade the process of programmed cell death that normally removes cancer cells from the body,” said study author Guillaume Lessene, PhD, of the Walter and Eliza Hall Institute in Melbourne, Australia.

“Extensive studies performed in a variety of cancer models have shown that S63845 potently targets cancer cells dependent on MCL1 for their survival.”

About S63845

Dr Lessene and his colleagues said S63845 binds with high affinity to the BH3-binding groove of MCL1. And the compound kills MCL1-dependent cancer cells by activating the BAX/BAK-dependent mitochondrial apoptotic pathway.

In solid tumors, S63845 often wasn’t effective enough on its own. However, when the compound was combined with various kinase inhibitors, it induced a “potent cytotoxic response” in breast cancer, lung cancer, and melanoma cells.

In hematologic malignancies, S63845 proved effective when given alone.

Myeloma

The investigators said 17 of 25 MM cell lines tested were highly sensitive to S63845 (IC₅₀ < 0.1 μ M), 6 cell lines were moderately sensitive (0.1 μ M < IC₅₀ < 1 μ M), and 2 cell lines were insensitive (IC₅₀ > 1 μ M).

The team also administered S63845 (at 25 mg/kg) to mice with MM. Seven of 8 mice had complete regression at 100 days after treatment.

Lymphoma

The investigators tested S63845 in 11 cell lines representative of human lymphomas. Five were highly sensitive to the compound (IC₅₀ < 0.1 μ M), 3 were moderately sensitive (0.1 μ M < IC₅₀ < 1 μ M), and 3 were insensitive (IC₅₀ > 1 μ M).

The team also tested S63845 in 7 c-MYC-driven human Burkitt lymphoma cell lines and found the compound exhibited “potent cytotoxic activity” in all of them.

The investigators then tested S63845 in a c-MYC-driven mouse lymphoma model. They noted that both tumor cells and normal tissues express mouse MCL1 protein in this model.

Treatment with S63845 (25 mg/kg) for 5 consecutive days cured 70% of these mice, and the investigators said there were no evident side effects in normal tissues.

Leukemia

The investigators tested S63845 in 5 chronic myeloid leukemia cell lines, and none of them were sensitive to the compound.

However, the team also tested S63845 in 8 acute myeloid leukemia (AML) cell lines, and all of them were sensitive to the compound (IC₅₀ 4–233 nM).

When S63845 was given to mice with AML (25 mg/kg), 6 of the 8 mice achieved complete remission after 80 days.

The investigators also tested S63845 in 25 freshly derived samples from patients with AML. The team said these samples displayed a wide range of responses to S63845.

The most sensitive samples required 100- to 1000-fold less drug (to induce apoptosis) than the resistant samples or normal CD34+ progenitor cells.

Development/funding

S63845 was discovered through a collaboration between 2 pharmaceutical companies—Servier, which is headquartered in France, and Vernalis (R&D), which is based in the UK.

“[C]linical development of a MCL1 inhibitor should be launched in the near future,” said Olivier Geneste, director of oncology research at Servier.

The current research was supported through a collaboration with Servier and through funding from the National Health and Medical Research Council of Australia, the Leukemia and Lymphoma Society, Cancer Council Victoria, the Kay Kendall Leukemia Fund, Victorian Cancer Agency, Australian Cancer Research Foundation, the Victorian Government Operational Infrastructure Scheme, and the estate of Anthony Redstone.

As many as 5 million older Americans are at risk because they aren’t taking their blood pressure medicine properly, according to a Vital Signs report.

CDC researchers analyzed data from more than 18.5 million people enrolled in Medicare Advantage or Original Medicare with Part D prescription drug coverage during 2014. Among their findings:

• Seven out of 10 adults aged 65 and older have high blood pressure, but nearly half don’t have it under control.
• American Indians/Alaska Natives, blacks, and Hispanics are more likely to not take their blood pressure medicine as directed.
• Southern U.S. states, Puerto Rico, and the U.S. Virgin Islands had the highest overall rates of not taking medicine as directed.North Dakota, Wisconsin, and Minnesota had the highest rates of adherence.

The CDC gave examples of how health care systems and providers can help:

• Simplify blood pressure treatments by offering 90-day refills and combination medicines, coordinating pill refills for the same date, and prescribing generic medicines.
• Involve the whole health care team at several points of care to ensure patients are taking medicine as directed, answer questions, and provide counseling.
• Encourage the use of home blood pressure monitors and easy-to-use tools, such as mobile apps to track and share readings.

As many as 5 million older Americans are at risk because they aren’t taking their blood pressure medicine properly, according to a Vital Signs report.

CDC researchers analyzed data from more than 18.5 million people enrolled in Medicare Advantage or Original Medicare with Part D prescription drug coverage during 2014. Among their findings:

• Seven out of 10 adults aged 65 and older have high blood pressure, but nearly half don’t have it under control.
• American Indians/Alaska Natives, blacks, and Hispanics are more likely to not take their blood pressure medicine as directed.
• Southern U.S. states, Puerto Rico, and the U.S. Virgin Islands had the highest overall rates of not taking medicine as directed.North Dakota, Wisconsin, and Minnesota had the highest rates of adherence.

The CDC gave examples of how health care systems and providers can help:

• Simplify blood pressure treatments by offering 90-day refills and combination medicines, coordinating pill refills for the same date, and prescribing generic medicines.
• Involve the whole health care team at several points of care to ensure patients are taking medicine as directed, answer questions, and provide counseling.
• Encourage the use of home blood pressure monitors and easy-to-use tools, such as mobile apps to track and share readings.

As many as 5 million older Americans are at risk because they aren’t taking their blood pressure medicine properly, according to a Vital Signs report.

CDC researchers analyzed data from more than 18.5 million people enrolled in Medicare Advantage or Original Medicare with Part D prescription drug coverage during 2014. Among their findings:

• Seven out of 10 adults aged 65 and older have high blood pressure, but nearly half don’t have it under control.
• American Indians/Alaska Natives, blacks, and Hispanics are more likely to not take their blood pressure medicine as directed.
• Southern U.S. states, Puerto Rico, and the U.S. Virgin Islands had the highest overall rates of not taking medicine as directed.North Dakota, Wisconsin, and Minnesota had the highest rates of adherence.

The CDC gave examples of how health care systems and providers can help:

• Simplify blood pressure treatments by offering 90-day refills and combination medicines, coordinating pill refills for the same date, and prescribing generic medicines.
• Involve the whole health care team at several points of care to ensure patients are taking medicine as directed, answer questions, and provide counseling.
• Encourage the use of home blood pressure monitors and easy-to-use tools, such as mobile apps to track and share readings.

SAN FRANCISCO – By choosing your words carefully, counseling families about divorce can tactfully address sensitive issues and help parents and children better cope with this life transition, Nerissa S. Bauer, MD, said at the annual meeting of the American Academy of Pediatrics.

About one in five children born within a marriage and one in two of those born within a cohabiting union will experience breakup of that relationship by the age of 9 years, she said.

You must, therefore, be prepared to monitor for and identify outcomes that commonly result from divorce, and to counsel families about how to help children cope and manage. Yet, you may feel uneasy or ill-prepared to do so.

“Turn this thought of ‘I wasn’t trained for this’ into ‘I can help,’ ” recommended Dr. Bauer, who is a specialist in behavioral pediatrics at the Indiana University in Indianapolis.

Risk and protective factors

Divorce can have an impact on all facets of a child’s life: behavior, physical and mental health, academic performance, social relationships, delinquency, substance use, and more. A variety of factors determine how well kids adjust to this stressor, for better or worse.

Marital conflict, both during and after divorce, is a more important predictor than the divorce itself. “The biggest risk factor to consider is the ongoing parental fighting and how that plays out,” Dr. Bauer elaborated. Although parents may report that they try to limit altercations in front of their children, kids usually sense what is going on anyway.

“One of the ways that I like to phrase this when I’m trying to figure out how bad the conflict is in the household is, ‘Has Johnny ever witnessed your arguments, and if so, have those arguments ever been more than just yelling?’ Or another way to say it is, ‘How do adults in your home resolve conflicts?’ ” she shared.

Divorce may negatively affect children through its impact on the household’s socioeconomic status too. For example, the standard of living often declines and the mother’s economic resources can take a hit, possibly forcing a move to a less expensive neighborhood with weaker schools and more crime.

To sound parents out on this sensitive issue, “You can say something like, ‘I’m really sorry that you’re going through this right now. Sometimes, it can cause a lot of stress and strain, especially when it comes to making ends meet, making sure you can get food on the table, and making sure you’re paying the bills. Do you have worries like this now?’ ” Dr. Bauer suggested.

Factors that are known to protect children from adverse divorce outcomes include a good relationship with at least one parent or caregiver, parental warmth, sibling support, and for teens, good self-esteem and peer support. Joint custody with shared decision making and greater paternal involvement also are protective.

“I like to say, ‘So I can understand how this affects your daily life, can you describe what your current arrangements are between you and your ex?’ just to sort of probe into that custody situation,” she said. “Or, ‘How are you (parents) handling this?’ ”

Surveillance and monitoring

“Perform surveillance on family structure and conflict at all well-child visits, as well as with any new family that comes to your practice,” Dr. Bauer recommended. You can do this by simply chatting with the family or by using screening tools such as the Family Psychosocial Screen or the Finding Your ACE Score.

Once you know that a family is dealing with divorce, perform ongoing monitoring for warning signs in the child: sleep problems; school problems, such as poor concentration, acting out, or not doing schoolwork; angry outbursts; withdrawal; and no longer participating in activities once enjoyed.

You may worry about getting dragged into the conflict. “You may feel that you’re in this position of being the mediator, but that’s not really your role. And you shouldn’t offer legal advice,” she cautioned. “You should make it clear that although you are there to support the child and the parents, your role is really to monitor how the child responds and adjusts.”

Parents will sometimes ask whether and how best to tell their children about the divorce. “I oftentimes coach parents to use kid-friendly terms, saying things such as, ‘Mommy and Daddy are having a hard time getting along, and you’ve probably noticed we argue or fight a lot.’ Just throwing it out there and pausing and waiting to see what the child says, and then always following that by answering their questions as they bring them up,” Dr. Bauer said.

Parents should be counseled not to rush children as they will vary in the time needed to process information. Additionally, they should be forewarned that children’s reactions can vary widely and that their feelings can change and resurface at any moment, particularly as they mature and at events that stir up emotions.

Messages of reassurance are essential. “The messages should always contain, ‘We are always going to be your parents no matter what’ and ‘We love you no matter what,’ and probably the most important, ‘This is not your fault.’ This is a message that kids need to hear again and again,” Dr. Bauer said.
 

Ongoing counseling

Over time, parents may consult you about specific situations that arise because of the divorce. For example, they may become frustrated by differences in how things are handled in the two households.

“The most important message to convey is that we can control only what we can control,” Dr. Bauer said. “Regardless of divorce or separation, kids thrive on structure and routine. Divorce is often messy, and it sometimes means that families have to find a new rhythm between households, but routines in each house should be as consistent as possible.”

Acrimony between the mother and father may persist or escalate. As children don’t want to have to choose between parents, parents should be encouraged not to undermine or talk negatively about each other in front of the child. If necessary, you can arrange to have time separately with parents to allow them to air their grievances.

If parents give permission to broach the topic of divorce, you can role model conversational strategies during visits. “You can say something like, ‘I understand there are a lot of changes going on. Through it all, your mom and dad will always be your parents. I know this isn’t easy for anybody, especially for you. Kids in this situation feel a lot of things from sadness to anger but know that you can always talk to me or your parents about your feelings,’” Dr. Bauer elaborated.

“Listening is key,” she stressed; therefore, parents should be encouraged to just sit in silence and let their children process their feelings. “In these types of situations, there’s no right or wrong: When the child has feelings, they have feelings. We can’t force them to feel a certain way, we have to acknowledge that. So tell parents to try this: ‘Thanks for telling me how you feel. I want you to know that you can always come to me when you feel this way.’ See what happens.”

Parents should be advised not to be too quick to dismiss their child’s concerns, Dr. Bauer recommended. “So, instead of saying, ‘Oh honey, you don’t have to worry about that, I’ll take care of it,’ try this: ‘It sounds like you are sad and upset right now. What can I do to help?’ Sometimes a kid will say, ‘I don’t know,’ but that’s okay. Then the parent can respond in kind and say, ‘I don’t know either, but how about a hug? Let’s start there.’ ”

Some kids simply aren’t talkers and shouldn’t be forced to share, she pointed out. This group can be given other ways to express their feelings, such as journaling, drawing, art, music, yoga, or writing a letter that they then throw away or put in a drawer.

Finally, “reminding parents that even giving children a little control with daily things – what they wear, how they do their chores, and homework, and what to make for dinner – can also help,” she noted. “Those little things can represent a lot for children who don’t feel like they have any control.”

Building resources

Explore various media and online tools to develop a set of resources on divorce for families, Dr. Bauer recommended.

Books on the topic can be great conversation starters, and many are available for various age-groups, she noted. Examples include “Was It the Chocolate Pudding? A Story for Little Kids About Divorce” (Washington: Magination Press, 2005) for ages 4-7 years, “Divorced but Still My Parents” (Longmont, Colo. : Springboard Publications, 1997) for ages 6-12 years, and “My Mom and Dad Don’t Live Together Anymore: A Drawing Book for Children of Separated or Divorced Parents” (Washington: Magination Press, 2002) for ages 8-12 years.

Sesame Street has a toolkit on divorce that offers printable materials, songs, and an app that features conversation starters and vignettes, according to Dr. Bauer; go to sesamestreet.org and type in “divorce.” Additionally, the documentary SPLIT at splitfilm.org follows real families going through divorce and helps show the child’s perspective.

When parents ask about legal references, they can be referred to the UpToParents website, a free resource and curriculum developed by attorneys on topics such as divorce, in both English and Spanish.

Finally, familiarize yourself with resources available in your local community, such as divorce education programs, and services offered for divorce and custody mediation, so that you can link parents to them as needed.

Dr. Bauer said she has no relevant financial disclosures.

SAN FRANCISCO – By choosing your words carefully, counseling families about divorce can tactfully address sensitive issues and help parents and children better cope with this life transition, Nerissa S. Bauer, MD, said at the annual meeting of the American Academy of Pediatrics.

About one in five children born within a marriage and one in two of those born within a cohabiting union will experience breakup of that relationship by the age of 9 years, she said.

You must, therefore, be prepared to monitor for and identify outcomes that commonly result from divorce, and to counsel families about how to help children cope and manage. Yet, you may feel uneasy or ill-prepared to do so.

“Turn this thought of ‘I wasn’t trained for this’ into ‘I can help,’ ” recommended Dr. Bauer, who is a specialist in behavioral pediatrics at the Indiana University in Indianapolis.

Risk and protective factors

Divorce can have an impact on all facets of a child’s life: behavior, physical and mental health, academic performance, social relationships, delinquency, substance use, and more. A variety of factors determine how well kids adjust to this stressor, for better or worse.

Marital conflict, both during and after divorce, is a more important predictor than the divorce itself. “The biggest risk factor to consider is the ongoing parental fighting and how that plays out,” Dr. Bauer elaborated. Although parents may report that they try to limit altercations in front of their children, kids usually sense what is going on anyway.

“One of the ways that I like to phrase this when I’m trying to figure out how bad the conflict is in the household is, ‘Has Johnny ever witnessed your arguments, and if so, have those arguments ever been more than just yelling?’ Or another way to say it is, ‘How do adults in your home resolve conflicts?’ ” she shared.

Divorce may negatively affect children through its impact on the household’s socioeconomic status too. For example, the standard of living often declines and the mother’s economic resources can take a hit, possibly forcing a move to a less expensive neighborhood with weaker schools and more crime.

To sound parents out on this sensitive issue, “You can say something like, ‘I’m really sorry that you’re going through this right now. Sometimes, it can cause a lot of stress and strain, especially when it comes to making ends meet, making sure you can get food on the table, and making sure you’re paying the bills. Do you have worries like this now?’ ” Dr. Bauer suggested.

Factors that are known to protect children from adverse divorce outcomes include a good relationship with at least one parent or caregiver, parental warmth, sibling support, and for teens, good self-esteem and peer support. Joint custody with shared decision making and greater paternal involvement also are protective.

“I like to say, ‘So I can understand how this affects your daily life, can you describe what your current arrangements are between you and your ex?’ just to sort of probe into that custody situation,” she said. “Or, ‘How are you (parents) handling this?’ ”

Surveillance and monitoring

“Perform surveillance on family structure and conflict at all well-child visits, as well as with any new family that comes to your practice,” Dr. Bauer recommended. You can do this by simply chatting with the family or by using screening tools such as the Family Psychosocial Screen or the Finding Your ACE Score.

Once you know that a family is dealing with divorce, perform ongoing monitoring for warning signs in the child: sleep problems; school problems, such as poor concentration, acting out, or not doing schoolwork; angry outbursts; withdrawal; and no longer participating in activities once enjoyed.

You may worry about getting dragged into the conflict. “You may feel that you’re in this position of being the mediator, but that’s not really your role. And you shouldn’t offer legal advice,” she cautioned. “You should make it clear that although you are there to support the child and the parents, your role is really to monitor how the child responds and adjusts.”

Parents will sometimes ask whether and how best to tell their children about the divorce. “I oftentimes coach parents to use kid-friendly terms, saying things such as, ‘Mommy and Daddy are having a hard time getting along, and you’ve probably noticed we argue or fight a lot.’ Just throwing it out there and pausing and waiting to see what the child says, and then always following that by answering their questions as they bring them up,” Dr. Bauer said.

Parents should be counseled not to rush children as they will vary in the time needed to process information. Additionally, they should be forewarned that children’s reactions can vary widely and that their feelings can change and resurface at any moment, particularly as they mature and at events that stir up emotions.

Messages of reassurance are essential. “The messages should always contain, ‘We are always going to be your parents no matter what’ and ‘We love you no matter what,’ and probably the most important, ‘This is not your fault.’ This is a message that kids need to hear again and again,” Dr. Bauer said.
 

Ongoing counseling

Over time, parents may consult you about specific situations that arise because of the divorce. For example, they may become frustrated by differences in how things are handled in the two households.

“The most important message to convey is that we can control only what we can control,” Dr. Bauer said. “Regardless of divorce or separation, kids thrive on structure and routine. Divorce is often messy, and it sometimes means that families have to find a new rhythm between households, but routines in each house should be as consistent as possible.”

Acrimony between the mother and father may persist or escalate. As children don’t want to have to choose between parents, parents should be encouraged not to undermine or talk negatively about each other in front of the child. If necessary, you can arrange to have time separately with parents to allow them to air their grievances.

If parents give permission to broach the topic of divorce, you can role model conversational strategies during visits. “You can say something like, ‘I understand there are a lot of changes going on. Through it all, your mom and dad will always be your parents. I know this isn’t easy for anybody, especially for you. Kids in this situation feel a lot of things from sadness to anger but know that you can always talk to me or your parents about your feelings,’” Dr. Bauer elaborated.

“Listening is key,” she stressed; therefore, parents should be encouraged to just sit in silence and let their children process their feelings. “In these types of situations, there’s no right or wrong: When the child has feelings, they have feelings. We can’t force them to feel a certain way, we have to acknowledge that. So tell parents to try this: ‘Thanks for telling me how you feel. I want you to know that you can always come to me when you feel this way.’ See what happens.”

Parents should be advised not to be too quick to dismiss their child’s concerns, Dr. Bauer recommended. “So, instead of saying, ‘Oh honey, you don’t have to worry about that, I’ll take care of it,’ try this: ‘It sounds like you are sad and upset right now. What can I do to help?’ Sometimes a kid will say, ‘I don’t know,’ but that’s okay. Then the parent can respond in kind and say, ‘I don’t know either, but how about a hug? Let’s start there.’ ”

Some kids simply aren’t talkers and shouldn’t be forced to share, she pointed out. This group can be given other ways to express their feelings, such as journaling, drawing, art, music, yoga, or writing a letter that they then throw away or put in a drawer.

Finally, “reminding parents that even giving children a little control with daily things – what they wear, how they do their chores, and homework, and what to make for dinner – can also help,” she noted. “Those little things can represent a lot for children who don’t feel like they have any control.”

Building resources

Explore various media and online tools to develop a set of resources on divorce for families, Dr. Bauer recommended.

Books on the topic can be great conversation starters, and many are available for various age-groups, she noted. Examples include “Was It the Chocolate Pudding? A Story for Little Kids About Divorce” (Washington: Magination Press, 2005) for ages 4-7 years, “Divorced but Still My Parents” (Longmont, Colo. : Springboard Publications, 1997) for ages 6-12 years, and “My Mom and Dad Don’t Live Together Anymore: A Drawing Book for Children of Separated or Divorced Parents” (Washington: Magination Press, 2002) for ages 8-12 years.

Sesame Street has a toolkit on divorce that offers printable materials, songs, and an app that features conversation starters and vignettes, according to Dr. Bauer; go to sesamestreet.org and type in “divorce.” Additionally, the documentary SPLIT at splitfilm.org follows real families going through divorce and helps show the child’s perspective.

When parents ask about legal references, they can be referred to the UpToParents website, a free resource and curriculum developed by attorneys on topics such as divorce, in both English and Spanish.

Finally, familiarize yourself with resources available in your local community, such as divorce education programs, and services offered for divorce and custody mediation, so that you can link parents to them as needed.

Dr. Bauer said she has no relevant financial disclosures.

SAN FRANCISCO – By choosing your words carefully, counseling families about divorce can tactfully address sensitive issues and help parents and children better cope with this life transition, Nerissa S. Bauer, MD, said at the annual meeting of the American Academy of Pediatrics.

About one in five children born within a marriage and one in two of those born within a cohabiting union will experience breakup of that relationship by the age of 9 years, she said.

You must, therefore, be prepared to monitor for and identify outcomes that commonly result from divorce, and to counsel families about how to help children cope and manage. Yet, you may feel uneasy or ill-prepared to do so.

“Turn this thought of ‘I wasn’t trained for this’ into ‘I can help,’ ” recommended Dr. Bauer, who is a specialist in behavioral pediatrics at the Indiana University in Indianapolis.

Risk and protective factors

Divorce can have an impact on all facets of a child’s life: behavior, physical and mental health, academic performance, social relationships, delinquency, substance use, and more. A variety of factors determine how well kids adjust to this stressor, for better or worse.

Marital conflict, both during and after divorce, is a more important predictor than the divorce itself. “The biggest risk factor to consider is the ongoing parental fighting and how that plays out,” Dr. Bauer elaborated. Although parents may report that they try to limit altercations in front of their children, kids usually sense what is going on anyway.

“One of the ways that I like to phrase this when I’m trying to figure out how bad the conflict is in the household is, ‘Has Johnny ever witnessed your arguments, and if so, have those arguments ever been more than just yelling?’ Or another way to say it is, ‘How do adults in your home resolve conflicts?’ ” she shared.

Divorce may negatively affect children through its impact on the household’s socioeconomic status too. For example, the standard of living often declines and the mother’s economic resources can take a hit, possibly forcing a move to a less expensive neighborhood with weaker schools and more crime.

To sound parents out on this sensitive issue, “You can say something like, ‘I’m really sorry that you’re going through this right now. Sometimes, it can cause a lot of stress and strain, especially when it comes to making ends meet, making sure you can get food on the table, and making sure you’re paying the bills. Do you have worries like this now?’ ” Dr. Bauer suggested.

Factors that are known to protect children from adverse divorce outcomes include a good relationship with at least one parent or caregiver, parental warmth, sibling support, and for teens, good self-esteem and peer support. Joint custody with shared decision making and greater paternal involvement also are protective.

“I like to say, ‘So I can understand how this affects your daily life, can you describe what your current arrangements are between you and your ex?’ just to sort of probe into that custody situation,” she said. “Or, ‘How are you (parents) handling this?’ ”

Surveillance and monitoring

“Perform surveillance on family structure and conflict at all well-child visits, as well as with any new family that comes to your practice,” Dr. Bauer recommended. You can do this by simply chatting with the family or by using screening tools such as the Family Psychosocial Screen or the Finding Your ACE Score.

Once you know that a family is dealing with divorce, perform ongoing monitoring for warning signs in the child: sleep problems; school problems, such as poor concentration, acting out, or not doing schoolwork; angry outbursts; withdrawal; and no longer participating in activities once enjoyed.

You may worry about getting dragged into the conflict. “You may feel that you’re in this position of being the mediator, but that’s not really your role. And you shouldn’t offer legal advice,” she cautioned. “You should make it clear that although you are there to support the child and the parents, your role is really to monitor how the child responds and adjusts.”

Parents will sometimes ask whether and how best to tell their children about the divorce. “I oftentimes coach parents to use kid-friendly terms, saying things such as, ‘Mommy and Daddy are having a hard time getting along, and you’ve probably noticed we argue or fight a lot.’ Just throwing it out there and pausing and waiting to see what the child says, and then always following that by answering their questions as they bring them up,” Dr. Bauer said.

Parents should be counseled not to rush children as they will vary in the time needed to process information. Additionally, they should be forewarned that children’s reactions can vary widely and that their feelings can change and resurface at any moment, particularly as they mature and at events that stir up emotions.

Messages of reassurance are essential. “The messages should always contain, ‘We are always going to be your parents no matter what’ and ‘We love you no matter what,’ and probably the most important, ‘This is not your fault.’ This is a message that kids need to hear again and again,” Dr. Bauer said.
 

Ongoing counseling

Over time, parents may consult you about specific situations that arise because of the divorce. For example, they may become frustrated by differences in how things are handled in the two households.

“The most important message to convey is that we can control only what we can control,” Dr. Bauer said. “Regardless of divorce or separation, kids thrive on structure and routine. Divorce is often messy, and it sometimes means that families have to find a new rhythm between households, but routines in each house should be as consistent as possible.”

Acrimony between the mother and father may persist or escalate. As children don’t want to have to choose between parents, parents should be encouraged not to undermine or talk negatively about each other in front of the child. If necessary, you can arrange to have time separately with parents to allow them to air their grievances.

If parents give permission to broach the topic of divorce, you can role model conversational strategies during visits. “You can say something like, ‘I understand there are a lot of changes going on. Through it all, your mom and dad will always be your parents. I know this isn’t easy for anybody, especially for you. Kids in this situation feel a lot of things from sadness to anger but know that you can always talk to me or your parents about your feelings,’” Dr. Bauer elaborated.

“Listening is key,” she stressed; therefore, parents should be encouraged to just sit in silence and let their children process their feelings. “In these types of situations, there’s no right or wrong: When the child has feelings, they have feelings. We can’t force them to feel a certain way, we have to acknowledge that. So tell parents to try this: ‘Thanks for telling me how you feel. I want you to know that you can always come to me when you feel this way.’ See what happens.”

Parents should be advised not to be too quick to dismiss their child’s concerns, Dr. Bauer recommended. “So, instead of saying, ‘Oh honey, you don’t have to worry about that, I’ll take care of it,’ try this: ‘It sounds like you are sad and upset right now. What can I do to help?’ Sometimes a kid will say, ‘I don’t know,’ but that’s okay. Then the parent can respond in kind and say, ‘I don’t know either, but how about a hug? Let’s start there.’ ”

Some kids simply aren’t talkers and shouldn’t be forced to share, she pointed out. This group can be given other ways to express their feelings, such as journaling, drawing, art, music, yoga, or writing a letter that they then throw away or put in a drawer.

Finally, “reminding parents that even giving children a little control with daily things – what they wear, how they do their chores, and homework, and what to make for dinner – can also help,” she noted. “Those little things can represent a lot for children who don’t feel like they have any control.”

Building resources

Explore various media and online tools to develop a set of resources on divorce for families, Dr. Bauer recommended.

Books on the topic can be great conversation starters, and many are available for various age-groups, she noted. Examples include “Was It the Chocolate Pudding? A Story for Little Kids About Divorce” (Washington: Magination Press, 2005) for ages 4-7 years, “Divorced but Still My Parents” (Longmont, Colo. : Springboard Publications, 1997) for ages 6-12 years, and “My Mom and Dad Don’t Live Together Anymore: A Drawing Book for Children of Separated or Divorced Parents” (Washington: Magination Press, 2002) for ages 8-12 years.

Sesame Street has a toolkit on divorce that offers printable materials, songs, and an app that features conversation starters and vignettes, according to Dr. Bauer; go to sesamestreet.org and type in “divorce.” Additionally, the documentary SPLIT at splitfilm.org follows real families going through divorce and helps show the child’s perspective.

When parents ask about legal references, they can be referred to the UpToParents website, a free resource and curriculum developed by attorneys on topics such as divorce, in both English and Spanish.

Finally, familiarize yourself with resources available in your local community, such as divorce education programs, and services offered for divorce and custody mediation, so that you can link parents to them as needed.

Dr. Bauer said she has no relevant financial disclosures.

As articulated by Steve Daviss, MD, DFAPA, in the inaugural column of Techiatry, the adoption and diffusion of telepsychiatry (live two-way interactive videoconferencing) have not been as rapid and universal as expected from those of us immersed in the field.

Despite having yet to achieve its full promise, telepsychiatry has reached maturity, and is being widely deployed and used across multiple systems, settings, and applications, albeit at times in an uneven, unsystematic manner. Emerging over the past decade of development are two distinct models/approaches to telepsychiatry, which I refer to as “doc in a box” and “tele-teaming.” Those models coexist, compete, and conflict within and across organizations. The dynamic between those two models highlights a larger emergent dialogue within psychiatry around psychiatrists’ core clinical roles and functions in our evolving health care systems.

Alternatively, the center could set up a service where the psychiatrist became a virtual team member working to provide complete assessments, treatment planning, supervision, and psychiatric consultation, as well as pharmacologic management. Although in this scenario, the psychiatrist still could devote time to managing prescriptions, she/he also could spend time in team meetings, supervision, and seeing patients, often with her colleagues. In addition, the psychiatrist could work to coordinate care beyond the EMR, for example, through tele-teaming. Either of these scenarios can and do occur with in-person care as well, and the choice of which model to use would not be decided by the technology but by the underlying health care system in which it is being used.

Telepsychiatry begins to become transformative when it’s leveraged to shift, change, or innovate the model of care delivery. Historically, telepsychiatry has been thought of as a solution to patient access issues and as a way to address workforce shortages. The real promise of telepsychiatry in the form of tele-teaming is how it can begin to fundamentally change how care is delivered. The triple aim calls for decreased costs, improved health care for individuals, and a focus on population health.

We know that most Americans with major mental health issues will be seen in primary care, and that providing behavioral health care in primary care settings leads to lower overall health care costs, and improved behavioral and general health outcomes. Telepsychiatry will be essential in the further dissemination and expansion of integrated care, not only in rural and underserved areas, but across large health care systems. Tele-teaming will be essential in other arenas as well, as psychiatry faces the future challenges of an aging and decreasing (per capita) workforce. Team approaches help maximize psychiatrists’ role in the health care system, and help magnify the number of patients their skills and training can support.

Team approaches also help to broaden the scope of psychiatric practice and reclaim psychiatry’s place within the house of medicine. Telepsychiatry, if structured correctly, helps increase flexibility for psychiatrists. It expands the settings available to practice and provides more opportunities to engage in team-based care. Both the doc in a box and tele-teaming models have arisen from forces in the health care marketplace. The differing application of those two models across and within health care systems illustrates overall tensions within psychiatry about the current and future roles of psychiatrists.

Telepsychiatry is a powerful tool that can be leveraged to shape models of psychiatric care delivery or reinforce our existing structures. Which models are embraced will affect how psychiatry continues to evolve and address the challenges before the specialty.
 

Dr. Shore chairs the American Psychiatric Association’s Committee on Telepsychiatry, and is director of telemedicine at the Helen & Arthur E. Johnson Depression Center and associate professor of psychiatry at the University of Colorado at Denver, Aurora.

As articulated by Steve Daviss, MD, DFAPA, in the inaugural column of Techiatry, the adoption and diffusion of telepsychiatry (live two-way interactive videoconferencing) have not been as rapid and universal as expected from those of us immersed in the field.

Despite having yet to achieve its full promise, telepsychiatry has reached maturity, and is being widely deployed and used across multiple systems, settings, and applications, albeit at times in an uneven, unsystematic manner. Emerging over the past decade of development are two distinct models/approaches to telepsychiatry, which I refer to as “doc in a box” and “tele-teaming.” Those models coexist, compete, and conflict within and across organizations. The dynamic between those two models highlights a larger emergent dialogue within psychiatry around psychiatrists’ core clinical roles and functions in our evolving health care systems.

Alternatively, the center could set up a service where the psychiatrist became a virtual team member working to provide complete assessments, treatment planning, supervision, and psychiatric consultation, as well as pharmacologic management. Although in this scenario, the psychiatrist still could devote time to managing prescriptions, she/he also could spend time in team meetings, supervision, and seeing patients, often with her colleagues. In addition, the psychiatrist could work to coordinate care beyond the EMR, for example, through tele-teaming. Either of these scenarios can and do occur with in-person care as well, and the choice of which model to use would not be decided by the technology but by the underlying health care system in which it is being used.

Telepsychiatry begins to become transformative when it’s leveraged to shift, change, or innovate the model of care delivery. Historically, telepsychiatry has been thought of as a solution to patient access issues and as a way to address workforce shortages. The real promise of telepsychiatry in the form of tele-teaming is how it can begin to fundamentally change how care is delivered. The triple aim calls for decreased costs, improved health care for individuals, and a focus on population health.

We know that most Americans with major mental health issues will be seen in primary care, and that providing behavioral health care in primary care settings leads to lower overall health care costs, and improved behavioral and general health outcomes. Telepsychiatry will be essential in the further dissemination and expansion of integrated care, not only in rural and underserved areas, but across large health care systems. Tele-teaming will be essential in other arenas as well, as psychiatry faces the future challenges of an aging and decreasing (per capita) workforce. Team approaches help maximize psychiatrists’ role in the health care system, and help magnify the number of patients their skills and training can support.

Team approaches also help to broaden the scope of psychiatric practice and reclaim psychiatry’s place within the house of medicine. Telepsychiatry, if structured correctly, helps increase flexibility for psychiatrists. It expands the settings available to practice and provides more opportunities to engage in team-based care. Both the doc in a box and tele-teaming models have arisen from forces in the health care marketplace. The differing application of those two models across and within health care systems illustrates overall tensions within psychiatry about the current and future roles of psychiatrists.

Telepsychiatry is a powerful tool that can be leveraged to shape models of psychiatric care delivery or reinforce our existing structures. Which models are embraced will affect how psychiatry continues to evolve and address the challenges before the specialty.
 

Dr. Shore chairs the American Psychiatric Association’s Committee on Telepsychiatry, and is director of telemedicine at the Helen & Arthur E. Johnson Depression Center and associate professor of psychiatry at the University of Colorado at Denver, Aurora.

As articulated by Steve Daviss, MD, DFAPA, in the inaugural column of Techiatry, the adoption and diffusion of telepsychiatry (live two-way interactive videoconferencing) have not been as rapid and universal as expected from those of us immersed in the field.

Despite having yet to achieve its full promise, telepsychiatry has reached maturity, and is being widely deployed and used across multiple systems, settings, and applications, albeit at times in an uneven, unsystematic manner. Emerging over the past decade of development are two distinct models/approaches to telepsychiatry, which I refer to as “doc in a box” and “tele-teaming.” Those models coexist, compete, and conflict within and across organizations. The dynamic between those two models highlights a larger emergent dialogue within psychiatry around psychiatrists’ core clinical roles and functions in our evolving health care systems.

Alternatively, the center could set up a service where the psychiatrist became a virtual team member working to provide complete assessments, treatment planning, supervision, and psychiatric consultation, as well as pharmacologic management. Although in this scenario, the psychiatrist still could devote time to managing prescriptions, she/he also could spend time in team meetings, supervision, and seeing patients, often with her colleagues. In addition, the psychiatrist could work to coordinate care beyond the EMR, for example, through tele-teaming. Either of these scenarios can and do occur with in-person care as well, and the choice of which model to use would not be decided by the technology but by the underlying health care system in which it is being used.

Telepsychiatry begins to become transformative when it’s leveraged to shift, change, or innovate the model of care delivery. Historically, telepsychiatry has been thought of as a solution to patient access issues and as a way to address workforce shortages. The real promise of telepsychiatry in the form of tele-teaming is how it can begin to fundamentally change how care is delivered. The triple aim calls for decreased costs, improved health care for individuals, and a focus on population health.

We know that most Americans with major mental health issues will be seen in primary care, and that providing behavioral health care in primary care settings leads to lower overall health care costs, and improved behavioral and general health outcomes. Telepsychiatry will be essential in the further dissemination and expansion of integrated care, not only in rural and underserved areas, but across large health care systems. Tele-teaming will be essential in other arenas as well, as psychiatry faces the future challenges of an aging and decreasing (per capita) workforce. Team approaches help maximize psychiatrists’ role in the health care system, and help magnify the number of patients their skills and training can support.

Team approaches also help to broaden the scope of psychiatric practice and reclaim psychiatry’s place within the house of medicine. Telepsychiatry, if structured correctly, helps increase flexibility for psychiatrists. It expands the settings available to practice and provides more opportunities to engage in team-based care. Both the doc in a box and tele-teaming models have arisen from forces in the health care marketplace. The differing application of those two models across and within health care systems illustrates overall tensions within psychiatry about the current and future roles of psychiatrists.

Telepsychiatry is a powerful tool that can be leveraged to shape models of psychiatric care delivery or reinforce our existing structures. Which models are embraced will affect how psychiatry continues to evolve and address the challenges before the specialty.
 

Dr. Shore chairs the American Psychiatric Association’s Committee on Telepsychiatry, and is director of telemedicine at the Helen & Arthur E. Johnson Depression Center and associate professor of psychiatry at the University of Colorado at Denver, Aurora.

AT CHEST 2016

LOS ANGELES – Long-term inhaled ciprofloxacin therapy appears to be a safe and effective treatment option in patients with bronchiectasis, results from an international phase III trial showed.

“This is really exciting; it’s the first large study of an inhaled antibiotic to show a benefit in this population,” study investigator Kevin Winthrop, MD, said in an interview prior to the annual meeting of the American College of Chest Physicians. “There’s a tremendous unmet need and a lot of these patients have daily struggles and their quality of life is low. To have something that would improve that would be a benefit for patients and physicians alike.”

[email protected]

This article was updated on 10/25/2016 at 9:51 AM Est

AT CHEST 2016

LOS ANGELES – Long-term inhaled ciprofloxacin therapy appears to be a safe and effective treatment option in patients with bronchiectasis, results from an international phase III trial showed.

“This is really exciting; it’s the first large study of an inhaled antibiotic to show a benefit in this population,” study investigator Kevin Winthrop, MD, said in an interview prior to the annual meeting of the American College of Chest Physicians. “There’s a tremendous unmet need and a lot of these patients have daily struggles and their quality of life is low. To have something that would improve that would be a benefit for patients and physicians alike.”

[email protected]

This article was updated on 10/25/2016 at 9:51 AM Est

AT CHEST 2016

LOS ANGELES – Long-term inhaled ciprofloxacin therapy appears to be a safe and effective treatment option in patients with bronchiectasis, results from an international phase III trial showed.

“This is really exciting; it’s the first large study of an inhaled antibiotic to show a benefit in this population,” study investigator Kevin Winthrop, MD, said in an interview prior to the annual meeting of the American College of Chest Physicians. “There’s a tremendous unmet need and a lot of these patients have daily struggles and their quality of life is low. To have something that would improve that would be a benefit for patients and physicians alike.”

[email protected]

This article was updated on 10/25/2016 at 9:51 AM Est

Both dietary and supplemental calcium should be considered safe for the cardiovascular system as long as total intake doesn’t exceed 2,000-2,500 mg/day – the maximal tolerable level defined by the National Academy of Medicine, according to an updated Clinical Practice Guideline published online October 24 in Annals of Internal Medicine.

For generally healthy patients who don’t consume adequate calcium and take supplements, either alone or in combination with vitamin D, to prevent osteoporosis and related fractures, “discontinuation of supplemental calcium for safety reasons is not necessary and may be harmful to bone health,” said Stephen L. Kopecky, MD, of the Mayo Clinic, Rochester Minn., and his associates on the expert panel that wrote the new guideline.

Both dietary and supplemental calcium should be considered safe for the cardiovascular system as long as total intake doesn’t exceed 2,000-2,500 mg/day – the maximal tolerable level defined by the National Academy of Medicine, according to an updated Clinical Practice Guideline published online October 24 in Annals of Internal Medicine.

For generally healthy patients who don’t consume adequate calcium and take supplements, either alone or in combination with vitamin D, to prevent osteoporosis and related fractures, “discontinuation of supplemental calcium for safety reasons is not necessary and may be harmful to bone health,” said Stephen L. Kopecky, MD, of the Mayo Clinic, Rochester Minn., and his associates on the expert panel that wrote the new guideline.

Both dietary and supplemental calcium should be considered safe for the cardiovascular system as long as total intake doesn’t exceed 2,000-2,500 mg/day – the maximal tolerable level defined by the National Academy of Medicine, according to an updated Clinical Practice Guideline published online October 24 in Annals of Internal Medicine.

For generally healthy patients who don’t consume adequate calcium and take supplements, either alone or in combination with vitamin D, to prevent osteoporosis and related fractures, “discontinuation of supplemental calcium for safety reasons is not necessary and may be harmful to bone health,” said Stephen L. Kopecky, MD, of the Mayo Clinic, Rochester Minn., and his associates on the expert panel that wrote the new guideline.

LOS ANGELES – Spirometry is the standard for diagnosing chronic obstructive pulmonary disease, but it’s underused and misused in primary care, according to investigators from the Corpus Christi (Tex.) Medical Center.

The conclusion is based on a review of just 65 patients from internal medicine and family practice clinics near the medical center, but “I do think this [pattern] is representative of what we are seeing in every primary care office. This has been a problem [documented] in the literature for a decade, and it remains a problem,” said lead investigator Stephen Eikermann, DO, an internal medicine resident at the center.

[email protected]

LOS ANGELES – Spirometry is the standard for diagnosing chronic obstructive pulmonary disease, but it’s underused and misused in primary care, according to investigators from the Corpus Christi (Tex.) Medical Center.

The conclusion is based on a review of just 65 patients from internal medicine and family practice clinics near the medical center, but “I do think this [pattern] is representative of what we are seeing in every primary care office. This has been a problem [documented] in the literature for a decade, and it remains a problem,” said lead investigator Stephen Eikermann, DO, an internal medicine resident at the center.

[email protected]

LOS ANGELES – Spirometry is the standard for diagnosing chronic obstructive pulmonary disease, but it’s underused and misused in primary care, according to investigators from the Corpus Christi (Tex.) Medical Center.

The conclusion is based on a review of just 65 patients from internal medicine and family practice clinics near the medical center, but “I do think this [pattern] is representative of what we are seeing in every primary care office. This has been a problem [documented] in the literature for a decade, and it remains a problem,” said lead investigator Stephen Eikermann, DO, an internal medicine resident at the center.

[email protected]