NEW YORK – There’s more to induction therapy for transplant-eligible multiple myeloma patients than the go-to combination of bortezomib, lenalidomide, and dexamethasone, commonly known as VRD, according to Joseph R. Mikhael, MD.

“Outstanding evidence” has emerged that demonstrates the value of combining multiple mechanisms of action, but there are numerous options available – there is a trend toward increasing use of carfilzomib, for example – and VRD isn’t necessarily the best option for all patients, nor is it available in all cases, Dr. Mikhael of Mayo Clinic Arizona, Scottsdale, said at an international congress on hematologic malignancies.

Further, choosing the treatment method shown to give the most powerful or deepest response as a default isn’t necessarily the best option, either, he said, noting data showing that the regimen most often associated with at least very good partial response (VGPR) after four cycles in newly diagnosed multiple myeloma (carfilzomib, lenalidomide, dexamethasone, or KRD, about a 90% response rate) costs 2.5 times more than does the regimen (lenalidomide, dexamethasone, or RD) that provided about a 50% response rate ($250,000 vs. $100,000 per year).“But it’s also the toxicity cost ... do we need that many [drugs]?” he said, adding that “just because a clinical trial shows that three drugs work better than two, it doesn’t mean that every time I have a patient who is eligible I’m going to go with all three.”

It may be that a patient can start on two, with a third added if needed, he added.

“That being said, we want to maximize the synergy of those three, especially in high-risk patients,” he said.

Prior to 2016, popular regimens included CyBorD (cyclophosphamide, bortezomib, dexamethasone) and VTD (bortezomib, thalidomide, dexamethasone), which were commonly used worldwide. CTD (cyclophosphamide, thalidomide, dexamethasone) was used in Brazil and other countries where it was difficult to obtain bortezomib; VRD was “king of the hill” in the United States, and transplant was routinely recommended, Dr. Mikhael said.

A number of recent studies are changing that paradigm, he said.

One such study, the prospective randomized Intergroupe Francophone du Myélome (IFM) 2013-04 trial, showed that VTD is superior to bortezomib-cyclophosphamide-dexamethasone (VCD) for induction in patients with de novo multiple myeloma. VGPR and PR rates were significantly superior in the VTD arm.

Of note, hematologic toxicity increased in the VCD arm, and the peripheral neuropathy rate was higher in the VTD arm. However, the study was conducted at a time when bortezomib was generally used twice weekly; now it is standard to use it once weekly and subcutaneously, which significantly reduces the risk of peripheral neuropathy.

The authors advocated the preferential use of VTD over VCD for induction, based on the synergistic effect of a proteasome inhibitor and immunomodulatory drug, Dr. Mikhael said.

“Meanwhile, back in the United States, many trials were starting to be built with VRD,” he said, noting that “really extraordinary” responses were seen in phase I and phase II studies.

Perhaps the VRD study (called RVD in this case) that is most cited is the phase III IFM 2009 study comparing RVD with and without autologous stem cell transplant in newly diagnosed younger multiple myeloma patients. Although final results are still pending, interim results reported at the American Society of Hematology 2015 meeting (abstract 391) have been very helpful, Dr. Mikhael said.

The authors reported a 31% reduction in the risk of progression or death with autologous stem cell transplant versus RVD alone in patients with newly diagnosed multiple myeloma, as well as improved rates of thrombotic thrombocytopenic purpura (TTP) and minimal residual disease negativity (MRD). Mortality rates were similar.

The findings show that transplantation is feasible (93%), and associated with acceptable mortality (1.4%), an increased rate of negative MRD versus with RVD alone (80% vs. 65%), an improved 4-year progression-free survival (47% vs. 35%), and improved 4-year TTP (49% vs. 35%).

“Here the question was not so much is RVD the standard ... but is RVD plus transplant superior to RVD alone,” he said.

Surprising to many, especially the “dissenters in the crowd” who thought perhaps RVD would be the death knell to autologous stem cell transplant, transplant actually significantly improved the depth of response, he added.

Median progression-free survival at 10 months was 43% with versus 34% without transplantation.

“So there was definitely an argument here that transplant remains the standard of care,” he said, noting that transplant should be considered as decisions are made about up-front therapy.

As for the trend of bringing carfilzomib in earlier on in treatment, a number of studies, including the phase II CYKLONE study by Dr. Mikhael and his colleagues, suggest it improves the rates of deep response; some show that is especially true when used with transplant.

One study looking at KRD showed that the regimen provides high rates of deep and durable responses with acceptable tolerability – a finding that needs confirmation in a randomized setting.

Other studies are comparing KRD and VRD, and KRD and KCyd (carfilzomib, cyclophosphamide), as well as adding monoclonal antibodies such as daratumumab to treatment regimens, and results are very much anticipated, Dr. Mikhael said.

Currently, however, VRD remains the standard of care in standard risk and intermediate risk patients.

“But consideration in the highest-risk patients should be given to something like KRD,” he said. “We still recommend transplant across the board, we still recommend some form of maintenance therapy, be it with lenalidomide for most patients, but potentially bortezomib combined with carfilzomib in the highest risk patients.”

Dr. Mikhael reported consulting for Abbvie, Celgene, Onyx, and Sanofi.

[email protected]

NEW YORK – There’s more to induction therapy for transplant-eligible multiple myeloma patients than the go-to combination of bortezomib, lenalidomide, and dexamethasone, commonly known as VRD, according to Joseph R. Mikhael, MD.

“Outstanding evidence” has emerged that demonstrates the value of combining multiple mechanisms of action, but there are numerous options available – there is a trend toward increasing use of carfilzomib, for example – and VRD isn’t necessarily the best option for all patients, nor is it available in all cases, Dr. Mikhael of Mayo Clinic Arizona, Scottsdale, said at an international congress on hematologic malignancies.

Further, choosing the treatment method shown to give the most powerful or deepest response as a default isn’t necessarily the best option, either, he said, noting data showing that the regimen most often associated with at least very good partial response (VGPR) after four cycles in newly diagnosed multiple myeloma (carfilzomib, lenalidomide, dexamethasone, or KRD, about a 90% response rate) costs 2.5 times more than does the regimen (lenalidomide, dexamethasone, or RD) that provided about a 50% response rate ($250,000 vs. $100,000 per year).“But it’s also the toxicity cost ... do we need that many [drugs]?” he said, adding that “just because a clinical trial shows that three drugs work better than two, it doesn’t mean that every time I have a patient who is eligible I’m going to go with all three.”

It may be that a patient can start on two, with a third added if needed, he added.

“That being said, we want to maximize the synergy of those three, especially in high-risk patients,” he said.

Prior to 2016, popular regimens included CyBorD (cyclophosphamide, bortezomib, dexamethasone) and VTD (bortezomib, thalidomide, dexamethasone), which were commonly used worldwide. CTD (cyclophosphamide, thalidomide, dexamethasone) was used in Brazil and other countries where it was difficult to obtain bortezomib; VRD was “king of the hill” in the United States, and transplant was routinely recommended, Dr. Mikhael said.

A number of recent studies are changing that paradigm, he said.

One such study, the prospective randomized Intergroupe Francophone du Myélome (IFM) 2013-04 trial, showed that VTD is superior to bortezomib-cyclophosphamide-dexamethasone (VCD) for induction in patients with de novo multiple myeloma. VGPR and PR rates were significantly superior in the VTD arm.

Of note, hematologic toxicity increased in the VCD arm, and the peripheral neuropathy rate was higher in the VTD arm. However, the study was conducted at a time when bortezomib was generally used twice weekly; now it is standard to use it once weekly and subcutaneously, which significantly reduces the risk of peripheral neuropathy.

The authors advocated the preferential use of VTD over VCD for induction, based on the synergistic effect of a proteasome inhibitor and immunomodulatory drug, Dr. Mikhael said.

“Meanwhile, back in the United States, many trials were starting to be built with VRD,” he said, noting that “really extraordinary” responses were seen in phase I and phase II studies.

Perhaps the VRD study (called RVD in this case) that is most cited is the phase III IFM 2009 study comparing RVD with and without autologous stem cell transplant in newly diagnosed younger multiple myeloma patients. Although final results are still pending, interim results reported at the American Society of Hematology 2015 meeting (abstract 391) have been very helpful, Dr. Mikhael said.

The authors reported a 31% reduction in the risk of progression or death with autologous stem cell transplant versus RVD alone in patients with newly diagnosed multiple myeloma, as well as improved rates of thrombotic thrombocytopenic purpura (TTP) and minimal residual disease negativity (MRD). Mortality rates were similar.

The findings show that transplantation is feasible (93%), and associated with acceptable mortality (1.4%), an increased rate of negative MRD versus with RVD alone (80% vs. 65%), an improved 4-year progression-free survival (47% vs. 35%), and improved 4-year TTP (49% vs. 35%).

“Here the question was not so much is RVD the standard ... but is RVD plus transplant superior to RVD alone,” he said.

Surprising to many, especially the “dissenters in the crowd” who thought perhaps RVD would be the death knell to autologous stem cell transplant, transplant actually significantly improved the depth of response, he added.

Median progression-free survival at 10 months was 43% with versus 34% without transplantation.

“So there was definitely an argument here that transplant remains the standard of care,” he said, noting that transplant should be considered as decisions are made about up-front therapy.

As for the trend of bringing carfilzomib in earlier on in treatment, a number of studies, including the phase II CYKLONE study by Dr. Mikhael and his colleagues, suggest it improves the rates of deep response; some show that is especially true when used with transplant.

One study looking at KRD showed that the regimen provides high rates of deep and durable responses with acceptable tolerability – a finding that needs confirmation in a randomized setting.

Other studies are comparing KRD and VRD, and KRD and KCyd (carfilzomib, cyclophosphamide), as well as adding monoclonal antibodies such as daratumumab to treatment regimens, and results are very much anticipated, Dr. Mikhael said.

Currently, however, VRD remains the standard of care in standard risk and intermediate risk patients.

“But consideration in the highest-risk patients should be given to something like KRD,” he said. “We still recommend transplant across the board, we still recommend some form of maintenance therapy, be it with lenalidomide for most patients, but potentially bortezomib combined with carfilzomib in the highest risk patients.”

Dr. Mikhael reported consulting for Abbvie, Celgene, Onyx, and Sanofi.

[email protected]

NEW YORK – There’s more to induction therapy for transplant-eligible multiple myeloma patients than the go-to combination of bortezomib, lenalidomide, and dexamethasone, commonly known as VRD, according to Joseph R. Mikhael, MD.

“Outstanding evidence” has emerged that demonstrates the value of combining multiple mechanisms of action, but there are numerous options available – there is a trend toward increasing use of carfilzomib, for example – and VRD isn’t necessarily the best option for all patients, nor is it available in all cases, Dr. Mikhael of Mayo Clinic Arizona, Scottsdale, said at an international congress on hematologic malignancies.

Further, choosing the treatment method shown to give the most powerful or deepest response as a default isn’t necessarily the best option, either, he said, noting data showing that the regimen most often associated with at least very good partial response (VGPR) after four cycles in newly diagnosed multiple myeloma (carfilzomib, lenalidomide, dexamethasone, or KRD, about a 90% response rate) costs 2.5 times more than does the regimen (lenalidomide, dexamethasone, or RD) that provided about a 50% response rate ($250,000 vs. $100,000 per year).“But it’s also the toxicity cost ... do we need that many [drugs]?” he said, adding that “just because a clinical trial shows that three drugs work better than two, it doesn’t mean that every time I have a patient who is eligible I’m going to go with all three.”

It may be that a patient can start on two, with a third added if needed, he added.

“That being said, we want to maximize the synergy of those three, especially in high-risk patients,” he said.

Prior to 2016, popular regimens included CyBorD (cyclophosphamide, bortezomib, dexamethasone) and VTD (bortezomib, thalidomide, dexamethasone), which were commonly used worldwide. CTD (cyclophosphamide, thalidomide, dexamethasone) was used in Brazil and other countries where it was difficult to obtain bortezomib; VRD was “king of the hill” in the United States, and transplant was routinely recommended, Dr. Mikhael said.

A number of recent studies are changing that paradigm, he said.

One such study, the prospective randomized Intergroupe Francophone du Myélome (IFM) 2013-04 trial, showed that VTD is superior to bortezomib-cyclophosphamide-dexamethasone (VCD) for induction in patients with de novo multiple myeloma. VGPR and PR rates were significantly superior in the VTD arm.

Of note, hematologic toxicity increased in the VCD arm, and the peripheral neuropathy rate was higher in the VTD arm. However, the study was conducted at a time when bortezomib was generally used twice weekly; now it is standard to use it once weekly and subcutaneously, which significantly reduces the risk of peripheral neuropathy.

The authors advocated the preferential use of VTD over VCD for induction, based on the synergistic effect of a proteasome inhibitor and immunomodulatory drug, Dr. Mikhael said.

“Meanwhile, back in the United States, many trials were starting to be built with VRD,” he said, noting that “really extraordinary” responses were seen in phase I and phase II studies.

Perhaps the VRD study (called RVD in this case) that is most cited is the phase III IFM 2009 study comparing RVD with and without autologous stem cell transplant in newly diagnosed younger multiple myeloma patients. Although final results are still pending, interim results reported at the American Society of Hematology 2015 meeting (abstract 391) have been very helpful, Dr. Mikhael said.

The authors reported a 31% reduction in the risk of progression or death with autologous stem cell transplant versus RVD alone in patients with newly diagnosed multiple myeloma, as well as improved rates of thrombotic thrombocytopenic purpura (TTP) and minimal residual disease negativity (MRD). Mortality rates were similar.

The findings show that transplantation is feasible (93%), and associated with acceptable mortality (1.4%), an increased rate of negative MRD versus with RVD alone (80% vs. 65%), an improved 4-year progression-free survival (47% vs. 35%), and improved 4-year TTP (49% vs. 35%).

“Here the question was not so much is RVD the standard ... but is RVD plus transplant superior to RVD alone,” he said.

Surprising to many, especially the “dissenters in the crowd” who thought perhaps RVD would be the death knell to autologous stem cell transplant, transplant actually significantly improved the depth of response, he added.

Median progression-free survival at 10 months was 43% with versus 34% without transplantation.

“So there was definitely an argument here that transplant remains the standard of care,” he said, noting that transplant should be considered as decisions are made about up-front therapy.

As for the trend of bringing carfilzomib in earlier on in treatment, a number of studies, including the phase II CYKLONE study by Dr. Mikhael and his colleagues, suggest it improves the rates of deep response; some show that is especially true when used with transplant.

One study looking at KRD showed that the regimen provides high rates of deep and durable responses with acceptable tolerability – a finding that needs confirmation in a randomized setting.

Other studies are comparing KRD and VRD, and KRD and KCyd (carfilzomib, cyclophosphamide), as well as adding monoclonal antibodies such as daratumumab to treatment regimens, and results are very much anticipated, Dr. Mikhael said.

Currently, however, VRD remains the standard of care in standard risk and intermediate risk patients.

“But consideration in the highest-risk patients should be given to something like KRD,” he said. “We still recommend transplant across the board, we still recommend some form of maintenance therapy, be it with lenalidomide for most patients, but potentially bortezomib combined with carfilzomib in the highest risk patients.”

Dr. Mikhael reported consulting for Abbvie, Celgene, Onyx, and Sanofi.

[email protected]

A new consensus bundle of recommendations calls on ob.gyns. to integrate mental health care into their care of pregnant and postpartum women.

The interdisciplinary Council on Patient Safety in Women’s Health Care issued a consensus document summarizing existing recommendations on maternal mental health and pairing them with appropriate screening and other resources. The bundle of recommendations was jointly issued by the American College of Obstetricians and Gynecologists, the National Association of Nurse Practitioners in Women’s Health, and other groups (Obstet Gynecol. 2017 Mar;129(3):422-430)*.

KatarzynaBialasiewicz/Thinkstock

“Embedding a mental health professional with the women’s health care provider would seem to be the ideal, [but] in reality, this may not be available in every setting or geographic location,” Susan Kendig, JD, MSN, WHNP-BC, FAANP, policy director for the National Association of Nurse Practitioners in Women’s Health, and one of the authors of the document, said in an interview. “The purpose of the consensus bundle is to provide a framework for women’s health care providers to use in developing a system of care that includes standardized risk assessment for existing or emerging mental health issues, strategies for brief interventions, identification of community resources available to the woman, and/or resources to support the provider in addressing the woman’s needs and facilitating appropriate referrals, and addressing emergencies to prevent harm.”

The framework is grouped in four domains: readiness, recognition and prevention, response, and reporting and systems learning.

Readiness is focused largely on setting up clinical and administrative protocols, including mental health screening that is seamlessly integrated into the patient visit, established algorithms that are triggered according to screening results, and designated staff to both educate colleagues on the protocols and to drive their implementation.

The goal for physicians in all settings, according to the authors, is to balance cost, availability of tools, ease of use, and the validity of the tools against the need to capture often unrecognized signs and symptoms of mood and anxiety disorders, including changes in sleep patterns, appetite, or anxiety levels that often are attributed to the physiologic and neuroendocrinologic changes inherent in childbirth. More than 80% of women know something is “off” but do not bring up their symptoms to their clinician, according to the recommendation document.

“Coordination and team cohesiveness is not necessarily dependent on co-location,” Ms. Kendig said. “Virtual teams, where care is coordinated among providers at different locations, can also achieve positive outcomes.”

The follow-on to this – recognition and prevention – views every patient visit as an opportunity to draw a thorough picture of mental and physical health by taking a complete family and patient history, maintaining routine screening, and offering psychoeducation to patients and their families or others on whom they rely for emotional support.

When a woman does screen positive for perinatal mood or anxiety disorders, the next bundle offers a rough outline of a stage-based response for intervention and follow-up.

“Screening alone does not appear to improve pregnancy or maternal-child outcomes,” the authors wrote.

Several possible algorithms are included in the document, including for emergent mental health concerns such as suicidal or homicidal ideation.

The final domain relies on data capture, taking a systems approach to not only delivering care, but also improving it. This includes scheduling regular staff debriefings after severe maternal mental health crises, troubleshooting why some patients become lost to follow-up, and examining data to see patterns.

[email protected]

On Twitter @whitneymcknight

CORRECTION, 3/20/17: An earlier version of this article misstated the citation.

A new consensus bundle of recommendations calls on ob.gyns. to integrate mental health care into their care of pregnant and postpartum women.

The interdisciplinary Council on Patient Safety in Women’s Health Care issued a consensus document summarizing existing recommendations on maternal mental health and pairing them with appropriate screening and other resources. The bundle of recommendations was jointly issued by the American College of Obstetricians and Gynecologists, the National Association of Nurse Practitioners in Women’s Health, and other groups (Obstet Gynecol. 2017 Mar;129(3):422-430)*.

KatarzynaBialasiewicz/Thinkstock

“Embedding a mental health professional with the women’s health care provider would seem to be the ideal, [but] in reality, this may not be available in every setting or geographic location,” Susan Kendig, JD, MSN, WHNP-BC, FAANP, policy director for the National Association of Nurse Practitioners in Women’s Health, and one of the authors of the document, said in an interview. “The purpose of the consensus bundle is to provide a framework for women’s health care providers to use in developing a system of care that includes standardized risk assessment for existing or emerging mental health issues, strategies for brief interventions, identification of community resources available to the woman, and/or resources to support the provider in addressing the woman’s needs and facilitating appropriate referrals, and addressing emergencies to prevent harm.”

The framework is grouped in four domains: readiness, recognition and prevention, response, and reporting and systems learning.

Readiness is focused largely on setting up clinical and administrative protocols, including mental health screening that is seamlessly integrated into the patient visit, established algorithms that are triggered according to screening results, and designated staff to both educate colleagues on the protocols and to drive their implementation.

The goal for physicians in all settings, according to the authors, is to balance cost, availability of tools, ease of use, and the validity of the tools against the need to capture often unrecognized signs and symptoms of mood and anxiety disorders, including changes in sleep patterns, appetite, or anxiety levels that often are attributed to the physiologic and neuroendocrinologic changes inherent in childbirth. More than 80% of women know something is “off” but do not bring up their symptoms to their clinician, according to the recommendation document.

“Coordination and team cohesiveness is not necessarily dependent on co-location,” Ms. Kendig said. “Virtual teams, where care is coordinated among providers at different locations, can also achieve positive outcomes.”

The follow-on to this – recognition and prevention – views every patient visit as an opportunity to draw a thorough picture of mental and physical health by taking a complete family and patient history, maintaining routine screening, and offering psychoeducation to patients and their families or others on whom they rely for emotional support.

When a woman does screen positive for perinatal mood or anxiety disorders, the next bundle offers a rough outline of a stage-based response for intervention and follow-up.

“Screening alone does not appear to improve pregnancy or maternal-child outcomes,” the authors wrote.

Several possible algorithms are included in the document, including for emergent mental health concerns such as suicidal or homicidal ideation.

The final domain relies on data capture, taking a systems approach to not only delivering care, but also improving it. This includes scheduling regular staff debriefings after severe maternal mental health crises, troubleshooting why some patients become lost to follow-up, and examining data to see patterns.

[email protected]

On Twitter @whitneymcknight

CORRECTION, 3/20/17: An earlier version of this article misstated the citation.

A new consensus bundle of recommendations calls on ob.gyns. to integrate mental health care into their care of pregnant and postpartum women.

The interdisciplinary Council on Patient Safety in Women’s Health Care issued a consensus document summarizing existing recommendations on maternal mental health and pairing them with appropriate screening and other resources. The bundle of recommendations was jointly issued by the American College of Obstetricians and Gynecologists, the National Association of Nurse Practitioners in Women’s Health, and other groups (Obstet Gynecol. 2017 Mar;129(3):422-430)*.

KatarzynaBialasiewicz/Thinkstock

“Embedding a mental health professional with the women’s health care provider would seem to be the ideal, [but] in reality, this may not be available in every setting or geographic location,” Susan Kendig, JD, MSN, WHNP-BC, FAANP, policy director for the National Association of Nurse Practitioners in Women’s Health, and one of the authors of the document, said in an interview. “The purpose of the consensus bundle is to provide a framework for women’s health care providers to use in developing a system of care that includes standardized risk assessment for existing or emerging mental health issues, strategies for brief interventions, identification of community resources available to the woman, and/or resources to support the provider in addressing the woman’s needs and facilitating appropriate referrals, and addressing emergencies to prevent harm.”

The framework is grouped in four domains: readiness, recognition and prevention, response, and reporting and systems learning.

Readiness is focused largely on setting up clinical and administrative protocols, including mental health screening that is seamlessly integrated into the patient visit, established algorithms that are triggered according to screening results, and designated staff to both educate colleagues on the protocols and to drive their implementation.

The goal for physicians in all settings, according to the authors, is to balance cost, availability of tools, ease of use, and the validity of the tools against the need to capture often unrecognized signs and symptoms of mood and anxiety disorders, including changes in sleep patterns, appetite, or anxiety levels that often are attributed to the physiologic and neuroendocrinologic changes inherent in childbirth. More than 80% of women know something is “off” but do not bring up their symptoms to their clinician, according to the recommendation document.

“Coordination and team cohesiveness is not necessarily dependent on co-location,” Ms. Kendig said. “Virtual teams, where care is coordinated among providers at different locations, can also achieve positive outcomes.”

The follow-on to this – recognition and prevention – views every patient visit as an opportunity to draw a thorough picture of mental and physical health by taking a complete family and patient history, maintaining routine screening, and offering psychoeducation to patients and their families or others on whom they rely for emotional support.

When a woman does screen positive for perinatal mood or anxiety disorders, the next bundle offers a rough outline of a stage-based response for intervention and follow-up.

“Screening alone does not appear to improve pregnancy or maternal-child outcomes,” the authors wrote.

Several possible algorithms are included in the document, including for emergent mental health concerns such as suicidal or homicidal ideation.

The final domain relies on data capture, taking a systems approach to not only delivering care, but also improving it. This includes scheduling regular staff debriefings after severe maternal mental health crises, troubleshooting why some patients become lost to follow-up, and examining data to see patterns.

[email protected]

On Twitter @whitneymcknight

CORRECTION, 3/20/17: An earlier version of this article misstated the citation.

RBCs made by iPSCs generated
from cells from a DBA patient
Image courtesy of
Boston Children’s Hospital

Researchers have used induced pluripotent stem cells (iPSCs) to identify a compound that could treat Diamond Blackfan anemia (DBA).

The team used iPSCs to generate expandable hematopoietic progenitor cells (HPCs) that recapitulate the defects in erythroid differentiation observed in patients with DBA.

The researchers then used the HPCs to screen chemical compounds that might be used to treat DBA.

One of these compounds, SMER28, enhanced erythropoiesis in models of DBA.

“It is very satisfying as physician-scientists to find new potential treatments for rare blood diseases such as Diamond Blackfan anemia,” said study author Leonard Zon, MD, of Boston Children’s Hospital and Dana-Farber Cancer Institute in Boston, Massachusetts.

Dr Zon and his colleagues described this work in Science Translational Medicine.

The researchers first took fibroblasts from 2 patients with DBA and reprogrammed them into iPSCs. From the iPSCs, the team generated HPCs, which they loaded into a high-throughput drug screening system.

Testing a library of 1440 chemicals, the researchers found several that showed promise for treating DBA in vitro. One compound, SMER28, was able to induce red blood cell (RBC) production in mice and zebrafish.

The researchers believe this study marks an important advance in the stem cell field.

“[iPSCs] have been hard to instruct when it comes to making blood,” said study author Sergei Doulatov, PhD, of the University of Washington in Seattle.

“This is the first time [iPSCs] have been used to identify a drug to treat a blood disorder.”

Making RBCs

As in DBA itself, the patient-derived HPCs, studied in vitro, failed to generate erythroid cells. The same was true when the cells were transplanted into mice.

However, the chemical screen got several “hits.” In wells loaded with certain chemicals, erythroid cells began appearing. Because of its especially strong effect, SMER28 was put through additional testing.

When SMER28 was used to treat the marrow in zebrafish and mouse models of DBA, the animals made erythroid progenitor cells that, in turn, made RBCs, reversing or stabilizing anemia. The same was true in cells from DBA patients transplanted into mice.

The higher the dose of SMER28, the more RBCs were produced, and no ill effects were found. However, formal toxicity studies have not been conducted.

SMER28 has been tested preclinically for some neurodegenerative diseases. It activates an autophagy pathway that recycles damaged cellular components.

In DBA, SMER28 appears to turn on autophagy in erythroid progenitors. Dr Doulatov plans to further explore how this interferes with RBC production.

RBCs made by iPSCs generated
from cells from a DBA patient
Image courtesy of
Boston Children’s Hospital

Researchers have used induced pluripotent stem cells (iPSCs) to identify a compound that could treat Diamond Blackfan anemia (DBA).

The team used iPSCs to generate expandable hematopoietic progenitor cells (HPCs) that recapitulate the defects in erythroid differentiation observed in patients with DBA.

The researchers then used the HPCs to screen chemical compounds that might be used to treat DBA.

One of these compounds, SMER28, enhanced erythropoiesis in models of DBA.

“It is very satisfying as physician-scientists to find new potential treatments for rare blood diseases such as Diamond Blackfan anemia,” said study author Leonard Zon, MD, of Boston Children’s Hospital and Dana-Farber Cancer Institute in Boston, Massachusetts.

Dr Zon and his colleagues described this work in Science Translational Medicine.

The researchers first took fibroblasts from 2 patients with DBA and reprogrammed them into iPSCs. From the iPSCs, the team generated HPCs, which they loaded into a high-throughput drug screening system.

Testing a library of 1440 chemicals, the researchers found several that showed promise for treating DBA in vitro. One compound, SMER28, was able to induce red blood cell (RBC) production in mice and zebrafish.

The researchers believe this study marks an important advance in the stem cell field.

“[iPSCs] have been hard to instruct when it comes to making blood,” said study author Sergei Doulatov, PhD, of the University of Washington in Seattle.

“This is the first time [iPSCs] have been used to identify a drug to treat a blood disorder.”

Making RBCs

As in DBA itself, the patient-derived HPCs, studied in vitro, failed to generate erythroid cells. The same was true when the cells were transplanted into mice.

However, the chemical screen got several “hits.” In wells loaded with certain chemicals, erythroid cells began appearing. Because of its especially strong effect, SMER28 was put through additional testing.

When SMER28 was used to treat the marrow in zebrafish and mouse models of DBA, the animals made erythroid progenitor cells that, in turn, made RBCs, reversing or stabilizing anemia. The same was true in cells from DBA patients transplanted into mice.

The higher the dose of SMER28, the more RBCs were produced, and no ill effects were found. However, formal toxicity studies have not been conducted.

SMER28 has been tested preclinically for some neurodegenerative diseases. It activates an autophagy pathway that recycles damaged cellular components.

In DBA, SMER28 appears to turn on autophagy in erythroid progenitors. Dr Doulatov plans to further explore how this interferes with RBC production.

RBCs made by iPSCs generated
from cells from a DBA patient
Image courtesy of
Boston Children’s Hospital

Researchers have used induced pluripotent stem cells (iPSCs) to identify a compound that could treat Diamond Blackfan anemia (DBA).

The team used iPSCs to generate expandable hematopoietic progenitor cells (HPCs) that recapitulate the defects in erythroid differentiation observed in patients with DBA.

The researchers then used the HPCs to screen chemical compounds that might be used to treat DBA.

One of these compounds, SMER28, enhanced erythropoiesis in models of DBA.

“It is very satisfying as physician-scientists to find new potential treatments for rare blood diseases such as Diamond Blackfan anemia,” said study author Leonard Zon, MD, of Boston Children’s Hospital and Dana-Farber Cancer Institute in Boston, Massachusetts.

Dr Zon and his colleagues described this work in Science Translational Medicine.

The researchers first took fibroblasts from 2 patients with DBA and reprogrammed them into iPSCs. From the iPSCs, the team generated HPCs, which they loaded into a high-throughput drug screening system.

Testing a library of 1440 chemicals, the researchers found several that showed promise for treating DBA in vitro. One compound, SMER28, was able to induce red blood cell (RBC) production in mice and zebrafish.

The researchers believe this study marks an important advance in the stem cell field.

“[iPSCs] have been hard to instruct when it comes to making blood,” said study author Sergei Doulatov, PhD, of the University of Washington in Seattle.

“This is the first time [iPSCs] have been used to identify a drug to treat a blood disorder.”

Making RBCs

As in DBA itself, the patient-derived HPCs, studied in vitro, failed to generate erythroid cells. The same was true when the cells were transplanted into mice.

However, the chemical screen got several “hits.” In wells loaded with certain chemicals, erythroid cells began appearing. Because of its especially strong effect, SMER28 was put through additional testing.

When SMER28 was used to treat the marrow in zebrafish and mouse models of DBA, the animals made erythroid progenitor cells that, in turn, made RBCs, reversing or stabilizing anemia. The same was true in cells from DBA patients transplanted into mice.

The higher the dose of SMER28, the more RBCs were produced, and no ill effects were found. However, formal toxicity studies have not been conducted.

SMER28 has been tested preclinically for some neurodegenerative diseases. It activates an autophagy pathway that recycles damaged cellular components.

In DBA, SMER28 appears to turn on autophagy in erythroid progenitors. Dr Doulatov plans to further explore how this interferes with RBC production.

Plasmodium falciparum
Image courtesy of
CDC/Mae Melvin

A lineage of multidrug-resistant malaria parasite has spread widely and is now established in parts of Thailand, Laos, and Cambodia, according to a study published in The Lancet Infectious Diseases.

The

researchers said their findings suggest an artemisinin-resistant

Plasmodium falciparum lineage probably arose in western Cambodia and

then spread to Thailand and Laos, outcompeting other parasites and

acquiring resistance to piperaquine.

“We now see this very successful, resistant parasite lineage emerging, outcompeting its peers, and spreading over a wide area,” said study author Arjen Dondorp, MD, of Mahidol University in Bangkok, Thailand, and the University of Oxford in Oxford, UK.

“It has also picked up resistance to the partner drug piperaquine, causing high failure rates of the widely used artemisinin combination therapy, DHA-piperaquine. We hope this evidence will be used to re-emphasize the urgency of malaria elimination in the Asia region before falciparum malaria becomes close to untreatable.”

For this study, Dr Dondorp and his colleagues examined blood spot samples from patients with uncomplicated, P falciparum malaria collected at sites in Cambodia, Laos, Thailand, and Myanmar.

The researchers found evidence to suggest that PfKelch13 C580Y, a single mutant parasite lineage, has spread across Cambodia, Laos, and Thailand, replacing parasites containing other, less resistant mutations.

Although the C580Y mutation does not confer a higher level of artemisinin resistance than many other PfKelch13 mutations, it appears to be fitter, more transmissible, and spreading more widely.

“It isn’t that the C580Y mutation itself makes the malaria parasites fitter, it is the other genetic changes that go along with it—hence, the critical emphasis on the term ‘lineage,’” said Nicholas White, also of Mahidol University and the University of Oxford.

“This is what makes superbugs—the evolution of multiple factors that make them fitter and more transmissible. The spread and emergence of drug-resistant malaria parasites across Asia into Africa has occurred before. Last time, it killed millions. We need to work with our policy, research, and funding partners to respond to this threat in Asia urgently to avoid history repeating itself.”

In particular, the researchers are calling for accelerated efforts in the Greater Mekong subregion and closer collaboration to monitor any further spread in neighboring regions.

“We are losing a dangerous race to eliminate artemisinin-resistant falciparum malaria before widespread resistance to the partner antimalarials makes that impossible,” White said. “The consequences of resistance spreading further into India and Africa could be grave if drug resistance is not tackled from a global public health emergency perspective.”

Plasmodium falciparum
Image courtesy of
CDC/Mae Melvin

A lineage of multidrug-resistant malaria parasite has spread widely and is now established in parts of Thailand, Laos, and Cambodia, according to a study published in The Lancet Infectious Diseases.

The

researchers said their findings suggest an artemisinin-resistant

Plasmodium falciparum lineage probably arose in western Cambodia and

then spread to Thailand and Laos, outcompeting other parasites and

acquiring resistance to piperaquine.

“We now see this very successful, resistant parasite lineage emerging, outcompeting its peers, and spreading over a wide area,” said study author Arjen Dondorp, MD, of Mahidol University in Bangkok, Thailand, and the University of Oxford in Oxford, UK.

“It has also picked up resistance to the partner drug piperaquine, causing high failure rates of the widely used artemisinin combination therapy, DHA-piperaquine. We hope this evidence will be used to re-emphasize the urgency of malaria elimination in the Asia region before falciparum malaria becomes close to untreatable.”

For this study, Dr Dondorp and his colleagues examined blood spot samples from patients with uncomplicated, P falciparum malaria collected at sites in Cambodia, Laos, Thailand, and Myanmar.

The researchers found evidence to suggest that PfKelch13 C580Y, a single mutant parasite lineage, has spread across Cambodia, Laos, and Thailand, replacing parasites containing other, less resistant mutations.

Although the C580Y mutation does not confer a higher level of artemisinin resistance than many other PfKelch13 mutations, it appears to be fitter, more transmissible, and spreading more widely.

“It isn’t that the C580Y mutation itself makes the malaria parasites fitter, it is the other genetic changes that go along with it—hence, the critical emphasis on the term ‘lineage,’” said Nicholas White, also of Mahidol University and the University of Oxford.

“This is what makes superbugs—the evolution of multiple factors that make them fitter and more transmissible. The spread and emergence of drug-resistant malaria parasites across Asia into Africa has occurred before. Last time, it killed millions. We need to work with our policy, research, and funding partners to respond to this threat in Asia urgently to avoid history repeating itself.”

In particular, the researchers are calling for accelerated efforts in the Greater Mekong subregion and closer collaboration to monitor any further spread in neighboring regions.

“We are losing a dangerous race to eliminate artemisinin-resistant falciparum malaria before widespread resistance to the partner antimalarials makes that impossible,” White said. “The consequences of resistance spreading further into India and Africa could be grave if drug resistance is not tackled from a global public health emergency perspective.”

Plasmodium falciparum
Image courtesy of
CDC/Mae Melvin

A lineage of multidrug-resistant malaria parasite has spread widely and is now established in parts of Thailand, Laos, and Cambodia, according to a study published in The Lancet Infectious Diseases.

The

researchers said their findings suggest an artemisinin-resistant

Plasmodium falciparum lineage probably arose in western Cambodia and

then spread to Thailand and Laos, outcompeting other parasites and

acquiring resistance to piperaquine.

“We now see this very successful, resistant parasite lineage emerging, outcompeting its peers, and spreading over a wide area,” said study author Arjen Dondorp, MD, of Mahidol University in Bangkok, Thailand, and the University of Oxford in Oxford, UK.

“It has also picked up resistance to the partner drug piperaquine, causing high failure rates of the widely used artemisinin combination therapy, DHA-piperaquine. We hope this evidence will be used to re-emphasize the urgency of malaria elimination in the Asia region before falciparum malaria becomes close to untreatable.”

For this study, Dr Dondorp and his colleagues examined blood spot samples from patients with uncomplicated, P falciparum malaria collected at sites in Cambodia, Laos, Thailand, and Myanmar.

The researchers found evidence to suggest that PfKelch13 C580Y, a single mutant parasite lineage, has spread across Cambodia, Laos, and Thailand, replacing parasites containing other, less resistant mutations.

Although the C580Y mutation does not confer a higher level of artemisinin resistance than many other PfKelch13 mutations, it appears to be fitter, more transmissible, and spreading more widely.

“It isn’t that the C580Y mutation itself makes the malaria parasites fitter, it is the other genetic changes that go along with it—hence, the critical emphasis on the term ‘lineage,’” said Nicholas White, also of Mahidol University and the University of Oxford.

“This is what makes superbugs—the evolution of multiple factors that make them fitter and more transmissible. The spread and emergence of drug-resistant malaria parasites across Asia into Africa has occurred before. Last time, it killed millions. We need to work with our policy, research, and funding partners to respond to this threat in Asia urgently to avoid history repeating itself.”

In particular, the researchers are calling for accelerated efforts in the Greater Mekong subregion and closer collaboration to monitor any further spread in neighboring regions.

“We are losing a dangerous race to eliminate artemisinin-resistant falciparum malaria before widespread resistance to the partner antimalarials makes that impossible,” White said. “The consequences of resistance spreading further into India and Africa could be grave if drug resistance is not tackled from a global public health emergency perspective.”

Vials of product
Photo by Bill Branson

The US Food and Drug Administration (FDA) has approved an intravenous immunoglobulin (IVIG) product (Gammaplex® 10%) for the treatment of primary immunodeficiency (PI) and chronic immune thrombocytopenia (ITP) in adults. 

PI includes, but is not limited to,

the humoral immune defect in common variable immunodeficiency, X-linked and congenital

agammaglobulinemia, Wiskott-Aldrich

syndrome, and severe combined immunodeficiencies.

Gammaplex 10% is manufactured by Bio Products Laboratory Limited (BPL).

Gammaplex 10% is made with the same process as BPL’s previously approved IVIG treatment, Gammaplex® 5% (immune globulin intravenous [human], 5% liquid). 

Gammaplex 10% is more concentrated than Gammaplex 5%, with an immune globulin G (IgG) concentration of 100 g/L, and is stabilized with glycine. 

The FDA’s approval of Gammaplex 10% was based on a 2-phase, crossover bioequivalence study comparing Gammaplex 10% and Gammaplex 5% in 33 adult patients with PI. This study is the first direct comparison of 10% and 5% IVIG products in the treatment of PI.

The primary endpoint of bioequivalence between the products was achieved, and trough levels of IgG were well maintained throughout the study. 

Both Gammaplex 10% and Gammaplex 5% infusion rates were increased incrementally at 15-minute intervals if tolerated by the subject. The Gammaplex 10% infusion rate was increased to the maximum in 96% of infusions. 

The mean infusion time for Gammaplex 10% was 1 hour and 51 minutes, which was 57 minutes faster than Gammaplex 5%.

There were no notable differences in the safety and tolerability of the 2 products.

The most common adverse events in patients receiving Gammaplex 10% were headache (12.5%), migraine (6.3%), and pyrexia (6.3%). There were no serious product-related adverse events. 

The safety of Gammaplex 10% has not been established in adults with chronic ITP. The safety profile for Gammaplex 5% has been studied in a phase 3 trial of adults with chronic ITP, and it is anticipated that the safety profile for both formulations are comparable for ITP patients.

The most common adverse events in adults with chronic ITP receiving Gammaplex 5% were headache, vomiting, nausea, pyrexia, arthralgia, and dehydration. Serious adverse events were headache, vomiting, and dehydration.

The full prescribing information for Gammaplex 10%, which includes trial data, is available at http://www.gammaplex.com.

Vials of product
Photo by Bill Branson

The US Food and Drug Administration (FDA) has approved an intravenous immunoglobulin (IVIG) product (Gammaplex® 10%) for the treatment of primary immunodeficiency (PI) and chronic immune thrombocytopenia (ITP) in adults. 

PI includes, but is not limited to,

the humoral immune defect in common variable immunodeficiency, X-linked and congenital

agammaglobulinemia, Wiskott-Aldrich

syndrome, and severe combined immunodeficiencies.

Gammaplex 10% is manufactured by Bio Products Laboratory Limited (BPL).

Gammaplex 10% is made with the same process as BPL’s previously approved IVIG treatment, Gammaplex® 5% (immune globulin intravenous [human], 5% liquid). 

Gammaplex 10% is more concentrated than Gammaplex 5%, with an immune globulin G (IgG) concentration of 100 g/L, and is stabilized with glycine. 

The FDA’s approval of Gammaplex 10% was based on a 2-phase, crossover bioequivalence study comparing Gammaplex 10% and Gammaplex 5% in 33 adult patients with PI. This study is the first direct comparison of 10% and 5% IVIG products in the treatment of PI.

The primary endpoint of bioequivalence between the products was achieved, and trough levels of IgG were well maintained throughout the study. 

Both Gammaplex 10% and Gammaplex 5% infusion rates were increased incrementally at 15-minute intervals if tolerated by the subject. The Gammaplex 10% infusion rate was increased to the maximum in 96% of infusions. 

The mean infusion time for Gammaplex 10% was 1 hour and 51 minutes, which was 57 minutes faster than Gammaplex 5%.

There were no notable differences in the safety and tolerability of the 2 products.

The most common adverse events in patients receiving Gammaplex 10% were headache (12.5%), migraine (6.3%), and pyrexia (6.3%). There were no serious product-related adverse events. 

The safety of Gammaplex 10% has not been established in adults with chronic ITP. The safety profile for Gammaplex 5% has been studied in a phase 3 trial of adults with chronic ITP, and it is anticipated that the safety profile for both formulations are comparable for ITP patients.

The most common adverse events in adults with chronic ITP receiving Gammaplex 5% were headache, vomiting, nausea, pyrexia, arthralgia, and dehydration. Serious adverse events were headache, vomiting, and dehydration.

The full prescribing information for Gammaplex 10%, which includes trial data, is available at http://www.gammaplex.com.

Vials of product
Photo by Bill Branson

The US Food and Drug Administration (FDA) has approved an intravenous immunoglobulin (IVIG) product (Gammaplex® 10%) for the treatment of primary immunodeficiency (PI) and chronic immune thrombocytopenia (ITP) in adults. 

PI includes, but is not limited to,

the humoral immune defect in common variable immunodeficiency, X-linked and congenital

agammaglobulinemia, Wiskott-Aldrich

syndrome, and severe combined immunodeficiencies.

Gammaplex 10% is manufactured by Bio Products Laboratory Limited (BPL).

Gammaplex 10% is made with the same process as BPL’s previously approved IVIG treatment, Gammaplex® 5% (immune globulin intravenous [human], 5% liquid). 

Gammaplex 10% is more concentrated than Gammaplex 5%, with an immune globulin G (IgG) concentration of 100 g/L, and is stabilized with glycine. 

The FDA’s approval of Gammaplex 10% was based on a 2-phase, crossover bioequivalence study comparing Gammaplex 10% and Gammaplex 5% in 33 adult patients with PI. This study is the first direct comparison of 10% and 5% IVIG products in the treatment of PI.

The primary endpoint of bioequivalence between the products was achieved, and trough levels of IgG were well maintained throughout the study. 

Both Gammaplex 10% and Gammaplex 5% infusion rates were increased incrementally at 15-minute intervals if tolerated by the subject. The Gammaplex 10% infusion rate was increased to the maximum in 96% of infusions. 

The mean infusion time for Gammaplex 10% was 1 hour and 51 minutes, which was 57 minutes faster than Gammaplex 5%.

There were no notable differences in the safety and tolerability of the 2 products.

The most common adverse events in patients receiving Gammaplex 10% were headache (12.5%), migraine (6.3%), and pyrexia (6.3%). There were no serious product-related adverse events. 

The safety of Gammaplex 10% has not been established in adults with chronic ITP. The safety profile for Gammaplex 5% has been studied in a phase 3 trial of adults with chronic ITP, and it is anticipated that the safety profile for both formulations are comparable for ITP patients.

The most common adverse events in adults with chronic ITP receiving Gammaplex 5% were headache, vomiting, nausea, pyrexia, arthralgia, and dehydration. Serious adverse events were headache, vomiting, and dehydration.

The full prescribing information for Gammaplex 10%, which includes trial data, is available at http://www.gammaplex.com.

Micrograph showing CLL

Investigators say they have identified 9 new risk loci for chronic lymphocytic leukemia (CLL).

The team says the research, published in Nature Communications, provides additional evidence for genetic susceptibility to CLL and sheds new light on the biological basis of CLL development.

They also believe their findings could aid the development of new drugs for CLL or help in selecting existing therapies for CLL

patients.

“We knew people were more likely to develop chronic lymphocytic leukemia if someone in their family had suffered from the disease, but our new research takes a big step towards explaining the underlying genetics,” said study author Richard Houlston, MD, PhD, of The Institute of Cancer Research in London, UK.

“CLL is essentially a disease of the immune system, and it’s fascinating that so many of the new genetic variants we have uncovered seem to directly affect the behavior of white blood cells and their ability to fight disease. Understanding the genetics of CLL can point us towards new treatments for the disease and help us to use existing targeted drugs more effectively.”

For this study, Dr Houlston and his colleagues analyzed data from 8 studies involving a total of 6200 CLL patients and 17,598 controls.

From this, the team identified 9 CLL risk loci:

• 1p36.11 (rs34676223, P=5.04 × 10⁻¹³)
• 1q42.13 (rs41271473, P=1.06 × 10⁻¹⁰)
• 4q24 (rs71597109, P=1.37 × 10⁻¹⁰)
• 4q35.1 (rs57214277, P=3.69 × 10⁻⁸)
• 6p21.31 (rs3800461, P=1.97 × 10⁻⁸)
• 11q23.2 (rs61904987, P=2.64 × 10⁻¹¹)
• 18q21.1 (rs1036935, P=3.27 × 10⁻⁸)
• 19p13.3 (rs7254272, P=4.67 × 10⁻⁸)
• 22q13.33 (rs140522, P=2.70 × 10⁻⁹).

The investigators noted that the 4q24 association marked by rs71597109 maps to intron 1 of the gene encoding BANK1 (B-cell scaffold protein with ankyrin repeats 1). BANK1 is only ever activated in B cells and is linked to the autoimmune disease lupus.

The team also pointed out that the 19p13.3 association marked by rs7254272 maps 2.5 kb 5′ to ZBTB7A (zinc finger and BTB domain-containing protein 7a), which is a master regulator of B versus T lymphoid fate. So errors in ZBTB7A could lead to too many B cells in the bloodstream and bone marrow.

And rs140522 maps to 22q13.33, which has been linked to the development of multiple sclerosis. The investigators noted that this region of linkage disequilibrium contains 4 genes. One of them, NCAPH2 (non-SMC condensin II complex subunit H2), is differentially expressed in CLL and normal B cells.

“This fascinating study makes a link between genetic variants in the immune system and the development of leukemia and implicates regions of DNA which are also involved in autoimmune diseases,” said Paul Workman, PhD, chief executive and president of The Institute of Cancer Research, who was not involved in this research.

“The findings could point us towards new ways of treating leukemia or better ways of using existing treatments—potentially including immunotherapies.”

Micrograph showing CLL

Investigators say they have identified 9 new risk loci for chronic lymphocytic leukemia (CLL).

The team says the research, published in Nature Communications, provides additional evidence for genetic susceptibility to CLL and sheds new light on the biological basis of CLL development.

They also believe their findings could aid the development of new drugs for CLL or help in selecting existing therapies for CLL

patients.

“We knew people were more likely to develop chronic lymphocytic leukemia if someone in their family had suffered from the disease, but our new research takes a big step towards explaining the underlying genetics,” said study author Richard Houlston, MD, PhD, of The Institute of Cancer Research in London, UK.

“CLL is essentially a disease of the immune system, and it’s fascinating that so many of the new genetic variants we have uncovered seem to directly affect the behavior of white blood cells and their ability to fight disease. Understanding the genetics of CLL can point us towards new treatments for the disease and help us to use existing targeted drugs more effectively.”

For this study, Dr Houlston and his colleagues analyzed data from 8 studies involving a total of 6200 CLL patients and 17,598 controls.

From this, the team identified 9 CLL risk loci:

• 1p36.11 (rs34676223, P=5.04 × 10⁻¹³)
• 1q42.13 (rs41271473, P=1.06 × 10⁻¹⁰)
• 4q24 (rs71597109, P=1.37 × 10⁻¹⁰)
• 4q35.1 (rs57214277, P=3.69 × 10⁻⁸)
• 6p21.31 (rs3800461, P=1.97 × 10⁻⁸)
• 11q23.2 (rs61904987, P=2.64 × 10⁻¹¹)
• 18q21.1 (rs1036935, P=3.27 × 10⁻⁸)
• 19p13.3 (rs7254272, P=4.67 × 10⁻⁸)
• 22q13.33 (rs140522, P=2.70 × 10⁻⁹).

The investigators noted that the 4q24 association marked by rs71597109 maps to intron 1 of the gene encoding BANK1 (B-cell scaffold protein with ankyrin repeats 1). BANK1 is only ever activated in B cells and is linked to the autoimmune disease lupus.

The team also pointed out that the 19p13.3 association marked by rs7254272 maps 2.5 kb 5′ to ZBTB7A (zinc finger and BTB domain-containing protein 7a), which is a master regulator of B versus T lymphoid fate. So errors in ZBTB7A could lead to too many B cells in the bloodstream and bone marrow.

And rs140522 maps to 22q13.33, which has been linked to the development of multiple sclerosis. The investigators noted that this region of linkage disequilibrium contains 4 genes. One of them, NCAPH2 (non-SMC condensin II complex subunit H2), is differentially expressed in CLL and normal B cells.

“This fascinating study makes a link between genetic variants in the immune system and the development of leukemia and implicates regions of DNA which are also involved in autoimmune diseases,” said Paul Workman, PhD, chief executive and president of The Institute of Cancer Research, who was not involved in this research.

“The findings could point us towards new ways of treating leukemia or better ways of using existing treatments—potentially including immunotherapies.”

Micrograph showing CLL

Investigators say they have identified 9 new risk loci for chronic lymphocytic leukemia (CLL).

The team says the research, published in Nature Communications, provides additional evidence for genetic susceptibility to CLL and sheds new light on the biological basis of CLL development.

They also believe their findings could aid the development of new drugs for CLL or help in selecting existing therapies for CLL

patients.

“We knew people were more likely to develop chronic lymphocytic leukemia if someone in their family had suffered from the disease, but our new research takes a big step towards explaining the underlying genetics,” said study author Richard Houlston, MD, PhD, of The Institute of Cancer Research in London, UK.

“CLL is essentially a disease of the immune system, and it’s fascinating that so many of the new genetic variants we have uncovered seem to directly affect the behavior of white blood cells and their ability to fight disease. Understanding the genetics of CLL can point us towards new treatments for the disease and help us to use existing targeted drugs more effectively.”

For this study, Dr Houlston and his colleagues analyzed data from 8 studies involving a total of 6200 CLL patients and 17,598 controls.

From this, the team identified 9 CLL risk loci:

• 1p36.11 (rs34676223, P=5.04 × 10⁻¹³)
• 1q42.13 (rs41271473, P=1.06 × 10⁻¹⁰)
• 4q24 (rs71597109, P=1.37 × 10⁻¹⁰)
• 4q35.1 (rs57214277, P=3.69 × 10⁻⁸)
• 6p21.31 (rs3800461, P=1.97 × 10⁻⁸)
• 11q23.2 (rs61904987, P=2.64 × 10⁻¹¹)
• 18q21.1 (rs1036935, P=3.27 × 10⁻⁸)
• 19p13.3 (rs7254272, P=4.67 × 10⁻⁸)
• 22q13.33 (rs140522, P=2.70 × 10⁻⁹).

The investigators noted that the 4q24 association marked by rs71597109 maps to intron 1 of the gene encoding BANK1 (B-cell scaffold protein with ankyrin repeats 1). BANK1 is only ever activated in B cells and is linked to the autoimmune disease lupus.

The team also pointed out that the 19p13.3 association marked by rs7254272 maps 2.5 kb 5′ to ZBTB7A (zinc finger and BTB domain-containing protein 7a), which is a master regulator of B versus T lymphoid fate. So errors in ZBTB7A could lead to too many B cells in the bloodstream and bone marrow.

And rs140522 maps to 22q13.33, which has been linked to the development of multiple sclerosis. The investigators noted that this region of linkage disequilibrium contains 4 genes. One of them, NCAPH2 (non-SMC condensin II complex subunit H2), is differentially expressed in CLL and normal B cells.

“This fascinating study makes a link between genetic variants in the immune system and the development of leukemia and implicates regions of DNA which are also involved in autoimmune diseases,” said Paul Workman, PhD, chief executive and president of The Institute of Cancer Research, who was not involved in this research.

“The findings could point us towards new ways of treating leukemia or better ways of using existing treatments—potentially including immunotherapies.”

Diabetes-related kidney failure has declined dramatically among Native Americans—54% between 1996 and 2013— largely thanks to team- and population-based approaches begun by the IHS in the mid-1980s.

In addition to lowering the prevalence of kidney failure, those approaches led to other improvements:

•   Use of medicines to protect kidneys increased from 42% to 74% in 5 years
•      Average blood pressure in people with hypertension is well controlled (133/76 mm Hg in 2015)
•     Blood sugar control improved by 10% between 1996 and 2014
•     Kidney testing in adults aged ≥ 65 years increased  > 10% compared with the Medicare diabetes population

The CDC and IHS advise team-based care should include patient education; community outreach; care coordination; tracking of health outcomes; and access to health care providers, nutritionists, diabetes educators, pharmacists, community health workers, and behavioral health clinicians. For instance, care managers use clinical data to identify people who need to be linked to health care and call patients if they miss appointments. The care model also includes integrating kidney disease prevention and education into routine diabetes care.

Diabetes-related kidney failure has declined dramatically among Native Americans—54% between 1996 and 2013— largely thanks to team- and population-based approaches begun by the IHS in the mid-1980s.

In addition to lowering the prevalence of kidney failure, those approaches led to other improvements:

•   Use of medicines to protect kidneys increased from 42% to 74% in 5 years
•      Average blood pressure in people with hypertension is well controlled (133/76 mm Hg in 2015)
•     Blood sugar control improved by 10% between 1996 and 2014
•     Kidney testing in adults aged ≥ 65 years increased  > 10% compared with the Medicare diabetes population

The CDC and IHS advise team-based care should include patient education; community outreach; care coordination; tracking of health outcomes; and access to health care providers, nutritionists, diabetes educators, pharmacists, community health workers, and behavioral health clinicians. For instance, care managers use clinical data to identify people who need to be linked to health care and call patients if they miss appointments. The care model also includes integrating kidney disease prevention and education into routine diabetes care.

Diabetes-related kidney failure has declined dramatically among Native Americans—54% between 1996 and 2013— largely thanks to team- and population-based approaches begun by the IHS in the mid-1980s.

In addition to lowering the prevalence of kidney failure, those approaches led to other improvements:

•   Use of medicines to protect kidneys increased from 42% to 74% in 5 years
•      Average blood pressure in people with hypertension is well controlled (133/76 mm Hg in 2015)
•     Blood sugar control improved by 10% between 1996 and 2014
•     Kidney testing in adults aged ≥ 65 years increased  > 10% compared with the Medicare diabetes population

The CDC and IHS advise team-based care should include patient education; community outreach; care coordination; tracking of health outcomes; and access to health care providers, nutritionists, diabetes educators, pharmacists, community health workers, and behavioral health clinicians. For instance, care managers use clinical data to identify people who need to be linked to health care and call patients if they miss appointments. The care model also includes integrating kidney disease prevention and education into routine diabetes care.

A 25-year-old African-American woman presents for evaluation of an asymptomatic rash she has had for several months. It manifested shortly after she began an exercise program to help her lose weight. Her primary care provider made a presumptive diagnosis of tinea versicolor (TV), but the rash persists despite treatment attempts with  topical selenium sulfide shampoo and a 10-day course of fluconazole (200 mg/d).

The patient denies having endocrine problems, such as diabetes. However, she states that given her weight and family history, she was warned about the possibility.

EXAMINATION
The patient is obese and has type V skin. Her rash is dark brown and feels slightly rough. It appears solid brown on the central back and chest, peripherally becoming sparser and more reticular (net-like). It extends to involve the flexural surfaces of both arms.

What is the diagnosis?

At first glance, the appearance of CRP mimics that of TV. But the rough feel, reticular look, and dark color of CRP (which results from an increase in melanosomes) are totally missing in TV. Histologic studies of CRP show abnormal keratinocyte differentiation and maturation, a picture markedly at odds with that of TV.

TV, a result of the commensal yeast organism Malassezia furfur (M furfur) metabolizing normal sebum and leaving behind azelaic acid, causes color changes in the skin. But M furfur is not involved in CRP, and therefore the condition does not respond to oral or topical antiyeast medications.

The most effective treatment for CRP is minocycline (100 mg bid for 10 d). Long-term treatment includes weight loss and reduction of ambient heat.

TAKE-HOME LEARNING POINTS

• Confluent and reticulated papillomatosis (CRP) affects the trunk and extremities of obese patients with darker skin.
• In contrast with tinea versicolor (TV), CRP has a rough texture and reticulated look, especially on the periphery of the involved areas.
• Biopsy can help distinguish CRP from its lookalikes; it shows abnormal keratinocyte differentiation and maturation, as well as increased melanosomes.
• Oral minocycline is the best treatment, along with weight loss and reduction of ambient heat.

A 25-year-old African-American woman presents for evaluation of an asymptomatic rash she has had for several months. It manifested shortly after she began an exercise program to help her lose weight. Her primary care provider made a presumptive diagnosis of tinea versicolor (TV), but the rash persists despite treatment attempts with  topical selenium sulfide shampoo and a 10-day course of fluconazole (200 mg/d).

The patient denies having endocrine problems, such as diabetes. However, she states that given her weight and family history, she was warned about the possibility.

EXAMINATION
The patient is obese and has type V skin. Her rash is dark brown and feels slightly rough. It appears solid brown on the central back and chest, peripherally becoming sparser and more reticular (net-like). It extends to involve the flexural surfaces of both arms.

What is the diagnosis?

At first glance, the appearance of CRP mimics that of TV. But the rough feel, reticular look, and dark color of CRP (which results from an increase in melanosomes) are totally missing in TV. Histologic studies of CRP show abnormal keratinocyte differentiation and maturation, a picture markedly at odds with that of TV.

TV, a result of the commensal yeast organism Malassezia furfur (M furfur) metabolizing normal sebum and leaving behind azelaic acid, causes color changes in the skin. But M furfur is not involved in CRP, and therefore the condition does not respond to oral or topical antiyeast medications.

The most effective treatment for CRP is minocycline (100 mg bid for 10 d). Long-term treatment includes weight loss and reduction of ambient heat.

TAKE-HOME LEARNING POINTS

• Confluent and reticulated papillomatosis (CRP) affects the trunk and extremities of obese patients with darker skin.
• In contrast with tinea versicolor (TV), CRP has a rough texture and reticulated look, especially on the periphery of the involved areas.
• Biopsy can help distinguish CRP from its lookalikes; it shows abnormal keratinocyte differentiation and maturation, as well as increased melanosomes.
• Oral minocycline is the best treatment, along with weight loss and reduction of ambient heat.

A 25-year-old African-American woman presents for evaluation of an asymptomatic rash she has had for several months. It manifested shortly after she began an exercise program to help her lose weight. Her primary care provider made a presumptive diagnosis of tinea versicolor (TV), but the rash persists despite treatment attempts with  topical selenium sulfide shampoo and a 10-day course of fluconazole (200 mg/d).

The patient denies having endocrine problems, such as diabetes. However, she states that given her weight and family history, she was warned about the possibility.

EXAMINATION
The patient is obese and has type V skin. Her rash is dark brown and feels slightly rough. It appears solid brown on the central back and chest, peripherally becoming sparser and more reticular (net-like). It extends to involve the flexural surfaces of both arms.

What is the diagnosis?

At first glance, the appearance of CRP mimics that of TV. But the rough feel, reticular look, and dark color of CRP (which results from an increase in melanosomes) are totally missing in TV. Histologic studies of CRP show abnormal keratinocyte differentiation and maturation, a picture markedly at odds with that of TV.

TV, a result of the commensal yeast organism Malassezia furfur (M furfur) metabolizing normal sebum and leaving behind azelaic acid, causes color changes in the skin. But M furfur is not involved in CRP, and therefore the condition does not respond to oral or topical antiyeast medications.

The most effective treatment for CRP is minocycline (100 mg bid for 10 d). Long-term treatment includes weight loss and reduction of ambient heat.

TAKE-HOME LEARNING POINTS

• Confluent and reticulated papillomatosis (CRP) affects the trunk and extremities of obese patients with darker skin.
• In contrast with tinea versicolor (TV), CRP has a rough texture and reticulated look, especially on the periphery of the involved areas.
• Biopsy can help distinguish CRP from its lookalikes; it shows abnormal keratinocyte differentiation and maturation, as well as increased melanosomes.
• Oral minocycline is the best treatment, along with weight loss and reduction of ambient heat.

The FP recognized that the boy had a case of severe atopic dermatitis. There was considerable inflammation of the skin, but the erythema was less visible because of the boy’s darker skin color.

The father had the full atopic triad: asthma, allergic rhinitis, and atopic dermatitis. This explained the son’s inheritance of atopic dermatitis. The FP recommended aggressive treatment and the father was relieved, as it hurt him to see his son suffer.

The FP prescribed a tub (454 g) of 0.1% triamcinolone ointment to be used twice daily all over the involved skin, especially after bathing. The FP said that the child should be given a daily bath with mild soap. (There is no data to support the notion that bathing dries out the skin; bathing before the use of topical steroids actually helps the steroids absorb into the skin.)

Oral hydroxyzine was prescribed for use before bedtime, as this sedating antihistamine can improve sleep and diminish pruritus. Considering the severity of the condition, the FP decided to prescribe a short course of oral prednisolone for one week (1 mg/kg/d). There is some evidence that dilute bleach baths help atopic dermatitis, but the FP decided to discuss this at a future visit—after the flare had subsided. There was no evidence of a secondary infection, so antibiotics weren’t prescribed.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R, Finklea L. Atopic dermatitis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:584-590.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The FP recognized that the boy had a case of severe atopic dermatitis. There was considerable inflammation of the skin, but the erythema was less visible because of the boy’s darker skin color.

The father had the full atopic triad: asthma, allergic rhinitis, and atopic dermatitis. This explained the son’s inheritance of atopic dermatitis. The FP recommended aggressive treatment and the father was relieved, as it hurt him to see his son suffer.

The FP prescribed a tub (454 g) of 0.1% triamcinolone ointment to be used twice daily all over the involved skin, especially after bathing. The FP said that the child should be given a daily bath with mild soap. (There is no data to support the notion that bathing dries out the skin; bathing before the use of topical steroids actually helps the steroids absorb into the skin.)

Oral hydroxyzine was prescribed for use before bedtime, as this sedating antihistamine can improve sleep and diminish pruritus. Considering the severity of the condition, the FP decided to prescribe a short course of oral prednisolone for one week (1 mg/kg/d). There is some evidence that dilute bleach baths help atopic dermatitis, but the FP decided to discuss this at a future visit—after the flare had subsided. There was no evidence of a secondary infection, so antibiotics weren’t prescribed.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R, Finklea L. Atopic dermatitis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:584-590.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The FP recognized that the boy had a case of severe atopic dermatitis. There was considerable inflammation of the skin, but the erythema was less visible because of the boy’s darker skin color.

The father had the full atopic triad: asthma, allergic rhinitis, and atopic dermatitis. This explained the son’s inheritance of atopic dermatitis. The FP recommended aggressive treatment and the father was relieved, as it hurt him to see his son suffer.

The FP prescribed a tub (454 g) of 0.1% triamcinolone ointment to be used twice daily all over the involved skin, especially after bathing. The FP said that the child should be given a daily bath with mild soap. (There is no data to support the notion that bathing dries out the skin; bathing before the use of topical steroids actually helps the steroids absorb into the skin.)

Oral hydroxyzine was prescribed for use before bedtime, as this sedating antihistamine can improve sleep and diminish pruritus. Considering the severity of the condition, the FP decided to prescribe a short course of oral prednisolone for one week (1 mg/kg/d). There is some evidence that dilute bleach baths help atopic dermatitis, but the FP decided to discuss this at a future visit—after the flare had subsided. There was no evidence of a secondary infection, so antibiotics weren’t prescribed.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R, Finklea L. Atopic dermatitis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:584-590.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

NEW YORK – The approach to treating chronic lymphocytic leukemia (CLL) is evolving, and while chemoimmunotherapy remains a reasonable initial option in some cases, a “chemo-free” approach is also a very real possibility, according to Bruce D. Cheson, MD.

A number of studies showing survival benefits with targeted therapies vs. chemoimmunotherapy (CIT) regimens have been completed, including studies that look specifically at outcomes by mutation status and other factors. One example – a likely game changer – is the ALLIANCE trial, a randomized phase III study of bendamustine plus rituximab vs. ibrutinib plus rituximab vs. ibrutinib alone in untreated CLL patients aged 65 years or older, Dr. Cheson of Georgetown University Hospital, Washington, said at an international congress on hematologic malignancies.

“I think [the ALLIANCE] trial has the possibility of totally changing how we treat patients with CLL, even though it was done in older patients,” he said, noting that the study is completed, but final results are pending adequate follow-up.

Based on the available data, he suggests a treatment paradigm for untreated CLL patients who require therapy that begins with consideration of patient age, comorbidities, functional status, and fluorescence in situ hybridization (FISH).

While clinical trial enrollment is preferable, those who are CIT eligible based on age and comorbidities can be treated with bendamustine/rituximab (BR), fludarabine/cyclophosphamide/rituximab (FCR), or ibrutinib.

“I think BR and FCR are both reasonable options, although the latter primarily for young, IGHV-mutated patients, and certainly ibrutinib remains an option for this patient population,” he said.

For those not eligible for CIT, options include ibrutinib and chlorambucil/obinutuzumab. For those with deletion 17p, ibrutinib is the standard for frontline therapy. And for those who are frail, ibrutinib is a good option.

“Some might use an anti-CD20, but as a single agent, it’s not what I would prefer,” Dr. Cheson said, explaining that response rates with such agents are low and tend to lack durability.

CIT remains a reasonable initial option for those patients who are mutated, but with the prolonged progression-free survival seen with ibrutinib in several trials, he predicted that will change over time.

“The role of targeted approaches is a subject of discussion. It takes the most time in my clinic of any discussion I have. [Patients ask] ‘Should I get ibrutinib? Should I get chemoimmunotherapy?’ ” he said. “One needs to take into account patient age and comorbidities, the fact that with CIT you are six [treatments] and done vs. indefinite therapy [with ibrutinib]. There is cost and there is compliance that one needs to consider.”

As for relapsed/refractory CLL, the role of CIT is particularly diminished in the wake of trials such as HELIOS and RESONATE, showing survival benefits with ibrutinib, others showing survival benefits with rituximab/idelalisib (R-idelalisib), and trials showing better results with venetoclax non-CIT regimens than would be expected with CIT regimens. As with treatment-naive CLL patients, age, comorbidities, functional status, and FISH should be considered in those with previously treated CLL who require therapy, and if clinical trial enrollment is not possible, treatment options depend on certain patient characteristics.

“For patients who had a long first response to chemoimmunotherapy, I would still use ibrutinib, and in select patients, R-idelalisib,” he said.

If they had a long response with BR, or FCR, retreatment with those can be considered as well, he noted, adding, “But I don’t see the point when the results with kinase inhibitors are at least as good as, if not better than one would expect with CIT in this context.”

In patients who had short first response, ibrutinib and R-idelalisib are the best options. For those with deletion 17p, the best options are ibrutinib or venetoclax, and possibly R-idelalisib. For frail patients, options include ibrutinib, R-idelalisib, or anti-CD20, although, as with untreated patients, the latter is his least favorite option because of the increased risk of toxicity in this population, he said.

“I think the role of chemoimmunotherapy in CLL is vanishing, and a chemo-free world for CLL patients is a reality,” he said.

Dr. Cheson reported consulting for Acerta, Celgene Pharmacyclics, and Roche-Genentech.

[email protected]

NEW YORK – The approach to treating chronic lymphocytic leukemia (CLL) is evolving, and while chemoimmunotherapy remains a reasonable initial option in some cases, a “chemo-free” approach is also a very real possibility, according to Bruce D. Cheson, MD.

A number of studies showing survival benefits with targeted therapies vs. chemoimmunotherapy (CIT) regimens have been completed, including studies that look specifically at outcomes by mutation status and other factors. One example – a likely game changer – is the ALLIANCE trial, a randomized phase III study of bendamustine plus rituximab vs. ibrutinib plus rituximab vs. ibrutinib alone in untreated CLL patients aged 65 years or older, Dr. Cheson of Georgetown University Hospital, Washington, said at an international congress on hematologic malignancies.

“I think [the ALLIANCE] trial has the possibility of totally changing how we treat patients with CLL, even though it was done in older patients,” he said, noting that the study is completed, but final results are pending adequate follow-up.

Based on the available data, he suggests a treatment paradigm for untreated CLL patients who require therapy that begins with consideration of patient age, comorbidities, functional status, and fluorescence in situ hybridization (FISH).

While clinical trial enrollment is preferable, those who are CIT eligible based on age and comorbidities can be treated with bendamustine/rituximab (BR), fludarabine/cyclophosphamide/rituximab (FCR), or ibrutinib.

“I think BR and FCR are both reasonable options, although the latter primarily for young, IGHV-mutated patients, and certainly ibrutinib remains an option for this patient population,” he said.

For those not eligible for CIT, options include ibrutinib and chlorambucil/obinutuzumab. For those with deletion 17p, ibrutinib is the standard for frontline therapy. And for those who are frail, ibrutinib is a good option.

“Some might use an anti-CD20, but as a single agent, it’s not what I would prefer,” Dr. Cheson said, explaining that response rates with such agents are low and tend to lack durability.

CIT remains a reasonable initial option for those patients who are mutated, but with the prolonged progression-free survival seen with ibrutinib in several trials, he predicted that will change over time.

“The role of targeted approaches is a subject of discussion. It takes the most time in my clinic of any discussion I have. [Patients ask] ‘Should I get ibrutinib? Should I get chemoimmunotherapy?’ ” he said. “One needs to take into account patient age and comorbidities, the fact that with CIT you are six [treatments] and done vs. indefinite therapy [with ibrutinib]. There is cost and there is compliance that one needs to consider.”

As for relapsed/refractory CLL, the role of CIT is particularly diminished in the wake of trials such as HELIOS and RESONATE, showing survival benefits with ibrutinib, others showing survival benefits with rituximab/idelalisib (R-idelalisib), and trials showing better results with venetoclax non-CIT regimens than would be expected with CIT regimens. As with treatment-naive CLL patients, age, comorbidities, functional status, and FISH should be considered in those with previously treated CLL who require therapy, and if clinical trial enrollment is not possible, treatment options depend on certain patient characteristics.

“For patients who had a long first response to chemoimmunotherapy, I would still use ibrutinib, and in select patients, R-idelalisib,” he said.

If they had a long response with BR, or FCR, retreatment with those can be considered as well, he noted, adding, “But I don’t see the point when the results with kinase inhibitors are at least as good as, if not better than one would expect with CIT in this context.”

In patients who had short first response, ibrutinib and R-idelalisib are the best options. For those with deletion 17p, the best options are ibrutinib or venetoclax, and possibly R-idelalisib. For frail patients, options include ibrutinib, R-idelalisib, or anti-CD20, although, as with untreated patients, the latter is his least favorite option because of the increased risk of toxicity in this population, he said.

“I think the role of chemoimmunotherapy in CLL is vanishing, and a chemo-free world for CLL patients is a reality,” he said.

Dr. Cheson reported consulting for Acerta, Celgene Pharmacyclics, and Roche-Genentech.

[email protected]

NEW YORK – The approach to treating chronic lymphocytic leukemia (CLL) is evolving, and while chemoimmunotherapy remains a reasonable initial option in some cases, a “chemo-free” approach is also a very real possibility, according to Bruce D. Cheson, MD.

A number of studies showing survival benefits with targeted therapies vs. chemoimmunotherapy (CIT) regimens have been completed, including studies that look specifically at outcomes by mutation status and other factors. One example – a likely game changer – is the ALLIANCE trial, a randomized phase III study of bendamustine plus rituximab vs. ibrutinib plus rituximab vs. ibrutinib alone in untreated CLL patients aged 65 years or older, Dr. Cheson of Georgetown University Hospital, Washington, said at an international congress on hematologic malignancies.

“I think [the ALLIANCE] trial has the possibility of totally changing how we treat patients with CLL, even though it was done in older patients,” he said, noting that the study is completed, but final results are pending adequate follow-up.

Based on the available data, he suggests a treatment paradigm for untreated CLL patients who require therapy that begins with consideration of patient age, comorbidities, functional status, and fluorescence in situ hybridization (FISH).

While clinical trial enrollment is preferable, those who are CIT eligible based on age and comorbidities can be treated with bendamustine/rituximab (BR), fludarabine/cyclophosphamide/rituximab (FCR), or ibrutinib.

“I think BR and FCR are both reasonable options, although the latter primarily for young, IGHV-mutated patients, and certainly ibrutinib remains an option for this patient population,” he said.

For those not eligible for CIT, options include ibrutinib and chlorambucil/obinutuzumab. For those with deletion 17p, ibrutinib is the standard for frontline therapy. And for those who are frail, ibrutinib is a good option.

“Some might use an anti-CD20, but as a single agent, it’s not what I would prefer,” Dr. Cheson said, explaining that response rates with such agents are low and tend to lack durability.

CIT remains a reasonable initial option for those patients who are mutated, but with the prolonged progression-free survival seen with ibrutinib in several trials, he predicted that will change over time.

“The role of targeted approaches is a subject of discussion. It takes the most time in my clinic of any discussion I have. [Patients ask] ‘Should I get ibrutinib? Should I get chemoimmunotherapy?’ ” he said. “One needs to take into account patient age and comorbidities, the fact that with CIT you are six [treatments] and done vs. indefinite therapy [with ibrutinib]. There is cost and there is compliance that one needs to consider.”

As for relapsed/refractory CLL, the role of CIT is particularly diminished in the wake of trials such as HELIOS and RESONATE, showing survival benefits with ibrutinib, others showing survival benefits with rituximab/idelalisib (R-idelalisib), and trials showing better results with venetoclax non-CIT regimens than would be expected with CIT regimens. As with treatment-naive CLL patients, age, comorbidities, functional status, and FISH should be considered in those with previously treated CLL who require therapy, and if clinical trial enrollment is not possible, treatment options depend on certain patient characteristics.

“For patients who had a long first response to chemoimmunotherapy, I would still use ibrutinib, and in select patients, R-idelalisib,” he said.

If they had a long response with BR, or FCR, retreatment with those can be considered as well, he noted, adding, “But I don’t see the point when the results with kinase inhibitors are at least as good as, if not better than one would expect with CIT in this context.”

In patients who had short first response, ibrutinib and R-idelalisib are the best options. For those with deletion 17p, the best options are ibrutinib or venetoclax, and possibly R-idelalisib. For frail patients, options include ibrutinib, R-idelalisib, or anti-CD20, although, as with untreated patients, the latter is his least favorite option because of the increased risk of toxicity in this population, he said.

“I think the role of chemoimmunotherapy in CLL is vanishing, and a chemo-free world for CLL patients is a reality,” he said.

Dr. Cheson reported consulting for Acerta, Celgene Pharmacyclics, and Roche-Genentech.

[email protected]