Patrice Wendling

The presence of minimal residual disease predicts relapse in patients with NMP1-mutated acute myeloid leukemia and is superior to currently used molecular genetic markers in determining whether these patients should be considered for stem cell transplantation, a new study has found.

At 3 years, patients with minimal residual disease (MRD) had a significantly greater risk of relapse than those with no MRD (82% vs. 30%; univariate hazard ratio, 4.80; P less than .001) and a lower rate of survival (24% vs. 75%; univariate HR, 4.38; P less than .001), Adam Ivey of King’s College London reported (N Engl J Med. 2016; doi:10.1056/NEJMoa1507471).

In an editorial that accompanied the study Dr. Michael J. Burke from the Children’s Hospital of Wisconsin in Milwaukee wrote, “Time will tell, but this moment may prove to be a pivotal one in the assessment of minimal residual disease to assign treatment in patients with AML” (N Engl J Med. 2016; doi:10.1056/NEJMe1515525).

In adult AML, assessment of MRD has taken a back seat to analyses of cytogenetic and molecular lesions in determining a patient’s risk and treatment strategy. Typically, allogeneic stem cell transplantation is used for patients with high-risk features such as chromosome 3, 5, or 7 abnormalities or the FLT3-internal tandem duplication (ITD) mutation, while chemotherapy alone is used for low-risk disease.

The role of transplantation is unclear, however, for cytogenetically standard-risk patients, which includes those with a mutation in the gene encoding nucleophosmin (NPM1).

To address this issue, the investigators used a reverse-transcriptase quantitative polymerase chain reaction assay to evaluate 2,569 bone marrow and peripheral-blood samples from 346 patients with NPM1 mutations who had completed two cycles of induction chemotherapy in the U.K. National Cancer Research Institute AML17 trial.

MRD, defined as persistence of NPM1-mutated transcripts in peripheral blood, was present in 15% of patients after the second chemotherapy cycle.

Patients with MRD were significantly more likely than those without MRD to have a high U.K. Medical Research Council clinical risk score and to carry the FLT3-ITD mutation.

On univariate analysis, the risk of relapse was significantly higher with the presence of MRD in peripheral blood, an increased white cell count, and with the DNMT3A and FLT3-ITD mutations.

Only the presence of MRD and an elevated white cell count significantly predicted survival, Mr. Ivey reported.

“We could find no specific molecular subgroup consisting of 10 patients or more that had a rate of survival less than 52%; in contrast, the rate in the group with the presence of minimal residual disease was 24%,” he observed.

In multivariate analysis, the presence of MRD was the only significant prognostic factor for relapse (HR, 5.09; P less than .001) or death (HR, 4.84; P less than .001).

The results were validated in an independent cohort of 91 AML17 study patients. It confirmed that MRD in peripheral blood predicts worse outcome at 2 years than the absence of MRD, with a cumulative incidence of relapse of 70% vs. 31% (P = .001) and overall survival rates of 40% vs. 87% (P = .001), reported the investigators, including senior author Professor David Grimwade, also from King’s College London.

The clinical implications of these results “are substantive” because NPM-1 mutated AML is the most common subtype of AML and because of the uncertainty over the best treatment strategy for patients typically classified as standard risk, editorialist Dr. Burke observed.

“Now with the ability to reclassify standard-risk or low-risk patients as high-risk on the basis of the persistent expression of mutant NPM1 transcripts, it may be possible that stem-cell transplantation is a better approach in patients who otherwise would be treated with chemotherapy alone and that transplantation may be avoidable in high-risk patients who have no evidence of minimal residual disease,” he wrote. “Such predictions will need to be tested prospectively.”

The presence of MRD is also known to be an important independent prognostic factor in acute lymphoblastic leukemia, but since AML has a greater molecular heterogeneity, routine MRD assessment has not been as quickly adopted in AML, Dr. Burke noted.

The Children’s Oncology Group, however, recently adopted MRD assessment by flow cytometry to further stratify children with newly diagnosed AML after first induction therapy into low-risk or high-risk groups.

The study was supported by grants from Bloodwise and the National Institute for Health Research. Mr. Ivey and Dr. Burke reported having no disclosures.

pwendling@frontlinemedcom.com

The presence of minimal residual disease predicts relapse in patients with NMP1-mutated acute myeloid leukemia and is superior to currently used molecular genetic markers in determining whether these patients should be considered for stem cell transplantation, a new study has found.

At 3 years, patients with minimal residual disease (MRD) had a significantly greater risk of relapse than those with no MRD (82% vs. 30%; univariate hazard ratio, 4.80; P less than .001) and a lower rate of survival (24% vs. 75%; univariate HR, 4.38; P less than .001), Adam Ivey of King’s College London reported (N Engl J Med. 2016; doi:10.1056/NEJMoa1507471).

In an editorial that accompanied the study Dr. Michael J. Burke from the Children’s Hospital of Wisconsin in Milwaukee wrote, “Time will tell, but this moment may prove to be a pivotal one in the assessment of minimal residual disease to assign treatment in patients with AML” (N Engl J Med. 2016; doi:10.1056/NEJMe1515525).

In adult AML, assessment of MRD has taken a back seat to analyses of cytogenetic and molecular lesions in determining a patient’s risk and treatment strategy. Typically, allogeneic stem cell transplantation is used for patients with high-risk features such as chromosome 3, 5, or 7 abnormalities or the FLT3-internal tandem duplication (ITD) mutation, while chemotherapy alone is used for low-risk disease.

The role of transplantation is unclear, however, for cytogenetically standard-risk patients, which includes those with a mutation in the gene encoding nucleophosmin (NPM1).

To address this issue, the investigators used a reverse-transcriptase quantitative polymerase chain reaction assay to evaluate 2,569 bone marrow and peripheral-blood samples from 346 patients with NPM1 mutations who had completed two cycles of induction chemotherapy in the U.K. National Cancer Research Institute AML17 trial.

MRD, defined as persistence of NPM1-mutated transcripts in peripheral blood, was present in 15% of patients after the second chemotherapy cycle.

Patients with MRD were significantly more likely than those without MRD to have a high U.K. Medical Research Council clinical risk score and to carry the FLT3-ITD mutation.

On univariate analysis, the risk of relapse was significantly higher with the presence of MRD in peripheral blood, an increased white cell count, and with the DNMT3A and FLT3-ITD mutations.

Only the presence of MRD and an elevated white cell count significantly predicted survival, Mr. Ivey reported.

“We could find no specific molecular subgroup consisting of 10 patients or more that had a rate of survival less than 52%; in contrast, the rate in the group with the presence of minimal residual disease was 24%,” he observed.

In multivariate analysis, the presence of MRD was the only significant prognostic factor for relapse (HR, 5.09; P less than .001) or death (HR, 4.84; P less than .001).

The results were validated in an independent cohort of 91 AML17 study patients. It confirmed that MRD in peripheral blood predicts worse outcome at 2 years than the absence of MRD, with a cumulative incidence of relapse of 70% vs. 31% (P = .001) and overall survival rates of 40% vs. 87% (P = .001), reported the investigators, including senior author Professor David Grimwade, also from King’s College London.

The clinical implications of these results “are substantive” because NPM-1 mutated AML is the most common subtype of AML and because of the uncertainty over the best treatment strategy for patients typically classified as standard risk, editorialist Dr. Burke observed.

“Now with the ability to reclassify standard-risk or low-risk patients as high-risk on the basis of the persistent expression of mutant NPM1 transcripts, it may be possible that stem-cell transplantation is a better approach in patients who otherwise would be treated with chemotherapy alone and that transplantation may be avoidable in high-risk patients who have no evidence of minimal residual disease,” he wrote. “Such predictions will need to be tested prospectively.”

The presence of MRD is also known to be an important independent prognostic factor in acute lymphoblastic leukemia, but since AML has a greater molecular heterogeneity, routine MRD assessment has not been as quickly adopted in AML, Dr. Burke noted.

The Children’s Oncology Group, however, recently adopted MRD assessment by flow cytometry to further stratify children with newly diagnosed AML after first induction therapy into low-risk or high-risk groups.

The study was supported by grants from Bloodwise and the National Institute for Health Research. Mr. Ivey and Dr. Burke reported having no disclosures.

pwendling@frontlinemedcom.com

The presence of minimal residual disease predicts relapse in patients with NMP1-mutated acute myeloid leukemia and is superior to currently used molecular genetic markers in determining whether these patients should be considered for stem cell transplantation, a new study has found.

At 3 years, patients with minimal residual disease (MRD) had a significantly greater risk of relapse than those with no MRD (82% vs. 30%; univariate hazard ratio, 4.80; P less than .001) and a lower rate of survival (24% vs. 75%; univariate HR, 4.38; P less than .001), Adam Ivey of King’s College London reported (N Engl J Med. 2016; doi:10.1056/NEJMoa1507471).

In an editorial that accompanied the study Dr. Michael J. Burke from the Children’s Hospital of Wisconsin in Milwaukee wrote, “Time will tell, but this moment may prove to be a pivotal one in the assessment of minimal residual disease to assign treatment in patients with AML” (N Engl J Med. 2016; doi:10.1056/NEJMe1515525).

In adult AML, assessment of MRD has taken a back seat to analyses of cytogenetic and molecular lesions in determining a patient’s risk and treatment strategy. Typically, allogeneic stem cell transplantation is used for patients with high-risk features such as chromosome 3, 5, or 7 abnormalities or the FLT3-internal tandem duplication (ITD) mutation, while chemotherapy alone is used for low-risk disease.

The role of transplantation is unclear, however, for cytogenetically standard-risk patients, which includes those with a mutation in the gene encoding nucleophosmin (NPM1).

To address this issue, the investigators used a reverse-transcriptase quantitative polymerase chain reaction assay to evaluate 2,569 bone marrow and peripheral-blood samples from 346 patients with NPM1 mutations who had completed two cycles of induction chemotherapy in the U.K. National Cancer Research Institute AML17 trial.

MRD, defined as persistence of NPM1-mutated transcripts in peripheral blood, was present in 15% of patients after the second chemotherapy cycle.

Patients with MRD were significantly more likely than those without MRD to have a high U.K. Medical Research Council clinical risk score and to carry the FLT3-ITD mutation.

On univariate analysis, the risk of relapse was significantly higher with the presence of MRD in peripheral blood, an increased white cell count, and with the DNMT3A and FLT3-ITD mutations.

Only the presence of MRD and an elevated white cell count significantly predicted survival, Mr. Ivey reported.

“We could find no specific molecular subgroup consisting of 10 patients or more that had a rate of survival less than 52%; in contrast, the rate in the group with the presence of minimal residual disease was 24%,” he observed.

In multivariate analysis, the presence of MRD was the only significant prognostic factor for relapse (HR, 5.09; P less than .001) or death (HR, 4.84; P less than .001).

The results were validated in an independent cohort of 91 AML17 study patients. It confirmed that MRD in peripheral blood predicts worse outcome at 2 years than the absence of MRD, with a cumulative incidence of relapse of 70% vs. 31% (P = .001) and overall survival rates of 40% vs. 87% (P = .001), reported the investigators, including senior author Professor David Grimwade, also from King’s College London.

The clinical implications of these results “are substantive” because NPM-1 mutated AML is the most common subtype of AML and because of the uncertainty over the best treatment strategy for patients typically classified as standard risk, editorialist Dr. Burke observed.

“Now with the ability to reclassify standard-risk or low-risk patients as high-risk on the basis of the persistent expression of mutant NPM1 transcripts, it may be possible that stem-cell transplantation is a better approach in patients who otherwise would be treated with chemotherapy alone and that transplantation may be avoidable in high-risk patients who have no evidence of minimal residual disease,” he wrote. “Such predictions will need to be tested prospectively.”

The presence of MRD is also known to be an important independent prognostic factor in acute lymphoblastic leukemia, but since AML has a greater molecular heterogeneity, routine MRD assessment has not been as quickly adopted in AML, Dr. Burke noted.

The Children’s Oncology Group, however, recently adopted MRD assessment by flow cytometry to further stratify children with newly diagnosed AML after first induction therapy into low-risk or high-risk groups.

The study was supported by grants from Bloodwise and the National Institute for Health Research. Mr. Ivey and Dr. Burke reported having no disclosures.

pwendling@frontlinemedcom.com

CHICAGO – Microsurgery does not cure lymphedema, in most cases. But, in most cases, it does improve the severity of lymphedema and reduce the complications of this chronic and debilitating disease. And “it certainly improves patients’ quality of life,” lymphedema treatment pioneer Dr. David W. Chang said at the 40th annual Northwestern Vascular Symposium.

Surgical treatment for limb lymphedema has come into its own since a lymphovenous shunt was first used in a dog model in 1962, with Dr. Chang and others now anastomosing subdermal lymphatics to subdermal venules less than 0.8 mm in diameter. The rationale behind “super-microsurgery” is that venous pressure is low in the subdermal venules and has minimal back flow, he said.

Patrice Wendling/Frontline Medical News

One of the big problems early on was knowing exactly where the lymphatic vessels were, but newer technology like indocyanine green (ICG) lymphangiography helps visualize functioning lymphatic channels for potential bypass and determine the severity of the disease. Understanding the disease stage is key to selecting the appropriate surgical procedure.

Lymphovenous bypass (LVB) is best in patients with stage 1 or 2 upper extremity lymphedema, while lymph node transfer (LNT) works for patients who are poor candidates for LVB or require combined breast reconstruction, said Dr. Chang, a plastic surgeon with the University of Chicago.

More recently, Dr. Chang has begun combining LVB and LNT, particularly for the more severe cases with stage 3 or 4 upper or lower extremity disease.

In Dr. Chang’s first 100 consecutive LVB cases while at the M.D. Anderson Cancer Center in Houston, quantitative improvement occurred in 74% of patients, symptom improvement in 96%, and the average volume differential reduction was 42% at 12 months (Plast Reconstr Surg. 2013 Nov;132:1305-14). The reduction was significantly larger in patients with earlier stage 1 or 2 vs. later stage 3 or 4 disease (61% vs. 17%).

Images courtesy of Dr. David W. Chang

During lymphovenous bypass, ICG is injected into the dermis of the web space and the superficial lymphatics evaluated with near-infrared fluorescence. It is easy to identify discrete functioning lymphatic channels in early-stage disease, but in late-stage disease significant dermal back flow is present, Dr. Chang said.

Dissection is performed under the microscope in the superficial subcutaneous plane to locate a good venule and lymph channel. Lymphatics are confirmed with isosulfan blue and ICG, and once the bypass site is determined, the lymphatic is anastomosed to the venule using 11-0 or 12-0 nylon, preferably in an end-to-side fashion. It’s thought this creates a more favorable flow pattern for the lymph to empty into the venule than an end-to-end anastomosis, he observed.

After the anastomosis is complete, patency is confirmed with isosulfan blue and ICG and the incision is closed under the microscope to ensure that the delicate anastomosis isn’t damaged. To avoid shear injury to the anastomosis, the limb is wrapped postoperatively for about a month without use of compression garments, he said.

Lymph node transfer (LNT) is increasingly being offered at centers to provide relief from lymphedema, although the mechanism by which it works is yet unclear; either the healthy lymph nodes act as a sponge to absorb lymphatic fluid or they induce lymphangiogenesis. Experience has shown, however, that rather than just grafting the lymph nodes, they need to be harvested with a vascular pedicle before transfer and anastomosed to the recipient artery and vein, although reconnecting the actual lymphatics may not be necessary, Dr. Chang observed.

Despite its popularity as a donor site, Dr. Chang said he is reluctant to use the groin because of the potential for iatrogenic lymphedema and prefers to harvest the supraclavicular nodes based off the transverse cervical artery. The external jugular vein can be harvested with the nodes if adequate venae comitantes are not present with the artery. Dissection of this flap can be difficult and care should be taken not to injure the lymphatic ducts, he noted.

It is also important to excise all scar tissue in the recipient site as this can impair lymphatic flow and inhibits lymphangiogenesis. If it is difficult to access or remove the scar, the vascularized lymph nodes are best placed just distal on the limb to the site of lymphatic obstruction, he added.

A recent meta-analysis (Plast Reconstr Surg. 2014 Apr;133:905-13) in five LNT studies reported that 91% of patients had a quantitative improvement, 78% discontinued compression garments, and complications were infection (8%), lymphorrhea (15%), and need for additional procedures (36%). There was great heterogeneity between studies, so the results should be interpreted with caution, Dr. Chang advised.

LNT is frequently combined with autologous breast reconstruction in patients with breast cancer, who comprise a significant percentage of Dr. Chang’s practice. The overall incidence of arm lymphedema after breast cancer can range from 8% to 56% at 2 years’ post-surgery, with the risk higher among women undergoing axillary lymph node dissection and/or axillary radiation.

Outcomes with combined LNT and breast reconstruction have been favorable, with one series reporting evidence of improved lymphatic flow on lymphoscintigraphy in five of six cases and one-third of patients no longer needing compression therapy (Ann Surg. 2012 Mar;255:468-73).

In cases where the patient requires a large skin paddle or seeks breast reconstruction after a previous mastectomy, lateral superficial groin lymph nodes can be harvested for transfer, leaving the deeper lymph nodes that drain the leg behind, Dr. Chang said. The nodes are usually clustered at the junction of the superior inferior epigastric and superficial circumflex iliac veins.

When combining LNT with breast reconstruction, this tissue is harvested together with the free abdominal flap used to reconstruct the breast. The superficial circumflex iliac vein is anastomosed in the axilla in addition to the arterial and venous anastomosis of the deep inferior epigastric vessels to the internal mammary vessels for the breast reconstruction. Reverse lymphatic mapping with technetium and ICG is used to decrease the risk of donor site lymphedema.

An algorithmic approach to simultaneous LNT with microvascular breast reconstruction proposed by Dr. Chang resulted in a 47% reduction in mean volume differential 12 months after reconstruction in 29 consecutive patients with refractory lymphedema following breast cancer treatment. These early results also showed no flap losses or donor-site lymphedema and donor-site wound complications in six patients (21%) that resolved with conservative measures (Ann Surg Oncol. 2015 Sep;22:2919-24).

The holy grail may be to strike lymphedema before it develops. To that end, Italian surgeons have proposed the Lymphatic Microsurgical Preventing Healing Approach (LYMPHA), which involves anastomosing arm lymphatics to a collateral branch of the axillary vein at the time of nodal dissection.

Over more than 4 years’ follow-up, only 3 of 74 breast cancer patients who underwent axillary nodal dissection with LYMPHA developed lymphedema, translating into a an exceptionally low 4% risk of lymphedema (Microsurgery. 2014 Sep;34:421-4). However, this approach is controversial because of unknown oncological risk and the uncertainty of its effectiveness in patients who may receive radiation after the surgery, Dr. Chang said in an interview.

Although these techniques show promise, currently no optimal solution exists and more research is needed to better understand lymphatic anatomy and physiology and the pathophysiology of lymphedema, concluded Dr. Chang, who reported no relevant conflicts of interest.

pwendling@frontlinemedcom.com

CHICAGO – Microsurgery does not cure lymphedema, in most cases. But, in most cases, it does improve the severity of lymphedema and reduce the complications of this chronic and debilitating disease. And “it certainly improves patients’ quality of life,” lymphedema treatment pioneer Dr. David W. Chang said at the 40th annual Northwestern Vascular Symposium.

Surgical treatment for limb lymphedema has come into its own since a lymphovenous shunt was first used in a dog model in 1962, with Dr. Chang and others now anastomosing subdermal lymphatics to subdermal venules less than 0.8 mm in diameter. The rationale behind “super-microsurgery” is that venous pressure is low in the subdermal venules and has minimal back flow, he said.

Patrice Wendling/Frontline Medical News

One of the big problems early on was knowing exactly where the lymphatic vessels were, but newer technology like indocyanine green (ICG) lymphangiography helps visualize functioning lymphatic channels for potential bypass and determine the severity of the disease. Understanding the disease stage is key to selecting the appropriate surgical procedure.

Lymphovenous bypass (LVB) is best in patients with stage 1 or 2 upper extremity lymphedema, while lymph node transfer (LNT) works for patients who are poor candidates for LVB or require combined breast reconstruction, said Dr. Chang, a plastic surgeon with the University of Chicago.

More recently, Dr. Chang has begun combining LVB and LNT, particularly for the more severe cases with stage 3 or 4 upper or lower extremity disease.

In Dr. Chang’s first 100 consecutive LVB cases while at the M.D. Anderson Cancer Center in Houston, quantitative improvement occurred in 74% of patients, symptom improvement in 96%, and the average volume differential reduction was 42% at 12 months (Plast Reconstr Surg. 2013 Nov;132:1305-14). The reduction was significantly larger in patients with earlier stage 1 or 2 vs. later stage 3 or 4 disease (61% vs. 17%).

Images courtesy of Dr. David W. Chang

During lymphovenous bypass, ICG is injected into the dermis of the web space and the superficial lymphatics evaluated with near-infrared fluorescence. It is easy to identify discrete functioning lymphatic channels in early-stage disease, but in late-stage disease significant dermal back flow is present, Dr. Chang said.

Dissection is performed under the microscope in the superficial subcutaneous plane to locate a good venule and lymph channel. Lymphatics are confirmed with isosulfan blue and ICG, and once the bypass site is determined, the lymphatic is anastomosed to the venule using 11-0 or 12-0 nylon, preferably in an end-to-side fashion. It’s thought this creates a more favorable flow pattern for the lymph to empty into the venule than an end-to-end anastomosis, he observed.

After the anastomosis is complete, patency is confirmed with isosulfan blue and ICG and the incision is closed under the microscope to ensure that the delicate anastomosis isn’t damaged. To avoid shear injury to the anastomosis, the limb is wrapped postoperatively for about a month without use of compression garments, he said.

Lymph node transfer (LNT) is increasingly being offered at centers to provide relief from lymphedema, although the mechanism by which it works is yet unclear; either the healthy lymph nodes act as a sponge to absorb lymphatic fluid or they induce lymphangiogenesis. Experience has shown, however, that rather than just grafting the lymph nodes, they need to be harvested with a vascular pedicle before transfer and anastomosed to the recipient artery and vein, although reconnecting the actual lymphatics may not be necessary, Dr. Chang observed.

Despite its popularity as a donor site, Dr. Chang said he is reluctant to use the groin because of the potential for iatrogenic lymphedema and prefers to harvest the supraclavicular nodes based off the transverse cervical artery. The external jugular vein can be harvested with the nodes if adequate venae comitantes are not present with the artery. Dissection of this flap can be difficult and care should be taken not to injure the lymphatic ducts, he noted.

It is also important to excise all scar tissue in the recipient site as this can impair lymphatic flow and inhibits lymphangiogenesis. If it is difficult to access or remove the scar, the vascularized lymph nodes are best placed just distal on the limb to the site of lymphatic obstruction, he added.

A recent meta-analysis (Plast Reconstr Surg. 2014 Apr;133:905-13) in five LNT studies reported that 91% of patients had a quantitative improvement, 78% discontinued compression garments, and complications were infection (8%), lymphorrhea (15%), and need for additional procedures (36%). There was great heterogeneity between studies, so the results should be interpreted with caution, Dr. Chang advised.

LNT is frequently combined with autologous breast reconstruction in patients with breast cancer, who comprise a significant percentage of Dr. Chang’s practice. The overall incidence of arm lymphedema after breast cancer can range from 8% to 56% at 2 years’ post-surgery, with the risk higher among women undergoing axillary lymph node dissection and/or axillary radiation.

Outcomes with combined LNT and breast reconstruction have been favorable, with one series reporting evidence of improved lymphatic flow on lymphoscintigraphy in five of six cases and one-third of patients no longer needing compression therapy (Ann Surg. 2012 Mar;255:468-73).

In cases where the patient requires a large skin paddle or seeks breast reconstruction after a previous mastectomy, lateral superficial groin lymph nodes can be harvested for transfer, leaving the deeper lymph nodes that drain the leg behind, Dr. Chang said. The nodes are usually clustered at the junction of the superior inferior epigastric and superficial circumflex iliac veins.

When combining LNT with breast reconstruction, this tissue is harvested together with the free abdominal flap used to reconstruct the breast. The superficial circumflex iliac vein is anastomosed in the axilla in addition to the arterial and venous anastomosis of the deep inferior epigastric vessels to the internal mammary vessels for the breast reconstruction. Reverse lymphatic mapping with technetium and ICG is used to decrease the risk of donor site lymphedema.

An algorithmic approach to simultaneous LNT with microvascular breast reconstruction proposed by Dr. Chang resulted in a 47% reduction in mean volume differential 12 months after reconstruction in 29 consecutive patients with refractory lymphedema following breast cancer treatment. These early results also showed no flap losses or donor-site lymphedema and donor-site wound complications in six patients (21%) that resolved with conservative measures (Ann Surg Oncol. 2015 Sep;22:2919-24).

The holy grail may be to strike lymphedema before it develops. To that end, Italian surgeons have proposed the Lymphatic Microsurgical Preventing Healing Approach (LYMPHA), which involves anastomosing arm lymphatics to a collateral branch of the axillary vein at the time of nodal dissection.

Over more than 4 years’ follow-up, only 3 of 74 breast cancer patients who underwent axillary nodal dissection with LYMPHA developed lymphedema, translating into a an exceptionally low 4% risk of lymphedema (Microsurgery. 2014 Sep;34:421-4). However, this approach is controversial because of unknown oncological risk and the uncertainty of its effectiveness in patients who may receive radiation after the surgery, Dr. Chang said in an interview.

Although these techniques show promise, currently no optimal solution exists and more research is needed to better understand lymphatic anatomy and physiology and the pathophysiology of lymphedema, concluded Dr. Chang, who reported no relevant conflicts of interest.

pwendling@frontlinemedcom.com

CHICAGO – Microsurgery does not cure lymphedema, in most cases. But, in most cases, it does improve the severity of lymphedema and reduce the complications of this chronic and debilitating disease. And “it certainly improves patients’ quality of life,” lymphedema treatment pioneer Dr. David W. Chang said at the 40th annual Northwestern Vascular Symposium.

Surgical treatment for limb lymphedema has come into its own since a lymphovenous shunt was first used in a dog model in 1962, with Dr. Chang and others now anastomosing subdermal lymphatics to subdermal venules less than 0.8 mm in diameter. The rationale behind “super-microsurgery” is that venous pressure is low in the subdermal venules and has minimal back flow, he said.

Patrice Wendling/Frontline Medical News

One of the big problems early on was knowing exactly where the lymphatic vessels were, but newer technology like indocyanine green (ICG) lymphangiography helps visualize functioning lymphatic channels for potential bypass and determine the severity of the disease. Understanding the disease stage is key to selecting the appropriate surgical procedure.

Lymphovenous bypass (LVB) is best in patients with stage 1 or 2 upper extremity lymphedema, while lymph node transfer (LNT) works for patients who are poor candidates for LVB or require combined breast reconstruction, said Dr. Chang, a plastic surgeon with the University of Chicago.

More recently, Dr. Chang has begun combining LVB and LNT, particularly for the more severe cases with stage 3 or 4 upper or lower extremity disease.

In Dr. Chang’s first 100 consecutive LVB cases while at the M.D. Anderson Cancer Center in Houston, quantitative improvement occurred in 74% of patients, symptom improvement in 96%, and the average volume differential reduction was 42% at 12 months (Plast Reconstr Surg. 2013 Nov;132:1305-14). The reduction was significantly larger in patients with earlier stage 1 or 2 vs. later stage 3 or 4 disease (61% vs. 17%).

Images courtesy of Dr. David W. Chang

During lymphovenous bypass, ICG is injected into the dermis of the web space and the superficial lymphatics evaluated with near-infrared fluorescence. It is easy to identify discrete functioning lymphatic channels in early-stage disease, but in late-stage disease significant dermal back flow is present, Dr. Chang said.

Dissection is performed under the microscope in the superficial subcutaneous plane to locate a good venule and lymph channel. Lymphatics are confirmed with isosulfan blue and ICG, and once the bypass site is determined, the lymphatic is anastomosed to the venule using 11-0 or 12-0 nylon, preferably in an end-to-side fashion. It’s thought this creates a more favorable flow pattern for the lymph to empty into the venule than an end-to-end anastomosis, he observed.

After the anastomosis is complete, patency is confirmed with isosulfan blue and ICG and the incision is closed under the microscope to ensure that the delicate anastomosis isn’t damaged. To avoid shear injury to the anastomosis, the limb is wrapped postoperatively for about a month without use of compression garments, he said.

Lymph node transfer (LNT) is increasingly being offered at centers to provide relief from lymphedema, although the mechanism by which it works is yet unclear; either the healthy lymph nodes act as a sponge to absorb lymphatic fluid or they induce lymphangiogenesis. Experience has shown, however, that rather than just grafting the lymph nodes, they need to be harvested with a vascular pedicle before transfer and anastomosed to the recipient artery and vein, although reconnecting the actual lymphatics may not be necessary, Dr. Chang observed.

Despite its popularity as a donor site, Dr. Chang said he is reluctant to use the groin because of the potential for iatrogenic lymphedema and prefers to harvest the supraclavicular nodes based off the transverse cervical artery. The external jugular vein can be harvested with the nodes if adequate venae comitantes are not present with the artery. Dissection of this flap can be difficult and care should be taken not to injure the lymphatic ducts, he noted.

It is also important to excise all scar tissue in the recipient site as this can impair lymphatic flow and inhibits lymphangiogenesis. If it is difficult to access or remove the scar, the vascularized lymph nodes are best placed just distal on the limb to the site of lymphatic obstruction, he added.

A recent meta-analysis (Plast Reconstr Surg. 2014 Apr;133:905-13) in five LNT studies reported that 91% of patients had a quantitative improvement, 78% discontinued compression garments, and complications were infection (8%), lymphorrhea (15%), and need for additional procedures (36%). There was great heterogeneity between studies, so the results should be interpreted with caution, Dr. Chang advised.

LNT is frequently combined with autologous breast reconstruction in patients with breast cancer, who comprise a significant percentage of Dr. Chang’s practice. The overall incidence of arm lymphedema after breast cancer can range from 8% to 56% at 2 years’ post-surgery, with the risk higher among women undergoing axillary lymph node dissection and/or axillary radiation.

Outcomes with combined LNT and breast reconstruction have been favorable, with one series reporting evidence of improved lymphatic flow on lymphoscintigraphy in five of six cases and one-third of patients no longer needing compression therapy (Ann Surg. 2012 Mar;255:468-73).

In cases where the patient requires a large skin paddle or seeks breast reconstruction after a previous mastectomy, lateral superficial groin lymph nodes can be harvested for transfer, leaving the deeper lymph nodes that drain the leg behind, Dr. Chang said. The nodes are usually clustered at the junction of the superior inferior epigastric and superficial circumflex iliac veins.

When combining LNT with breast reconstruction, this tissue is harvested together with the free abdominal flap used to reconstruct the breast. The superficial circumflex iliac vein is anastomosed in the axilla in addition to the arterial and venous anastomosis of the deep inferior epigastric vessels to the internal mammary vessels for the breast reconstruction. Reverse lymphatic mapping with technetium and ICG is used to decrease the risk of donor site lymphedema.

An algorithmic approach to simultaneous LNT with microvascular breast reconstruction proposed by Dr. Chang resulted in a 47% reduction in mean volume differential 12 months after reconstruction in 29 consecutive patients with refractory lymphedema following breast cancer treatment. These early results also showed no flap losses or donor-site lymphedema and donor-site wound complications in six patients (21%) that resolved with conservative measures (Ann Surg Oncol. 2015 Sep;22:2919-24).

The holy grail may be to strike lymphedema before it develops. To that end, Italian surgeons have proposed the Lymphatic Microsurgical Preventing Healing Approach (LYMPHA), which involves anastomosing arm lymphatics to a collateral branch of the axillary vein at the time of nodal dissection.

Over more than 4 years’ follow-up, only 3 of 74 breast cancer patients who underwent axillary nodal dissection with LYMPHA developed lymphedema, translating into a an exceptionally low 4% risk of lymphedema (Microsurgery. 2014 Sep;34:421-4). However, this approach is controversial because of unknown oncological risk and the uncertainty of its effectiveness in patients who may receive radiation after the surgery, Dr. Chang said in an interview.

Although these techniques show promise, currently no optimal solution exists and more research is needed to better understand lymphatic anatomy and physiology and the pathophysiology of lymphedema, concluded Dr. Chang, who reported no relevant conflicts of interest.

pwendling@frontlinemedcom.com

New guidelines on the diagnosis and management of primary adrenal insufficiency stress the importance of early recognition and the need to prevent life-threatening adrenal crises in these patients.

©SomkiatFakmee/thinkstockphotos.com

These are the first clinical practice guidelines on primary adrenal insufficiency (PAI), also known as Addison’s disease, issued by Endocrine Society (J Clin Endocrinol Metab. 2016 Jan 13:jc20151710 [Epub ahead of print]).

“Because it’s a rare disease and symptoms can mimic common conditions, adrenal insufficiency is often, at least initially, overlooked,” guideline co-author Dr. Deborah Merke, a senior investigator with the National Institutes of Health Clinical Center in Bethesda, Md., said. “So the main goal of these clinical practice guidelines is to improve patient care.”

The guidelines suggest clinicians should have a low diagnostic threshold in acutely ill patients with unexplained symptoms or signs suggestive of PAI such as volume depletion, hypotension, hyponatremia, hyperkalemia, fever, abdominal pain, hyperpigmentation, or, especially in children, hypoglycemia.

This low diagnostic threshold for PAI should also be extended to pregnant women with unexplained persistent nausea, fatigue, and hypotension.

For adult patients with a suspected adrenal crisis, an immediate parenteral injection of hydrocortisone 100 mg should be given, followed by appropriate fluid resuscitation and 200 mg of hydrocortisone for 24 hours, according to the guidelines, which were co-sponsored by the European Society of Endocrinology and American Association for Clinical Chemistry.

Despite a known association between adrenal crisis and mortality, there is a knowledge gap regarding how to prevent, recognize, and reduce the risk of these life-threatening events, Dr. Merke said.

To that end, the task force has taken a page from the diabetes community in recommending all PAI patients carry steroid emergency identification cards and be equipped with a glucocorticoid injection kit for emergency use and be educated on how to use it.

The guidelines also advocate education about stress dosing to counter the increased demand for corticosteroids during periods of stress, which can encompass something as common as the flu.

“Just like diabetics carry around emergency medicines, it’s important for patients with adrenal insufficiency to carry around an emergency kit and to realize that should they start to get sick, they need to increase their doses,” she said. “There often seems to be a lack of awareness among physicians as well that these patients have a potentially life-threatening condition, should they get a common illness.”

One of the key unanswered clinical questions the task force sought to address was whether the widely used high-dose (250 mcg) corticotropin stimulation test, also known as the adrenocorticotropin (ACTH) or short Synacthen test, should be replaced by the low-dose test (1 mcg) to diagnosis PAI.

Despite a review of published data and a systematic review commissioned by the task force, “We didn’t come up with much scientific evidence to say we should be changing the historic standard,” Dr. Merke said.

The systematic review identified only five studies of high-dose corticotropin testing specifically in PAI and none of low-dose testing. The low-dose test has shown higher sensitivity in the detection of adrenal insufficiency in critically ill patients and secondary adrenal insufficiency, but the limited available data suggest it does not provide better diagnostic accuracy for PAI than the high-dose test.

As a result, the guidelines recommend the standard, short corticotropin test (250 mcg for adults and children aged at least 2 years) as the “gold standard” diagnostic test to establish a PAI diagnosis.

The low-dose (1 mcg) test is recommended only when corticotropin is in short supply, which is not typically a problem in the United States, she said.

If corticotropin testing isn’t feasible, a combination of a morning plasma ACTH and cortisol levels (less than 5 mcg/dL) can be used as an initial screening, though confirmatory testing with corticotropin stimulation is strongly recommended.

Glucocorticoid therapy is recommended in all patients with confirmed PAI based on the highest quality of evidence, with a clear preference given for the short-acting steroids, Dr. Merke observed.

Hydrocortisone 15 mg-25 mg or cortisone acetate 20 mg-35 mg given in two to three divided doses per day is suggested for adults, with the highest dose to be given in the morning. Once- or twice-daily prednisolone 3 mg-5 mg is suggested as an alternative.

Hydrocortisone is also suggested over cortisone acetate, prednisolone, or prednisone for pregnant women and recommended for children (about 8 mg/m² per day), but the evidence supporting these items was of low quality.

The guidelines suggest against using dexamethasone, the longest-acting glucocorticoid, because of the potential long-term side effects of overt-treatment and the frequent appearance of cushingoid side effects. They also recommend against dexamethasone in pregnant women because it is not inactivated in the placenta.

The guidelines are also quite clear in their suggestion against hormonal monitoring of glucocorticoid replacement and instead favor adjusting treatment based only on clinical response.

“This is a very important suggestion that we made because often clinicians use ACTH to adjust doses and this commonly results in overreplacement and there are side effects to overreplacement,” including weight gain, insomnia, and peripheral edema, Dr. Merke said.

A second systematic review commissioned by the task force involving 15 observational studies of glucocorticoid replacement regimens uncovered very sparse data on mortality, bone density, and incidence of adrenal crisis.

It has been suggested that newer extended-release and dual-release glucocorticoid formulations may result in higher health-reality quality of life than once-, twice-, or thrice-daily regimens, but once again, the evidence was insufficient to support a specific recommendation.

Dr. Merke acknowledged that many of the guidelines recommendations were ungraded or best practices, reflecting the lack of randomized clinical trials in PAI.

“I think that’s why it was so important for us to do this,” she said. “We had a group of experts that were very familiar with this disease providing guidance, but I think it’s also one reason why physicians out there in practice get confused about exactly what to do because of the lack of hard evidence. ... It does certainly cry for the need for more studies in these rare diseases.”

The guidelines were funded by the Endocrine Society, and the authors reported receiving no external funding or remuneration.

pwendling@frontlinemedcom.com

New guidelines on the diagnosis and management of primary adrenal insufficiency stress the importance of early recognition and the need to prevent life-threatening adrenal crises in these patients.

©SomkiatFakmee/thinkstockphotos.com

These are the first clinical practice guidelines on primary adrenal insufficiency (PAI), also known as Addison’s disease, issued by Endocrine Society (J Clin Endocrinol Metab. 2016 Jan 13:jc20151710 [Epub ahead of print]).

“Because it’s a rare disease and symptoms can mimic common conditions, adrenal insufficiency is often, at least initially, overlooked,” guideline co-author Dr. Deborah Merke, a senior investigator with the National Institutes of Health Clinical Center in Bethesda, Md., said. “So the main goal of these clinical practice guidelines is to improve patient care.”

The guidelines suggest clinicians should have a low diagnostic threshold in acutely ill patients with unexplained symptoms or signs suggestive of PAI such as volume depletion, hypotension, hyponatremia, hyperkalemia, fever, abdominal pain, hyperpigmentation, or, especially in children, hypoglycemia.

This low diagnostic threshold for PAI should also be extended to pregnant women with unexplained persistent nausea, fatigue, and hypotension.

For adult patients with a suspected adrenal crisis, an immediate parenteral injection of hydrocortisone 100 mg should be given, followed by appropriate fluid resuscitation and 200 mg of hydrocortisone for 24 hours, according to the guidelines, which were co-sponsored by the European Society of Endocrinology and American Association for Clinical Chemistry.

Despite a known association between adrenal crisis and mortality, there is a knowledge gap regarding how to prevent, recognize, and reduce the risk of these life-threatening events, Dr. Merke said.

To that end, the task force has taken a page from the diabetes community in recommending all PAI patients carry steroid emergency identification cards and be equipped with a glucocorticoid injection kit for emergency use and be educated on how to use it.

The guidelines also advocate education about stress dosing to counter the increased demand for corticosteroids during periods of stress, which can encompass something as common as the flu.

“Just like diabetics carry around emergency medicines, it’s important for patients with adrenal insufficiency to carry around an emergency kit and to realize that should they start to get sick, they need to increase their doses,” she said. “There often seems to be a lack of awareness among physicians as well that these patients have a potentially life-threatening condition, should they get a common illness.”

One of the key unanswered clinical questions the task force sought to address was whether the widely used high-dose (250 mcg) corticotropin stimulation test, also known as the adrenocorticotropin (ACTH) or short Synacthen test, should be replaced by the low-dose test (1 mcg) to diagnosis PAI.

Despite a review of published data and a systematic review commissioned by the task force, “We didn’t come up with much scientific evidence to say we should be changing the historic standard,” Dr. Merke said.

The systematic review identified only five studies of high-dose corticotropin testing specifically in PAI and none of low-dose testing. The low-dose test has shown higher sensitivity in the detection of adrenal insufficiency in critically ill patients and secondary adrenal insufficiency, but the limited available data suggest it does not provide better diagnostic accuracy for PAI than the high-dose test.

As a result, the guidelines recommend the standard, short corticotropin test (250 mcg for adults and children aged at least 2 years) as the “gold standard” diagnostic test to establish a PAI diagnosis.

The low-dose (1 mcg) test is recommended only when corticotropin is in short supply, which is not typically a problem in the United States, she said.

If corticotropin testing isn’t feasible, a combination of a morning plasma ACTH and cortisol levels (less than 5 mcg/dL) can be used as an initial screening, though confirmatory testing with corticotropin stimulation is strongly recommended.

Glucocorticoid therapy is recommended in all patients with confirmed PAI based on the highest quality of evidence, with a clear preference given for the short-acting steroids, Dr. Merke observed.

Hydrocortisone 15 mg-25 mg or cortisone acetate 20 mg-35 mg given in two to three divided doses per day is suggested for adults, with the highest dose to be given in the morning. Once- or twice-daily prednisolone 3 mg-5 mg is suggested as an alternative.

Hydrocortisone is also suggested over cortisone acetate, prednisolone, or prednisone for pregnant women and recommended for children (about 8 mg/m² per day), but the evidence supporting these items was of low quality.

The guidelines suggest against using dexamethasone, the longest-acting glucocorticoid, because of the potential long-term side effects of overt-treatment and the frequent appearance of cushingoid side effects. They also recommend against dexamethasone in pregnant women because it is not inactivated in the placenta.

The guidelines are also quite clear in their suggestion against hormonal monitoring of glucocorticoid replacement and instead favor adjusting treatment based only on clinical response.

“This is a very important suggestion that we made because often clinicians use ACTH to adjust doses and this commonly results in overreplacement and there are side effects to overreplacement,” including weight gain, insomnia, and peripheral edema, Dr. Merke said.

A second systematic review commissioned by the task force involving 15 observational studies of glucocorticoid replacement regimens uncovered very sparse data on mortality, bone density, and incidence of adrenal crisis.

It has been suggested that newer extended-release and dual-release glucocorticoid formulations may result in higher health-reality quality of life than once-, twice-, or thrice-daily regimens, but once again, the evidence was insufficient to support a specific recommendation.

Dr. Merke acknowledged that many of the guidelines recommendations were ungraded or best practices, reflecting the lack of randomized clinical trials in PAI.

“I think that’s why it was so important for us to do this,” she said. “We had a group of experts that were very familiar with this disease providing guidance, but I think it’s also one reason why physicians out there in practice get confused about exactly what to do because of the lack of hard evidence. ... It does certainly cry for the need for more studies in these rare diseases.”

The guidelines were funded by the Endocrine Society, and the authors reported receiving no external funding or remuneration.

pwendling@frontlinemedcom.com

New guidelines on the diagnosis and management of primary adrenal insufficiency stress the importance of early recognition and the need to prevent life-threatening adrenal crises in these patients.

©SomkiatFakmee/thinkstockphotos.com

These are the first clinical practice guidelines on primary adrenal insufficiency (PAI), also known as Addison’s disease, issued by Endocrine Society (J Clin Endocrinol Metab. 2016 Jan 13:jc20151710 [Epub ahead of print]).

“Because it’s a rare disease and symptoms can mimic common conditions, adrenal insufficiency is often, at least initially, overlooked,” guideline co-author Dr. Deborah Merke, a senior investigator with the National Institutes of Health Clinical Center in Bethesda, Md., said. “So the main goal of these clinical practice guidelines is to improve patient care.”

The guidelines suggest clinicians should have a low diagnostic threshold in acutely ill patients with unexplained symptoms or signs suggestive of PAI such as volume depletion, hypotension, hyponatremia, hyperkalemia, fever, abdominal pain, hyperpigmentation, or, especially in children, hypoglycemia.

This low diagnostic threshold for PAI should also be extended to pregnant women with unexplained persistent nausea, fatigue, and hypotension.

For adult patients with a suspected adrenal crisis, an immediate parenteral injection of hydrocortisone 100 mg should be given, followed by appropriate fluid resuscitation and 200 mg of hydrocortisone for 24 hours, according to the guidelines, which were co-sponsored by the European Society of Endocrinology and American Association for Clinical Chemistry.

Despite a known association between adrenal crisis and mortality, there is a knowledge gap regarding how to prevent, recognize, and reduce the risk of these life-threatening events, Dr. Merke said.

To that end, the task force has taken a page from the diabetes community in recommending all PAI patients carry steroid emergency identification cards and be equipped with a glucocorticoid injection kit for emergency use and be educated on how to use it.

The guidelines also advocate education about stress dosing to counter the increased demand for corticosteroids during periods of stress, which can encompass something as common as the flu.

“Just like diabetics carry around emergency medicines, it’s important for patients with adrenal insufficiency to carry around an emergency kit and to realize that should they start to get sick, they need to increase their doses,” she said. “There often seems to be a lack of awareness among physicians as well that these patients have a potentially life-threatening condition, should they get a common illness.”

One of the key unanswered clinical questions the task force sought to address was whether the widely used high-dose (250 mcg) corticotropin stimulation test, also known as the adrenocorticotropin (ACTH) or short Synacthen test, should be replaced by the low-dose test (1 mcg) to diagnosis PAI.

Despite a review of published data and a systematic review commissioned by the task force, “We didn’t come up with much scientific evidence to say we should be changing the historic standard,” Dr. Merke said.

The systematic review identified only five studies of high-dose corticotropin testing specifically in PAI and none of low-dose testing. The low-dose test has shown higher sensitivity in the detection of adrenal insufficiency in critically ill patients and secondary adrenal insufficiency, but the limited available data suggest it does not provide better diagnostic accuracy for PAI than the high-dose test.

As a result, the guidelines recommend the standard, short corticotropin test (250 mcg for adults and children aged at least 2 years) as the “gold standard” diagnostic test to establish a PAI diagnosis.

The low-dose (1 mcg) test is recommended only when corticotropin is in short supply, which is not typically a problem in the United States, she said.

If corticotropin testing isn’t feasible, a combination of a morning plasma ACTH and cortisol levels (less than 5 mcg/dL) can be used as an initial screening, though confirmatory testing with corticotropin stimulation is strongly recommended.

Glucocorticoid therapy is recommended in all patients with confirmed PAI based on the highest quality of evidence, with a clear preference given for the short-acting steroids, Dr. Merke observed.

Hydrocortisone 15 mg-25 mg or cortisone acetate 20 mg-35 mg given in two to three divided doses per day is suggested for adults, with the highest dose to be given in the morning. Once- or twice-daily prednisolone 3 mg-5 mg is suggested as an alternative.

Hydrocortisone is also suggested over cortisone acetate, prednisolone, or prednisone for pregnant women and recommended for children (about 8 mg/m² per day), but the evidence supporting these items was of low quality.

The guidelines suggest against using dexamethasone, the longest-acting glucocorticoid, because of the potential long-term side effects of overt-treatment and the frequent appearance of cushingoid side effects. They also recommend against dexamethasone in pregnant women because it is not inactivated in the placenta.

The guidelines are also quite clear in their suggestion against hormonal monitoring of glucocorticoid replacement and instead favor adjusting treatment based only on clinical response.

“This is a very important suggestion that we made because often clinicians use ACTH to adjust doses and this commonly results in overreplacement and there are side effects to overreplacement,” including weight gain, insomnia, and peripheral edema, Dr. Merke said.

A second systematic review commissioned by the task force involving 15 observational studies of glucocorticoid replacement regimens uncovered very sparse data on mortality, bone density, and incidence of adrenal crisis.

It has been suggested that newer extended-release and dual-release glucocorticoid formulations may result in higher health-reality quality of life than once-, twice-, or thrice-daily regimens, but once again, the evidence was insufficient to support a specific recommendation.

Dr. Merke acknowledged that many of the guidelines recommendations were ungraded or best practices, reflecting the lack of randomized clinical trials in PAI.

“I think that’s why it was so important for us to do this,” she said. “We had a group of experts that were very familiar with this disease providing guidance, but I think it’s also one reason why physicians out there in practice get confused about exactly what to do because of the lack of hard evidence. ... It does certainly cry for the need for more studies in these rare diseases.”

The guidelines were funded by the Endocrine Society, and the authors reported receiving no external funding or remuneration.

pwendling@frontlinemedcom.com

ORLANDO – The moment the Food and Drug Administration approved daratumumab, ixazomib, and elotuzumab in rapid-fire succession over 15 days in November 2015, Dr. S. Vincent Rajkumar’s phone started ringing.

As with other multiple myeloma experts, three common questions kept cropping up:

• For previously untreated patients, should we add bortezomib to lenalidomide plus dexamethasone (Rd) based on the S0777 results?

• For previously treated patients, should we add ixazomib or elotuzumab to Rd?

• Should we add daratumumab to frontline therapy right out of the box?

Daratumumab (Darzalex), ixazomib (Ninlaro), and elotuzumab (Empliciti) are welcome additions to the armamentarium, but the problem with this plethora of riches is that numerous treatments already exist for frontline multiple myeloma, observed Dr. Rajkumar, professor of medicine at the Mayo Clinic in Rochester, Minn.

Patrice Wendling/Frontline Medical News

In fact, the National Comprehensive Cancer Network guidelines list 22 possible newly diagnosed myeloma regimens that can be potentially recommended for patients.

“This definitely leads to confusion in the community. And this was the result of the fact that we didn’t have a single, good randomized trial with a survival benefit of a modern therapy against another modern therapy,” Dr. Rajkumar said at the annual meeting of the American Society of Hematology during a joint FDA/ASH symposium on the three newly approved agents.

This quandary was solved at ASH with phase III randomized data from the Southwest Oncology Group S0777 study showing a significant overall survival advantage with a triplet of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) followed by continuous Rd maintenance compared with Rd alone and ongoing maintenance in untreated patients who did not intend to receive stem cell transplant, he said.

Median overall survival was 75 months for the triplet vs. 64 months for the Rd doublet (hazard ratio, 0.709; two-sided log-rank P = .0250), and median PFS 43 months vs. 30 months (HR, 0.712; one-sided P = .0018), study author Dr. Brian Durie, of Cedars-Sinai Comprehensive Cancer Center in Los Angeles, reported (Abstract 25).

The VRd triplet is already in use in the United States, but based on the S0777 results, many groups, including the Mayo Clinic, have changed treatment guidelines and now “prefer bortezomib, len-dex for frontline therapy, not just in transplant candidates, but also in non-transplant candidates,” Dr. Rajkumar said.

In countries where VRd is not possible, bortezomib, thalidomide, and dexamethasone (VTd) is a second option.

Rd is an appropriate therapy for non-transplant candidates who are frail or aged 75 years or older, he said, adding that there is no need to add bortezomib for patients already on Rd and doing well.

“If your patient is doing well on a doublet, leave them alone,” Dr. Rajkumar advised.

Similarly, for patients with relapsed myeloma who are doing well on Rd, there isn’t “an urgent need” to add ixazomib or elotuzumab, but rather, he said, “We can reserve those for when the patient progresses.”

Ixazomib is approved in combination with Rd after at least one prior therapy, but the oral proteasome inhibitor may have a role in the frontline treatment of standard-risk patients. It is a very simple regimen, just three pills a month, and “the side effect profile is outstanding; virtually difficult to tell who’s taking placebo and who’s taking drug,” Dr. Rajkumar observed.

In addition, some patients may not have access to bortezomib because of insurance reasons or can’t drive to the clinic once a week to get the shot, while others may be too frail to get an intravenous or subcutaneous shot or may have neuropathy.

“For whatever reason, I think it is reasonable to keep in mind that we may have a situation where we can use ixazomib/len-dex in clinical practice if the patient’s best interests so dictate,” he said.

For high-risk patients (deletion 17p or translocations t(4;14), t(14;16), t(14;20), VRd or VTd are obvious upfront choices. Based on four phase II trials and the ASPIRE results in the relapsed and refractory setting, however, the Mayo Clinic has already decided that the recently approved second-generation proteasome inhibitor carfilzomib (Kyprolis) plus Rd is also worth considering.

Adding a monoclonal antibody such as elotuzumab or daratumumab to a VRd triplet or ixazomib, lenalidomide, and dexamethasone (IRd) triplet may be another way to improve outcomes in high-risk patients, who still die with a median overall survival of 3 years, Dr. Rajkumar said. This strategy is already being used in the ongoing SWOG S1211 study.

For maintenance therapy after VRd or VTd and autologous stem cell transplant, he recommended lenalidomide for standard-risk patients and bortezomib-based maintenance for high-risk patients, but said ixazomib-based maintenance with the addition of monoclonal antibodies may also have a role in high-risk patients.

What may be more important going forward is how these three drugs will be used in clinical trials, Dr. Rajkumar observed.

“We’d rather put all patients on clinical trials than any of the recommendations I made,” he said. “The problem is that clinical trials have to be appropriately designed.”

Several phase III trials are already ongoing comparing a doublet versus a triplet (IRd vs. Rd, elotuzumab-Rd vs. Rd, and daratumumab-Rd vs. Rd) in the frontline setting, so the key question for future trials is which triplet: VRd, KRd, elotuzumab-Rd, or daratumumab-Rd, and to what endpoint.

Progression-free survival can remain a primary endpoint for comparing two triplets in the frontline, but PFS alone is not enough in the maintenance setting and investigators should look to other primary endpoints such as PFS2, PFS1 vs. PFS2, overall survival with a higher type 1 error than currently used, or PFS plus validated patient-reported or quality of life outcomes, Dr. Rajkumar said.

Relapsed/refractory disease

Speaking on how the three new agents fit into the relapsed or refractory space,Dr. Paul Richardson, of Dana-Farber Cancer Institute, Boston, said three-drug platforms are emerging as a standard of care for relapsed or refractory disease after studies have shown time and time again they are better than doublets.

Patrice Wendling/Frontline Medical News

He highlighted phase III data reported at ASH by Dr. Philippe Moreau from TOURMALINE-MM1 (Abstract 727) showing a 35% improvement in PFS with weekly oral ixazomib plus lenalidomide-dexamethasone vs. Rd alone in relapsed and/or refractory multiple myeloma.

This translated into a median 6-month gain in PFS compared with an almost 9-month PFS benefit seen in ASPIRE with carfilzomib plus Rd, but cross-trial comparisons should be approached with some caution and both hazard ratios were very robust, he said. In addition, as previously observed, ixazomib is remarkably well tolerated.

“I think ixazomib, particularly in older patients and particularly in patients with high-risk disease, will be very useful in the context of the three-drug or even greater combinations. So there’s a strong rationale for its use,” Dr. Richardson said.

He went on to say that elotuzumab has shown remarkable anti-myeloma activity in the relapsed and refractory setting, improving both the overall response rate and PFS when used in combination with Ld vs. Ld alone in the ELOQUENT-2 trial. Updated results from ELOQUENT-2 were presented at the ASH meeting (Abstract 28).

A PFS benefit was also seen when elotuzumab was added to bortezomib and dexamethasone, with a 24% reduction in the risk of disease progression or death reported in a study presented at ASH by myeloma expert Dr. Antonio Palumbo (Abstract 510).

“My point in showing this is that when you think of elotuzumab being used with lenalidomide and dexamethasone in relapse, many of our patients are actually on them as maintenance when it occurs, therefore elotuzumab may have a role in combination, for example, with proteasome inhibitors in this same setting,” Dr. Richardson said.

Several pomalidomide-based triple therapy combinations have been evaluated in advanced relapsed or refractory myeloma, with a phase II study (Abstract 506) reported that morning at ASH showing the third-generation immunomodulatory drug (IMiD) pomalidomide induced responses in 60% of heavily pretreated patients when partnered with pembrolizumab and dexamethasone.

Combination strategies with daratumumab are also very provocative, particularly in the context of IMiDs, he noted. A phase Ib study reported in the same early morning session by Dr. Ajai Chari (Abstract 508) had a “very encouraging” overall response rate of 71% with daratumumab plus pomalidomide and dexamethasone in heavily pretreated patients, including 43% very good partial responses or better, and an overall response rate of 67% among double-refractory patients.

“Daratumumab and elotuzumab, in my view, as first-in-class monoclonal antibodies, are paradigm-changing agents,” Dr. Richardson concluded. “They provide us with this mutation-driven ability to overdrive the impact of those mutations and the important point is that they prescribe an entirely non-crossresistant strategy that can be easily added to existing platforms of drugs.”

Dr. Rajkumar reported discussion of off-label drug use for elotuzumab, daratumumab, ixazomib, and carfilzomib in untreated myeloma, maintenance, and early relapse. Dr. Richardson reported membership on a board of directors or advisory committee for Millennium Takeda, Celgene, Janssen, Bristol-Myers Squibb, and Novartis, and research funding from Millennium Takeda and Celgene.

pwendling@frontlinemedcom.com

ORLANDO – The moment the Food and Drug Administration approved daratumumab, ixazomib, and elotuzumab in rapid-fire succession over 15 days in November 2015, Dr. S. Vincent Rajkumar’s phone started ringing.

As with other multiple myeloma experts, three common questions kept cropping up:

• For previously untreated patients, should we add bortezomib to lenalidomide plus dexamethasone (Rd) based on the S0777 results?

• For previously treated patients, should we add ixazomib or elotuzumab to Rd?

• Should we add daratumumab to frontline therapy right out of the box?

Daratumumab (Darzalex), ixazomib (Ninlaro), and elotuzumab (Empliciti) are welcome additions to the armamentarium, but the problem with this plethora of riches is that numerous treatments already exist for frontline multiple myeloma, observed Dr. Rajkumar, professor of medicine at the Mayo Clinic in Rochester, Minn.

Patrice Wendling/Frontline Medical News

In fact, the National Comprehensive Cancer Network guidelines list 22 possible newly diagnosed myeloma regimens that can be potentially recommended for patients.

“This definitely leads to confusion in the community. And this was the result of the fact that we didn’t have a single, good randomized trial with a survival benefit of a modern therapy against another modern therapy,” Dr. Rajkumar said at the annual meeting of the American Society of Hematology during a joint FDA/ASH symposium on the three newly approved agents.

This quandary was solved at ASH with phase III randomized data from the Southwest Oncology Group S0777 study showing a significant overall survival advantage with a triplet of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) followed by continuous Rd maintenance compared with Rd alone and ongoing maintenance in untreated patients who did not intend to receive stem cell transplant, he said.

Median overall survival was 75 months for the triplet vs. 64 months for the Rd doublet (hazard ratio, 0.709; two-sided log-rank P = .0250), and median PFS 43 months vs. 30 months (HR, 0.712; one-sided P = .0018), study author Dr. Brian Durie, of Cedars-Sinai Comprehensive Cancer Center in Los Angeles, reported (Abstract 25).

The VRd triplet is already in use in the United States, but based on the S0777 results, many groups, including the Mayo Clinic, have changed treatment guidelines and now “prefer bortezomib, len-dex for frontline therapy, not just in transplant candidates, but also in non-transplant candidates,” Dr. Rajkumar said.

In countries where VRd is not possible, bortezomib, thalidomide, and dexamethasone (VTd) is a second option.

Rd is an appropriate therapy for non-transplant candidates who are frail or aged 75 years or older, he said, adding that there is no need to add bortezomib for patients already on Rd and doing well.

“If your patient is doing well on a doublet, leave them alone,” Dr. Rajkumar advised.

Similarly, for patients with relapsed myeloma who are doing well on Rd, there isn’t “an urgent need” to add ixazomib or elotuzumab, but rather, he said, “We can reserve those for when the patient progresses.”

Ixazomib is approved in combination with Rd after at least one prior therapy, but the oral proteasome inhibitor may have a role in the frontline treatment of standard-risk patients. It is a very simple regimen, just three pills a month, and “the side effect profile is outstanding; virtually difficult to tell who’s taking placebo and who’s taking drug,” Dr. Rajkumar observed.

In addition, some patients may not have access to bortezomib because of insurance reasons or can’t drive to the clinic once a week to get the shot, while others may be too frail to get an intravenous or subcutaneous shot or may have neuropathy.

“For whatever reason, I think it is reasonable to keep in mind that we may have a situation where we can use ixazomib/len-dex in clinical practice if the patient’s best interests so dictate,” he said.

For high-risk patients (deletion 17p or translocations t(4;14), t(14;16), t(14;20), VRd or VTd are obvious upfront choices. Based on four phase II trials and the ASPIRE results in the relapsed and refractory setting, however, the Mayo Clinic has already decided that the recently approved second-generation proteasome inhibitor carfilzomib (Kyprolis) plus Rd is also worth considering.

Adding a monoclonal antibody such as elotuzumab or daratumumab to a VRd triplet or ixazomib, lenalidomide, and dexamethasone (IRd) triplet may be another way to improve outcomes in high-risk patients, who still die with a median overall survival of 3 years, Dr. Rajkumar said. This strategy is already being used in the ongoing SWOG S1211 study.

For maintenance therapy after VRd or VTd and autologous stem cell transplant, he recommended lenalidomide for standard-risk patients and bortezomib-based maintenance for high-risk patients, but said ixazomib-based maintenance with the addition of monoclonal antibodies may also have a role in high-risk patients.

What may be more important going forward is how these three drugs will be used in clinical trials, Dr. Rajkumar observed.

“We’d rather put all patients on clinical trials than any of the recommendations I made,” he said. “The problem is that clinical trials have to be appropriately designed.”

Several phase III trials are already ongoing comparing a doublet versus a triplet (IRd vs. Rd, elotuzumab-Rd vs. Rd, and daratumumab-Rd vs. Rd) in the frontline setting, so the key question for future trials is which triplet: VRd, KRd, elotuzumab-Rd, or daratumumab-Rd, and to what endpoint.

Progression-free survival can remain a primary endpoint for comparing two triplets in the frontline, but PFS alone is not enough in the maintenance setting and investigators should look to other primary endpoints such as PFS2, PFS1 vs. PFS2, overall survival with a higher type 1 error than currently used, or PFS plus validated patient-reported or quality of life outcomes, Dr. Rajkumar said.

Relapsed/refractory disease

Speaking on how the three new agents fit into the relapsed or refractory space,Dr. Paul Richardson, of Dana-Farber Cancer Institute, Boston, said three-drug platforms are emerging as a standard of care for relapsed or refractory disease after studies have shown time and time again they are better than doublets.

Patrice Wendling/Frontline Medical News

He highlighted phase III data reported at ASH by Dr. Philippe Moreau from TOURMALINE-MM1 (Abstract 727) showing a 35% improvement in PFS with weekly oral ixazomib plus lenalidomide-dexamethasone vs. Rd alone in relapsed and/or refractory multiple myeloma.

This translated into a median 6-month gain in PFS compared with an almost 9-month PFS benefit seen in ASPIRE with carfilzomib plus Rd, but cross-trial comparisons should be approached with some caution and both hazard ratios were very robust, he said. In addition, as previously observed, ixazomib is remarkably well tolerated.

“I think ixazomib, particularly in older patients and particularly in patients with high-risk disease, will be very useful in the context of the three-drug or even greater combinations. So there’s a strong rationale for its use,” Dr. Richardson said.

He went on to say that elotuzumab has shown remarkable anti-myeloma activity in the relapsed and refractory setting, improving both the overall response rate and PFS when used in combination with Ld vs. Ld alone in the ELOQUENT-2 trial. Updated results from ELOQUENT-2 were presented at the ASH meeting (Abstract 28).

A PFS benefit was also seen when elotuzumab was added to bortezomib and dexamethasone, with a 24% reduction in the risk of disease progression or death reported in a study presented at ASH by myeloma expert Dr. Antonio Palumbo (Abstract 510).

“My point in showing this is that when you think of elotuzumab being used with lenalidomide and dexamethasone in relapse, many of our patients are actually on them as maintenance when it occurs, therefore elotuzumab may have a role in combination, for example, with proteasome inhibitors in this same setting,” Dr. Richardson said.

Several pomalidomide-based triple therapy combinations have been evaluated in advanced relapsed or refractory myeloma, with a phase II study (Abstract 506) reported that morning at ASH showing the third-generation immunomodulatory drug (IMiD) pomalidomide induced responses in 60% of heavily pretreated patients when partnered with pembrolizumab and dexamethasone.

Combination strategies with daratumumab are also very provocative, particularly in the context of IMiDs, he noted. A phase Ib study reported in the same early morning session by Dr. Ajai Chari (Abstract 508) had a “very encouraging” overall response rate of 71% with daratumumab plus pomalidomide and dexamethasone in heavily pretreated patients, including 43% very good partial responses or better, and an overall response rate of 67% among double-refractory patients.

“Daratumumab and elotuzumab, in my view, as first-in-class monoclonal antibodies, are paradigm-changing agents,” Dr. Richardson concluded. “They provide us with this mutation-driven ability to overdrive the impact of those mutations and the important point is that they prescribe an entirely non-crossresistant strategy that can be easily added to existing platforms of drugs.”

Dr. Rajkumar reported discussion of off-label drug use for elotuzumab, daratumumab, ixazomib, and carfilzomib in untreated myeloma, maintenance, and early relapse. Dr. Richardson reported membership on a board of directors or advisory committee for Millennium Takeda, Celgene, Janssen, Bristol-Myers Squibb, and Novartis, and research funding from Millennium Takeda and Celgene.

pwendling@frontlinemedcom.com

ORLANDO – The moment the Food and Drug Administration approved daratumumab, ixazomib, and elotuzumab in rapid-fire succession over 15 days in November 2015, Dr. S. Vincent Rajkumar’s phone started ringing.

As with other multiple myeloma experts, three common questions kept cropping up:

• For previously untreated patients, should we add bortezomib to lenalidomide plus dexamethasone (Rd) based on the S0777 results?

• For previously treated patients, should we add ixazomib or elotuzumab to Rd?

• Should we add daratumumab to frontline therapy right out of the box?

Daratumumab (Darzalex), ixazomib (Ninlaro), and elotuzumab (Empliciti) are welcome additions to the armamentarium, but the problem with this plethora of riches is that numerous treatments already exist for frontline multiple myeloma, observed Dr. Rajkumar, professor of medicine at the Mayo Clinic in Rochester, Minn.

Patrice Wendling/Frontline Medical News

In fact, the National Comprehensive Cancer Network guidelines list 22 possible newly diagnosed myeloma regimens that can be potentially recommended for patients.

“This definitely leads to confusion in the community. And this was the result of the fact that we didn’t have a single, good randomized trial with a survival benefit of a modern therapy against another modern therapy,” Dr. Rajkumar said at the annual meeting of the American Society of Hematology during a joint FDA/ASH symposium on the three newly approved agents.

This quandary was solved at ASH with phase III randomized data from the Southwest Oncology Group S0777 study showing a significant overall survival advantage with a triplet of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) followed by continuous Rd maintenance compared with Rd alone and ongoing maintenance in untreated patients who did not intend to receive stem cell transplant, he said.

Median overall survival was 75 months for the triplet vs. 64 months for the Rd doublet (hazard ratio, 0.709; two-sided log-rank P = .0250), and median PFS 43 months vs. 30 months (HR, 0.712; one-sided P = .0018), study author Dr. Brian Durie, of Cedars-Sinai Comprehensive Cancer Center in Los Angeles, reported (Abstract 25).

The VRd triplet is already in use in the United States, but based on the S0777 results, many groups, including the Mayo Clinic, have changed treatment guidelines and now “prefer bortezomib, len-dex for frontline therapy, not just in transplant candidates, but also in non-transplant candidates,” Dr. Rajkumar said.

In countries where VRd is not possible, bortezomib, thalidomide, and dexamethasone (VTd) is a second option.

Rd is an appropriate therapy for non-transplant candidates who are frail or aged 75 years or older, he said, adding that there is no need to add bortezomib for patients already on Rd and doing well.

“If your patient is doing well on a doublet, leave them alone,” Dr. Rajkumar advised.

Similarly, for patients with relapsed myeloma who are doing well on Rd, there isn’t “an urgent need” to add ixazomib or elotuzumab, but rather, he said, “We can reserve those for when the patient progresses.”

Ixazomib is approved in combination with Rd after at least one prior therapy, but the oral proteasome inhibitor may have a role in the frontline treatment of standard-risk patients. It is a very simple regimen, just three pills a month, and “the side effect profile is outstanding; virtually difficult to tell who’s taking placebo and who’s taking drug,” Dr. Rajkumar observed.

In addition, some patients may not have access to bortezomib because of insurance reasons or can’t drive to the clinic once a week to get the shot, while others may be too frail to get an intravenous or subcutaneous shot or may have neuropathy.

“For whatever reason, I think it is reasonable to keep in mind that we may have a situation where we can use ixazomib/len-dex in clinical practice if the patient’s best interests so dictate,” he said.

For high-risk patients (deletion 17p or translocations t(4;14), t(14;16), t(14;20), VRd or VTd are obvious upfront choices. Based on four phase II trials and the ASPIRE results in the relapsed and refractory setting, however, the Mayo Clinic has already decided that the recently approved second-generation proteasome inhibitor carfilzomib (Kyprolis) plus Rd is also worth considering.

Adding a monoclonal antibody such as elotuzumab or daratumumab to a VRd triplet or ixazomib, lenalidomide, and dexamethasone (IRd) triplet may be another way to improve outcomes in high-risk patients, who still die with a median overall survival of 3 years, Dr. Rajkumar said. This strategy is already being used in the ongoing SWOG S1211 study.

For maintenance therapy after VRd or VTd and autologous stem cell transplant, he recommended lenalidomide for standard-risk patients and bortezomib-based maintenance for high-risk patients, but said ixazomib-based maintenance with the addition of monoclonal antibodies may also have a role in high-risk patients.

What may be more important going forward is how these three drugs will be used in clinical trials, Dr. Rajkumar observed.

“We’d rather put all patients on clinical trials than any of the recommendations I made,” he said. “The problem is that clinical trials have to be appropriately designed.”

Several phase III trials are already ongoing comparing a doublet versus a triplet (IRd vs. Rd, elotuzumab-Rd vs. Rd, and daratumumab-Rd vs. Rd) in the frontline setting, so the key question for future trials is which triplet: VRd, KRd, elotuzumab-Rd, or daratumumab-Rd, and to what endpoint.

Progression-free survival can remain a primary endpoint for comparing two triplets in the frontline, but PFS alone is not enough in the maintenance setting and investigators should look to other primary endpoints such as PFS2, PFS1 vs. PFS2, overall survival with a higher type 1 error than currently used, or PFS plus validated patient-reported or quality of life outcomes, Dr. Rajkumar said.

Relapsed/refractory disease

Speaking on how the three new agents fit into the relapsed or refractory space,Dr. Paul Richardson, of Dana-Farber Cancer Institute, Boston, said three-drug platforms are emerging as a standard of care for relapsed or refractory disease after studies have shown time and time again they are better than doublets.

Patrice Wendling/Frontline Medical News

He highlighted phase III data reported at ASH by Dr. Philippe Moreau from TOURMALINE-MM1 (Abstract 727) showing a 35% improvement in PFS with weekly oral ixazomib plus lenalidomide-dexamethasone vs. Rd alone in relapsed and/or refractory multiple myeloma.

This translated into a median 6-month gain in PFS compared with an almost 9-month PFS benefit seen in ASPIRE with carfilzomib plus Rd, but cross-trial comparisons should be approached with some caution and both hazard ratios were very robust, he said. In addition, as previously observed, ixazomib is remarkably well tolerated.

“I think ixazomib, particularly in older patients and particularly in patients with high-risk disease, will be very useful in the context of the three-drug or even greater combinations. So there’s a strong rationale for its use,” Dr. Richardson said.

He went on to say that elotuzumab has shown remarkable anti-myeloma activity in the relapsed and refractory setting, improving both the overall response rate and PFS when used in combination with Ld vs. Ld alone in the ELOQUENT-2 trial. Updated results from ELOQUENT-2 were presented at the ASH meeting (Abstract 28).

A PFS benefit was also seen when elotuzumab was added to bortezomib and dexamethasone, with a 24% reduction in the risk of disease progression or death reported in a study presented at ASH by myeloma expert Dr. Antonio Palumbo (Abstract 510).

“My point in showing this is that when you think of elotuzumab being used with lenalidomide and dexamethasone in relapse, many of our patients are actually on them as maintenance when it occurs, therefore elotuzumab may have a role in combination, for example, with proteasome inhibitors in this same setting,” Dr. Richardson said.

Several pomalidomide-based triple therapy combinations have been evaluated in advanced relapsed or refractory myeloma, with a phase II study (Abstract 506) reported that morning at ASH showing the third-generation immunomodulatory drug (IMiD) pomalidomide induced responses in 60% of heavily pretreated patients when partnered with pembrolizumab and dexamethasone.

Combination strategies with daratumumab are also very provocative, particularly in the context of IMiDs, he noted. A phase Ib study reported in the same early morning session by Dr. Ajai Chari (Abstract 508) had a “very encouraging” overall response rate of 71% with daratumumab plus pomalidomide and dexamethasone in heavily pretreated patients, including 43% very good partial responses or better, and an overall response rate of 67% among double-refractory patients.

“Daratumumab and elotuzumab, in my view, as first-in-class monoclonal antibodies, are paradigm-changing agents,” Dr. Richardson concluded. “They provide us with this mutation-driven ability to overdrive the impact of those mutations and the important point is that they prescribe an entirely non-crossresistant strategy that can be easily added to existing platforms of drugs.”

Dr. Rajkumar reported discussion of off-label drug use for elotuzumab, daratumumab, ixazomib, and carfilzomib in untreated myeloma, maintenance, and early relapse. Dr. Richardson reported membership on a board of directors or advisory committee for Millennium Takeda, Celgene, Janssen, Bristol-Myers Squibb, and Novartis, and research funding from Millennium Takeda and Celgene.

pwendling@frontlinemedcom.com

The new year has us all looking forward and the cancer prevention community is no exception.

In a special report entitled “Transforming Cancer Prevention through Precision Medicine and Immune-Oncology,” a team of experts offer a brief look at what we can expect in the near future for cancer prevention research, including a Pre-Cancer Genome Atlas (PCGA), and highlight some of the recent advances shaping their optimism.

“Just as precision therapy and immunotherapy are transforming cancer treatment, precision medicine and immunoprevention approaches are being translated to the clinic and showing great promise. We stand at the edge of a new frontier that will include comprehensively characterizing the molecular and cellular events that drive premalignant progression (e.g. PCGA),” Dr. Scott M. Lippman, director of the University of California San Diego Moores Cancer Center, and his coauthors wrote (Cancer Prev Res. 2016;9:2-10).

The report details some of the clinical firsts in 2015 including genomic studies suggesting that clonal hematopoiesis is a premalignant state for blood cancer, the first precision medicine trial in cancer prevention (EPOC) reporting that loss of heterozygosity can predict which patients with premalignant mouth lesions are most likely to develop oral cancer, and the U.S. Preventive Services Task Force recommending low-dose aspirin for colorectal cancer prevention based on age and risk.

Randomized trials have also suggested that a single dose of human papillomavirus vaccine can provide durable protection against HPV infection. Tumor biology studies established new chemoprevention for familial adenomatous polyposis syndrome and universal tumor screening guidelines based on DNA mismatch repair mutations and microsatellite instability for colorectal cancer in patients with Lynch syndrome.

Further, remarkable advances have been made in liquid biopsy technology, high-throughput functional screening, and computational biology methods and algorithms that “provide unprecedented opportunities to interrogate the biology of premalignancy...” they noted.

In an American Association for Cancer Research blog post, Dr. Lippman acknowledges that not everyone is the same page when it comes to the underlying principles of cancer prevention.

A “contentious” paper published at the start of 2015 suggested that variations in cancer risk are due to random mutations or what might otherwise be called bad luck. The new year was heralded in by a second paper, however, that came to roughly the opposite conclusion or that most cancers are preventable.

In February, an AACR Cancer Prevention Summit will bring together various stakeholders to discuss the current state of cancer prevention and to identify top priorities and research directions for the field, he noted.

The authors acknowledged grant support from the National Institutes of Health/National Cancer Institute.

pwendling@frontlinemedcom.com

The new year has us all looking forward and the cancer prevention community is no exception.

In a special report entitled “Transforming Cancer Prevention through Precision Medicine and Immune-Oncology,” a team of experts offer a brief look at what we can expect in the near future for cancer prevention research, including a Pre-Cancer Genome Atlas (PCGA), and highlight some of the recent advances shaping their optimism.

“Just as precision therapy and immunotherapy are transforming cancer treatment, precision medicine and immunoprevention approaches are being translated to the clinic and showing great promise. We stand at the edge of a new frontier that will include comprehensively characterizing the molecular and cellular events that drive premalignant progression (e.g. PCGA),” Dr. Scott M. Lippman, director of the University of California San Diego Moores Cancer Center, and his coauthors wrote (Cancer Prev Res. 2016;9:2-10).

The report details some of the clinical firsts in 2015 including genomic studies suggesting that clonal hematopoiesis is a premalignant state for blood cancer, the first precision medicine trial in cancer prevention (EPOC) reporting that loss of heterozygosity can predict which patients with premalignant mouth lesions are most likely to develop oral cancer, and the U.S. Preventive Services Task Force recommending low-dose aspirin for colorectal cancer prevention based on age and risk.

Randomized trials have also suggested that a single dose of human papillomavirus vaccine can provide durable protection against HPV infection. Tumor biology studies established new chemoprevention for familial adenomatous polyposis syndrome and universal tumor screening guidelines based on DNA mismatch repair mutations and microsatellite instability for colorectal cancer in patients with Lynch syndrome.

Further, remarkable advances have been made in liquid biopsy technology, high-throughput functional screening, and computational biology methods and algorithms that “provide unprecedented opportunities to interrogate the biology of premalignancy...” they noted.

In an American Association for Cancer Research blog post, Dr. Lippman acknowledges that not everyone is the same page when it comes to the underlying principles of cancer prevention.

A “contentious” paper published at the start of 2015 suggested that variations in cancer risk are due to random mutations or what might otherwise be called bad luck. The new year was heralded in by a second paper, however, that came to roughly the opposite conclusion or that most cancers are preventable.

In February, an AACR Cancer Prevention Summit will bring together various stakeholders to discuss the current state of cancer prevention and to identify top priorities and research directions for the field, he noted.

The authors acknowledged grant support from the National Institutes of Health/National Cancer Institute.

pwendling@frontlinemedcom.com

The new year has us all looking forward and the cancer prevention community is no exception.

In a special report entitled “Transforming Cancer Prevention through Precision Medicine and Immune-Oncology,” a team of experts offer a brief look at what we can expect in the near future for cancer prevention research, including a Pre-Cancer Genome Atlas (PCGA), and highlight some of the recent advances shaping their optimism.

“Just as precision therapy and immunotherapy are transforming cancer treatment, precision medicine and immunoprevention approaches are being translated to the clinic and showing great promise. We stand at the edge of a new frontier that will include comprehensively characterizing the molecular and cellular events that drive premalignant progression (e.g. PCGA),” Dr. Scott M. Lippman, director of the University of California San Diego Moores Cancer Center, and his coauthors wrote (Cancer Prev Res. 2016;9:2-10).

The report details some of the clinical firsts in 2015 including genomic studies suggesting that clonal hematopoiesis is a premalignant state for blood cancer, the first precision medicine trial in cancer prevention (EPOC) reporting that loss of heterozygosity can predict which patients with premalignant mouth lesions are most likely to develop oral cancer, and the U.S. Preventive Services Task Force recommending low-dose aspirin for colorectal cancer prevention based on age and risk.

Randomized trials have also suggested that a single dose of human papillomavirus vaccine can provide durable protection against HPV infection. Tumor biology studies established new chemoprevention for familial adenomatous polyposis syndrome and universal tumor screening guidelines based on DNA mismatch repair mutations and microsatellite instability for colorectal cancer in patients with Lynch syndrome.

Further, remarkable advances have been made in liquid biopsy technology, high-throughput functional screening, and computational biology methods and algorithms that “provide unprecedented opportunities to interrogate the biology of premalignancy...” they noted.

In an American Association for Cancer Research blog post, Dr. Lippman acknowledges that not everyone is the same page when it comes to the underlying principles of cancer prevention.

A “contentious” paper published at the start of 2015 suggested that variations in cancer risk are due to random mutations or what might otherwise be called bad luck. The new year was heralded in by a second paper, however, that came to roughly the opposite conclusion or that most cancers are preventable.

In February, an AACR Cancer Prevention Summit will bring together various stakeholders to discuss the current state of cancer prevention and to identify top priorities and research directions for the field, he noted.

The authors acknowledged grant support from the National Institutes of Health/National Cancer Institute.

pwendling@frontlinemedcom.com