A randomized trial designed to compare autologous to allogeneic stem cell transplantation as first-line therapy in younger patients with peripheral T-cell lymphoma was discontinued early because nearly 40% of the patients had early disease progression and did not undergo transplantation.

Peripheral T-cell lymphoma generally yields a poor prognosis when treated with conventional chemotherapy, but autologous or allogeneic stem cell transplants were thought to be an option for patients with relapsing or refractory disease. Based on this hypothesis, the AATT (Autologous or Allogeneic Transplantation in T-Cell Lymphoma) study explored stem cell transplant as a first-line therapy, enrolling 104 patients aged 18-60 between 2011 and 2014.

All patients received four courses of chemotherapy with CHOEP-14 (cyclophosphamide, adriamycin, vincristine, etoposide, and prednisone).

Those in the autologous stem cell group and those without a suitable donor proceeded to one course of DHAP (high-dose ara-C, cis-platinum, and dexamethasone) and stem cell collection. Patients randomized to autologous transplantation received high dose therapy (BCNU, etoposide, cytarabine, melphalan: BEAM) followed 4-6 weeks later by transplantation of autologous stem cells.

Patients randomized to allogeneic transplantation received high dose therapy (fludarabine, busulfan, cyclophosphamide: FBC) followed by transplantation of allogeneic stem cells. GvHD prophylaxis included antithymocyte globuline (ATG), cyclosporine A, and mycophenolate mofetil.

Among the 58 patients eligible for the interim analysis, the mean age was 50 and 64% were male. Thirteen of the 28 patients randomized for allogeneic transplants underwent transplants; the others were not allografted because of progressive disease or lack of a donor. Of the 30 patients randomized to autologous SCT, 19 had the procedure; 11 did not receive transplants because of progressive disease or infection, Dr. Norbert Schmitz of Asklepios Klinik St. Georg, Hamburg, Germany, reported at the International Congress on Malignant Lymphoma in Lugano, Switzerland.

The primary outcome, 1-year event-free survival (EFS), was 41% in the intent-to-treat population (95% CI, 27%–54%).

Causes of death included lymphoma (seven autologous, five allogeneic), salvage therapy (two), early or late infections (four), and graft vs. host disease (two).

Survival rates did not significantly differ in the two stem cell transplant groups, but the findings lend themselves to limited interpretation as more than 30% of patients did not receive the procedure. Based on the low probability of meeting the primary outcome, the data safety monitoring board decided to stop patient accrual and discontinue the trial.

*This article was updated 7/8/2015.

A randomized trial designed to compare autologous to allogeneic stem cell transplantation as first-line therapy in younger patients with peripheral T-cell lymphoma was discontinued early because nearly 40% of the patients had early disease progression and did not undergo transplantation.

Peripheral T-cell lymphoma generally yields a poor prognosis when treated with conventional chemotherapy, but autologous or allogeneic stem cell transplants were thought to be an option for patients with relapsing or refractory disease. Based on this hypothesis, the AATT (Autologous or Allogeneic Transplantation in T-Cell Lymphoma) study explored stem cell transplant as a first-line therapy, enrolling 104 patients aged 18-60 between 2011 and 2014.

All patients received four courses of chemotherapy with CHOEP-14 (cyclophosphamide, adriamycin, vincristine, etoposide, and prednisone).

Those in the autologous stem cell group and those without a suitable donor proceeded to one course of DHAP (high-dose ara-C, cis-platinum, and dexamethasone) and stem cell collection. Patients randomized to autologous transplantation received high dose therapy (BCNU, etoposide, cytarabine, melphalan: BEAM) followed 4-6 weeks later by transplantation of autologous stem cells.

Patients randomized to allogeneic transplantation received high dose therapy (fludarabine, busulfan, cyclophosphamide: FBC) followed by transplantation of allogeneic stem cells. GvHD prophylaxis included antithymocyte globuline (ATG), cyclosporine A, and mycophenolate mofetil.

Among the 58 patients eligible for the interim analysis, the mean age was 50 and 64% were male. Thirteen of the 28 patients randomized for allogeneic transplants underwent transplants; the others were not allografted because of progressive disease or lack of a donor. Of the 30 patients randomized to autologous SCT, 19 had the procedure; 11 did not receive transplants because of progressive disease or infection, Dr. Norbert Schmitz of Asklepios Klinik St. Georg, Hamburg, Germany, reported at the International Congress on Malignant Lymphoma in Lugano, Switzerland.

The primary outcome, 1-year event-free survival (EFS), was 41% in the intent-to-treat population (95% CI, 27%–54%).

Causes of death included lymphoma (seven autologous, five allogeneic), salvage therapy (two), early or late infections (four), and graft vs. host disease (two).

Survival rates did not significantly differ in the two stem cell transplant groups, but the findings lend themselves to limited interpretation as more than 30% of patients did not receive the procedure. Based on the low probability of meeting the primary outcome, the data safety monitoring board decided to stop patient accrual and discontinue the trial.

*This article was updated 7/8/2015.

A randomized trial designed to compare autologous to allogeneic stem cell transplantation as first-line therapy in younger patients with peripheral T-cell lymphoma was discontinued early because nearly 40% of the patients had early disease progression and did not undergo transplantation.

Peripheral T-cell lymphoma generally yields a poor prognosis when treated with conventional chemotherapy, but autologous or allogeneic stem cell transplants were thought to be an option for patients with relapsing or refractory disease. Based on this hypothesis, the AATT (Autologous or Allogeneic Transplantation in T-Cell Lymphoma) study explored stem cell transplant as a first-line therapy, enrolling 104 patients aged 18-60 between 2011 and 2014.

All patients received four courses of chemotherapy with CHOEP-14 (cyclophosphamide, adriamycin, vincristine, etoposide, and prednisone).

Those in the autologous stem cell group and those without a suitable donor proceeded to one course of DHAP (high-dose ara-C, cis-platinum, and dexamethasone) and stem cell collection. Patients randomized to autologous transplantation received high dose therapy (BCNU, etoposide, cytarabine, melphalan: BEAM) followed 4-6 weeks later by transplantation of autologous stem cells.

Patients randomized to allogeneic transplantation received high dose therapy (fludarabine, busulfan, cyclophosphamide: FBC) followed by transplantation of allogeneic stem cells. GvHD prophylaxis included antithymocyte globuline (ATG), cyclosporine A, and mycophenolate mofetil.

Among the 58 patients eligible for the interim analysis, the mean age was 50 and 64% were male. Thirteen of the 28 patients randomized for allogeneic transplants underwent transplants; the others were not allografted because of progressive disease or lack of a donor. Of the 30 patients randomized to autologous SCT, 19 had the procedure; 11 did not receive transplants because of progressive disease or infection, Dr. Norbert Schmitz of Asklepios Klinik St. Georg, Hamburg, Germany, reported at the International Congress on Malignant Lymphoma in Lugano, Switzerland.

The primary outcome, 1-year event-free survival (EFS), was 41% in the intent-to-treat population (95% CI, 27%–54%).

Causes of death included lymphoma (seven autologous, five allogeneic), salvage therapy (two), early or late infections (four), and graft vs. host disease (two).

Survival rates did not significantly differ in the two stem cell transplant groups, but the findings lend themselves to limited interpretation as more than 30% of patients did not receive the procedure. Based on the low probability of meeting the primary outcome, the data safety monitoring board decided to stop patient accrual and discontinue the trial.

*This article was updated 7/8/2015.

Rituximab plus bendamustine may prove to be an induction-therapy option for younger patients with mantle cell lymphoma, Dr. Richard Chen and his colleagues in a SWOG (Southwest Oncology Group) trial reported at the International Congress on Malignant Lymphoma in Lugano, Switzerland.

Compared with a more aggressive combination regimen, a rituximab plus bendamustine (Treanda) option is a simple regimen that can be given in an outpatient setting and was associated with fewer adverse events and similar 2-year outcomes, the researchers found. The more aggressive regimen, however, was associated with lower-than-expected stem cell mobilization rates and the trial was prematurely closed, allowing no significant results.

Courtesy Wikimedia Commons/Nephron/Creative Commons

For this study, two induction-therapy regimens were compared in 53 patients with untreated stage III or IV (or bulky stage II) mantle cell lymphoma. All patients were less than age 65 years and received rituximab (R) in combination with one of two regimens: 18 patients received four cycles of R-HyperCVAD + methotrexate + cytarabine (R-HyperCVAD/MTX/ARA-C) and 35 patients received six cycles of R-bendamustine.

The overall response rate was 94% with R-HyperCVAD/MTX/ARA-C and 86% with R-bendamustine; the complete response rates were 31% and 43%, respectively; the partial response rates were 62% and 43%, respectively, Dr. Chen and his associates reported.

The median follow-up for surviving patients is nearly 24 months. The estimated 2-year progression-free survival was 87% for patients in both treatment groups.

Significantly higher rates of bone marrow toxicity occurred in the group receiving the R-HyperCVAD/MTX/ARA-C regimen, compared with the bendamustine regimen. Grade 3 and 4 thrombocytopenia occurred in 69% given R-HyperCVAD/MTX/ARA-C and 17% given R-bendamustine. Anemia affected 56% of those given R-HyperCVAD/MTX/ARA-C and 8.6% given R-bendamustine. Neutropenia was seen in 63% given R-HyperCVAD/MTX/ARA-C and 34% of patients given R-bendamustine. Febrile neutropenia occurred in 31% given R-HyperCVAD/MTX/ARA-C and 14% given R-bendamustine.

The study was discontinued prematurely because of the low mobilization of stem cells at the transplant phase of the study in patients given R-HyperCVAD/MTX/ARA-C. Just 4 of 16 patients on R-HyperCVAD/MTX/ARA-C and 21 of 35 patients given R-bendamustine underwent autologous stem cell transplants.

The R-bendamustine regimen seems less myelosuppressive. Because of the premature closure of the trial, the study did not reach statistical significance for 2-year progression-free survival, the researchers reported. Since bendamustine in combination with rituximab was associated with lower rates of hematologic toxicity, however, it warrants further study as an induction regimen, they concluded.

Rituximab plus bendamustine may prove to be an induction-therapy option for younger patients with mantle cell lymphoma, Dr. Richard Chen and his colleagues in a SWOG (Southwest Oncology Group) trial reported at the International Congress on Malignant Lymphoma in Lugano, Switzerland.

Compared with a more aggressive combination regimen, a rituximab plus bendamustine (Treanda) option is a simple regimen that can be given in an outpatient setting and was associated with fewer adverse events and similar 2-year outcomes, the researchers found. The more aggressive regimen, however, was associated with lower-than-expected stem cell mobilization rates and the trial was prematurely closed, allowing no significant results.

Courtesy Wikimedia Commons/Nephron/Creative Commons

For this study, two induction-therapy regimens were compared in 53 patients with untreated stage III or IV (or bulky stage II) mantle cell lymphoma. All patients were less than age 65 years and received rituximab (R) in combination with one of two regimens: 18 patients received four cycles of R-HyperCVAD + methotrexate + cytarabine (R-HyperCVAD/MTX/ARA-C) and 35 patients received six cycles of R-bendamustine.

The overall response rate was 94% with R-HyperCVAD/MTX/ARA-C and 86% with R-bendamustine; the complete response rates were 31% and 43%, respectively; the partial response rates were 62% and 43%, respectively, Dr. Chen and his associates reported.

The median follow-up for surviving patients is nearly 24 months. The estimated 2-year progression-free survival was 87% for patients in both treatment groups.

Significantly higher rates of bone marrow toxicity occurred in the group receiving the R-HyperCVAD/MTX/ARA-C regimen, compared with the bendamustine regimen. Grade 3 and 4 thrombocytopenia occurred in 69% given R-HyperCVAD/MTX/ARA-C and 17% given R-bendamustine. Anemia affected 56% of those given R-HyperCVAD/MTX/ARA-C and 8.6% given R-bendamustine. Neutropenia was seen in 63% given R-HyperCVAD/MTX/ARA-C and 34% of patients given R-bendamustine. Febrile neutropenia occurred in 31% given R-HyperCVAD/MTX/ARA-C and 14% given R-bendamustine.

The study was discontinued prematurely because of the low mobilization of stem cells at the transplant phase of the study in patients given R-HyperCVAD/MTX/ARA-C. Just 4 of 16 patients on R-HyperCVAD/MTX/ARA-C and 21 of 35 patients given R-bendamustine underwent autologous stem cell transplants.

The R-bendamustine regimen seems less myelosuppressive. Because of the premature closure of the trial, the study did not reach statistical significance for 2-year progression-free survival, the researchers reported. Since bendamustine in combination with rituximab was associated with lower rates of hematologic toxicity, however, it warrants further study as an induction regimen, they concluded.

Rituximab plus bendamustine may prove to be an induction-therapy option for younger patients with mantle cell lymphoma, Dr. Richard Chen and his colleagues in a SWOG (Southwest Oncology Group) trial reported at the International Congress on Malignant Lymphoma in Lugano, Switzerland.

Compared with a more aggressive combination regimen, a rituximab plus bendamustine (Treanda) option is a simple regimen that can be given in an outpatient setting and was associated with fewer adverse events and similar 2-year outcomes, the researchers found. The more aggressive regimen, however, was associated with lower-than-expected stem cell mobilization rates and the trial was prematurely closed, allowing no significant results.

Courtesy Wikimedia Commons/Nephron/Creative Commons

For this study, two induction-therapy regimens were compared in 53 patients with untreated stage III or IV (or bulky stage II) mantle cell lymphoma. All patients were less than age 65 years and received rituximab (R) in combination with one of two regimens: 18 patients received four cycles of R-HyperCVAD + methotrexate + cytarabine (R-HyperCVAD/MTX/ARA-C) and 35 patients received six cycles of R-bendamustine.

The overall response rate was 94% with R-HyperCVAD/MTX/ARA-C and 86% with R-bendamustine; the complete response rates were 31% and 43%, respectively; the partial response rates were 62% and 43%, respectively, Dr. Chen and his associates reported.

The median follow-up for surviving patients is nearly 24 months. The estimated 2-year progression-free survival was 87% for patients in both treatment groups.

Significantly higher rates of bone marrow toxicity occurred in the group receiving the R-HyperCVAD/MTX/ARA-C regimen, compared with the bendamustine regimen. Grade 3 and 4 thrombocytopenia occurred in 69% given R-HyperCVAD/MTX/ARA-C and 17% given R-bendamustine. Anemia affected 56% of those given R-HyperCVAD/MTX/ARA-C and 8.6% given R-bendamustine. Neutropenia was seen in 63% given R-HyperCVAD/MTX/ARA-C and 34% of patients given R-bendamustine. Febrile neutropenia occurred in 31% given R-HyperCVAD/MTX/ARA-C and 14% given R-bendamustine.

The study was discontinued prematurely because of the low mobilization of stem cells at the transplant phase of the study in patients given R-HyperCVAD/MTX/ARA-C. Just 4 of 16 patients on R-HyperCVAD/MTX/ARA-C and 21 of 35 patients given R-bendamustine underwent autologous stem cell transplants.

The R-bendamustine regimen seems less myelosuppressive. Because of the premature closure of the trial, the study did not reach statistical significance for 2-year progression-free survival, the researchers reported. Since bendamustine in combination with rituximab was associated with lower rates of hematologic toxicity, however, it warrants further study as an induction regimen, they concluded.

Warfarin tablets

Results of the PADIS-PE trial suggest that patients with a first episode of pulmonary embolism (PE) benefit from extended anticoagulation therapy, but that benefit is lost after the treatment is stopped.

When patients received warfarin for 18 months after an initial 6 months of anticoagulation therapy, they had a lower risk of venous thromboembolism (VTE)

recurrence than patients who did not receive additional anticoagulation.

However, this benefit was lost once the patients stopped taking warfarin.

Francis Couturaud, MD, PhD, of the Universite de Bretagne Occidentale in Brest, France, and his colleagues reported these findings in JAMA.

The researchers analyzed 371 adult patients who had experienced a first episode of symptomatic, unprovoked PE and were initially treated for 6 months with a vitamin K antagonist.

The patients were then randomized to warfarin or placebo for 18 months. After randomization, 4 patients were lost to follow-up, all after month 18, and 1 withdrew due to an adverse event.

The median follow-up was 24 months. The primary outcome was a composite of recurrent VTE and major bleeding at 18 months after randomization.

During the 18-month treatment period, the primary outcome occurred in 3% (6/184) of patients in the warfarin arm and 13.5% (25/187) in the placebo arm (hazard ratio [HR]=0.22, P=0.001).

This was driven by a reduction in the risk of recurrent VTE, as the risk of major bleeding was higher in the warfarin arm. Recurrent VTE occurred in 3 patients in the warfarin arm and 25 in the placebo arm (HR=0.15, P<0.001). And major bleeding occurred in 4 patients in the warfarin arm and 1 in the placebo arm (HR=3.96, P=0.22).

Once patients stopped receiving warfarin, the reduction in risk of VTE recurrence was lost. During the entire study period (a median of 41 months), the primary outcome occurred in 21% (n=33) of patients in the warfarin arm and 24% (n=42) in the placebo arm (HR=0.75, P=0.22).

There was no significant difference between the treatment arms with regard to recurrent VTE (HR=0.69, P=0.14) or major bleeding (HR=1.12, P=0.85).

The researchers said these results suggest patients with an unprovoked PE require long-term VTE prevention measures. But further investigation is needed to determine whether these should include systematic treatment with vitamin K antagonists, new anticoagulants, or aspirin, or whether the measures should be tailored according to patient risk factors.

Warfarin tablets

Results of the PADIS-PE trial suggest that patients with a first episode of pulmonary embolism (PE) benefit from extended anticoagulation therapy, but that benefit is lost after the treatment is stopped.

When patients received warfarin for 18 months after an initial 6 months of anticoagulation therapy, they had a lower risk of venous thromboembolism (VTE)

recurrence than patients who did not receive additional anticoagulation.

However, this benefit was lost once the patients stopped taking warfarin.

Francis Couturaud, MD, PhD, of the Universite de Bretagne Occidentale in Brest, France, and his colleagues reported these findings in JAMA.

The researchers analyzed 371 adult patients who had experienced a first episode of symptomatic, unprovoked PE and were initially treated for 6 months with a vitamin K antagonist.

The patients were then randomized to warfarin or placebo for 18 months. After randomization, 4 patients were lost to follow-up, all after month 18, and 1 withdrew due to an adverse event.

The median follow-up was 24 months. The primary outcome was a composite of recurrent VTE and major bleeding at 18 months after randomization.

During the 18-month treatment period, the primary outcome occurred in 3% (6/184) of patients in the warfarin arm and 13.5% (25/187) in the placebo arm (hazard ratio [HR]=0.22, P=0.001).

This was driven by a reduction in the risk of recurrent VTE, as the risk of major bleeding was higher in the warfarin arm. Recurrent VTE occurred in 3 patients in the warfarin arm and 25 in the placebo arm (HR=0.15, P<0.001). And major bleeding occurred in 4 patients in the warfarin arm and 1 in the placebo arm (HR=3.96, P=0.22).

Once patients stopped receiving warfarin, the reduction in risk of VTE recurrence was lost. During the entire study period (a median of 41 months), the primary outcome occurred in 21% (n=33) of patients in the warfarin arm and 24% (n=42) in the placebo arm (HR=0.75, P=0.22).

There was no significant difference between the treatment arms with regard to recurrent VTE (HR=0.69, P=0.14) or major bleeding (HR=1.12, P=0.85).

The researchers said these results suggest patients with an unprovoked PE require long-term VTE prevention measures. But further investigation is needed to determine whether these should include systematic treatment with vitamin K antagonists, new anticoagulants, or aspirin, or whether the measures should be tailored according to patient risk factors.

Warfarin tablets

Results of the PADIS-PE trial suggest that patients with a first episode of pulmonary embolism (PE) benefit from extended anticoagulation therapy, but that benefit is lost after the treatment is stopped.

When patients received warfarin for 18 months after an initial 6 months of anticoagulation therapy, they had a lower risk of venous thromboembolism (VTE)

recurrence than patients who did not receive additional anticoagulation.

However, this benefit was lost once the patients stopped taking warfarin.

Francis Couturaud, MD, PhD, of the Universite de Bretagne Occidentale in Brest, France, and his colleagues reported these findings in JAMA.

The researchers analyzed 371 adult patients who had experienced a first episode of symptomatic, unprovoked PE and were initially treated for 6 months with a vitamin K antagonist.

The patients were then randomized to warfarin or placebo for 18 months. After randomization, 4 patients were lost to follow-up, all after month 18, and 1 withdrew due to an adverse event.

The median follow-up was 24 months. The primary outcome was a composite of recurrent VTE and major bleeding at 18 months after randomization.

During the 18-month treatment period, the primary outcome occurred in 3% (6/184) of patients in the warfarin arm and 13.5% (25/187) in the placebo arm (hazard ratio [HR]=0.22, P=0.001).

This was driven by a reduction in the risk of recurrent VTE, as the risk of major bleeding was higher in the warfarin arm. Recurrent VTE occurred in 3 patients in the warfarin arm and 25 in the placebo arm (HR=0.15, P<0.001). And major bleeding occurred in 4 patients in the warfarin arm and 1 in the placebo arm (HR=3.96, P=0.22).

Once patients stopped receiving warfarin, the reduction in risk of VTE recurrence was lost. During the entire study period (a median of 41 months), the primary outcome occurred in 21% (n=33) of patients in the warfarin arm and 24% (n=42) in the placebo arm (HR=0.75, P=0.22).

There was no significant difference between the treatment arms with regard to recurrent VTE (HR=0.69, P=0.14) or major bleeding (HR=1.12, P=0.85).

The researchers said these results suggest patients with an unprovoked PE require long-term VTE prevention measures. But further investigation is needed to determine whether these should include systematic treatment with vitamin K antagonists, new anticoagulants, or aspirin, or whether the measures should be tailored according to patient risk factors.

 

 

Growing monoclonal antibodies

Photo by Linda Bartlett

 

LUGANO—The defucosylated monoclonal antibody (mAb) ARGX-110, which is active against CD70-bearing tumor cells and CD70-dependent stimulation of regulatory T cells, has shown activity in relapsed/refractory T-cell lymphoma (TCL), according to investigators.

Of the 8 TCL patients enrolled in a phase 1 trial of ARGX-110, 3 had a biological response to the mAb.

In this dose-escalation trial, the maximum tolerated dose of ARGX-110 was not reached.

Marie Maerevoet, MD, of the Institut Jules Bordet in Brussels, Belgium, presented results from the lymphoma cohort of this trial at the 13th International Congress on Malignant Lymphoma (abstract 040*). The study was sponsored by arGEN-X, the company developing ARGX-110.

Dr  Maerevoet pointed out that more than half the tumor cells in 71% of patients with cutaneous T-cell lymphoma (CTCL) and 22% with peripheral T-cell lymphoma (PTCL) are CD70-positive. CD70 signaling occurs via CD27, and CD27 shedding is a biomarker for an active pathway.

Since ARGX-110 has an affinity for CD70, inhibits CD27 signaling, and mediates the lysis of TCL in Sézary syndrome (SS), mycosis fungoides, and anaplastic large cell lymphoma (ALCL) cell lines, researchers decided to investigate the safety and clinical pharmacology of ARGX-110 monotherapy in metastatic, relapsed or refractory, solid tumors and hematologic malignancies.

Patients’ tumors had to express CD70 by immunohistochemistry, defined as more than 10% tumor cells of 2+ or 3+ intensity.

The primary endpoint was to determine the maximum tolerated dose. Secondary endpoints were pharmacology, immunogenicity, and efficacy signals.

Patient demographics

Between February 2013 and April 2015, investigators assigned 63 patients to receive ARGX-110 at doses ranging from 0.1 to 10 mg/kg intravenously once every 3 weeks until disease progression or withdrawal due to toxicity. Patients were pre-medicated with corticoid regimens.

Eighteen patients had lymphoid malignancies—8 with B-cell lymphomas, 8 with TCL, and 2 with Hodgkin lymphoma.

The TCL cohort consisted of 1 patient with SS, 1 with transformed SS, 1 with T-helper CTCL, 2 with angioimmunoblastic T-cell lymphoma (AITL), 2 with PTCL not otherwise specified (NOS), and 1 with ALCL.

Patients were a median age of 62 (range, 55–78), had a median of 4 prior treatment regimens (range, 2–6), and received a median of 2 cycles of ARGX-110 (range, 1–6).

Dr Maerevoet noted that most lymphoma patients received a dose of 5 mg/kg every 3 weeks.

Safety

In the entire lymphoma cohort of 18 patients, 4 patients (22%) experienced a grade 1 or 2 infusion-related reaction. Three patients (18%) developed grade 3 sepsis—1 with Waldenstrom’s macroglobulinemia, 1 with AITL, and 1 with PTCL-NOS.

Two patients (11%) had hematologic toxicity consisting of a grade 3 decrease in hemoglobin and absolute neutrophil count, which was considered not related to treatment with ARGX-110.

“The maximum tolerated dose was not reached,” Dr Maerevoet said. “We didn’t observe auto-immune adverse events or impact on serum IgG or IgM.”

Efficacy outcomes

The main reason for withdrawal was progressive disease, which occurred in 14 lymphoma patients.

Two patients—1 with Waldenstrom’s macroglobulinemia and 1 with AITL—withdrew due to adverse events of sepsis (catheter infection, pneumonia), 1 patient with SS withdrew for social reasons, and 1 patient with follicular T-cell lymphoma (currently classified as PTCL-NOS) remains on study.

Dr Maerevoet described the 3 TCL patients who had a biologic response to ARGX-110. One patient with SS had a hematologic complete remission after 6 cycles at the 0.1 mg/kg dose.

Another patient with transformed SS experienced a depletion of circulating clones after 2 cycles of the 10 mg/kg dose. However, the patient ultimately died of progressive disease.

A third patient had resolution of autoimmune hemolytic anemia. This 61-year-old male with AITL achieved a partial response with normalization of LDH levels and an increase in hemoglobin to 7.9 g/dL without transfusion support after 2 doses of ARGX-110 at 5 mg/kg.

The patient became Coombs-negative and had a 16% reduction in tumor size by CT scan. However, the patient subsequently died of pneumonia.

The investigators also observed clinical activity in the peripheral blood, lymph nodes, and skin of 2 additional patients.

The biological activity of ARGX-110 as demonstrated by these TCL patients, in addition to the safety and tolerability of this mAb, led the team to conclude that further clinical investigation of ARGX-110 in TCL is warranted.

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

 

 

Growing monoclonal antibodies

Photo by Linda Bartlett

 

LUGANO—The defucosylated monoclonal antibody (mAb) ARGX-110, which is active against CD70-bearing tumor cells and CD70-dependent stimulation of regulatory T cells, has shown activity in relapsed/refractory T-cell lymphoma (TCL), according to investigators.

Of the 8 TCL patients enrolled in a phase 1 trial of ARGX-110, 3 had a biological response to the mAb.

In this dose-escalation trial, the maximum tolerated dose of ARGX-110 was not reached.

Marie Maerevoet, MD, of the Institut Jules Bordet in Brussels, Belgium, presented results from the lymphoma cohort of this trial at the 13th International Congress on Malignant Lymphoma (abstract 040*). The study was sponsored by arGEN-X, the company developing ARGX-110.

Dr  Maerevoet pointed out that more than half the tumor cells in 71% of patients with cutaneous T-cell lymphoma (CTCL) and 22% with peripheral T-cell lymphoma (PTCL) are CD70-positive. CD70 signaling occurs via CD27, and CD27 shedding is a biomarker for an active pathway.

Since ARGX-110 has an affinity for CD70, inhibits CD27 signaling, and mediates the lysis of TCL in Sézary syndrome (SS), mycosis fungoides, and anaplastic large cell lymphoma (ALCL) cell lines, researchers decided to investigate the safety and clinical pharmacology of ARGX-110 monotherapy in metastatic, relapsed or refractory, solid tumors and hematologic malignancies.

Patients’ tumors had to express CD70 by immunohistochemistry, defined as more than 10% tumor cells of 2+ or 3+ intensity.

The primary endpoint was to determine the maximum tolerated dose. Secondary endpoints were pharmacology, immunogenicity, and efficacy signals.

Patient demographics

Between February 2013 and April 2015, investigators assigned 63 patients to receive ARGX-110 at doses ranging from 0.1 to 10 mg/kg intravenously once every 3 weeks until disease progression or withdrawal due to toxicity. Patients were pre-medicated with corticoid regimens.

Eighteen patients had lymphoid malignancies—8 with B-cell lymphomas, 8 with TCL, and 2 with Hodgkin lymphoma.

The TCL cohort consisted of 1 patient with SS, 1 with transformed SS, 1 with T-helper CTCL, 2 with angioimmunoblastic T-cell lymphoma (AITL), 2 with PTCL not otherwise specified (NOS), and 1 with ALCL.

Patients were a median age of 62 (range, 55–78), had a median of 4 prior treatment regimens (range, 2–6), and received a median of 2 cycles of ARGX-110 (range, 1–6).

Dr Maerevoet noted that most lymphoma patients received a dose of 5 mg/kg every 3 weeks.

Safety

In the entire lymphoma cohort of 18 patients, 4 patients (22%) experienced a grade 1 or 2 infusion-related reaction. Three patients (18%) developed grade 3 sepsis—1 with Waldenstrom’s macroglobulinemia, 1 with AITL, and 1 with PTCL-NOS.

Two patients (11%) had hematologic toxicity consisting of a grade 3 decrease in hemoglobin and absolute neutrophil count, which was considered not related to treatment with ARGX-110.

“The maximum tolerated dose was not reached,” Dr Maerevoet said. “We didn’t observe auto-immune adverse events or impact on serum IgG or IgM.”

Efficacy outcomes

The main reason for withdrawal was progressive disease, which occurred in 14 lymphoma patients.

Two patients—1 with Waldenstrom’s macroglobulinemia and 1 with AITL—withdrew due to adverse events of sepsis (catheter infection, pneumonia), 1 patient with SS withdrew for social reasons, and 1 patient with follicular T-cell lymphoma (currently classified as PTCL-NOS) remains on study.

Dr Maerevoet described the 3 TCL patients who had a biologic response to ARGX-110. One patient with SS had a hematologic complete remission after 6 cycles at the 0.1 mg/kg dose.

Another patient with transformed SS experienced a depletion of circulating clones after 2 cycles of the 10 mg/kg dose. However, the patient ultimately died of progressive disease.

A third patient had resolution of autoimmune hemolytic anemia. This 61-year-old male with AITL achieved a partial response with normalization of LDH levels and an increase in hemoglobin to 7.9 g/dL without transfusion support after 2 doses of ARGX-110 at 5 mg/kg.

The patient became Coombs-negative and had a 16% reduction in tumor size by CT scan. However, the patient subsequently died of pneumonia.

The investigators also observed clinical activity in the peripheral blood, lymph nodes, and skin of 2 additional patients.

The biological activity of ARGX-110 as demonstrated by these TCL patients, in addition to the safety and tolerability of this mAb, led the team to conclude that further clinical investigation of ARGX-110 in TCL is warranted.

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

 

 

Growing monoclonal antibodies

Photo by Linda Bartlett

 

LUGANO—The defucosylated monoclonal antibody (mAb) ARGX-110, which is active against CD70-bearing tumor cells and CD70-dependent stimulation of regulatory T cells, has shown activity in relapsed/refractory T-cell lymphoma (TCL), according to investigators.

Of the 8 TCL patients enrolled in a phase 1 trial of ARGX-110, 3 had a biological response to the mAb.

In this dose-escalation trial, the maximum tolerated dose of ARGX-110 was not reached.

Marie Maerevoet, MD, of the Institut Jules Bordet in Brussels, Belgium, presented results from the lymphoma cohort of this trial at the 13th International Congress on Malignant Lymphoma (abstract 040*). The study was sponsored by arGEN-X, the company developing ARGX-110.

Dr  Maerevoet pointed out that more than half the tumor cells in 71% of patients with cutaneous T-cell lymphoma (CTCL) and 22% with peripheral T-cell lymphoma (PTCL) are CD70-positive. CD70 signaling occurs via CD27, and CD27 shedding is a biomarker for an active pathway.

Since ARGX-110 has an affinity for CD70, inhibits CD27 signaling, and mediates the lysis of TCL in Sézary syndrome (SS), mycosis fungoides, and anaplastic large cell lymphoma (ALCL) cell lines, researchers decided to investigate the safety and clinical pharmacology of ARGX-110 monotherapy in metastatic, relapsed or refractory, solid tumors and hematologic malignancies.

Patients’ tumors had to express CD70 by immunohistochemistry, defined as more than 10% tumor cells of 2+ or 3+ intensity.

The primary endpoint was to determine the maximum tolerated dose. Secondary endpoints were pharmacology, immunogenicity, and efficacy signals.

Patient demographics

Between February 2013 and April 2015, investigators assigned 63 patients to receive ARGX-110 at doses ranging from 0.1 to 10 mg/kg intravenously once every 3 weeks until disease progression or withdrawal due to toxicity. Patients were pre-medicated with corticoid regimens.

Eighteen patients had lymphoid malignancies—8 with B-cell lymphomas, 8 with TCL, and 2 with Hodgkin lymphoma.

The TCL cohort consisted of 1 patient with SS, 1 with transformed SS, 1 with T-helper CTCL, 2 with angioimmunoblastic T-cell lymphoma (AITL), 2 with PTCL not otherwise specified (NOS), and 1 with ALCL.

Patients were a median age of 62 (range, 55–78), had a median of 4 prior treatment regimens (range, 2–6), and received a median of 2 cycles of ARGX-110 (range, 1–6).

Dr Maerevoet noted that most lymphoma patients received a dose of 5 mg/kg every 3 weeks.

Safety

In the entire lymphoma cohort of 18 patients, 4 patients (22%) experienced a grade 1 or 2 infusion-related reaction. Three patients (18%) developed grade 3 sepsis—1 with Waldenstrom’s macroglobulinemia, 1 with AITL, and 1 with PTCL-NOS.

Two patients (11%) had hematologic toxicity consisting of a grade 3 decrease in hemoglobin and absolute neutrophil count, which was considered not related to treatment with ARGX-110.

“The maximum tolerated dose was not reached,” Dr Maerevoet said. “We didn’t observe auto-immune adverse events or impact on serum IgG or IgM.”

Efficacy outcomes

The main reason for withdrawal was progressive disease, which occurred in 14 lymphoma patients.

Two patients—1 with Waldenstrom’s macroglobulinemia and 1 with AITL—withdrew due to adverse events of sepsis (catheter infection, pneumonia), 1 patient with SS withdrew for social reasons, and 1 patient with follicular T-cell lymphoma (currently classified as PTCL-NOS) remains on study.

Dr Maerevoet described the 3 TCL patients who had a biologic response to ARGX-110. One patient with SS had a hematologic complete remission after 6 cycles at the 0.1 mg/kg dose.

Another patient with transformed SS experienced a depletion of circulating clones after 2 cycles of the 10 mg/kg dose. However, the patient ultimately died of progressive disease.

A third patient had resolution of autoimmune hemolytic anemia. This 61-year-old male with AITL achieved a partial response with normalization of LDH levels and an increase in hemoglobin to 7.9 g/dL without transfusion support after 2 doses of ARGX-110 at 5 mg/kg.

The patient became Coombs-negative and had a 16% reduction in tumor size by CT scan. However, the patient subsequently died of pneumonia.

The investigators also observed clinical activity in the peripheral blood, lymph nodes, and skin of 2 additional patients.

The biological activity of ARGX-110 as demonstrated by these TCL patients, in addition to the safety and tolerability of this mAb, led the team to conclude that further clinical investigation of ARGX-110 in TCL is warranted.

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

Micrograph showing CLL

The UK’s National Institute for Health and Care Excellence (NICE) has opened a consultation on a preliminary draft guidance for the PI3Kδ inhibitor idelalisib (Zydelig).

The agency has requested additional information from Gilead Sciences, the company developing idelalisib, to inform a decision on the use of this drug

in combination with rituximab for adults with chronic lymphocytic

leukemia (CLL).

NICE said it has questions about the cost-effectiveness of this treatment that have not been answered. Idelalisib costs £3114.75 for sixty 150-mg tablets, and the mean cost of a 1-year treatment course is £37,922.

Until NICE receives the requested information, the agency said it cannot recommend idelalisib plus rituximab for adults with untreated CLL who have 17p deletion or TP53 mutation, adults with relapsed CLL, or adults whose CLL is refractory and retreatment with previous regimens is not considered appropriate.

“The independent appraisal committee, which is developing the guidance on behalf of NICE, considered evidence from the company, clinical experts, and patient representatives,” said Carole Longson, NICE Health Technology Evaluation Centre Director.

“It concluded there were still questions to be answered about the cost-effectiveness of the treatment. We have requested further analysis from the company. We want to ensure we have as much information as possible to make an informed recommendation.”

Specifically, NICE has requested:

• A revised cost-effectiveness analysis for the comparison of idelalisib plus rituximab with rituximab alone, best supportive care, and ofatumumab
• A sensitivity analysis exploring the length of treatment benefit of idelalisib plus rituximab from treatment discontinuation up to 5 years
• A sensitivity analysis exploring the effects of reducing the proportion of non-responders having intravenous immunoglobulin from 45% to 20% or less and increasing the number of responders having intravenous immunoglobulin from 0% to 20%
• A sensitivity analysis exploring the effect of using clinical effectiveness data from the subgroup of people in Study 116 whose disease is refractory.

The independent appraisal committee will review this information and develop further draft guidance.

Until final guidance is issued, National Health Service bodies should make decisions locally on the funding of specific treatments. Once NICE issues its final guidance on a technology, it replaces local recommendations.

Micrograph showing CLL

The UK’s National Institute for Health and Care Excellence (NICE) has opened a consultation on a preliminary draft guidance for the PI3Kδ inhibitor idelalisib (Zydelig).

The agency has requested additional information from Gilead Sciences, the company developing idelalisib, to inform a decision on the use of this drug

in combination with rituximab for adults with chronic lymphocytic

leukemia (CLL).

NICE said it has questions about the cost-effectiveness of this treatment that have not been answered. Idelalisib costs £3114.75 for sixty 150-mg tablets, and the mean cost of a 1-year treatment course is £37,922.

Until NICE receives the requested information, the agency said it cannot recommend idelalisib plus rituximab for adults with untreated CLL who have 17p deletion or TP53 mutation, adults with relapsed CLL, or adults whose CLL is refractory and retreatment with previous regimens is not considered appropriate.

“The independent appraisal committee, which is developing the guidance on behalf of NICE, considered evidence from the company, clinical experts, and patient representatives,” said Carole Longson, NICE Health Technology Evaluation Centre Director.

“It concluded there were still questions to be answered about the cost-effectiveness of the treatment. We have requested further analysis from the company. We want to ensure we have as much information as possible to make an informed recommendation.”

Specifically, NICE has requested:

• A revised cost-effectiveness analysis for the comparison of idelalisib plus rituximab with rituximab alone, best supportive care, and ofatumumab
• A sensitivity analysis exploring the length of treatment benefit of idelalisib plus rituximab from treatment discontinuation up to 5 years
• A sensitivity analysis exploring the effects of reducing the proportion of non-responders having intravenous immunoglobulin from 45% to 20% or less and increasing the number of responders having intravenous immunoglobulin from 0% to 20%
• A sensitivity analysis exploring the effect of using clinical effectiveness data from the subgroup of people in Study 116 whose disease is refractory.

The independent appraisal committee will review this information and develop further draft guidance.

Until final guidance is issued, National Health Service bodies should make decisions locally on the funding of specific treatments. Once NICE issues its final guidance on a technology, it replaces local recommendations.

Micrograph showing CLL

The UK’s National Institute for Health and Care Excellence (NICE) has opened a consultation on a preliminary draft guidance for the PI3Kδ inhibitor idelalisib (Zydelig).

The agency has requested additional information from Gilead Sciences, the company developing idelalisib, to inform a decision on the use of this drug

in combination with rituximab for adults with chronic lymphocytic

leukemia (CLL).

NICE said it has questions about the cost-effectiveness of this treatment that have not been answered. Idelalisib costs £3114.75 for sixty 150-mg tablets, and the mean cost of a 1-year treatment course is £37,922.

Until NICE receives the requested information, the agency said it cannot recommend idelalisib plus rituximab for adults with untreated CLL who have 17p deletion or TP53 mutation, adults with relapsed CLL, or adults whose CLL is refractory and retreatment with previous regimens is not considered appropriate.

“The independent appraisal committee, which is developing the guidance on behalf of NICE, considered evidence from the company, clinical experts, and patient representatives,” said Carole Longson, NICE Health Technology Evaluation Centre Director.

“It concluded there were still questions to be answered about the cost-effectiveness of the treatment. We have requested further analysis from the company. We want to ensure we have as much information as possible to make an informed recommendation.”

Specifically, NICE has requested:

• A revised cost-effectiveness analysis for the comparison of idelalisib plus rituximab with rituximab alone, best supportive care, and ofatumumab
• A sensitivity analysis exploring the length of treatment benefit of idelalisib plus rituximab from treatment discontinuation up to 5 years
• A sensitivity analysis exploring the effects of reducing the proportion of non-responders having intravenous immunoglobulin from 45% to 20% or less and increasing the number of responders having intravenous immunoglobulin from 0% to 20%
• A sensitivity analysis exploring the effect of using clinical effectiveness data from the subgroup of people in Study 116 whose disease is refractory.

The independent appraisal committee will review this information and develop further draft guidance.

Until final guidance is issued, National Health Service bodies should make decisions locally on the funding of specific treatments. Once NICE issues its final guidance on a technology, it replaces local recommendations.

Lab mouse

Intermittent dosing with the immunosuppressant rapamycin can break an inflammatory loop that fuels cancer relapse, according to researchers.

The team found that rapamycin selectively breaks the cascade of inflammatory events that follow cellular senescence.

Once disrupted, it takes time for the inflammatory loop to re-establish itself. This suggests intermittent dosing could provide a way to reap the benefits of rapamycin while reducing side effects.

The researchers described these findings in Nature Cell Biology.

“We think this could provide a paradigm shift in the treatment of age-related disease, including cancer,” said study author Judith Campisi, PhD, of the Buck Institute for Research on Aging in Novato, California.

“Imagine the possibility of taking a pill for a few days or weeks every few years, as opposed to taking something with side effects every day for the rest of your life. It’s a new way of looking at how we could deal with age-related maladies.”

For this study, Dr Campisi and her colleagues administered rapamycin to mice with prostate cancer after they had received treatment with DNA-damaging chemotherapy.

The rapamycin reduced the secretion of inflammatory cytokines from senescent cells by suppressing the mTOR pathway. This suppressed the cells’ ability to stimulate tumor growth.

“DNA-damaging chemotherapy causes senescence, both to the tumor and its microenvironment,” Dr Campisi explained. “The tumor shrinks, but the immediate tissue environment is inflamed. We think signals from those inflamed cells trigger residual cancer cells to grow again. In the mice, rapamycin suppressed the ability of the tumor cells to relapse.”

The researchers said the paradigm-shifting potential of intermittent rapamycin dosing is based on the fact that it takes time for the inflammatory loop—fueled by the senescence-associated secretory phenotype (SASP)—to form and time for it to re-establish itself after a brief treatment period with rapamycin.

“Rapamycin blocks the production of a protein called IL-1α,” explained study author Remi-Martin Laberge, PhD, also of the Buck Institute.

“This in turn, suppresses IL6, a well-known inflammatory cytokine, at the level of transcription, which prevents the production of the IL6 protein. Because it acts at a deeper level within the cellular process, it takes longer for it to get started again.”

Dr Laberge also pointed out that treatment with rapamycin selectivity impacts the SASP, preserving the function of factors essential for wound healing.

“It’s an elegant solution,” Dr Laberge said. “Imagine using a small hammer to delicately knock out one thing that is causing problems. We knocked it out, and it stayed out long enough to benefit the health of the animal.”

“We have yet to fully understand why suppressing the mTOR pathway via rapamycin increases lifespan and health span in mice,” Dr Campisi added. “This work helps illuminate the puzzle. Perhaps the mice are living longer because they have less overall inflammation, and maybe intermittent dosing will make it possible for us to use [rapamycin] more widely in humans.”

Lab mouse

Intermittent dosing with the immunosuppressant rapamycin can break an inflammatory loop that fuels cancer relapse, according to researchers.

The team found that rapamycin selectively breaks the cascade of inflammatory events that follow cellular senescence.

Once disrupted, it takes time for the inflammatory loop to re-establish itself. This suggests intermittent dosing could provide a way to reap the benefits of rapamycin while reducing side effects.

The researchers described these findings in Nature Cell Biology.

“We think this could provide a paradigm shift in the treatment of age-related disease, including cancer,” said study author Judith Campisi, PhD, of the Buck Institute for Research on Aging in Novato, California.

“Imagine the possibility of taking a pill for a few days or weeks every few years, as opposed to taking something with side effects every day for the rest of your life. It’s a new way of looking at how we could deal with age-related maladies.”

For this study, Dr Campisi and her colleagues administered rapamycin to mice with prostate cancer after they had received treatment with DNA-damaging chemotherapy.

The rapamycin reduced the secretion of inflammatory cytokines from senescent cells by suppressing the mTOR pathway. This suppressed the cells’ ability to stimulate tumor growth.

“DNA-damaging chemotherapy causes senescence, both to the tumor and its microenvironment,” Dr Campisi explained. “The tumor shrinks, but the immediate tissue environment is inflamed. We think signals from those inflamed cells trigger residual cancer cells to grow again. In the mice, rapamycin suppressed the ability of the tumor cells to relapse.”

The researchers said the paradigm-shifting potential of intermittent rapamycin dosing is based on the fact that it takes time for the inflammatory loop—fueled by the senescence-associated secretory phenotype (SASP)—to form and time for it to re-establish itself after a brief treatment period with rapamycin.

“Rapamycin blocks the production of a protein called IL-1α,” explained study author Remi-Martin Laberge, PhD, also of the Buck Institute.

“This in turn, suppresses IL6, a well-known inflammatory cytokine, at the level of transcription, which prevents the production of the IL6 protein. Because it acts at a deeper level within the cellular process, it takes longer for it to get started again.”

Dr Laberge also pointed out that treatment with rapamycin selectivity impacts the SASP, preserving the function of factors essential for wound healing.

“It’s an elegant solution,” Dr Laberge said. “Imagine using a small hammer to delicately knock out one thing that is causing problems. We knocked it out, and it stayed out long enough to benefit the health of the animal.”

“We have yet to fully understand why suppressing the mTOR pathway via rapamycin increases lifespan and health span in mice,” Dr Campisi added. “This work helps illuminate the puzzle. Perhaps the mice are living longer because they have less overall inflammation, and maybe intermittent dosing will make it possible for us to use [rapamycin] more widely in humans.”

Lab mouse

Intermittent dosing with the immunosuppressant rapamycin can break an inflammatory loop that fuels cancer relapse, according to researchers.

The team found that rapamycin selectively breaks the cascade of inflammatory events that follow cellular senescence.

Once disrupted, it takes time for the inflammatory loop to re-establish itself. This suggests intermittent dosing could provide a way to reap the benefits of rapamycin while reducing side effects.

The researchers described these findings in Nature Cell Biology.

“We think this could provide a paradigm shift in the treatment of age-related disease, including cancer,” said study author Judith Campisi, PhD, of the Buck Institute for Research on Aging in Novato, California.

“Imagine the possibility of taking a pill for a few days or weeks every few years, as opposed to taking something with side effects every day for the rest of your life. It’s a new way of looking at how we could deal with age-related maladies.”

For this study, Dr Campisi and her colleagues administered rapamycin to mice with prostate cancer after they had received treatment with DNA-damaging chemotherapy.

The rapamycin reduced the secretion of inflammatory cytokines from senescent cells by suppressing the mTOR pathway. This suppressed the cells’ ability to stimulate tumor growth.

“DNA-damaging chemotherapy causes senescence, both to the tumor and its microenvironment,” Dr Campisi explained. “The tumor shrinks, but the immediate tissue environment is inflamed. We think signals from those inflamed cells trigger residual cancer cells to grow again. In the mice, rapamycin suppressed the ability of the tumor cells to relapse.”

The researchers said the paradigm-shifting potential of intermittent rapamycin dosing is based on the fact that it takes time for the inflammatory loop—fueled by the senescence-associated secretory phenotype (SASP)—to form and time for it to re-establish itself after a brief treatment period with rapamycin.

“Rapamycin blocks the production of a protein called IL-1α,” explained study author Remi-Martin Laberge, PhD, also of the Buck Institute.

“This in turn, suppresses IL6, a well-known inflammatory cytokine, at the level of transcription, which prevents the production of the IL6 protein. Because it acts at a deeper level within the cellular process, it takes longer for it to get started again.”

Dr Laberge also pointed out that treatment with rapamycin selectivity impacts the SASP, preserving the function of factors essential for wound healing.

“It’s an elegant solution,” Dr Laberge said. “Imagine using a small hammer to delicately knock out one thing that is causing problems. We knocked it out, and it stayed out long enough to benefit the health of the animal.”

“We have yet to fully understand why suppressing the mTOR pathway via rapamycin increases lifespan and health span in mice,” Dr Campisi added. “This work helps illuminate the puzzle. Perhaps the mice are living longer because they have less overall inflammation, and maybe intermittent dosing will make it possible for us to use [rapamycin] more widely in humans.”

Emotionally distressed Canadian students who completed a school-based cognitive-behavioral therapy program experienced significant improvements in depression and suicidality, according to a multicenter prospective study published in PLoS One.

At the end of the pilot program entitled Empowering a Multimodal Pathway Toward Healthy Youth (EMPATHY), the number of students who were actively suicidal fell by 73%, and depression scores dropped by about 15% across all schools and age groups, Dr. Peter Silverstone, a professor of psychiatry at the University of Alberta, Edmonton, said in an interview.

Depressive disorders affect at least 10% of U.S. young people, and about 8% who live in the United States attempt suicide each year, according to the Centers for Disease Control and Prevention. To explore solutions, Dr. Silverstone and his associates used tablets loaded with a specially designed software “app” to screen 3,244 Canadian students aged 11-18 years (6^th-12^th grades). The students attended the five middle schools and high schools in a single Alberta school district, and the screen incorporated questions from several short, free mental health scales (PLoS One 2015 [doi:10.1371/journal.pone.0125527]).

Trained staff then interviewed students who were assessed as actively suicidal and met with them and their parents in order to create a safety plan, make referrals to appropriate health services, and invite students to participate in the guided Internet cognitive behavioral therapy (CBT) program. Students who scored in the top 10% of a combined measure of depression, anxiety, and low self-esteem also were invited to participate in the CBT program, and an eight-session version of the program was deployed for all seventh and eighth graders.

Among 503 high-risk students who were offered the CBT program, 151 (30%) enrolled, and 90% completed the program.

Parents and students had only a week to sign and return the consent forms, which led to the low participation rate in the pilot phase of the study, Dr. Silverstone noted. “We changed the processes after the pilot and got much higher acceptance rates, nearer to 70% percent.”

At 12-week follow-up, program participants had significantly improved from baseline, compared with nonparticipants in terms of the combined mental health, depression, anxiety, self-esteem, and quality of life scales, but not in terms of self-reported use of drugs, alcohol, or tobacco, the investigators reported.

Of the 104 actively suicidal students at baseline who completed both assessments, 76 (73%) were in the no-risk group at 12 weeks, a significant difference.

The results are promising, but their durability remains unclear, as other studies have reported strong short-term results that did not hold several years later, the investigators noted.

“All staff hired in the schools to implement the program had to have some experience working with youth, and many had an undergraduate degree,” the investigators added. “However, it is important to note that they were specifically not highly trained individuals (such as psychologists or teachers), as it was felt that it would not be feasible for widespread expansion if such highly trained (and expensive) staff were required.”

“We have follow-up data for 15 months, until the end of June 2015, that we hope to be able to start analyzing before the end of the year,” Dr. Silverstone said. But in the meantime, the new provincial government has cut the program’s funding, which he called a “major disappointment. We have had to abandon all further plans for the program,” he said, adding that it will terminate at the end of 2015.

Alberta Health Services funded the study. The researchers declared having no relevant competing interests.

Emotionally distressed Canadian students who completed a school-based cognitive-behavioral therapy program experienced significant improvements in depression and suicidality, according to a multicenter prospective study published in PLoS One.

At the end of the pilot program entitled Empowering a Multimodal Pathway Toward Healthy Youth (EMPATHY), the number of students who were actively suicidal fell by 73%, and depression scores dropped by about 15% across all schools and age groups, Dr. Peter Silverstone, a professor of psychiatry at the University of Alberta, Edmonton, said in an interview.

Depressive disorders affect at least 10% of U.S. young people, and about 8% who live in the United States attempt suicide each year, according to the Centers for Disease Control and Prevention. To explore solutions, Dr. Silverstone and his associates used tablets loaded with a specially designed software “app” to screen 3,244 Canadian students aged 11-18 years (6^th-12^th grades). The students attended the five middle schools and high schools in a single Alberta school district, and the screen incorporated questions from several short, free mental health scales (PLoS One 2015 [doi:10.1371/journal.pone.0125527]).

Trained staff then interviewed students who were assessed as actively suicidal and met with them and their parents in order to create a safety plan, make referrals to appropriate health services, and invite students to participate in the guided Internet cognitive behavioral therapy (CBT) program. Students who scored in the top 10% of a combined measure of depression, anxiety, and low self-esteem also were invited to participate in the CBT program, and an eight-session version of the program was deployed for all seventh and eighth graders.

Among 503 high-risk students who were offered the CBT program, 151 (30%) enrolled, and 90% completed the program.

Parents and students had only a week to sign and return the consent forms, which led to the low participation rate in the pilot phase of the study, Dr. Silverstone noted. “We changed the processes after the pilot and got much higher acceptance rates, nearer to 70% percent.”

At 12-week follow-up, program participants had significantly improved from baseline, compared with nonparticipants in terms of the combined mental health, depression, anxiety, self-esteem, and quality of life scales, but not in terms of self-reported use of drugs, alcohol, or tobacco, the investigators reported.

Of the 104 actively suicidal students at baseline who completed both assessments, 76 (73%) were in the no-risk group at 12 weeks, a significant difference.

The results are promising, but their durability remains unclear, as other studies have reported strong short-term results that did not hold several years later, the investigators noted.

“All staff hired in the schools to implement the program had to have some experience working with youth, and many had an undergraduate degree,” the investigators added. “However, it is important to note that they were specifically not highly trained individuals (such as psychologists or teachers), as it was felt that it would not be feasible for widespread expansion if such highly trained (and expensive) staff were required.”

“We have follow-up data for 15 months, until the end of June 2015, that we hope to be able to start analyzing before the end of the year,” Dr. Silverstone said. But in the meantime, the new provincial government has cut the program’s funding, which he called a “major disappointment. We have had to abandon all further plans for the program,” he said, adding that it will terminate at the end of 2015.

Alberta Health Services funded the study. The researchers declared having no relevant competing interests.

Emotionally distressed Canadian students who completed a school-based cognitive-behavioral therapy program experienced significant improvements in depression and suicidality, according to a multicenter prospective study published in PLoS One.

At the end of the pilot program entitled Empowering a Multimodal Pathway Toward Healthy Youth (EMPATHY), the number of students who were actively suicidal fell by 73%, and depression scores dropped by about 15% across all schools and age groups, Dr. Peter Silverstone, a professor of psychiatry at the University of Alberta, Edmonton, said in an interview.

Depressive disorders affect at least 10% of U.S. young people, and about 8% who live in the United States attempt suicide each year, according to the Centers for Disease Control and Prevention. To explore solutions, Dr. Silverstone and his associates used tablets loaded with a specially designed software “app” to screen 3,244 Canadian students aged 11-18 years (6^th-12^th grades). The students attended the five middle schools and high schools in a single Alberta school district, and the screen incorporated questions from several short, free mental health scales (PLoS One 2015 [doi:10.1371/journal.pone.0125527]).

Trained staff then interviewed students who were assessed as actively suicidal and met with them and their parents in order to create a safety plan, make referrals to appropriate health services, and invite students to participate in the guided Internet cognitive behavioral therapy (CBT) program. Students who scored in the top 10% of a combined measure of depression, anxiety, and low self-esteem also were invited to participate in the CBT program, and an eight-session version of the program was deployed for all seventh and eighth graders.

Among 503 high-risk students who were offered the CBT program, 151 (30%) enrolled, and 90% completed the program.

Parents and students had only a week to sign and return the consent forms, which led to the low participation rate in the pilot phase of the study, Dr. Silverstone noted. “We changed the processes after the pilot and got much higher acceptance rates, nearer to 70% percent.”

At 12-week follow-up, program participants had significantly improved from baseline, compared with nonparticipants in terms of the combined mental health, depression, anxiety, self-esteem, and quality of life scales, but not in terms of self-reported use of drugs, alcohol, or tobacco, the investigators reported.

Of the 104 actively suicidal students at baseline who completed both assessments, 76 (73%) were in the no-risk group at 12 weeks, a significant difference.

The results are promising, but their durability remains unclear, as other studies have reported strong short-term results that did not hold several years later, the investigators noted.

“All staff hired in the schools to implement the program had to have some experience working with youth, and many had an undergraduate degree,” the investigators added. “However, it is important to note that they were specifically not highly trained individuals (such as psychologists or teachers), as it was felt that it would not be feasible for widespread expansion if such highly trained (and expensive) staff were required.”

“We have follow-up data for 15 months, until the end of June 2015, that we hope to be able to start analyzing before the end of the year,” Dr. Silverstone said. But in the meantime, the new provincial government has cut the program’s funding, which he called a “major disappointment. We have had to abandon all further plans for the program,” he said, adding that it will terminate at the end of 2015.

Alberta Health Services funded the study. The researchers declared having no relevant competing interests.

To the Editor:

A 68-year-old man with a history of myelodysplastic syndrome and recurrent Sweet syndrome presented with left leg lesions of 3 months’ duration. The lesions originated as a solitary nodule on the left calf and subsequently developed into multiple nonpainful, nonpruritic, erythematous plaques of varying sizes with violaceous coloration and overlying necrotic eschar, occupying the entire anterior aspect of the left lower leg and left popliteal fossa (Figure). The patient denied any trauma or associated symptoms but had a history of Sweet syndrome that manifested as lesions on the arms and legs for which he took 6 mg of prednisone daily to prevent recurrence.

Multiple erythematous to violaceous plaques with overlying necrotic eschar on the anterior aspect of the left lower leg.

Histologic examination revealed nodular and diffuse chronic granulomatous and acute inflammatory infiltrate. Stains for bacteria, fungi, and acid-fast bacilli were negative. Cultures subsequently grew Mycobacterium kansasii, and the patient was started on isoniazid 300 mg daily, rifampin 600 mg daily, ethambutol 800 mg daily, and pyridoxine 50 mg daily. Chest radiograph and computed tomography showed no evidence of pulmonary disease and 2 blood cultures were negative for growth. The patient subsequently developed weakness that he attributed to the antibiotics and he decided to discontinue all treatment.

At 11 months the lesions showed no change; however, magnetic resonance imaging of the leg was suggestive of osteomyelitis. The patient was started on clarithromycin 500 mg twice daily with planned addition of isoniazid. The patient refused any additional antibiotics but agreed to continue the clarithromycin treatment for one year. He was subsequently lost to dermatology follow-up.

Nontuberculous mycobacteria (NTM) infection is a rare sequela of hematologic malignancy, seen in only 1.5% of patients.¹ The NTM most commonly seen in hematologic malignancy are generally the fast-growing species Mycobacterium abscessus, Mycobacterium chelonae, Mycobacterium fortuitum, or Mycobacterium phlei, rather than slow growers Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium marinum, and Mycobacterium xenopi. Mycobacterium kansasii infection, such as seen in our patient, accounts for only 18% of cases.¹ This case is further distinguished by the fact that cutaneous infections with NTM also are generally caused by fast-growing organisms such as Mycobacterium abscessus-chelonae complex and M fortuitum, rather than the slow-growing M kansasii.^2,3

Mycobacterium kansasii is a slow-growing, acid-fast bacillus found in local water reservoirs, swimming pools, sewers, and tap water where it can live for up to 12 months.^2,4,5Mycobacterium kansasii is traditionally considered the most virulent NTM.^3,6 It most frequently causes a pulmonary infection in the immunosuppressed and patients with chronic bronchopulmonary disease.^6,7 Disseminated disease is less common and is primarily seen in immunocompromised patients, particularly in human immunodeficiency virus–positive patients, transplant recipients, and patients with hematologic malignancies.^1,6,8 Disseminated disease rarely has been seen in patients with normal immune function.^2,3

Cutaneous M kansasii infection has only infrequently been described. Most patients tend to be middle-aged men, with a median affected age of 43 years.^2,7,9,10 One review of cutaneous cases found that 72% had some form of altered immunity and more than 50% of those patients were on chronic steroids. The same review found that of the cases of cutaneous M kansasii in patients with altered immunity, only 30% had disseminated disease.¹⁰ Our patient was immunocompromised but showed no evidence of disseminated disease, as displayed by negative chest radiograph and computed tomography, lack of pulmonary symptoms, and negative blood cultures. As a 68-year-old man with myelodysplastic syndrome on chronic steroids with no disseminated disease, our patient fits well into these demographics, aside from his advanced age.

Cutaneous M kansasii infection has a variable presentation, manifesting as solitary lesions, nodules, pustules, seromas, erythematous plaques, verrucous lesions, ulcers, and as cellulitis.^5,7,9-12 Immune competent individuals were more likely to present with raised lesions or ulcers, whereas immune compromised individuals had a more diffuse presentation of cellulitis or seromas with variable histology.^6,8 Our patient, though immune compromised, presented with multiple erythematous plaques with eschars, which further endorses having a high clinical suspicion, as the lesions display marked heterogeneity.

Treatment of M kansasii infection consists of at least 1 year of isoniazid 300 mg daily, rifampin 600 mg daily, and ethambutol 15 mg/kg daily, with possible addition of streptomycin.^8,13Mycobacterium kansasii infection necessitates multidrug treatment due to the broad range of resistance exhibited by different isolated strains.¹⁴

Response to treatment in cutaneous M kansasii greatly depends on the underlying disease state of the individual. Generally, immune competent individuals do very well, while the course in immune compromised patients depends on their degree of illness. Patients with disseminated disease generally do poorly.^4,7,10 In at least one case of cutaneous disease, dissemination developed as a sequela, thus suggesting treatment is needed even in stable lesions.² Dissemination was a concern with our patient given the magnetic resonance imaging findings suggestive of osteomyelitis. Although treatment generally consists of triple therapy with isoniazid, rifampin, and ethambutol, given the high frequency of adverse effects due to isoniazid or rifampin, as was seen in our patient, the drug regimen might have to be altered to suit the patient. Susceptibility testing is desirable to aid in tailoring the treatment.^8,13 Furthermore, as the duration of treatment is at least 1 year, diligent follow-up must be maintained to avoid incomplete treatment.

The unpredictable presentation of cutaneous M kansasii infection coupled with the variable history necessitates a high level of clinical suspicion and a low threshold for culturing lesions. Furthermore, the long duration and complexity of the antibiotic regimen and the high incidence of adverse reactions demands strict follow-up, especially given the risk for progression to disseminated disease.

To the Editor:

A 68-year-old man with a history of myelodysplastic syndrome and recurrent Sweet syndrome presented with left leg lesions of 3 months’ duration. The lesions originated as a solitary nodule on the left calf and subsequently developed into multiple nonpainful, nonpruritic, erythematous plaques of varying sizes with violaceous coloration and overlying necrotic eschar, occupying the entire anterior aspect of the left lower leg and left popliteal fossa (Figure). The patient denied any trauma or associated symptoms but had a history of Sweet syndrome that manifested as lesions on the arms and legs for which he took 6 mg of prednisone daily to prevent recurrence.

Multiple erythematous to violaceous plaques with overlying necrotic eschar on the anterior aspect of the left lower leg.

Histologic examination revealed nodular and diffuse chronic granulomatous and acute inflammatory infiltrate. Stains for bacteria, fungi, and acid-fast bacilli were negative. Cultures subsequently grew Mycobacterium kansasii, and the patient was started on isoniazid 300 mg daily, rifampin 600 mg daily, ethambutol 800 mg daily, and pyridoxine 50 mg daily. Chest radiograph and computed tomography showed no evidence of pulmonary disease and 2 blood cultures were negative for growth. The patient subsequently developed weakness that he attributed to the antibiotics and he decided to discontinue all treatment.

At 11 months the lesions showed no change; however, magnetic resonance imaging of the leg was suggestive of osteomyelitis. The patient was started on clarithromycin 500 mg twice daily with planned addition of isoniazid. The patient refused any additional antibiotics but agreed to continue the clarithromycin treatment for one year. He was subsequently lost to dermatology follow-up.

Nontuberculous mycobacteria (NTM) infection is a rare sequela of hematologic malignancy, seen in only 1.5% of patients.¹ The NTM most commonly seen in hematologic malignancy are generally the fast-growing species Mycobacterium abscessus, Mycobacterium chelonae, Mycobacterium fortuitum, or Mycobacterium phlei, rather than slow growers Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium marinum, and Mycobacterium xenopi. Mycobacterium kansasii infection, such as seen in our patient, accounts for only 18% of cases.¹ This case is further distinguished by the fact that cutaneous infections with NTM also are generally caused by fast-growing organisms such as Mycobacterium abscessus-chelonae complex and M fortuitum, rather than the slow-growing M kansasii.^2,3

Mycobacterium kansasii is a slow-growing, acid-fast bacillus found in local water reservoirs, swimming pools, sewers, and tap water where it can live for up to 12 months.^2,4,5Mycobacterium kansasii is traditionally considered the most virulent NTM.^3,6 It most frequently causes a pulmonary infection in the immunosuppressed and patients with chronic bronchopulmonary disease.^6,7 Disseminated disease is less common and is primarily seen in immunocompromised patients, particularly in human immunodeficiency virus–positive patients, transplant recipients, and patients with hematologic malignancies.^1,6,8 Disseminated disease rarely has been seen in patients with normal immune function.^2,3

Cutaneous M kansasii infection has only infrequently been described. Most patients tend to be middle-aged men, with a median affected age of 43 years.^2,7,9,10 One review of cutaneous cases found that 72% had some form of altered immunity and more than 50% of those patients were on chronic steroids. The same review found that of the cases of cutaneous M kansasii in patients with altered immunity, only 30% had disseminated disease.¹⁰ Our patient was immunocompromised but showed no evidence of disseminated disease, as displayed by negative chest radiograph and computed tomography, lack of pulmonary symptoms, and negative blood cultures. As a 68-year-old man with myelodysplastic syndrome on chronic steroids with no disseminated disease, our patient fits well into these demographics, aside from his advanced age.

Cutaneous M kansasii infection has a variable presentation, manifesting as solitary lesions, nodules, pustules, seromas, erythematous plaques, verrucous lesions, ulcers, and as cellulitis.^5,7,9-12 Immune competent individuals were more likely to present with raised lesions or ulcers, whereas immune compromised individuals had a more diffuse presentation of cellulitis or seromas with variable histology.^6,8 Our patient, though immune compromised, presented with multiple erythematous plaques with eschars, which further endorses having a high clinical suspicion, as the lesions display marked heterogeneity.

Treatment of M kansasii infection consists of at least 1 year of isoniazid 300 mg daily, rifampin 600 mg daily, and ethambutol 15 mg/kg daily, with possible addition of streptomycin.^8,13Mycobacterium kansasii infection necessitates multidrug treatment due to the broad range of resistance exhibited by different isolated strains.¹⁴

Response to treatment in cutaneous M kansasii greatly depends on the underlying disease state of the individual. Generally, immune competent individuals do very well, while the course in immune compromised patients depends on their degree of illness. Patients with disseminated disease generally do poorly.^4,7,10 In at least one case of cutaneous disease, dissemination developed as a sequela, thus suggesting treatment is needed even in stable lesions.² Dissemination was a concern with our patient given the magnetic resonance imaging findings suggestive of osteomyelitis. Although treatment generally consists of triple therapy with isoniazid, rifampin, and ethambutol, given the high frequency of adverse effects due to isoniazid or rifampin, as was seen in our patient, the drug regimen might have to be altered to suit the patient. Susceptibility testing is desirable to aid in tailoring the treatment.^8,13 Furthermore, as the duration of treatment is at least 1 year, diligent follow-up must be maintained to avoid incomplete treatment.

The unpredictable presentation of cutaneous M kansasii infection coupled with the variable history necessitates a high level of clinical suspicion and a low threshold for culturing lesions. Furthermore, the long duration and complexity of the antibiotic regimen and the high incidence of adverse reactions demands strict follow-up, especially given the risk for progression to disseminated disease.

To the Editor:

A 68-year-old man with a history of myelodysplastic syndrome and recurrent Sweet syndrome presented with left leg lesions of 3 months’ duration. The lesions originated as a solitary nodule on the left calf and subsequently developed into multiple nonpainful, nonpruritic, erythematous plaques of varying sizes with violaceous coloration and overlying necrotic eschar, occupying the entire anterior aspect of the left lower leg and left popliteal fossa (Figure). The patient denied any trauma or associated symptoms but had a history of Sweet syndrome that manifested as lesions on the arms and legs for which he took 6 mg of prednisone daily to prevent recurrence.

Multiple erythematous to violaceous plaques with overlying necrotic eschar on the anterior aspect of the left lower leg.

Histologic examination revealed nodular and diffuse chronic granulomatous and acute inflammatory infiltrate. Stains for bacteria, fungi, and acid-fast bacilli were negative. Cultures subsequently grew Mycobacterium kansasii, and the patient was started on isoniazid 300 mg daily, rifampin 600 mg daily, ethambutol 800 mg daily, and pyridoxine 50 mg daily. Chest radiograph and computed tomography showed no evidence of pulmonary disease and 2 blood cultures were negative for growth. The patient subsequently developed weakness that he attributed to the antibiotics and he decided to discontinue all treatment.

At 11 months the lesions showed no change; however, magnetic resonance imaging of the leg was suggestive of osteomyelitis. The patient was started on clarithromycin 500 mg twice daily with planned addition of isoniazid. The patient refused any additional antibiotics but agreed to continue the clarithromycin treatment for one year. He was subsequently lost to dermatology follow-up.

Nontuberculous mycobacteria (NTM) infection is a rare sequela of hematologic malignancy, seen in only 1.5% of patients.¹ The NTM most commonly seen in hematologic malignancy are generally the fast-growing species Mycobacterium abscessus, Mycobacterium chelonae, Mycobacterium fortuitum, or Mycobacterium phlei, rather than slow growers Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium marinum, and Mycobacterium xenopi. Mycobacterium kansasii infection, such as seen in our patient, accounts for only 18% of cases.¹ This case is further distinguished by the fact that cutaneous infections with NTM also are generally caused by fast-growing organisms such as Mycobacterium abscessus-chelonae complex and M fortuitum, rather than the slow-growing M kansasii.^2,3

Mycobacterium kansasii is a slow-growing, acid-fast bacillus found in local water reservoirs, swimming pools, sewers, and tap water where it can live for up to 12 months.^2,4,5Mycobacterium kansasii is traditionally considered the most virulent NTM.^3,6 It most frequently causes a pulmonary infection in the immunosuppressed and patients with chronic bronchopulmonary disease.^6,7 Disseminated disease is less common and is primarily seen in immunocompromised patients, particularly in human immunodeficiency virus–positive patients, transplant recipients, and patients with hematologic malignancies.^1,6,8 Disseminated disease rarely has been seen in patients with normal immune function.^2,3

Cutaneous M kansasii infection has only infrequently been described. Most patients tend to be middle-aged men, with a median affected age of 43 years.^2,7,9,10 One review of cutaneous cases found that 72% had some form of altered immunity and more than 50% of those patients were on chronic steroids. The same review found that of the cases of cutaneous M kansasii in patients with altered immunity, only 30% had disseminated disease.¹⁰ Our patient was immunocompromised but showed no evidence of disseminated disease, as displayed by negative chest radiograph and computed tomography, lack of pulmonary symptoms, and negative blood cultures. As a 68-year-old man with myelodysplastic syndrome on chronic steroids with no disseminated disease, our patient fits well into these demographics, aside from his advanced age.

Cutaneous M kansasii infection has a variable presentation, manifesting as solitary lesions, nodules, pustules, seromas, erythematous plaques, verrucous lesions, ulcers, and as cellulitis.^5,7,9-12 Immune competent individuals were more likely to present with raised lesions or ulcers, whereas immune compromised individuals had a more diffuse presentation of cellulitis or seromas with variable histology.^6,8 Our patient, though immune compromised, presented with multiple erythematous plaques with eschars, which further endorses having a high clinical suspicion, as the lesions display marked heterogeneity.

Treatment of M kansasii infection consists of at least 1 year of isoniazid 300 mg daily, rifampin 600 mg daily, and ethambutol 15 mg/kg daily, with possible addition of streptomycin.^8,13Mycobacterium kansasii infection necessitates multidrug treatment due to the broad range of resistance exhibited by different isolated strains.¹⁴

Response to treatment in cutaneous M kansasii greatly depends on the underlying disease state of the individual. Generally, immune competent individuals do very well, while the course in immune compromised patients depends on their degree of illness. Patients with disseminated disease generally do poorly.^4,7,10 In at least one case of cutaneous disease, dissemination developed as a sequela, thus suggesting treatment is needed even in stable lesions.² Dissemination was a concern with our patient given the magnetic resonance imaging findings suggestive of osteomyelitis. Although treatment generally consists of triple therapy with isoniazid, rifampin, and ethambutol, given the high frequency of adverse effects due to isoniazid or rifampin, as was seen in our patient, the drug regimen might have to be altered to suit the patient. Susceptibility testing is desirable to aid in tailoring the treatment.^8,13 Furthermore, as the duration of treatment is at least 1 year, diligent follow-up must be maintained to avoid incomplete treatment.

The unpredictable presentation of cutaneous M kansasii infection coupled with the variable history necessitates a high level of clinical suspicion and a low threshold for culturing lesions. Furthermore, the long duration and complexity of the antibiotic regimen and the high incidence of adverse reactions demands strict follow-up, especially given the risk for progression to disseminated disease.

Though acute coronary syndromes are the leading cause of death in U.S. women, an analysis of clinical trials showed that enrollment among women remained disproportionately low from 1994 to 2010, reported Dr. Kristian Kragholm and coauthors at Duke Clinical Research Institute.

An analysis of data in 76,148 non–ST-segment elevation acute coronary syndrome patients from 11 phase III clinical trials found that women comprised just 33.3% of participants, which did not change significantly over the 17-year period. Women consistently had higher incidence of diabetes, hypertension, and heart failure, the authors reported.

Use of ACE inhibitors/angiotensin II receptor blockers, thienopyridines, beta-blockers, and lipid-lowering drugs significantly increased over time for both sexes, as did use of coronary angiography and percutaneous coronary intervention. Observed in-hospital, 30-day, and 6-month mortality decreased significantly in both men and women, Dr. Kragholm and colleagues said.

The findings suggest that “current efforts to representatively enroll women in NSTE ACS trials are insufficient,” the authors wrote. “Because safety and efficacy findings may differ according to sex, this disparity could undermine generalizability of clinical trial results to treatment of the overall NSTE ACS population.”

Read the full article here.

Though acute coronary syndromes are the leading cause of death in U.S. women, an analysis of clinical trials showed that enrollment among women remained disproportionately low from 1994 to 2010, reported Dr. Kristian Kragholm and coauthors at Duke Clinical Research Institute.

An analysis of data in 76,148 non–ST-segment elevation acute coronary syndrome patients from 11 phase III clinical trials found that women comprised just 33.3% of participants, which did not change significantly over the 17-year period. Women consistently had higher incidence of diabetes, hypertension, and heart failure, the authors reported.

Use of ACE inhibitors/angiotensin II receptor blockers, thienopyridines, beta-blockers, and lipid-lowering drugs significantly increased over time for both sexes, as did use of coronary angiography and percutaneous coronary intervention. Observed in-hospital, 30-day, and 6-month mortality decreased significantly in both men and women, Dr. Kragholm and colleagues said.

The findings suggest that “current efforts to representatively enroll women in NSTE ACS trials are insufficient,” the authors wrote. “Because safety and efficacy findings may differ according to sex, this disparity could undermine generalizability of clinical trial results to treatment of the overall NSTE ACS population.”

Read the full article here.

Though acute coronary syndromes are the leading cause of death in U.S. women, an analysis of clinical trials showed that enrollment among women remained disproportionately low from 1994 to 2010, reported Dr. Kristian Kragholm and coauthors at Duke Clinical Research Institute.

An analysis of data in 76,148 non–ST-segment elevation acute coronary syndrome patients from 11 phase III clinical trials found that women comprised just 33.3% of participants, which did not change significantly over the 17-year period. Women consistently had higher incidence of diabetes, hypertension, and heart failure, the authors reported.

Use of ACE inhibitors/angiotensin II receptor blockers, thienopyridines, beta-blockers, and lipid-lowering drugs significantly increased over time for both sexes, as did use of coronary angiography and percutaneous coronary intervention. Observed in-hospital, 30-day, and 6-month mortality decreased significantly in both men and women, Dr. Kragholm and colleagues said.

The findings suggest that “current efforts to representatively enroll women in NSTE ACS trials are insufficient,” the authors wrote. “Because safety and efficacy findings may differ according to sex, this disparity could undermine generalizability of clinical trial results to treatment of the overall NSTE ACS population.”

Read the full article here.

At the recent American Society of Clinical Oncology Annual Meeting, Martin et al presented data from the Australian Oral Nicotinamide to Reduce Actinic Cancer (ONTRAC) study. This prospective double-blind, randomized, controlled trial examined 386 immunocompetent patients with 2 or more nonmelanoma skin cancers (NMSCs) in the last 5 years (average, 8). The patients were randomized to receive oral nicotinamide 500 mg twice daily or placebo for 1 year, resulting in significant reduction of new NMSCs (average rate 1.77 vs 2.42; relative rate reduction, 23%; P=.02), with similar results for basal and squamous cell carcinomas. Actinic keratosis counts were reduced throughout the year by up to 20%, peaking at 9 months. No differences in adverse events were noted between the treatment and placebo groups.

What’s the issue?

High-risk NMSC patients present a challenge to dermatologists, as their need for constant surveillance, field therapy for actinic keratoses, and revolving visits between skin examinations and procedural modalities such as Mohs micrographic surgery can be staggering. Chemopreventive strategies pose difficulties, especially for elderly patients, due to tolerability and adherence, skin irritation and cosmetic limitations of topical therapies such as 5-fluorouracil, and inadequacy or financial inaccessibility of oral therapies such as acitretin.

Nicotinamide is a confusing supplement, as it is also called niacinamide. One of the 2 forms of vitamin B₃, nicotinic acid (or niacin) is the other form and can be converted to nicotinamide in the body. It has cholesterol and vasodilatory/flushing effects that nicotinamide itself does not. Therefore, these supplement subtypes are not generally interchangeable.

Nicotinamide is postulated to enhance DNA repair and reverse UV immunosuppression in NMSC patients and is a well-tolerated and inexpensive supplement (approximately $10 a month for the dosage in this study). Although the decrease in skin cancer number per year seems modest in this study, my patients would likely welcome at least 1 fewer surgery per year and much less cryotherapy or 5-fluorouracil cream, especially if it is as simple as buying the supplement at the grocery store as they do for their fish oil capsules and probiotics. Does vitamin B₃ hold promise for your high-risk NMSC patients?

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

At the recent American Society of Clinical Oncology Annual Meeting, Martin et al presented data from the Australian Oral Nicotinamide to Reduce Actinic Cancer (ONTRAC) study. This prospective double-blind, randomized, controlled trial examined 386 immunocompetent patients with 2 or more nonmelanoma skin cancers (NMSCs) in the last 5 years (average, 8). The patients were randomized to receive oral nicotinamide 500 mg twice daily or placebo for 1 year, resulting in significant reduction of new NMSCs (average rate 1.77 vs 2.42; relative rate reduction, 23%; P=.02), with similar results for basal and squamous cell carcinomas. Actinic keratosis counts were reduced throughout the year by up to 20%, peaking at 9 months. No differences in adverse events were noted between the treatment and placebo groups.

What’s the issue?

High-risk NMSC patients present a challenge to dermatologists, as their need for constant surveillance, field therapy for actinic keratoses, and revolving visits between skin examinations and procedural modalities such as Mohs micrographic surgery can be staggering. Chemopreventive strategies pose difficulties, especially for elderly patients, due to tolerability and adherence, skin irritation and cosmetic limitations of topical therapies such as 5-fluorouracil, and inadequacy or financial inaccessibility of oral therapies such as acitretin.

Nicotinamide is a confusing supplement, as it is also called niacinamide. One of the 2 forms of vitamin B₃, nicotinic acid (or niacin) is the other form and can be converted to nicotinamide in the body. It has cholesterol and vasodilatory/flushing effects that nicotinamide itself does not. Therefore, these supplement subtypes are not generally interchangeable.

Nicotinamide is postulated to enhance DNA repair and reverse UV immunosuppression in NMSC patients and is a well-tolerated and inexpensive supplement (approximately $10 a month for the dosage in this study). Although the decrease in skin cancer number per year seems modest in this study, my patients would likely welcome at least 1 fewer surgery per year and much less cryotherapy or 5-fluorouracil cream, especially if it is as simple as buying the supplement at the grocery store as they do for their fish oil capsules and probiotics. Does vitamin B₃ hold promise for your high-risk NMSC patients?

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

At the recent American Society of Clinical Oncology Annual Meeting, Martin et al presented data from the Australian Oral Nicotinamide to Reduce Actinic Cancer (ONTRAC) study. This prospective double-blind, randomized, controlled trial examined 386 immunocompetent patients with 2 or more nonmelanoma skin cancers (NMSCs) in the last 5 years (average, 8). The patients were randomized to receive oral nicotinamide 500 mg twice daily or placebo for 1 year, resulting in significant reduction of new NMSCs (average rate 1.77 vs 2.42; relative rate reduction, 23%; P=.02), with similar results for basal and squamous cell carcinomas. Actinic keratosis counts were reduced throughout the year by up to 20%, peaking at 9 months. No differences in adverse events were noted between the treatment and placebo groups.

What’s the issue?

High-risk NMSC patients present a challenge to dermatologists, as their need for constant surveillance, field therapy for actinic keratoses, and revolving visits between skin examinations and procedural modalities such as Mohs micrographic surgery can be staggering. Chemopreventive strategies pose difficulties, especially for elderly patients, due to tolerability and adherence, skin irritation and cosmetic limitations of topical therapies such as 5-fluorouracil, and inadequacy or financial inaccessibility of oral therapies such as acitretin.

Nicotinamide is a confusing supplement, as it is also called niacinamide. One of the 2 forms of vitamin B₃, nicotinic acid (or niacin) is the other form and can be converted to nicotinamide in the body. It has cholesterol and vasodilatory/flushing effects that nicotinamide itself does not. Therefore, these supplement subtypes are not generally interchangeable.

Nicotinamide is postulated to enhance DNA repair and reverse UV immunosuppression in NMSC patients and is a well-tolerated and inexpensive supplement (approximately $10 a month for the dosage in this study). Although the decrease in skin cancer number per year seems modest in this study, my patients would likely welcome at least 1 fewer surgery per year and much less cryotherapy or 5-fluorouracil cream, especially if it is as simple as buying the supplement at the grocery store as they do for their fish oil capsules and probiotics. Does vitamin B₃ hold promise for your high-risk NMSC patients?

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