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Is CLL chemoimmunotherapy dead? Not yet
CHICAGO – Chemoimmunotherapy for chronic lymphocytic leukemia is on the way out, but there’s one scenario where it still plays a key role, according to one leukemia expert.
That scenario is not in relapsed or refractory chronic lymphocytic leukemia (CLL), where the use of fludarabine, cyclophosphamide, and rituximab (FCR) may be hard to justify today. Data supporting use of FCR in relapsed CLL show a median progression-free survival (PFS) of about 21 months, Susan M. O’Brien, MD, of the University of California, Irvine, said at the annual meeting of the American Society of Clinical Oncology. There is also data for bendamustine-rituximab retreatment showing a median event-free survival of about 15 months, she added.
By contrast, the 5-year follow-up data for the Bruton tyrosine kinase inhibitor ibrutinib in the relapsed/refractory setting shows a median PFS of 52 months, which is “extraordinary,” given that the patients had a median of four prior regimens, Dr. O’Brien said.
Similarly, recently published results from the randomized, phase 3 MURANO study of venetoclax plus rituximab in relapsed/refractory CLL showed that median PFS was not reached at a median follow-up of 23.8 months, versus a median of 17 months for the bendamustine-rituximab comparison arm (N Engl J Med. 2018;378[12]:1107-20).
“Thanks to the MURANO study, we likely will have an expanded label for venetoclax that includes the combination of venetoclax and rituximab,” Dr. O’Brien said. “I think it’s quite clear that either of these is dramatically better than what you get with retreatment with chemotherapy, so I personally don’t think there is a role for chemoimmunotherapy in the relapsed patient.”
On June 8, 2018, the Food and Drug Administration granted regular approval for venetoclax for patients with CLL or small lymphocytic lymphoma, with or without 17p deletion, who have received at least one prior therapy. The FDA also approved its use in combination with rituximab.*
But frontline CLL treatment is currently a little bit more complicated, Dr. O’Brien said.
Recent studies show favorable long-term outcomes with FCR frontline therapy in the immunoglobulin heavy chain variable gene (IgHV) –mutated subgroup of patients, she noted.
The longest follow-up comes from a study from investigators at the University of Texas MD Anderson Cancer Center, Houston, published in 2016. In that study, the 12.8-year PFS was 53.9% for IgHV-mutated patients, versus just 8.7% for patients with unmutated IgHV. Of the IgHV-mutated group, more than half achieved minimal residual disease (MRD) negativity after treatment (Blood. 2016 Jan 21; 127[3]: 303-9).
“I’m going to go out on a limb and I’m going to suggest that I think there is a cure fraction here,” Dr. O’Brien said. “On the other hand, if there’s not a cure fraction and they’re going to relapse after 17 years, that’s a pretty attractive endpoint, even if it’s not a cure fraction.”
Clinical practice guidelines now recognize IgHV mutation status as an important marker that should be obtained when deciding on treatment, Dr. O’Brien noted.
For unmutated patients, the RESONATE-2 trial showed that ibrutinib was superior to chlorambucil in older patients, many of whom had comorbid conditions. In the 3-year update, median PFS was approximately 15 months for chlorambucil, while for ibrutinib the median PFS was “nowhere near” being reached, Dr. O’Brien said.
Those data may not be so relevant for fit, unmutated patients, and two randomized trials comparing FCR with bendamustine and rituximab have yet to report data. However, one recent cross-trial comparison found fairly overlapping survival curves for the two chemoimmunotherapy approaches.
Dr. O’Brien said she would put older patients with comorbidities on ibrutinib if a clinical trial was not available, and for fit, unmutated patients, while more data are needed, she would also use ibrutinib. However, patient preference sometimes tips the scale in favor of FCR.
“The discussions sometimes are quite long about whether the patient should opt to take ibrutinib or FCR,” Dr. O’Brien said. “The last patient I had that discussion with elected to take FCR. When I asked him why, he said because he liked the idea of being finished in six cycles, off all therapy, and hopefully in remission.”
While Dr. O’Brien said she views chemoimmunotherapy as still relevant in IgHV-mutated patients, eventually it will go away, she concluded. Toward that end, there is considerable interest in venetoclax plus ibrutinib, a combination that, in early reports, has yielded very encouraging MRD results in first-line CLL.
“We have no long-term data, but very, very exciting MRD negativity data,” Dr. O’Brien said.
Dr. O’Brien reported relationships with Abbvie, Amgen, Celgene, Gilead Sciences, Janssen, Pfizer, Pharmacyclics, Sunesis Pharmaceuticals, and others.
*This story was updated 6/25/2018.
CHICAGO – Chemoimmunotherapy for chronic lymphocytic leukemia is on the way out, but there’s one scenario where it still plays a key role, according to one leukemia expert.
That scenario is not in relapsed or refractory chronic lymphocytic leukemia (CLL), where the use of fludarabine, cyclophosphamide, and rituximab (FCR) may be hard to justify today. Data supporting use of FCR in relapsed CLL show a median progression-free survival (PFS) of about 21 months, Susan M. O’Brien, MD, of the University of California, Irvine, said at the annual meeting of the American Society of Clinical Oncology. There is also data for bendamustine-rituximab retreatment showing a median event-free survival of about 15 months, she added.
By contrast, the 5-year follow-up data for the Bruton tyrosine kinase inhibitor ibrutinib in the relapsed/refractory setting shows a median PFS of 52 months, which is “extraordinary,” given that the patients had a median of four prior regimens, Dr. O’Brien said.
Similarly, recently published results from the randomized, phase 3 MURANO study of venetoclax plus rituximab in relapsed/refractory CLL showed that median PFS was not reached at a median follow-up of 23.8 months, versus a median of 17 months for the bendamustine-rituximab comparison arm (N Engl J Med. 2018;378[12]:1107-20).
“Thanks to the MURANO study, we likely will have an expanded label for venetoclax that includes the combination of venetoclax and rituximab,” Dr. O’Brien said. “I think it’s quite clear that either of these is dramatically better than what you get with retreatment with chemotherapy, so I personally don’t think there is a role for chemoimmunotherapy in the relapsed patient.”
On June 8, 2018, the Food and Drug Administration granted regular approval for venetoclax for patients with CLL or small lymphocytic lymphoma, with or without 17p deletion, who have received at least one prior therapy. The FDA also approved its use in combination with rituximab.*
But frontline CLL treatment is currently a little bit more complicated, Dr. O’Brien said.
Recent studies show favorable long-term outcomes with FCR frontline therapy in the immunoglobulin heavy chain variable gene (IgHV) –mutated subgroup of patients, she noted.
The longest follow-up comes from a study from investigators at the University of Texas MD Anderson Cancer Center, Houston, published in 2016. In that study, the 12.8-year PFS was 53.9% for IgHV-mutated patients, versus just 8.7% for patients with unmutated IgHV. Of the IgHV-mutated group, more than half achieved minimal residual disease (MRD) negativity after treatment (Blood. 2016 Jan 21; 127[3]: 303-9).
“I’m going to go out on a limb and I’m going to suggest that I think there is a cure fraction here,” Dr. O’Brien said. “On the other hand, if there’s not a cure fraction and they’re going to relapse after 17 years, that’s a pretty attractive endpoint, even if it’s not a cure fraction.”
Clinical practice guidelines now recognize IgHV mutation status as an important marker that should be obtained when deciding on treatment, Dr. O’Brien noted.
For unmutated patients, the RESONATE-2 trial showed that ibrutinib was superior to chlorambucil in older patients, many of whom had comorbid conditions. In the 3-year update, median PFS was approximately 15 months for chlorambucil, while for ibrutinib the median PFS was “nowhere near” being reached, Dr. O’Brien said.
Those data may not be so relevant for fit, unmutated patients, and two randomized trials comparing FCR with bendamustine and rituximab have yet to report data. However, one recent cross-trial comparison found fairly overlapping survival curves for the two chemoimmunotherapy approaches.
Dr. O’Brien said she would put older patients with comorbidities on ibrutinib if a clinical trial was not available, and for fit, unmutated patients, while more data are needed, she would also use ibrutinib. However, patient preference sometimes tips the scale in favor of FCR.
“The discussions sometimes are quite long about whether the patient should opt to take ibrutinib or FCR,” Dr. O’Brien said. “The last patient I had that discussion with elected to take FCR. When I asked him why, he said because he liked the idea of being finished in six cycles, off all therapy, and hopefully in remission.”
While Dr. O’Brien said she views chemoimmunotherapy as still relevant in IgHV-mutated patients, eventually it will go away, she concluded. Toward that end, there is considerable interest in venetoclax plus ibrutinib, a combination that, in early reports, has yielded very encouraging MRD results in first-line CLL.
“We have no long-term data, but very, very exciting MRD negativity data,” Dr. O’Brien said.
Dr. O’Brien reported relationships with Abbvie, Amgen, Celgene, Gilead Sciences, Janssen, Pfizer, Pharmacyclics, Sunesis Pharmaceuticals, and others.
*This story was updated 6/25/2018.
CHICAGO – Chemoimmunotherapy for chronic lymphocytic leukemia is on the way out, but there’s one scenario where it still plays a key role, according to one leukemia expert.
That scenario is not in relapsed or refractory chronic lymphocytic leukemia (CLL), where the use of fludarabine, cyclophosphamide, and rituximab (FCR) may be hard to justify today. Data supporting use of FCR in relapsed CLL show a median progression-free survival (PFS) of about 21 months, Susan M. O’Brien, MD, of the University of California, Irvine, said at the annual meeting of the American Society of Clinical Oncology. There is also data for bendamustine-rituximab retreatment showing a median event-free survival of about 15 months, she added.
By contrast, the 5-year follow-up data for the Bruton tyrosine kinase inhibitor ibrutinib in the relapsed/refractory setting shows a median PFS of 52 months, which is “extraordinary,” given that the patients had a median of four prior regimens, Dr. O’Brien said.
Similarly, recently published results from the randomized, phase 3 MURANO study of venetoclax plus rituximab in relapsed/refractory CLL showed that median PFS was not reached at a median follow-up of 23.8 months, versus a median of 17 months for the bendamustine-rituximab comparison arm (N Engl J Med. 2018;378[12]:1107-20).
“Thanks to the MURANO study, we likely will have an expanded label for venetoclax that includes the combination of venetoclax and rituximab,” Dr. O’Brien said. “I think it’s quite clear that either of these is dramatically better than what you get with retreatment with chemotherapy, so I personally don’t think there is a role for chemoimmunotherapy in the relapsed patient.”
On June 8, 2018, the Food and Drug Administration granted regular approval for venetoclax for patients with CLL or small lymphocytic lymphoma, with or without 17p deletion, who have received at least one prior therapy. The FDA also approved its use in combination with rituximab.*
But frontline CLL treatment is currently a little bit more complicated, Dr. O’Brien said.
Recent studies show favorable long-term outcomes with FCR frontline therapy in the immunoglobulin heavy chain variable gene (IgHV) –mutated subgroup of patients, she noted.
The longest follow-up comes from a study from investigators at the University of Texas MD Anderson Cancer Center, Houston, published in 2016. In that study, the 12.8-year PFS was 53.9% for IgHV-mutated patients, versus just 8.7% for patients with unmutated IgHV. Of the IgHV-mutated group, more than half achieved minimal residual disease (MRD) negativity after treatment (Blood. 2016 Jan 21; 127[3]: 303-9).
“I’m going to go out on a limb and I’m going to suggest that I think there is a cure fraction here,” Dr. O’Brien said. “On the other hand, if there’s not a cure fraction and they’re going to relapse after 17 years, that’s a pretty attractive endpoint, even if it’s not a cure fraction.”
Clinical practice guidelines now recognize IgHV mutation status as an important marker that should be obtained when deciding on treatment, Dr. O’Brien noted.
For unmutated patients, the RESONATE-2 trial showed that ibrutinib was superior to chlorambucil in older patients, many of whom had comorbid conditions. In the 3-year update, median PFS was approximately 15 months for chlorambucil, while for ibrutinib the median PFS was “nowhere near” being reached, Dr. O’Brien said.
Those data may not be so relevant for fit, unmutated patients, and two randomized trials comparing FCR with bendamustine and rituximab have yet to report data. However, one recent cross-trial comparison found fairly overlapping survival curves for the two chemoimmunotherapy approaches.
Dr. O’Brien said she would put older patients with comorbidities on ibrutinib if a clinical trial was not available, and for fit, unmutated patients, while more data are needed, she would also use ibrutinib. However, patient preference sometimes tips the scale in favor of FCR.
“The discussions sometimes are quite long about whether the patient should opt to take ibrutinib or FCR,” Dr. O’Brien said. “The last patient I had that discussion with elected to take FCR. When I asked him why, he said because he liked the idea of being finished in six cycles, off all therapy, and hopefully in remission.”
While Dr. O’Brien said she views chemoimmunotherapy as still relevant in IgHV-mutated patients, eventually it will go away, she concluded. Toward that end, there is considerable interest in venetoclax plus ibrutinib, a combination that, in early reports, has yielded very encouraging MRD results in first-line CLL.
“We have no long-term data, but very, very exciting MRD negativity data,” Dr. O’Brien said.
Dr. O’Brien reported relationships with Abbvie, Amgen, Celgene, Gilead Sciences, Janssen, Pfizer, Pharmacyclics, Sunesis Pharmaceuticals, and others.
*This story was updated 6/25/2018.
EXPERT ANALYSIS FROM ASCO 2018
Study pinpoints skin cancer risk factors after hematopoietic cell transplant
CHICAGO – The 10-year incidence rates for both squamous cell carcinoma and basal cell carcinoma arising after hematopoietic cell transplantation are impressively high at 17%-plus for each, but the malignancies occur on two very different timelines, according to Jeffrey F. Scott, MD, a fellow in micrographic surgery and dermatologic oncology at Case Western Reserve University in Cleveland.
Most of the squamous cell carcinomas (SCCs) in a large multicenter retrospective study developed within the first 5 years following hematopoietic cell transplantation (HCT), while the majority of the basal cell carcinomas (BCCs) occurred after that point, Dr. Scott reported at the annual meeting of the American College of Mohs Surgery.
He presented the results of the study, which included 876 HCT recipients followed for a mean of 6.1 years. The study objective was to pin down the risk factors for skin cancer after HCT, especially the patient-specific ones. This has become a pressing issue because the use of HCT is steadily growing, and the 5-year survival rate now exceeds 50%.
The transplant-specific risk factors have previously been fairly well described by others. They include the donor source, type of disease, the conditioning regimen, whether whole body irradiation was used, immunosuppression, graft versus host disease (GVHD), and others.
The patient-centric risk factors, in contrast, have not been well characterized. And it’s critical to thoroughly understand these risk factors in order to develop targeted prevention and surveillance strategies, Dr. Scott said.
“There remains a significant knowledge gap within our field. I would venture that the majority of this audience has treated a patient with skin cancer who has had a transplant,” he said. “Yet when a patient asks us, ‘Doc, what is my risk for skin cancer after my HCT?’ we’re really unable to give them an accurate and complete assessment of that risk. That’s because we’re missing the second major category of risk factors: the patient-specific risk factors.”
The reason for that, he added, is that the major population-based studies and national HCT registries are run by hematologists and oncologists, and they haven’t adequately captured the patient-specific skin cancer risk factors. But these are variables very familiar to dermatologists. They include skin phenotype, history of UV radiation exposure, and history of pre-HCT skin cancer.
Dr. Scott said the multicenter study he presented has two major advantages over prior studies: its large size and thorough followup. Nearly all 876 patients were followed by both an oncologist and a dermatologist at the same institution.
During followup, the HCT recipients collectively developed 63 SCCs, 55 BCCs, and 16 malignant melanomas. The 5- and 10-year incidence rates for SCC were 10.6% and 17.2%. For BCC, the 5- and 10-year rates were 5.7% and 17.6%. All 16 cases of melanoma occurred within 5 years after HCT.
In multivariate Cox proportional hazard analyses, photodamage documented on examination was independently associated with a 3.2-fold increased risk of post-HCT SCC and a 3.5-fold increased risk of BCC.
A pre-transplant history of BCC was associated with a 3.9-fold increased likelihood of developing a BCC afterwards. Similarly, a pre-HCT history of SCC conferred a 4.2-fold increased risk of post-transplant SCC and was also independently associated with a 6.6-fold increased risk of developing melanoma post-HCT.
Fitzpatrick skin types I and II were respectively associated with 9.3- and 7.2-fold increased risks of post-HCT nonmelanoma skin cancer, compared with skin types III-VI.
Acute GVHD wasn’t associated with an increased risk of nonmelanoma skin cancer after HCT. However, in an observation that hasn’t previously been reported by others, chronic GVHD with skin involvement was associated with a 2.7-fold increased likelihood of SCC post-HCT, Dr. Scott noted.
What’s next for Dr. Scott and his coinvestigators? “Our ultimate goal with this project is to develop an interactive risk assessment tool like the National Cancer Institute’s Breast Cancer Risk Assessment Tool that can be online and used by patients and providers to estimate their individualized risk of basal cell carcinoma, squamous cell carcinoma, and melanoma after HCT,” he said.
Dr. Scott reported having no financial conflicts related to the study.
CHICAGO – The 10-year incidence rates for both squamous cell carcinoma and basal cell carcinoma arising after hematopoietic cell transplantation are impressively high at 17%-plus for each, but the malignancies occur on two very different timelines, according to Jeffrey F. Scott, MD, a fellow in micrographic surgery and dermatologic oncology at Case Western Reserve University in Cleveland.
Most of the squamous cell carcinomas (SCCs) in a large multicenter retrospective study developed within the first 5 years following hematopoietic cell transplantation (HCT), while the majority of the basal cell carcinomas (BCCs) occurred after that point, Dr. Scott reported at the annual meeting of the American College of Mohs Surgery.
He presented the results of the study, which included 876 HCT recipients followed for a mean of 6.1 years. The study objective was to pin down the risk factors for skin cancer after HCT, especially the patient-specific ones. This has become a pressing issue because the use of HCT is steadily growing, and the 5-year survival rate now exceeds 50%.
The transplant-specific risk factors have previously been fairly well described by others. They include the donor source, type of disease, the conditioning regimen, whether whole body irradiation was used, immunosuppression, graft versus host disease (GVHD), and others.
The patient-centric risk factors, in contrast, have not been well characterized. And it’s critical to thoroughly understand these risk factors in order to develop targeted prevention and surveillance strategies, Dr. Scott said.
“There remains a significant knowledge gap within our field. I would venture that the majority of this audience has treated a patient with skin cancer who has had a transplant,” he said. “Yet when a patient asks us, ‘Doc, what is my risk for skin cancer after my HCT?’ we’re really unable to give them an accurate and complete assessment of that risk. That’s because we’re missing the second major category of risk factors: the patient-specific risk factors.”
The reason for that, he added, is that the major population-based studies and national HCT registries are run by hematologists and oncologists, and they haven’t adequately captured the patient-specific skin cancer risk factors. But these are variables very familiar to dermatologists. They include skin phenotype, history of UV radiation exposure, and history of pre-HCT skin cancer.
Dr. Scott said the multicenter study he presented has two major advantages over prior studies: its large size and thorough followup. Nearly all 876 patients were followed by both an oncologist and a dermatologist at the same institution.
During followup, the HCT recipients collectively developed 63 SCCs, 55 BCCs, and 16 malignant melanomas. The 5- and 10-year incidence rates for SCC were 10.6% and 17.2%. For BCC, the 5- and 10-year rates were 5.7% and 17.6%. All 16 cases of melanoma occurred within 5 years after HCT.
In multivariate Cox proportional hazard analyses, photodamage documented on examination was independently associated with a 3.2-fold increased risk of post-HCT SCC and a 3.5-fold increased risk of BCC.
A pre-transplant history of BCC was associated with a 3.9-fold increased likelihood of developing a BCC afterwards. Similarly, a pre-HCT history of SCC conferred a 4.2-fold increased risk of post-transplant SCC and was also independently associated with a 6.6-fold increased risk of developing melanoma post-HCT.
Fitzpatrick skin types I and II were respectively associated with 9.3- and 7.2-fold increased risks of post-HCT nonmelanoma skin cancer, compared with skin types III-VI.
Acute GVHD wasn’t associated with an increased risk of nonmelanoma skin cancer after HCT. However, in an observation that hasn’t previously been reported by others, chronic GVHD with skin involvement was associated with a 2.7-fold increased likelihood of SCC post-HCT, Dr. Scott noted.
What’s next for Dr. Scott and his coinvestigators? “Our ultimate goal with this project is to develop an interactive risk assessment tool like the National Cancer Institute’s Breast Cancer Risk Assessment Tool that can be online and used by patients and providers to estimate their individualized risk of basal cell carcinoma, squamous cell carcinoma, and melanoma after HCT,” he said.
Dr. Scott reported having no financial conflicts related to the study.
CHICAGO – The 10-year incidence rates for both squamous cell carcinoma and basal cell carcinoma arising after hematopoietic cell transplantation are impressively high at 17%-plus for each, but the malignancies occur on two very different timelines, according to Jeffrey F. Scott, MD, a fellow in micrographic surgery and dermatologic oncology at Case Western Reserve University in Cleveland.
Most of the squamous cell carcinomas (SCCs) in a large multicenter retrospective study developed within the first 5 years following hematopoietic cell transplantation (HCT), while the majority of the basal cell carcinomas (BCCs) occurred after that point, Dr. Scott reported at the annual meeting of the American College of Mohs Surgery.
He presented the results of the study, which included 876 HCT recipients followed for a mean of 6.1 years. The study objective was to pin down the risk factors for skin cancer after HCT, especially the patient-specific ones. This has become a pressing issue because the use of HCT is steadily growing, and the 5-year survival rate now exceeds 50%.
The transplant-specific risk factors have previously been fairly well described by others. They include the donor source, type of disease, the conditioning regimen, whether whole body irradiation was used, immunosuppression, graft versus host disease (GVHD), and others.
The patient-centric risk factors, in contrast, have not been well characterized. And it’s critical to thoroughly understand these risk factors in order to develop targeted prevention and surveillance strategies, Dr. Scott said.
“There remains a significant knowledge gap within our field. I would venture that the majority of this audience has treated a patient with skin cancer who has had a transplant,” he said. “Yet when a patient asks us, ‘Doc, what is my risk for skin cancer after my HCT?’ we’re really unable to give them an accurate and complete assessment of that risk. That’s because we’re missing the second major category of risk factors: the patient-specific risk factors.”
The reason for that, he added, is that the major population-based studies and national HCT registries are run by hematologists and oncologists, and they haven’t adequately captured the patient-specific skin cancer risk factors. But these are variables very familiar to dermatologists. They include skin phenotype, history of UV radiation exposure, and history of pre-HCT skin cancer.
Dr. Scott said the multicenter study he presented has two major advantages over prior studies: its large size and thorough followup. Nearly all 876 patients were followed by both an oncologist and a dermatologist at the same institution.
During followup, the HCT recipients collectively developed 63 SCCs, 55 BCCs, and 16 malignant melanomas. The 5- and 10-year incidence rates for SCC were 10.6% and 17.2%. For BCC, the 5- and 10-year rates were 5.7% and 17.6%. All 16 cases of melanoma occurred within 5 years after HCT.
In multivariate Cox proportional hazard analyses, photodamage documented on examination was independently associated with a 3.2-fold increased risk of post-HCT SCC and a 3.5-fold increased risk of BCC.
A pre-transplant history of BCC was associated with a 3.9-fold increased likelihood of developing a BCC afterwards. Similarly, a pre-HCT history of SCC conferred a 4.2-fold increased risk of post-transplant SCC and was also independently associated with a 6.6-fold increased risk of developing melanoma post-HCT.
Fitzpatrick skin types I and II were respectively associated with 9.3- and 7.2-fold increased risks of post-HCT nonmelanoma skin cancer, compared with skin types III-VI.
Acute GVHD wasn’t associated with an increased risk of nonmelanoma skin cancer after HCT. However, in an observation that hasn’t previously been reported by others, chronic GVHD with skin involvement was associated with a 2.7-fold increased likelihood of SCC post-HCT, Dr. Scott noted.
What’s next for Dr. Scott and his coinvestigators? “Our ultimate goal with this project is to develop an interactive risk assessment tool like the National Cancer Institute’s Breast Cancer Risk Assessment Tool that can be online and used by patients and providers to estimate their individualized risk of basal cell carcinoma, squamous cell carcinoma, and melanoma after HCT,” he said.
Dr. Scott reported having no financial conflicts related to the study.
REPORTING FROM THE ACMS ANNUAL MEETING
Key clinical point:
Major finding: Photodamage documented on examination more than triples the risk of developing nonmelanoma skin cancer after hematopoietic cell transplantation.
Study details: A multicenter retrospective study of 876 hematopoietic cell recipients followed for a mean of 6.1 years.
Disclosures: The presenter reported having no financial conflicts related to the study, which was conducted without commercial support.
Ruxolitinib overcame lenalidomide resistance in myeloma
based on phase I trial results presented at the annual meeting of the American Society of Clinical Oncology (ASCO).
The clinical trial is the first to demonstrate the activity of a JAK inhibitor in the treatment of myeloma patients, according to investigator James R. Berenson, MD, medical and scientific director for the Institute for Myeloma & Bone Cancer Research (IMBCR), West Hollywood, Calif.
“These promising results have led to the expansion of the current clinical trial and provide the basis for exploration of this and other JAK inhibitor-containing combinations for treating patients with myeloma and other malignant diseases,” he added.
The dose-escalation study enrolled 28 patients with relapsed/refractory multiple myeloma who had previous treatment with lenalidomide/steroids and a proteasome inhibitor. Subjects received ruxolitinib twice daily continuously, lenalidomide daily on days 1-21 of a 28-day cycle, and methylprednisolone orally every other day. A traditional 3+3 dose escalation design was used to enroll subjects in four cohorts. In DL0, patients received ruxolitinib 5 mg, lenalidomide 5 mg, and methylprednisolone 40 mg. In DL+1 and +2, both doses of lenalidomide and methylprednisolone remained unchanged, and ruxolitinib was escalated to 10 and 15 mg, respectively. In DL+3, lenalidomide was escalated to 10 mg with methylprednisolone unchanged and ruxolitinib at 15 mg. A total of 19 patients were treated at the highest dose level, which was ruxolitinib 15 mg twice daily on days 1-28, lenalidomide 10 mg daily on days 1-21, and methylprednisolone 40 mg every other day.
The overall response rate was 39% (10 of 26 evaluable patients), Dr. Berenson reported. The clinical benefit rate was 50% (13 of 26 patients), with a median duration of response of 5.6 months in that group.
There were no dose-limiting toxicities. Grade 3 toxicities reported included thrombocytopenia in 11% (3 patients, gastrointestinal bleeding in 11% (3 patients), and anemia in 7% (2 patients).
These results are encouraging, though challenges remain, said Craig Hofmeister, MD, MPH, of Winship Cancer Institute, Emory University, Atlanta.
“Clearly in these patients who are 100% lenalidomide refractory, the overall response rate of anything greater than or close to 20, 30, 40% is very appealing,” Dr. Hofmeister said in an ASCO presentation discussing the results of this trial.
The usual rationale for JAK inhibition is targeting of the bone microenvironment, but the microenvironment is a formidable opponent, Dr. Hofmeister said in his presentation.
“That’s an uphill battle,” he said. “There is an upcoming carfilzomib and ruxolitinib trial in multiple myeloma moving forward, and I’d be excited to see” the results.
The study (NCT03110822) was sponsored by Oncotherapeutics in collaboration with Incyte, the maker of ruxolitinib (Jakafi). Dr. Berenson, the presenting author, had disclosures related to Incyte, as well as Amgen, Bristol-Myers Squibb, Celgene, Janssen, Takeda, and OncoTracker.
SOURCE: Berenson JR, et al. J Clin Oncol 36, 2018 (suppl; abstr 8005).
based on phase I trial results presented at the annual meeting of the American Society of Clinical Oncology (ASCO).
The clinical trial is the first to demonstrate the activity of a JAK inhibitor in the treatment of myeloma patients, according to investigator James R. Berenson, MD, medical and scientific director for the Institute for Myeloma & Bone Cancer Research (IMBCR), West Hollywood, Calif.
“These promising results have led to the expansion of the current clinical trial and provide the basis for exploration of this and other JAK inhibitor-containing combinations for treating patients with myeloma and other malignant diseases,” he added.
The dose-escalation study enrolled 28 patients with relapsed/refractory multiple myeloma who had previous treatment with lenalidomide/steroids and a proteasome inhibitor. Subjects received ruxolitinib twice daily continuously, lenalidomide daily on days 1-21 of a 28-day cycle, and methylprednisolone orally every other day. A traditional 3+3 dose escalation design was used to enroll subjects in four cohorts. In DL0, patients received ruxolitinib 5 mg, lenalidomide 5 mg, and methylprednisolone 40 mg. In DL+1 and +2, both doses of lenalidomide and methylprednisolone remained unchanged, and ruxolitinib was escalated to 10 and 15 mg, respectively. In DL+3, lenalidomide was escalated to 10 mg with methylprednisolone unchanged and ruxolitinib at 15 mg. A total of 19 patients were treated at the highest dose level, which was ruxolitinib 15 mg twice daily on days 1-28, lenalidomide 10 mg daily on days 1-21, and methylprednisolone 40 mg every other day.
The overall response rate was 39% (10 of 26 evaluable patients), Dr. Berenson reported. The clinical benefit rate was 50% (13 of 26 patients), with a median duration of response of 5.6 months in that group.
There were no dose-limiting toxicities. Grade 3 toxicities reported included thrombocytopenia in 11% (3 patients, gastrointestinal bleeding in 11% (3 patients), and anemia in 7% (2 patients).
These results are encouraging, though challenges remain, said Craig Hofmeister, MD, MPH, of Winship Cancer Institute, Emory University, Atlanta.
“Clearly in these patients who are 100% lenalidomide refractory, the overall response rate of anything greater than or close to 20, 30, 40% is very appealing,” Dr. Hofmeister said in an ASCO presentation discussing the results of this trial.
The usual rationale for JAK inhibition is targeting of the bone microenvironment, but the microenvironment is a formidable opponent, Dr. Hofmeister said in his presentation.
“That’s an uphill battle,” he said. “There is an upcoming carfilzomib and ruxolitinib trial in multiple myeloma moving forward, and I’d be excited to see” the results.
The study (NCT03110822) was sponsored by Oncotherapeutics in collaboration with Incyte, the maker of ruxolitinib (Jakafi). Dr. Berenson, the presenting author, had disclosures related to Incyte, as well as Amgen, Bristol-Myers Squibb, Celgene, Janssen, Takeda, and OncoTracker.
SOURCE: Berenson JR, et al. J Clin Oncol 36, 2018 (suppl; abstr 8005).
based on phase I trial results presented at the annual meeting of the American Society of Clinical Oncology (ASCO).
The clinical trial is the first to demonstrate the activity of a JAK inhibitor in the treatment of myeloma patients, according to investigator James R. Berenson, MD, medical and scientific director for the Institute for Myeloma & Bone Cancer Research (IMBCR), West Hollywood, Calif.
“These promising results have led to the expansion of the current clinical trial and provide the basis for exploration of this and other JAK inhibitor-containing combinations for treating patients with myeloma and other malignant diseases,” he added.
The dose-escalation study enrolled 28 patients with relapsed/refractory multiple myeloma who had previous treatment with lenalidomide/steroids and a proteasome inhibitor. Subjects received ruxolitinib twice daily continuously, lenalidomide daily on days 1-21 of a 28-day cycle, and methylprednisolone orally every other day. A traditional 3+3 dose escalation design was used to enroll subjects in four cohorts. In DL0, patients received ruxolitinib 5 mg, lenalidomide 5 mg, and methylprednisolone 40 mg. In DL+1 and +2, both doses of lenalidomide and methylprednisolone remained unchanged, and ruxolitinib was escalated to 10 and 15 mg, respectively. In DL+3, lenalidomide was escalated to 10 mg with methylprednisolone unchanged and ruxolitinib at 15 mg. A total of 19 patients were treated at the highest dose level, which was ruxolitinib 15 mg twice daily on days 1-28, lenalidomide 10 mg daily on days 1-21, and methylprednisolone 40 mg every other day.
The overall response rate was 39% (10 of 26 evaluable patients), Dr. Berenson reported. The clinical benefit rate was 50% (13 of 26 patients), with a median duration of response of 5.6 months in that group.
There were no dose-limiting toxicities. Grade 3 toxicities reported included thrombocytopenia in 11% (3 patients, gastrointestinal bleeding in 11% (3 patients), and anemia in 7% (2 patients).
These results are encouraging, though challenges remain, said Craig Hofmeister, MD, MPH, of Winship Cancer Institute, Emory University, Atlanta.
“Clearly in these patients who are 100% lenalidomide refractory, the overall response rate of anything greater than or close to 20, 30, 40% is very appealing,” Dr. Hofmeister said in an ASCO presentation discussing the results of this trial.
The usual rationale for JAK inhibition is targeting of the bone microenvironment, but the microenvironment is a formidable opponent, Dr. Hofmeister said in his presentation.
“That’s an uphill battle,” he said. “There is an upcoming carfilzomib and ruxolitinib trial in multiple myeloma moving forward, and I’d be excited to see” the results.
The study (NCT03110822) was sponsored by Oncotherapeutics in collaboration with Incyte, the maker of ruxolitinib (Jakafi). Dr. Berenson, the presenting author, had disclosures related to Incyte, as well as Amgen, Bristol-Myers Squibb, Celgene, Janssen, Takeda, and OncoTracker.
SOURCE: Berenson JR, et al. J Clin Oncol 36, 2018 (suppl; abstr 8005).
REPORTING FROM ASCO 2018
Key clinical point: The JAK 1/2 inhibitor ruxolitinib, in combination with lenalidomide and methylprednisolone, overcame resistance to lenalidomide in about half of heavily pre-treated patients with relapsed/refractory multiple myeloma in a phase I trial.
Major finding: The overall response rate was 39%, and the clinical benefit rate was 50% (13 of 26 patients).
Study details: A phase 1 study including 28 patients with relapsed/refractory multiple myeloma who had previous treatment with lenalidomide/steroids and a proteasome inhibitor.
Disclosures: Dr. Berenson, the presenting author, had disclosures related to Amgen, Bristol-Myers Squibb, Celgene, Incyte, Janssen, Takeda, and OncoTracker.
Source: Berenson JR, et al. J Clin Oncol 36, 2018 (suppl; abstr 8005).
CAR T therapy to enter early testing in multiple myeloma
Janssen Biotech is launching a phase 1b/2 trial of an .
The trial, which was cleared by the Food and Drug Administration to begin in the second half of 2018, will evaluate the safety and efficacy of LCAR-B38M (JNJ-68284528). The CAR T therapy targets B-cell Maturation Antigen and expresses a CAR protein that is identical to a product that was developed by Legend Biotech and evaluated in a first-in-human clinical study in China.
The drug is being developed as part of a collaboration between Legend Biotech and Janssen Biotech.
Janssen Biotech is launching a phase 1b/2 trial of an .
The trial, which was cleared by the Food and Drug Administration to begin in the second half of 2018, will evaluate the safety and efficacy of LCAR-B38M (JNJ-68284528). The CAR T therapy targets B-cell Maturation Antigen and expresses a CAR protein that is identical to a product that was developed by Legend Biotech and evaluated in a first-in-human clinical study in China.
The drug is being developed as part of a collaboration between Legend Biotech and Janssen Biotech.
Janssen Biotech is launching a phase 1b/2 trial of an .
The trial, which was cleared by the Food and Drug Administration to begin in the second half of 2018, will evaluate the safety and efficacy of LCAR-B38M (JNJ-68284528). The CAR T therapy targets B-cell Maturation Antigen and expresses a CAR protein that is identical to a product that was developed by Legend Biotech and evaluated in a first-in-human clinical study in China.
The drug is being developed as part of a collaboration between Legend Biotech and Janssen Biotech.
Novel Neuroendocrine Tumor in Multiple Endocrine Neoplasia Type 1 (FULL)
Neuroendocrine tumors (NETs) are uncommon and can occur in the context of genetic conditions. Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder of the tumor suppressor gene of the same name—MEN1, which encodes for the protein menin. Multiple endocrine neoplasia type 1 is characterized clinically by the presence of 2 or more of the following NETs: parathyroid, pituitary, and pancreaticoduodenal.1 Pancreaticoduodenal NETs occur in 30% to 80% of patients with MEN1 and have malignant potential. Although the majority of pancreaticoduodenal NETs are nonfunctioning, patients may present with symptoms secondary to mass effect.
Genetic testing exists for MEN1, but not all genetic mutations that cause MEN1 have been discovered. Therefore, because negative genetic testing does not rule out MEN1, a diagnosis is based on tumor type and location. Neuroendocrine tumors of the biliary tree are rare, and there
are no well-accepted guidelines on how to stage them.2-4 The following case demonstrates an unusual initial presentation of a NET in the context of MEN1.
Case Report
A 29-year-old, active-duty African-American man deployed in Kuwait presented with icterus, flank pain, and hematuria. His past medical history was significant for nephrolithiasis, and his family history was notable for hyperparathyroidism. Laboratory results showed primary hyperparathyroidism and evidence of biliary obstruction.
A sestamibi scan demonstrated uptake in a location corresponding with the right inferior parathyroid gland. A computed tomography (CT) scan showed nephrolithiasis and hepatic biliary ductal dilatation. Magnetic resonance cholangiopancreatography (MRCP) revealed both intra- and extrahepatic ductal dilatation, focal narrowing of the proximal common bile duct, and possible adenopathy that was concerning for cholangiocarcinoma. Endoscopic retrograde cholangiopancreatography (ERCP) demonstrated a 1 cm to 2 cm focal stricture within the mid-common bile duct with intra- and extrahepatic ductal dilatation (Figure 1). An endoscopy showed no masses in the duodenum, and anendoscopic ultrasound showed no masses in the pancreas. Endoscopic brushings and endoscopic, ultrasound-guided, fine-needle aspiration
cytology were nondiagnostic. Exploratory laparotomy revealed a dilated hepatic bile duct, an inflamed porta hepatis, and a mass involving the distal hepatic bile duct. 
The patient underwent cholecystectomy, radical extra hepatic bile duct resection to the level of the hepatic bifurcation, and hepaticojejunostomy. Gross examination of the specimen showed a nodule centered in the distal common hepatic duct with an adjacent, 2-cm lymph node. The histologic examination revealed a neoplastic proliferation consisting of epithelioid cells with round nuclei and granular chromatin with amphophilic cytoplasm in a trabecular and nested architecture.
The tumor was centered in the submucosa, which is typical of gastrointestinal NETs (Figure 2). There was no evidence of direct tumor extension elsewhere. About 40% of the tumor cells contained eosinophilic, intracytoplasmic inclusions (Figure 3). The tumor did not involve the margins or lymph node. 
Positive staining with the neuroendocrine markers synaptophysin and chromagranin A confirmed a well-differentiated NET. The intracytoplasmic inclusions stained strongly positive for cytokeratin CAM 5.2. The tumor had higher-grade features, including tumor cell necrosis, a Ki-67 labeling index of 3%, and perineural invasion. The 2010 World Health Organization (WHO) criteria for NET of the digestive system classified this tumor as a grade 2, well-differentiated NET and as stage 1a (limited to the bile duct).4
Postoperatively, octreotide scan with single-photon emission computed tomography (SPECT)-CT did not show additional masses or lesions. Serum pancreatic polypeptide was elevated, with the remaining serum and plasma NET markers—including gastrin, glucagon, insulin, chromogranin A, and vasoactive intestinal polypeptide (VIP)—being within reference ranges. Genetic testing (GeneDx, Inc, Gaithersburg, MD) showed an E563X nonsense mutation in the MEN1 gene, confirming a MEN1 disorder. The patient then underwent a 4-gland parathyroidectomy with reimplantation; the parathyroid glands demonstrated hyperplasia in all 4 glands.
Biochemical follow-up at 14 months showed that the serum pancreatic polypeptide had normalized. There was no evidence of pituitary orpancreatic hypersecretion. The patient developed hypoparathyroidism, requiring calcium and calcitriol supplementation. Radiographic follow-up using abdominal magnetic resonance imaging at 16 months showed no evidence of disease.
Discussion
This case illustrates a genetic disease with an unusual initial presentation. Primary extrahepatic bile duct NETs are rare and have been reported previously in patients without MEN1.5-9 Neuroendocrine tumors in the hepatic bile duct in patients with MEN1 also have been reported but only after these tumors first appeared in the pancreas or duodenum.10 An extensive literature search revealed no prior reports extrahepatic bile duct NETs with MEN1 as the primary site or with biliary obstruction, which is why this patient’s presentation is particularly interesting.5,6,10-13 The table summarizes select reports of NETs. 
Tumor location in this patient was atypical, and genetic testing guided the management. Serum MEN1 genetic testing is indicated in patients with ≥ 2 tumors that are atypical but possibly associated with MEN1 (such as adrenal tumors, gastrinomas, and carcinoids) and in patients aged < 45 years with primary hyperparathyroidism.14,15 The patient in this study was aged 29 years and had hyperparathyroidism and an NET of the hepatic bile duct. This condition was sufficient to warrant genetic testing, the results of which affected the patient’s subsequent parathyroid surgery.15 Despite the suggestion of unifocal localization on the sestamibi scan, the patient underwent the more appropriate subtotal parathyroidectomy.14 The patient’s tumor most likely originated from a germline mutation of the MEN1 gene.
As a result of the patient’s genetic test results, his daughter also was tested. She was found to have the same mutation as her father and will undergo proper tumor surveillance for MEN1. There was no personal or family history of hemangioblastomas, renal cell carcinomas, or cystadenomas, which would have prompted testing for von Hippel-Lindau disease. Likewise, there was no personal or family history of café-au-lait macules and neurofibromas, which would have prompted testing for neurofibromatosis type 1.
Due to the paucity of cases, there are currently no well-accepted guidelines on how to stage extrahepatic biliary NETs.3-5,16 The WHO recommends staging according to adenocarcinomas of the gallbladder and bile duct.3 As such, the pathologic stage of this tumor would be stage 1a.
The significance of the intracytoplasmic inclusion in this case is unknown. Pancreatic NETs and neuroendocrine carcinomas have demonstrated intracytoplasmic inclusions that stain positively for keratin and may indicate more aggressive tumor behavior.17-19 In 1 report, electron microscopic examination demonstrated intermediate filaments with entrapped neurosecretory granules.18 In a series of 84 cases of pancreatic endocrine tumors, 14 had intracytoplasmic inclusions; of these, 5 had MEN1.17 In the present case, the patient continues to show no evidence of tumor recurrence at 16 months after resection.
Conclusion
Extrahepatic biliary neuroendocrine tumors are rare. Further investigation into biliary tree NET staging and future studies to determine the significance of intracytoplasmic inclusions may be beneficial. This case highlights the appropriate use of genetic testing and supports expanding the clinical diagnosis of MEN1 to include NETs of the extrahepatic bile duct.
Click here to read the digital edition.
1. Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, eds. Williams Textbook of Endocrinology. 12th ed. Philadelphia, PA: WB Saunders; 2011.
2. American Joint Committee on Cancer. Neuroendocrine Tumors. In: Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, eds. American Joint Committee on Cancer Staging Handbook. 7th ed. From the AJCC Cancer Staging Manual. New York, NY: Springer-Verlag; 2010:227-236.
3. Komminoth P, Arnold R, Capella C, et al. Neuroendocrine neoplasms of the gallbladder and extrahepatic bile ducts. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, et al, eds. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon, France: IARC Press; 2010:274-276.
4. Rindi G, Arnold R, Bosman FT. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, et al, eds. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon, France: IARC Press; 2010:13.
5. Price TN, Thompson GB, Lewis JT, Lloyd RV, Young WF. Zollinger-Ellison syndrome due to primary gastrinoma of the extrahepatic biliary tree: three case reports and review of literature. Endocr Pract. 2009;15(7):737-749.
6. Bhandarwar AH, Shaikh TA, Borisa AD, et al. Primary neuroendocrine tumor of the left hepatic duct: a case report with review of the literature. Case Rep Surg. 2012:786432.
7. Bhalla P, Powle V, Shah RC, Jagannath P. Neuroendocrine tumor of common hepatic duct. Indian J Gastroenterol. 2012;31(3):144-146.
8. Khan FA, Stevens-Chase A, Chaudhry R, Hashmi A, Edelman D, Weaver D. Extrahepatic biliary obstrution secondary to neuroendocrine tumor of the common hepatic duct. Int J Surg Case Rep. 2017;30:46-49.
9. Hong N, Kim HJ, Byun JH, et al. Neuroendocrine neoplasms of the extrahepatic bile duct: radiologic and clinical characteristics. Abdom Imaging. 2015;40(1):181-191.
10. Tonelli F, Giudici F, Nesi G, Batignani G, Brandi ML. Biliary tree gastrinomas in multiple endocrine neoplasia type 1 syndrome. World J Gastroenterol. 2013;19(45):8312-8320.
11. Gibril F, Schumann M, Pace A, Jensen RT. Multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: a prospective study of 107 cases and comparison with 1009 cases from the literature. Medicine (Baltimore). 2004;83(1):43-83.
12. Pieterman CRC, Conemans EB, Dreijerink KMA, et al. Thoracic and duodenopancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1: natural history and function of menin in tumorigenesis. Endocr Relat Cancer. 2014;21(3):R121-R142.
13. Pipeleers-Marichal M, Somers G, Willems G, et al. Gastrinomas in the duodenums of patients with multiple endocrine neoplasia type 1 and the Zollinger-Ellison syndrome. N Engl J Med. 1990;322(11):723-727.
14. Thakker RV, Newey PJ, Walls GV, et al; Endocrine Society. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012;97(9):2990-3011.
15. Eastell R, Brandi ML, Costa AG, et al. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. J Clin Endocrinol Metab. 2014;99(10):3570-3579.
16. Michalopoulos N, Papavramidis TS, Karayannopoulou G, Pliakos I, Papavramidis ST, Kanellos I. Neuroendocrine tumors of extrahepatic biliary tract. Pathol Oncol Res. 2014;20(4):765-775.
17. Serra S, Asa SL, Chetty R. Intracytoplasmic inclusions (including the so-called “rhabdoid” phenotype) in pancreatic endocrine tumors. Endocr Pathol. 2006;17(1):75-81.
18. Shia J, Erlandson RA, Klimstra DS. Whorls of intermediate filaments with entrapped neurosecretory granules correspond to the “rhabdoid” inclusions seen in pancreatic endocrine
neoplasms. Am J Surg Pathol. 2004;28(2):271-273.
19. Perez-Montiel MD, Frankel WL, Suster S. Neuroendocrine carcinomas of the pancreas with ‘Rhabdoid’ features. Am J Surg Pathol. 2003;27(5):642-649.
Neuroendocrine tumors (NETs) are uncommon and can occur in the context of genetic conditions. Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder of the tumor suppressor gene of the same name—MEN1, which encodes for the protein menin. Multiple endocrine neoplasia type 1 is characterized clinically by the presence of 2 or more of the following NETs: parathyroid, pituitary, and pancreaticoduodenal.1 Pancreaticoduodenal NETs occur in 30% to 80% of patients with MEN1 and have malignant potential. Although the majority of pancreaticoduodenal NETs are nonfunctioning, patients may present with symptoms secondary to mass effect.
Genetic testing exists for MEN1, but not all genetic mutations that cause MEN1 have been discovered. Therefore, because negative genetic testing does not rule out MEN1, a diagnosis is based on tumor type and location. Neuroendocrine tumors of the biliary tree are rare, and there
are no well-accepted guidelines on how to stage them.2-4 The following case demonstrates an unusual initial presentation of a NET in the context of MEN1.
Case Report
A 29-year-old, active-duty African-American man deployed in Kuwait presented with icterus, flank pain, and hematuria. His past medical history was significant for nephrolithiasis, and his family history was notable for hyperparathyroidism. Laboratory results showed primary hyperparathyroidism and evidence of biliary obstruction.
A sestamibi scan demonstrated uptake in a location corresponding with the right inferior parathyroid gland. A computed tomography (CT) scan showed nephrolithiasis and hepatic biliary ductal dilatation. Magnetic resonance cholangiopancreatography (MRCP) revealed both intra- and extrahepatic ductal dilatation, focal narrowing of the proximal common bile duct, and possible adenopathy that was concerning for cholangiocarcinoma. Endoscopic retrograde cholangiopancreatography (ERCP) demonstrated a 1 cm to 2 cm focal stricture within the mid-common bile duct with intra- and extrahepatic ductal dilatation (Figure 1). An endoscopy showed no masses in the duodenum, and anendoscopic ultrasound showed no masses in the pancreas. Endoscopic brushings and endoscopic, ultrasound-guided, fine-needle aspiration
cytology were nondiagnostic. Exploratory laparotomy revealed a dilated hepatic bile duct, an inflamed porta hepatis, and a mass involving the distal hepatic bile duct.
The patient underwent cholecystectomy, radical extra hepatic bile duct resection to the level of the hepatic bifurcation, and hepaticojejunostomy. Gross examination of the specimen showed a nodule centered in the distal common hepatic duct with an adjacent, 2-cm lymph node. The histologic examination revealed a neoplastic proliferation consisting of epithelioid cells with round nuclei and granular chromatin with amphophilic cytoplasm in a trabecular and nested architecture.
The tumor was centered in the submucosa, which is typical of gastrointestinal NETs (Figure 2). There was no evidence of direct tumor extension elsewhere. About 40% of the tumor cells contained eosinophilic, intracytoplasmic inclusions (Figure 3). The tumor did not involve the margins or lymph node.
Positive staining with the neuroendocrine markers synaptophysin and chromagranin A confirmed a well-differentiated NET. The intracytoplasmic inclusions stained strongly positive for cytokeratin CAM 5.2. The tumor had higher-grade features, including tumor cell necrosis, a Ki-67 labeling index of 3%, and perineural invasion. The 2010 World Health Organization (WHO) criteria for NET of the digestive system classified this tumor as a grade 2, well-differentiated NET and as stage 1a (limited to the bile duct).4
Postoperatively, octreotide scan with single-photon emission computed tomography (SPECT)-CT did not show additional masses or lesions. Serum pancreatic polypeptide was elevated, with the remaining serum and plasma NET markers—including gastrin, glucagon, insulin, chromogranin A, and vasoactive intestinal polypeptide (VIP)—being within reference ranges. Genetic testing (GeneDx, Inc, Gaithersburg, MD) showed an E563X nonsense mutation in the MEN1 gene, confirming a MEN1 disorder. The patient then underwent a 4-gland parathyroidectomy with reimplantation; the parathyroid glands demonstrated hyperplasia in all 4 glands.
Biochemical follow-up at 14 months showed that the serum pancreatic polypeptide had normalized. There was no evidence of pituitary orpancreatic hypersecretion. The patient developed hypoparathyroidism, requiring calcium and calcitriol supplementation. Radiographic follow-up using abdominal magnetic resonance imaging at 16 months showed no evidence of disease.
Discussion
This case illustrates a genetic disease with an unusual initial presentation. Primary extrahepatic bile duct NETs are rare and have been reported previously in patients without MEN1.5-9 Neuroendocrine tumors in the hepatic bile duct in patients with MEN1 also have been reported but only after these tumors first appeared in the pancreas or duodenum.10 An extensive literature search revealed no prior reports extrahepatic bile duct NETs with MEN1 as the primary site or with biliary obstruction, which is why this patient’s presentation is particularly interesting.5,6,10-13 The table summarizes select reports of NETs.
Tumor location in this patient was atypical, and genetic testing guided the management. Serum MEN1 genetic testing is indicated in patients with ≥ 2 tumors that are atypical but possibly associated with MEN1 (such as adrenal tumors, gastrinomas, and carcinoids) and in patients aged < 45 years with primary hyperparathyroidism.14,15 The patient in this study was aged 29 years and had hyperparathyroidism and an NET of the hepatic bile duct. This condition was sufficient to warrant genetic testing, the results of which affected the patient’s subsequent parathyroid surgery.15 Despite the suggestion of unifocal localization on the sestamibi scan, the patient underwent the more appropriate subtotal parathyroidectomy.14 The patient’s tumor most likely originated from a germline mutation of the MEN1 gene.
As a result of the patient’s genetic test results, his daughter also was tested. She was found to have the same mutation as her father and will undergo proper tumor surveillance for MEN1. There was no personal or family history of hemangioblastomas, renal cell carcinomas, or cystadenomas, which would have prompted testing for von Hippel-Lindau disease. Likewise, there was no personal or family history of café-au-lait macules and neurofibromas, which would have prompted testing for neurofibromatosis type 1.
Due to the paucity of cases, there are currently no well-accepted guidelines on how to stage extrahepatic biliary NETs.3-5,16 The WHO recommends staging according to adenocarcinomas of the gallbladder and bile duct.3 As such, the pathologic stage of this tumor would be stage 1a.
The significance of the intracytoplasmic inclusion in this case is unknown. Pancreatic NETs and neuroendocrine carcinomas have demonstrated intracytoplasmic inclusions that stain positively for keratin and may indicate more aggressive tumor behavior.17-19 In 1 report, electron microscopic examination demonstrated intermediate filaments with entrapped neurosecretory granules.18 In a series of 84 cases of pancreatic endocrine tumors, 14 had intracytoplasmic inclusions; of these, 5 had MEN1.17 In the present case, the patient continues to show no evidence of tumor recurrence at 16 months after resection.
Conclusion
Extrahepatic biliary neuroendocrine tumors are rare. Further investigation into biliary tree NET staging and future studies to determine the significance of intracytoplasmic inclusions may be beneficial. This case highlights the appropriate use of genetic testing and supports expanding the clinical diagnosis of MEN1 to include NETs of the extrahepatic bile duct.
Click here to read the digital edition.
Neuroendocrine tumors (NETs) are uncommon and can occur in the context of genetic conditions. Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder of the tumor suppressor gene of the same name—MEN1, which encodes for the protein menin. Multiple endocrine neoplasia type 1 is characterized clinically by the presence of 2 or more of the following NETs: parathyroid, pituitary, and pancreaticoduodenal.1 Pancreaticoduodenal NETs occur in 30% to 80% of patients with MEN1 and have malignant potential. Although the majority of pancreaticoduodenal NETs are nonfunctioning, patients may present with symptoms secondary to mass effect.
Genetic testing exists for MEN1, but not all genetic mutations that cause MEN1 have been discovered. Therefore, because negative genetic testing does not rule out MEN1, a diagnosis is based on tumor type and location. Neuroendocrine tumors of the biliary tree are rare, and there
are no well-accepted guidelines on how to stage them.2-4 The following case demonstrates an unusual initial presentation of a NET in the context of MEN1.
Case Report
A 29-year-old, active-duty African-American man deployed in Kuwait presented with icterus, flank pain, and hematuria. His past medical history was significant for nephrolithiasis, and his family history was notable for hyperparathyroidism. Laboratory results showed primary hyperparathyroidism and evidence of biliary obstruction.
A sestamibi scan demonstrated uptake in a location corresponding with the right inferior parathyroid gland. A computed tomography (CT) scan showed nephrolithiasis and hepatic biliary ductal dilatation. Magnetic resonance cholangiopancreatography (MRCP) revealed both intra- and extrahepatic ductal dilatation, focal narrowing of the proximal common bile duct, and possible adenopathy that was concerning for cholangiocarcinoma. Endoscopic retrograde cholangiopancreatography (ERCP) demonstrated a 1 cm to 2 cm focal stricture within the mid-common bile duct with intra- and extrahepatic ductal dilatation (Figure 1). An endoscopy showed no masses in the duodenum, and anendoscopic ultrasound showed no masses in the pancreas. Endoscopic brushings and endoscopic, ultrasound-guided, fine-needle aspiration
cytology were nondiagnostic. Exploratory laparotomy revealed a dilated hepatic bile duct, an inflamed porta hepatis, and a mass involving the distal hepatic bile duct.
The patient underwent cholecystectomy, radical extra hepatic bile duct resection to the level of the hepatic bifurcation, and hepaticojejunostomy. Gross examination of the specimen showed a nodule centered in the distal common hepatic duct with an adjacent, 2-cm lymph node. The histologic examination revealed a neoplastic proliferation consisting of epithelioid cells with round nuclei and granular chromatin with amphophilic cytoplasm in a trabecular and nested architecture.
The tumor was centered in the submucosa, which is typical of gastrointestinal NETs (Figure 2). There was no evidence of direct tumor extension elsewhere. About 40% of the tumor cells contained eosinophilic, intracytoplasmic inclusions (Figure 3). The tumor did not involve the margins or lymph node.
Positive staining with the neuroendocrine markers synaptophysin and chromagranin A confirmed a well-differentiated NET. The intracytoplasmic inclusions stained strongly positive for cytokeratin CAM 5.2. The tumor had higher-grade features, including tumor cell necrosis, a Ki-67 labeling index of 3%, and perineural invasion. The 2010 World Health Organization (WHO) criteria for NET of the digestive system classified this tumor as a grade 2, well-differentiated NET and as stage 1a (limited to the bile duct).4
Postoperatively, octreotide scan with single-photon emission computed tomography (SPECT)-CT did not show additional masses or lesions. Serum pancreatic polypeptide was elevated, with the remaining serum and plasma NET markers—including gastrin, glucagon, insulin, chromogranin A, and vasoactive intestinal polypeptide (VIP)—being within reference ranges. Genetic testing (GeneDx, Inc, Gaithersburg, MD) showed an E563X nonsense mutation in the MEN1 gene, confirming a MEN1 disorder. The patient then underwent a 4-gland parathyroidectomy with reimplantation; the parathyroid glands demonstrated hyperplasia in all 4 glands.
Biochemical follow-up at 14 months showed that the serum pancreatic polypeptide had normalized. There was no evidence of pituitary orpancreatic hypersecretion. The patient developed hypoparathyroidism, requiring calcium and calcitriol supplementation. Radiographic follow-up using abdominal magnetic resonance imaging at 16 months showed no evidence of disease.
Discussion
This case illustrates a genetic disease with an unusual initial presentation. Primary extrahepatic bile duct NETs are rare and have been reported previously in patients without MEN1.5-9 Neuroendocrine tumors in the hepatic bile duct in patients with MEN1 also have been reported but only after these tumors first appeared in the pancreas or duodenum.10 An extensive literature search revealed no prior reports extrahepatic bile duct NETs with MEN1 as the primary site or with biliary obstruction, which is why this patient’s presentation is particularly interesting.5,6,10-13 The table summarizes select reports of NETs.
Tumor location in this patient was atypical, and genetic testing guided the management. Serum MEN1 genetic testing is indicated in patients with ≥ 2 tumors that are atypical but possibly associated with MEN1 (such as adrenal tumors, gastrinomas, and carcinoids) and in patients aged < 45 years with primary hyperparathyroidism.14,15 The patient in this study was aged 29 years and had hyperparathyroidism and an NET of the hepatic bile duct. This condition was sufficient to warrant genetic testing, the results of which affected the patient’s subsequent parathyroid surgery.15 Despite the suggestion of unifocal localization on the sestamibi scan, the patient underwent the more appropriate subtotal parathyroidectomy.14 The patient’s tumor most likely originated from a germline mutation of the MEN1 gene.
As a result of the patient’s genetic test results, his daughter also was tested. She was found to have the same mutation as her father and will undergo proper tumor surveillance for MEN1. There was no personal or family history of hemangioblastomas, renal cell carcinomas, or cystadenomas, which would have prompted testing for von Hippel-Lindau disease. Likewise, there was no personal or family history of café-au-lait macules and neurofibromas, which would have prompted testing for neurofibromatosis type 1.
Due to the paucity of cases, there are currently no well-accepted guidelines on how to stage extrahepatic biliary NETs.3-5,16 The WHO recommends staging according to adenocarcinomas of the gallbladder and bile duct.3 As such, the pathologic stage of this tumor would be stage 1a.
The significance of the intracytoplasmic inclusion in this case is unknown. Pancreatic NETs and neuroendocrine carcinomas have demonstrated intracytoplasmic inclusions that stain positively for keratin and may indicate more aggressive tumor behavior.17-19 In 1 report, electron microscopic examination demonstrated intermediate filaments with entrapped neurosecretory granules.18 In a series of 84 cases of pancreatic endocrine tumors, 14 had intracytoplasmic inclusions; of these, 5 had MEN1.17 In the present case, the patient continues to show no evidence of tumor recurrence at 16 months after resection.
Conclusion
Extrahepatic biliary neuroendocrine tumors are rare. Further investigation into biliary tree NET staging and future studies to determine the significance of intracytoplasmic inclusions may be beneficial. This case highlights the appropriate use of genetic testing and supports expanding the clinical diagnosis of MEN1 to include NETs of the extrahepatic bile duct.
Click here to read the digital edition.
1. Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, eds. Williams Textbook of Endocrinology. 12th ed. Philadelphia, PA: WB Saunders; 2011.
2. American Joint Committee on Cancer. Neuroendocrine Tumors. In: Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, eds. American Joint Committee on Cancer Staging Handbook. 7th ed. From the AJCC Cancer Staging Manual. New York, NY: Springer-Verlag; 2010:227-236.
3. Komminoth P, Arnold R, Capella C, et al. Neuroendocrine neoplasms of the gallbladder and extrahepatic bile ducts. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, et al, eds. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon, France: IARC Press; 2010:274-276.
4. Rindi G, Arnold R, Bosman FT. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, et al, eds. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon, France: IARC Press; 2010:13.
5. Price TN, Thompson GB, Lewis JT, Lloyd RV, Young WF. Zollinger-Ellison syndrome due to primary gastrinoma of the extrahepatic biliary tree: three case reports and review of literature. Endocr Pract. 2009;15(7):737-749.
6. Bhandarwar AH, Shaikh TA, Borisa AD, et al. Primary neuroendocrine tumor of the left hepatic duct: a case report with review of the literature. Case Rep Surg. 2012:786432.
7. Bhalla P, Powle V, Shah RC, Jagannath P. Neuroendocrine tumor of common hepatic duct. Indian J Gastroenterol. 2012;31(3):144-146.
8. Khan FA, Stevens-Chase A, Chaudhry R, Hashmi A, Edelman D, Weaver D. Extrahepatic biliary obstrution secondary to neuroendocrine tumor of the common hepatic duct. Int J Surg Case Rep. 2017;30:46-49.
9. Hong N, Kim HJ, Byun JH, et al. Neuroendocrine neoplasms of the extrahepatic bile duct: radiologic and clinical characteristics. Abdom Imaging. 2015;40(1):181-191.
10. Tonelli F, Giudici F, Nesi G, Batignani G, Brandi ML. Biliary tree gastrinomas in multiple endocrine neoplasia type 1 syndrome. World J Gastroenterol. 2013;19(45):8312-8320.
11. Gibril F, Schumann M, Pace A, Jensen RT. Multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: a prospective study of 107 cases and comparison with 1009 cases from the literature. Medicine (Baltimore). 2004;83(1):43-83.
12. Pieterman CRC, Conemans EB, Dreijerink KMA, et al. Thoracic and duodenopancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1: natural history and function of menin in tumorigenesis. Endocr Relat Cancer. 2014;21(3):R121-R142.
13. Pipeleers-Marichal M, Somers G, Willems G, et al. Gastrinomas in the duodenums of patients with multiple endocrine neoplasia type 1 and the Zollinger-Ellison syndrome. N Engl J Med. 1990;322(11):723-727.
14. Thakker RV, Newey PJ, Walls GV, et al; Endocrine Society. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012;97(9):2990-3011.
15. Eastell R, Brandi ML, Costa AG, et al. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. J Clin Endocrinol Metab. 2014;99(10):3570-3579.
16. Michalopoulos N, Papavramidis TS, Karayannopoulou G, Pliakos I, Papavramidis ST, Kanellos I. Neuroendocrine tumors of extrahepatic biliary tract. Pathol Oncol Res. 2014;20(4):765-775.
17. Serra S, Asa SL, Chetty R. Intracytoplasmic inclusions (including the so-called “rhabdoid” phenotype) in pancreatic endocrine tumors. Endocr Pathol. 2006;17(1):75-81.
18. Shia J, Erlandson RA, Klimstra DS. Whorls of intermediate filaments with entrapped neurosecretory granules correspond to the “rhabdoid” inclusions seen in pancreatic endocrine
neoplasms. Am J Surg Pathol. 2004;28(2):271-273.
19. Perez-Montiel MD, Frankel WL, Suster S. Neuroendocrine carcinomas of the pancreas with ‘Rhabdoid’ features. Am J Surg Pathol. 2003;27(5):642-649.
1. Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, eds. Williams Textbook of Endocrinology. 12th ed. Philadelphia, PA: WB Saunders; 2011.
2. American Joint Committee on Cancer. Neuroendocrine Tumors. In: Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, eds. American Joint Committee on Cancer Staging Handbook. 7th ed. From the AJCC Cancer Staging Manual. New York, NY: Springer-Verlag; 2010:227-236.
3. Komminoth P, Arnold R, Capella C, et al. Neuroendocrine neoplasms of the gallbladder and extrahepatic bile ducts. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, et al, eds. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon, France: IARC Press; 2010:274-276.
4. Rindi G, Arnold R, Bosman FT. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, et al, eds. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon, France: IARC Press; 2010:13.
5. Price TN, Thompson GB, Lewis JT, Lloyd RV, Young WF. Zollinger-Ellison syndrome due to primary gastrinoma of the extrahepatic biliary tree: three case reports and review of literature. Endocr Pract. 2009;15(7):737-749.
6. Bhandarwar AH, Shaikh TA, Borisa AD, et al. Primary neuroendocrine tumor of the left hepatic duct: a case report with review of the literature. Case Rep Surg. 2012:786432.
7. Bhalla P, Powle V, Shah RC, Jagannath P. Neuroendocrine tumor of common hepatic duct. Indian J Gastroenterol. 2012;31(3):144-146.
8. Khan FA, Stevens-Chase A, Chaudhry R, Hashmi A, Edelman D, Weaver D. Extrahepatic biliary obstrution secondary to neuroendocrine tumor of the common hepatic duct. Int J Surg Case Rep. 2017;30:46-49.
9. Hong N, Kim HJ, Byun JH, et al. Neuroendocrine neoplasms of the extrahepatic bile duct: radiologic and clinical characteristics. Abdom Imaging. 2015;40(1):181-191.
10. Tonelli F, Giudici F, Nesi G, Batignani G, Brandi ML. Biliary tree gastrinomas in multiple endocrine neoplasia type 1 syndrome. World J Gastroenterol. 2013;19(45):8312-8320.
11. Gibril F, Schumann M, Pace A, Jensen RT. Multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: a prospective study of 107 cases and comparison with 1009 cases from the literature. Medicine (Baltimore). 2004;83(1):43-83.
12. Pieterman CRC, Conemans EB, Dreijerink KMA, et al. Thoracic and duodenopancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1: natural history and function of menin in tumorigenesis. Endocr Relat Cancer. 2014;21(3):R121-R142.
13. Pipeleers-Marichal M, Somers G, Willems G, et al. Gastrinomas in the duodenums of patients with multiple endocrine neoplasia type 1 and the Zollinger-Ellison syndrome. N Engl J Med. 1990;322(11):723-727.
14. Thakker RV, Newey PJ, Walls GV, et al; Endocrine Society. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012;97(9):2990-3011.
15. Eastell R, Brandi ML, Costa AG, et al. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. J Clin Endocrinol Metab. 2014;99(10):3570-3579.
16. Michalopoulos N, Papavramidis TS, Karayannopoulou G, Pliakos I, Papavramidis ST, Kanellos I. Neuroendocrine tumors of extrahepatic biliary tract. Pathol Oncol Res. 2014;20(4):765-775.
17. Serra S, Asa SL, Chetty R. Intracytoplasmic inclusions (including the so-called “rhabdoid” phenotype) in pancreatic endocrine tumors. Endocr Pathol. 2006;17(1):75-81.
18. Shia J, Erlandson RA, Klimstra DS. Whorls of intermediate filaments with entrapped neurosecretory granules correspond to the “rhabdoid” inclusions seen in pancreatic endocrine
neoplasms. Am J Surg Pathol. 2004;28(2):271-273.
19. Perez-Montiel MD, Frankel WL, Suster S. Neuroendocrine carcinomas of the pancreas with ‘Rhabdoid’ features. Am J Surg Pathol. 2003;27(5):642-649.
What Makes Squamous Cell Cancers Different? Genomics May Explain
Squamous cell carcinomas (SCCs) associated with smoking and human papillomavirus (HPV) have distinct genomic signatures, say researchers from a National Institutes of Health-supported study. That is one of the findings that may help distinguish SCCs from other cancers and point the way to new research and treatment.
The researchers used new analytic tools and data from the recently completed PanCancer Atlas to investigate similarities and differences among SCCs in the head and neck, lung, esophagus, cervix, and bladder. The PanCancer Atlas is a detailed analysis from a dataset containing molecular and clinical information on more than 10,000 tumors from 33 forms of cancer.
The researchers combined multiple platforms of genomic data from 1,400 SCC samples into integrated analyses, creating visual clusters of tumors based on genomic characteristics.
Squamous cell carcinomas had genomic features that set them apart from other cancers, the researchers found. The most common were gains or losses of the sections of certain chromosomes, making it likely that those regions harbor genes important to the development of SCCs.
The current study expands on research reported in 2014 and 2015, which compared genomic features of SCCs in head and neck cancer associated with smoking (a risk factor for head and neck cancer [HNC]) and HPV (a risk factor for cervical and some HNCs). Certain features were present in tumors associated with both, whereas others were exclusive to only 1 of the 2. The researchers also found similarities in the genomic characteristics of HNCs with lung cancers, some bladder cancers, and cervical cancer.
Squamous cell carcinomas (SCCs) associated with smoking and human papillomavirus (HPV) have distinct genomic signatures, say researchers from a National Institutes of Health-supported study. That is one of the findings that may help distinguish SCCs from other cancers and point the way to new research and treatment.
The researchers used new analytic tools and data from the recently completed PanCancer Atlas to investigate similarities and differences among SCCs in the head and neck, lung, esophagus, cervix, and bladder. The PanCancer Atlas is a detailed analysis from a dataset containing molecular and clinical information on more than 10,000 tumors from 33 forms of cancer.
The researchers combined multiple platforms of genomic data from 1,400 SCC samples into integrated analyses, creating visual clusters of tumors based on genomic characteristics.
Squamous cell carcinomas had genomic features that set them apart from other cancers, the researchers found. The most common were gains or losses of the sections of certain chromosomes, making it likely that those regions harbor genes important to the development of SCCs.
The current study expands on research reported in 2014 and 2015, which compared genomic features of SCCs in head and neck cancer associated with smoking (a risk factor for head and neck cancer [HNC]) and HPV (a risk factor for cervical and some HNCs). Certain features were present in tumors associated with both, whereas others were exclusive to only 1 of the 2. The researchers also found similarities in the genomic characteristics of HNCs with lung cancers, some bladder cancers, and cervical cancer.
Squamous cell carcinomas (SCCs) associated with smoking and human papillomavirus (HPV) have distinct genomic signatures, say researchers from a National Institutes of Health-supported study. That is one of the findings that may help distinguish SCCs from other cancers and point the way to new research and treatment.
The researchers used new analytic tools and data from the recently completed PanCancer Atlas to investigate similarities and differences among SCCs in the head and neck, lung, esophagus, cervix, and bladder. The PanCancer Atlas is a detailed analysis from a dataset containing molecular and clinical information on more than 10,000 tumors from 33 forms of cancer.
The researchers combined multiple platforms of genomic data from 1,400 SCC samples into integrated analyses, creating visual clusters of tumors based on genomic characteristics.
Squamous cell carcinomas had genomic features that set them apart from other cancers, the researchers found. The most common were gains or losses of the sections of certain chromosomes, making it likely that those regions harbor genes important to the development of SCCs.
The current study expands on research reported in 2014 and 2015, which compared genomic features of SCCs in head and neck cancer associated with smoking (a risk factor for head and neck cancer [HNC]) and HPV (a risk factor for cervical and some HNCs). Certain features were present in tumors associated with both, whereas others were exclusive to only 1 of the 2. The researchers also found similarities in the genomic characteristics of HNCs with lung cancers, some bladder cancers, and cervical cancer.
Giving Dexamethasone a New Lease on Life
Dexamethasone (Dex), a synthetic glucocorticoid, for years has been widely used both to treat adverse effects of antitumor agents and in direct chemotherapy regimens for hematologic malignancies, such as leukemia and lymphoma. But might it be modified to work against solid cancers as well? Researchers from Advanced Radiation Technology Institute, Medical Device Development Center, and University of Science and Technology in South Korea, suggest that ionizing radiation could produce new anticancer options from an old drug.
The researchers irradiated Dex with γ- rays to produce ionizing-radiation-irradiated.
Dex (Dex-IR), then investigated its effects on human lung cancer cells (cell lines H1650, A549, and H1299). The researchers used ionizing radiation because introducing energy into materials can produce favorable changes; irradiated materials with sufficiently high energy can decompose to yield very reactive intermediate molecules and form new ones. In this study, γ -irradiation produced “remarkable changes” in the chemical properties of dexamethasone; changes included degradation products, such as methanol vapor and carbon monoxide.
Original Dex inhibits the proliferation of non-small cell lung cancer (NSCLC) cells but has minimal cytotoxic effects, the researchers say. However, Dex-IR not only significantly inhibited the proliferation of NSCLC cells, but also induced apoptosis, arrested cell cycles of H1650 lung cancer cells, and significantly reduced cells’ invasiveness.
The researchers say their results “strongly suggest” a direct link between the chemical derivatives of Dex and inhibition of NSCLC cell growth. Their findings are the first evidence that γ -irradiated Dex represents a novel class of anticancer agents for lung cancer.
Lee EH, Park CH, Choi HJ, Kawala RA, Bai HW, Chung BY. PLoS One. 2018;13(4):e0194341.
doi: 10.1371/journal.pone.0194341.
Dexamethasone (Dex), a synthetic glucocorticoid, for years has been widely used both to treat adverse effects of antitumor agents and in direct chemotherapy regimens for hematologic malignancies, such as leukemia and lymphoma. But might it be modified to work against solid cancers as well? Researchers from Advanced Radiation Technology Institute, Medical Device Development Center, and University of Science and Technology in South Korea, suggest that ionizing radiation could produce new anticancer options from an old drug.
The researchers irradiated Dex with γ- rays to produce ionizing-radiation-irradiated.
Dex (Dex-IR), then investigated its effects on human lung cancer cells (cell lines H1650, A549, and H1299). The researchers used ionizing radiation because introducing energy into materials can produce favorable changes; irradiated materials with sufficiently high energy can decompose to yield very reactive intermediate molecules and form new ones. In this study, γ -irradiation produced “remarkable changes” in the chemical properties of dexamethasone; changes included degradation products, such as methanol vapor and carbon monoxide.
Original Dex inhibits the proliferation of non-small cell lung cancer (NSCLC) cells but has minimal cytotoxic effects, the researchers say. However, Dex-IR not only significantly inhibited the proliferation of NSCLC cells, but also induced apoptosis, arrested cell cycles of H1650 lung cancer cells, and significantly reduced cells’ invasiveness.
The researchers say their results “strongly suggest” a direct link between the chemical derivatives of Dex and inhibition of NSCLC cell growth. Their findings are the first evidence that γ -irradiated Dex represents a novel class of anticancer agents for lung cancer.
Lee EH, Park CH, Choi HJ, Kawala RA, Bai HW, Chung BY. PLoS One. 2018;13(4):e0194341.
doi: 10.1371/journal.pone.0194341.
Dexamethasone (Dex), a synthetic glucocorticoid, for years has been widely used both to treat adverse effects of antitumor agents and in direct chemotherapy regimens for hematologic malignancies, such as leukemia and lymphoma. But might it be modified to work against solid cancers as well? Researchers from Advanced Radiation Technology Institute, Medical Device Development Center, and University of Science and Technology in South Korea, suggest that ionizing radiation could produce new anticancer options from an old drug.
The researchers irradiated Dex with γ- rays to produce ionizing-radiation-irradiated.
Dex (Dex-IR), then investigated its effects on human lung cancer cells (cell lines H1650, A549, and H1299). The researchers used ionizing radiation because introducing energy into materials can produce favorable changes; irradiated materials with sufficiently high energy can decompose to yield very reactive intermediate molecules and form new ones. In this study, γ -irradiation produced “remarkable changes” in the chemical properties of dexamethasone; changes included degradation products, such as methanol vapor and carbon monoxide.
Original Dex inhibits the proliferation of non-small cell lung cancer (NSCLC) cells but has minimal cytotoxic effects, the researchers say. However, Dex-IR not only significantly inhibited the proliferation of NSCLC cells, but also induced apoptosis, arrested cell cycles of H1650 lung cancer cells, and significantly reduced cells’ invasiveness.
The researchers say their results “strongly suggest” a direct link between the chemical derivatives of Dex and inhibition of NSCLC cell growth. Their findings are the first evidence that γ -irradiated Dex represents a novel class of anticancer agents for lung cancer.
Lee EH, Park CH, Choi HJ, Kawala RA, Bai HW, Chung BY. PLoS One. 2018;13(4):e0194341.
doi: 10.1371/journal.pone.0194341.
FDA places partial hold on trials after secondary lymphoma
The drugmaker after a pediatric patient developed a secondary T-cell lymphoma.
The Food and Drug Administration had issued a partial clinical hold in April on new enrollment of any patients with genetically defined solid tumors and hematologic malignancies. Patients already enrolled who have not had disease progression can continue to receive tazemetostat.
Tazemetostat is a first-in-class EZH2 inhibitor being studied as monotherapy in phase 1 and 2 trials for certain molecularly defined solid tumors, follicular lymphoma and diffuse large B-cell lymphoma, mesothelioma, and in combination studies of DLBCL and non–small cell lung cancer.
Epizyme is currently working to update informed consent, the investigator’s brochure, and study protocols, the company said in a statement.
The drugmaker after a pediatric patient developed a secondary T-cell lymphoma.
The Food and Drug Administration had issued a partial clinical hold in April on new enrollment of any patients with genetically defined solid tumors and hematologic malignancies. Patients already enrolled who have not had disease progression can continue to receive tazemetostat.
Tazemetostat is a first-in-class EZH2 inhibitor being studied as monotherapy in phase 1 and 2 trials for certain molecularly defined solid tumors, follicular lymphoma and diffuse large B-cell lymphoma, mesothelioma, and in combination studies of DLBCL and non–small cell lung cancer.
Epizyme is currently working to update informed consent, the investigator’s brochure, and study protocols, the company said in a statement.
The drugmaker after a pediatric patient developed a secondary T-cell lymphoma.
The Food and Drug Administration had issued a partial clinical hold in April on new enrollment of any patients with genetically defined solid tumors and hematologic malignancies. Patients already enrolled who have not had disease progression can continue to receive tazemetostat.
Tazemetostat is a first-in-class EZH2 inhibitor being studied as monotherapy in phase 1 and 2 trials for certain molecularly defined solid tumors, follicular lymphoma and diffuse large B-cell lymphoma, mesothelioma, and in combination studies of DLBCL and non–small cell lung cancer.
Epizyme is currently working to update informed consent, the investigator’s brochure, and study protocols, the company said in a statement.
PDPK1 could be novel target in MCL
Researchers may have found a new therapeutic approach for treating mantle cell lymphoma (MCL) by targeting 3-phosphoinositide-dependent protein kinase 1 (PDPK1).
Saori Maegawa and colleagues at Kyoto Prefectural University of Medicine in Japan, evaluated PDPK1 activity in patient-derived primary B-cell lymphoma cells by immunohistochemical staining of p-PDPK1Ser241 (p-PDPK1) in tissue specimens from seven patients with MCL, six patients with diffuse large B-cell lymphoma, and five patients with follicular lymphoma. All specimens were biopsied at initial diagnosis, before starting treatment.
“Our study showed that PDPK1 inhibition caused inactivation of RSK2-NTKD, as well as the decrease of total RSK2 protein, but not of AKT, in MCL-derived cells,” the researchers wrote in Experimental Hematology. “This implies that RSK2 activity is mainly regulated by PDPK1 at both the transcriptional expression and post-translational levels, but AKT activity is regulated by a signaling pathway that does not interact with a PDPK1-mediated pathway in MCL.”
If a PDPK1 inhibitor is pursued as clinical target, the researchers said careful monitoring for hyperglycemia may be required since impaired glucose metabolism is commonly seen with AKT inhibitors. Future research in MCL could also be directed toward the targeting of RSK2-NTKD, the researchers wrote.
SOURCE: Maegawa S et al. Exp Hematol. 2018 Mar;59:72-81.e2.
Researchers may have found a new therapeutic approach for treating mantle cell lymphoma (MCL) by targeting 3-phosphoinositide-dependent protein kinase 1 (PDPK1).
Saori Maegawa and colleagues at Kyoto Prefectural University of Medicine in Japan, evaluated PDPK1 activity in patient-derived primary B-cell lymphoma cells by immunohistochemical staining of p-PDPK1Ser241 (p-PDPK1) in tissue specimens from seven patients with MCL, six patients with diffuse large B-cell lymphoma, and five patients with follicular lymphoma. All specimens were biopsied at initial diagnosis, before starting treatment.
“Our study showed that PDPK1 inhibition caused inactivation of RSK2-NTKD, as well as the decrease of total RSK2 protein, but not of AKT, in MCL-derived cells,” the researchers wrote in Experimental Hematology. “This implies that RSK2 activity is mainly regulated by PDPK1 at both the transcriptional expression and post-translational levels, but AKT activity is regulated by a signaling pathway that does not interact with a PDPK1-mediated pathway in MCL.”
If a PDPK1 inhibitor is pursued as clinical target, the researchers said careful monitoring for hyperglycemia may be required since impaired glucose metabolism is commonly seen with AKT inhibitors. Future research in MCL could also be directed toward the targeting of RSK2-NTKD, the researchers wrote.
SOURCE: Maegawa S et al. Exp Hematol. 2018 Mar;59:72-81.e2.
Researchers may have found a new therapeutic approach for treating mantle cell lymphoma (MCL) by targeting 3-phosphoinositide-dependent protein kinase 1 (PDPK1).
Saori Maegawa and colleagues at Kyoto Prefectural University of Medicine in Japan, evaluated PDPK1 activity in patient-derived primary B-cell lymphoma cells by immunohistochemical staining of p-PDPK1Ser241 (p-PDPK1) in tissue specimens from seven patients with MCL, six patients with diffuse large B-cell lymphoma, and five patients with follicular lymphoma. All specimens were biopsied at initial diagnosis, before starting treatment.
“Our study showed that PDPK1 inhibition caused inactivation of RSK2-NTKD, as well as the decrease of total RSK2 protein, but not of AKT, in MCL-derived cells,” the researchers wrote in Experimental Hematology. “This implies that RSK2 activity is mainly regulated by PDPK1 at both the transcriptional expression and post-translational levels, but AKT activity is regulated by a signaling pathway that does not interact with a PDPK1-mediated pathway in MCL.”
If a PDPK1 inhibitor is pursued as clinical target, the researchers said careful monitoring for hyperglycemia may be required since impaired glucose metabolism is commonly seen with AKT inhibitors. Future research in MCL could also be directed toward the targeting of RSK2-NTKD, the researchers wrote.
SOURCE: Maegawa S et al. Exp Hematol. 2018 Mar;59:72-81.e2.
FROM EXPERIMENTAL HEMATOLOGY
Updated CLL guidelines incorporate a decade of advances
include new and revised recommendations based on major advances in genomics, targeted therapies, and biomarkers that have occurred since the last iteration in 2008.
The guidelines are an update from a consensus document issued a decade ago by the International Workshop on CLL, focusing on the conduct of clinical trials in patients with CLL. The new guidelines are published in Blood.
Major changes or additions include:
Molecular genetics: The updated guidelines recognize the clinical importance of specific genomic alterations/mutations on response to standard chemotherapy or chemoimmunotherapy, including the 17p deletion and mutations in TP53.
“Therefore, the assessment of both del(17p) and TP53 mutation has prognostic and predictive value and should guide therapeutic decisions in routine practice. For clinical trials, it is recommended that molecular genetics be performed prior to treating a patient on protocol,” the guidelines state.
IGHV mutational status: The mutational status of immunoglobulin variable heavy chain (IGHV) genes has been demonstrated to offer important prognostic information, according to the guidelines authors led by Michael Hallek, MD of the University of Cologne, Germany.
Specifically, leukemia with IGHV genes without somatic mutations are associated with worse clinical outcomes, compared with leukemia with IGHV mutations. Patients with mutated IGHV and other prognostic factors such as favorable cytogenetics or minimal residual disease (MRD) negativity generally have excellent outcomes with a chemoimmunotherapy regimen consisting of fludarabine, cyclophosphamide, and rituximab, the authors noted.
Biomarkers: The guidelines call for standardization and use in prospective clinical trials of assays for serum markers such as soluble CD23, thymidine kinase, and beta-2-microglobulin. These markers have been shown in several studies to be associated with overall survival or progression-free survival, and of these markers, beta-2-microglobulin “has retained independent prognostic value in several multiparameter scores,” the guidelines state.
The authors also tip their hats to recently developed or improved prognostic scores, especially the CLL International Prognostic Index (CLL-IPI), which incorporates clinical stage, age, IGHV mutational status, beta-2-microglobulin, and del(17p) and/or TP53 mutations.
Organ function assessment: Not new, but improved in the current version of the guidelines, are recommendations for evaluation of splenomegaly, hepatomegaly, and lymphadenopathy in response assessment. These recommendations were harmonized with the relevant sections of the updated lymphoma response guidelines.
Continuous therapy: The guidelines panel recommends assessment of response duration during continuous therapy with oral agents and after the end of therapy, especially after chemotherapy or chemoimmunotherapy.
“Study protocols should provide detailed specifications of the planned time points for the assessment of the treatment response under continuous therapy. Response durations of less than six months are not considered clinically relevant,” the panel cautioned.
Response assessments for treatments with a maintenance phase should be performed at a minimum of 2 months after patients achieve their best responses.
MRD: The guidelines call for minimal residual disease (MRD) assessment in clinical trials aimed at maximizing remission depth, with emphasis on reporting the sensitivity of the MRD evaluation method used, and the type of tissue assessed.
Antiviral prophylaxis: The guidelines caution that because patients treated with anti-CD20 antibodies, such as rituximab or obinutuzumab, could have reactivation of hepatitis B virus (HBV) infections, patients should be tested for HBV serological status before starting on an anti-CD20 agent.
“Progressive multifocal leukoencephalopathy has been reported in a few CLL patients treated with anti-CD20 antibodies; therefore, infections with John Cunningham (JC) virus should be ruled out in situations of unclear neurological symptoms,” the panel recommended.
They note that patients younger than 65 treated with fludarabine-based therapy in the first line do not require routine monitoring or infection prophylaxis, due to the low reported incidence of infections in this group.
The authors reported having no financial disclosures related to the guidelines.
include new and revised recommendations based on major advances in genomics, targeted therapies, and biomarkers that have occurred since the last iteration in 2008.
The guidelines are an update from a consensus document issued a decade ago by the International Workshop on CLL, focusing on the conduct of clinical trials in patients with CLL. The new guidelines are published in Blood.
Major changes or additions include:
Molecular genetics: The updated guidelines recognize the clinical importance of specific genomic alterations/mutations on response to standard chemotherapy or chemoimmunotherapy, including the 17p deletion and mutations in TP53.
“Therefore, the assessment of both del(17p) and TP53 mutation has prognostic and predictive value and should guide therapeutic decisions in routine practice. For clinical trials, it is recommended that molecular genetics be performed prior to treating a patient on protocol,” the guidelines state.
IGHV mutational status: The mutational status of immunoglobulin variable heavy chain (IGHV) genes has been demonstrated to offer important prognostic information, according to the guidelines authors led by Michael Hallek, MD of the University of Cologne, Germany.
Specifically, leukemia with IGHV genes without somatic mutations are associated with worse clinical outcomes, compared with leukemia with IGHV mutations. Patients with mutated IGHV and other prognostic factors such as favorable cytogenetics or minimal residual disease (MRD) negativity generally have excellent outcomes with a chemoimmunotherapy regimen consisting of fludarabine, cyclophosphamide, and rituximab, the authors noted.
Biomarkers: The guidelines call for standardization and use in prospective clinical trials of assays for serum markers such as soluble CD23, thymidine kinase, and beta-2-microglobulin. These markers have been shown in several studies to be associated with overall survival or progression-free survival, and of these markers, beta-2-microglobulin “has retained independent prognostic value in several multiparameter scores,” the guidelines state.
The authors also tip their hats to recently developed or improved prognostic scores, especially the CLL International Prognostic Index (CLL-IPI), which incorporates clinical stage, age, IGHV mutational status, beta-2-microglobulin, and del(17p) and/or TP53 mutations.
Organ function assessment: Not new, but improved in the current version of the guidelines, are recommendations for evaluation of splenomegaly, hepatomegaly, and lymphadenopathy in response assessment. These recommendations were harmonized with the relevant sections of the updated lymphoma response guidelines.
Continuous therapy: The guidelines panel recommends assessment of response duration during continuous therapy with oral agents and after the end of therapy, especially after chemotherapy or chemoimmunotherapy.
“Study protocols should provide detailed specifications of the planned time points for the assessment of the treatment response under continuous therapy. Response durations of less than six months are not considered clinically relevant,” the panel cautioned.
Response assessments for treatments with a maintenance phase should be performed at a minimum of 2 months after patients achieve their best responses.
MRD: The guidelines call for minimal residual disease (MRD) assessment in clinical trials aimed at maximizing remission depth, with emphasis on reporting the sensitivity of the MRD evaluation method used, and the type of tissue assessed.
Antiviral prophylaxis: The guidelines caution that because patients treated with anti-CD20 antibodies, such as rituximab or obinutuzumab, could have reactivation of hepatitis B virus (HBV) infections, patients should be tested for HBV serological status before starting on an anti-CD20 agent.
“Progressive multifocal leukoencephalopathy has been reported in a few CLL patients treated with anti-CD20 antibodies; therefore, infections with John Cunningham (JC) virus should be ruled out in situations of unclear neurological symptoms,” the panel recommended.
They note that patients younger than 65 treated with fludarabine-based therapy in the first line do not require routine monitoring or infection prophylaxis, due to the low reported incidence of infections in this group.
The authors reported having no financial disclosures related to the guidelines.
include new and revised recommendations based on major advances in genomics, targeted therapies, and biomarkers that have occurred since the last iteration in 2008.
The guidelines are an update from a consensus document issued a decade ago by the International Workshop on CLL, focusing on the conduct of clinical trials in patients with CLL. The new guidelines are published in Blood.
Major changes or additions include:
Molecular genetics: The updated guidelines recognize the clinical importance of specific genomic alterations/mutations on response to standard chemotherapy or chemoimmunotherapy, including the 17p deletion and mutations in TP53.
“Therefore, the assessment of both del(17p) and TP53 mutation has prognostic and predictive value and should guide therapeutic decisions in routine practice. For clinical trials, it is recommended that molecular genetics be performed prior to treating a patient on protocol,” the guidelines state.
IGHV mutational status: The mutational status of immunoglobulin variable heavy chain (IGHV) genes has been demonstrated to offer important prognostic information, according to the guidelines authors led by Michael Hallek, MD of the University of Cologne, Germany.
Specifically, leukemia with IGHV genes without somatic mutations are associated with worse clinical outcomes, compared with leukemia with IGHV mutations. Patients with mutated IGHV and other prognostic factors such as favorable cytogenetics or minimal residual disease (MRD) negativity generally have excellent outcomes with a chemoimmunotherapy regimen consisting of fludarabine, cyclophosphamide, and rituximab, the authors noted.
Biomarkers: The guidelines call for standardization and use in prospective clinical trials of assays for serum markers such as soluble CD23, thymidine kinase, and beta-2-microglobulin. These markers have been shown in several studies to be associated with overall survival or progression-free survival, and of these markers, beta-2-microglobulin “has retained independent prognostic value in several multiparameter scores,” the guidelines state.
The authors also tip their hats to recently developed or improved prognostic scores, especially the CLL International Prognostic Index (CLL-IPI), which incorporates clinical stage, age, IGHV mutational status, beta-2-microglobulin, and del(17p) and/or TP53 mutations.
Organ function assessment: Not new, but improved in the current version of the guidelines, are recommendations for evaluation of splenomegaly, hepatomegaly, and lymphadenopathy in response assessment. These recommendations were harmonized with the relevant sections of the updated lymphoma response guidelines.
Continuous therapy: The guidelines panel recommends assessment of response duration during continuous therapy with oral agents and after the end of therapy, especially after chemotherapy or chemoimmunotherapy.
“Study protocols should provide detailed specifications of the planned time points for the assessment of the treatment response under continuous therapy. Response durations of less than six months are not considered clinically relevant,” the panel cautioned.
Response assessments for treatments with a maintenance phase should be performed at a minimum of 2 months after patients achieve their best responses.
MRD: The guidelines call for minimal residual disease (MRD) assessment in clinical trials aimed at maximizing remission depth, with emphasis on reporting the sensitivity of the MRD evaluation method used, and the type of tissue assessed.
Antiviral prophylaxis: The guidelines caution that because patients treated with anti-CD20 antibodies, such as rituximab or obinutuzumab, could have reactivation of hepatitis B virus (HBV) infections, patients should be tested for HBV serological status before starting on an anti-CD20 agent.
“Progressive multifocal leukoencephalopathy has been reported in a few CLL patients treated with anti-CD20 antibodies; therefore, infections with John Cunningham (JC) virus should be ruled out in situations of unclear neurological symptoms,” the panel recommended.
They note that patients younger than 65 treated with fludarabine-based therapy in the first line do not require routine monitoring or infection prophylaxis, due to the low reported incidence of infections in this group.
The authors reported having no financial disclosures related to the guidelines.
FROM BLOOD