Hematology Times

Image by Ed Uthman

Preclinical research has revealed a potential strategy for treating Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL).

Investigators discovered that miR-28 inhibits the growth of B-cell lymphomas, but this microRNA is often lost in these lymphomas.

Re-expressing miR-28 in mouse models of BL and DLBCL inhibited tumor growth, which supports the potential of synthetic miR-28 analogs for the treatment of these lymphomas.

In fact, the investigators believe their work could lead to the development of the first miRNA analog therapy for the treatment of B-cell lymphoma and provide the basis for clinical trials.

Almudena Ramiro, PhD, of Centro Nacional de Investigaciones Cardiovasculares in Madrid, Spain, and her colleagues described the work in Blood.

The team characterized the function of miR-28 in the biology of mature B lymphocytes and in the development of lymphomas associated with this cell type.

The investigators found that miR-28 regulates the terminal differentiation of B lymphocytes, a fundamental process in the biology of these cells that generates memory B lymphocytes and highly specific plasma cells.

But the team found that miR-28 expression is lost in several germinal center-derived lymphoma subtypes, including BL, DLBCL, follicular lymphoma, and chronic lymphocytic leukemia.

In vitro experiments showed that miR-28 expression dampens B-cell receptor signaling and diminishes the proliferation and survival of primary B cells and lymphoma cells.

And in vivo experiments showed that re-establishing miR-28 expression slows tumor growth in DLBCL and BL.

The investigators re-expressed miR-28 in xenograft models of BL and DLBCL via the use of viral vectors or synthetic molecules and found that both methods blocked tumor growth. The same effect was observed in mice with established BL tumors.

Dr Ramiro and her colleagues said these results reveal the therapeutic potential of miR-28 and provide ample justification for the initiation of clinical trials of miR-28-based therapies to treat B-cell lymphomas.

Image by Ed Uthman

Preclinical research has revealed a potential strategy for treating Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL).

Investigators discovered that miR-28 inhibits the growth of B-cell lymphomas, but this microRNA is often lost in these lymphomas.

Re-expressing miR-28 in mouse models of BL and DLBCL inhibited tumor growth, which supports the potential of synthetic miR-28 analogs for the treatment of these lymphomas.

In fact, the investigators believe their work could lead to the development of the first miRNA analog therapy for the treatment of B-cell lymphoma and provide the basis for clinical trials.

Almudena Ramiro, PhD, of Centro Nacional de Investigaciones Cardiovasculares in Madrid, Spain, and her colleagues described the work in Blood.

The team characterized the function of miR-28 in the biology of mature B lymphocytes and in the development of lymphomas associated with this cell type.

The investigators found that miR-28 regulates the terminal differentiation of B lymphocytes, a fundamental process in the biology of these cells that generates memory B lymphocytes and highly specific plasma cells.

But the team found that miR-28 expression is lost in several germinal center-derived lymphoma subtypes, including BL, DLBCL, follicular lymphoma, and chronic lymphocytic leukemia.

In vitro experiments showed that miR-28 expression dampens B-cell receptor signaling and diminishes the proliferation and survival of primary B cells and lymphoma cells.

And in vivo experiments showed that re-establishing miR-28 expression slows tumor growth in DLBCL and BL.

The investigators re-expressed miR-28 in xenograft models of BL and DLBCL via the use of viral vectors or synthetic molecules and found that both methods blocked tumor growth. The same effect was observed in mice with established BL tumors.

Dr Ramiro and her colleagues said these results reveal the therapeutic potential of miR-28 and provide ample justification for the initiation of clinical trials of miR-28-based therapies to treat B-cell lymphomas.

Image by Ed Uthman

Preclinical research has revealed a potential strategy for treating Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL).

Investigators discovered that miR-28 inhibits the growth of B-cell lymphomas, but this microRNA is often lost in these lymphomas.

Re-expressing miR-28 in mouse models of BL and DLBCL inhibited tumor growth, which supports the potential of synthetic miR-28 analogs for the treatment of these lymphomas.

In fact, the investigators believe their work could lead to the development of the first miRNA analog therapy for the treatment of B-cell lymphoma and provide the basis for clinical trials.

Almudena Ramiro, PhD, of Centro Nacional de Investigaciones Cardiovasculares in Madrid, Spain, and her colleagues described the work in Blood.

The team characterized the function of miR-28 in the biology of mature B lymphocytes and in the development of lymphomas associated with this cell type.

The investigators found that miR-28 regulates the terminal differentiation of B lymphocytes, a fundamental process in the biology of these cells that generates memory B lymphocytes and highly specific plasma cells.

But the team found that miR-28 expression is lost in several germinal center-derived lymphoma subtypes, including BL, DLBCL, follicular lymphoma, and chronic lymphocytic leukemia.

In vitro experiments showed that miR-28 expression dampens B-cell receptor signaling and diminishes the proliferation and survival of primary B cells and lymphoma cells.

And in vivo experiments showed that re-establishing miR-28 expression slows tumor growth in DLBCL and BL.

The investigators re-expressed miR-28 in xenograft models of BL and DLBCL via the use of viral vectors or synthetic molecules and found that both methods blocked tumor growth. The same effect was observed in mice with established BL tumors.

Dr Ramiro and her colleagues said these results reveal the therapeutic potential of miR-28 and provide ample justification for the initiation of clinical trials of miR-28-based therapies to treat B-cell lymphomas.

AML cells

The US Food and Drug Administration (FDA) has granted priority review for the new drug application (NDA) for enasidenib (AG-221), an inhibitor of mutant IDH2.

The drug is under review for the treatment of patients with relapsed or refractory acute myeloid leukemia (AML) with an IDH2 mutation.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10-month period.

The NDA for enasidenib has been given a Prescription Drug User Fee Act action date of August 30, 2017.

Enasidenib is being developed by Celgene Corporation and Agios Pharmaceuticals.

Phase 1/2 trial

The NDA submission for enasidenib is based on results from AG221-C-001, a single-arm, phase 1/2 study of the drug in patients with advanced hematologic malignancies with an IDH2 mutation.

Early data from the relapsed or refractory AML patients in this study were presented at the 2015 ASH Annual Meeting. (The presentation included updated data that differ from the data in the abstract.)

The trial included a dose-escalation phase and 5 expansion cohorts. The first 4 expansion cohorts had completed enrollment as of the presentation.

• Arm 1: 25 patients with IDH2-mutant-positive relapsed or refractory AML age ≥60 years, or any patient with AML regardless of age who relapsed after a bone marrow transplant (BMT)
• Arm 2: 25 patients with IDH2-mutant-positive relapsed or refractory AML age <60 years, excluding patients with AML who relapsed after a BMT
• Arm 3: 25 patients with IDH2-mutant-positive untreated AML age ≥60 years who decline standard of care chemotherapy
• Arm 4: 25 patients with IDH2-mutant-positive advanced hematologic malignancies not eligible for arms 1 to 3
• Arm 5: The phase 2 portion of the trial included 125 patients with IDH2-mutant-positive AML who were in second or later relapse, refractory to second-line induction or reinduction treatment, or  relapsed after allogeneic transplant.

The data reported at ASH were from patients receiving enasidenib administered from 50-mg to 650-mg total daily doses in the dose-escalation arm and 100 mg once daily in the first 4 expansion arms, as of September 1, 2015.

The median age of these patients was 69 (range, 19-100). Patients with relapsed or refractory AML received a median of 2 prior lines of therapy (range, 1-6).

Safety data

A safety analysis was conducted for all 231 treated patients. As of the ASH presentation, a maximum tolerated dose of enasidenib had not been reached.

The majority of adverse events were mild to moderate, with the most common being nausea, diarrhea, fatigue, and febrile neutropenia.

Twenty-three percent of patients had treatment-related serious adverse events—notably, differentiation syndrome (4%), leukocytosis (4%), and nausea (2%).

Drug-related grade 5 serious adverse events include atrial flutter (n=1), cardiac tamponade (n=1), pericardial effusion (n=1), and respiratory failure (n=1).

Efficacy Data

Seventy-nine of the 209 response-evaluable patients achieved investigator-assessed objective responses, for an overall response rate of 38%.

There were 37 (18%) complete remissions (CR), 3 CRs with incomplete platelet recovery (CRp), 14 marrow CRs (mCR), 3 CRs with incomplete hematologic recovery (CRi), and 22 partial remissions (PR).

Of the 159 patients with relapsed or refractory AML, 59 (37%) achieved an objective response, including 29 (18%) CRs, 1 CRp, 9 mCRs, 3 CRis, and 17 PRs.

Of the 24 patients with AML who declined standard of care chemotherapy, 10 achieved an objective response, including 4 CRs, 1 CRp, 1 mCR, and 4 PRs.

The median duration of response was 6.9 months in patients with relapsed or refractory AML.

Responding relapsed/refractory AML patients were on study treatment for up to 18 months. The median duration of treatment was 6.8 months (range, 1.8 to 18 months).

AML cells

The US Food and Drug Administration (FDA) has granted priority review for the new drug application (NDA) for enasidenib (AG-221), an inhibitor of mutant IDH2.

The drug is under review for the treatment of patients with relapsed or refractory acute myeloid leukemia (AML) with an IDH2 mutation.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10-month period.

The NDA for enasidenib has been given a Prescription Drug User Fee Act action date of August 30, 2017.

Enasidenib is being developed by Celgene Corporation and Agios Pharmaceuticals.

Phase 1/2 trial

The NDA submission for enasidenib is based on results from AG221-C-001, a single-arm, phase 1/2 study of the drug in patients with advanced hematologic malignancies with an IDH2 mutation.

Early data from the relapsed or refractory AML patients in this study were presented at the 2015 ASH Annual Meeting. (The presentation included updated data that differ from the data in the abstract.)

The trial included a dose-escalation phase and 5 expansion cohorts. The first 4 expansion cohorts had completed enrollment as of the presentation.

• Arm 1: 25 patients with IDH2-mutant-positive relapsed or refractory AML age ≥60 years, or any patient with AML regardless of age who relapsed after a bone marrow transplant (BMT)
• Arm 2: 25 patients with IDH2-mutant-positive relapsed or refractory AML age <60 years, excluding patients with AML who relapsed after a BMT
• Arm 3: 25 patients with IDH2-mutant-positive untreated AML age ≥60 years who decline standard of care chemotherapy
• Arm 4: 25 patients with IDH2-mutant-positive advanced hematologic malignancies not eligible for arms 1 to 3
• Arm 5: The phase 2 portion of the trial included 125 patients with IDH2-mutant-positive AML who were in second or later relapse, refractory to second-line induction or reinduction treatment, or  relapsed after allogeneic transplant.

The data reported at ASH were from patients receiving enasidenib administered from 50-mg to 650-mg total daily doses in the dose-escalation arm and 100 mg once daily in the first 4 expansion arms, as of September 1, 2015.

The median age of these patients was 69 (range, 19-100). Patients with relapsed or refractory AML received a median of 2 prior lines of therapy (range, 1-6).

Safety data

A safety analysis was conducted for all 231 treated patients. As of the ASH presentation, a maximum tolerated dose of enasidenib had not been reached.

The majority of adverse events were mild to moderate, with the most common being nausea, diarrhea, fatigue, and febrile neutropenia.

Twenty-three percent of patients had treatment-related serious adverse events—notably, differentiation syndrome (4%), leukocytosis (4%), and nausea (2%).

Drug-related grade 5 serious adverse events include atrial flutter (n=1), cardiac tamponade (n=1), pericardial effusion (n=1), and respiratory failure (n=1).

Efficacy Data

Seventy-nine of the 209 response-evaluable patients achieved investigator-assessed objective responses, for an overall response rate of 38%.

There were 37 (18%) complete remissions (CR), 3 CRs with incomplete platelet recovery (CRp), 14 marrow CRs (mCR), 3 CRs with incomplete hematologic recovery (CRi), and 22 partial remissions (PR).

Of the 159 patients with relapsed or refractory AML, 59 (37%) achieved an objective response, including 29 (18%) CRs, 1 CRp, 9 mCRs, 3 CRis, and 17 PRs.

Of the 24 patients with AML who declined standard of care chemotherapy, 10 achieved an objective response, including 4 CRs, 1 CRp, 1 mCR, and 4 PRs.

The median duration of response was 6.9 months in patients with relapsed or refractory AML.

Responding relapsed/refractory AML patients were on study treatment for up to 18 months. The median duration of treatment was 6.8 months (range, 1.8 to 18 months).

AML cells

The US Food and Drug Administration (FDA) has granted priority review for the new drug application (NDA) for enasidenib (AG-221), an inhibitor of mutant IDH2.

The drug is under review for the treatment of patients with relapsed or refractory acute myeloid leukemia (AML) with an IDH2 mutation.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10-month period.

The NDA for enasidenib has been given a Prescription Drug User Fee Act action date of August 30, 2017.

Enasidenib is being developed by Celgene Corporation and Agios Pharmaceuticals.

Phase 1/2 trial

The NDA submission for enasidenib is based on results from AG221-C-001, a single-arm, phase 1/2 study of the drug in patients with advanced hematologic malignancies with an IDH2 mutation.

Early data from the relapsed or refractory AML patients in this study were presented at the 2015 ASH Annual Meeting. (The presentation included updated data that differ from the data in the abstract.)

The trial included a dose-escalation phase and 5 expansion cohorts. The first 4 expansion cohorts had completed enrollment as of the presentation.

• Arm 1: 25 patients with IDH2-mutant-positive relapsed or refractory AML age ≥60 years, or any patient with AML regardless of age who relapsed after a bone marrow transplant (BMT)
• Arm 2: 25 patients with IDH2-mutant-positive relapsed or refractory AML age <60 years, excluding patients with AML who relapsed after a BMT
• Arm 3: 25 patients with IDH2-mutant-positive untreated AML age ≥60 years who decline standard of care chemotherapy
• Arm 4: 25 patients with IDH2-mutant-positive advanced hematologic malignancies not eligible for arms 1 to 3
• Arm 5: The phase 2 portion of the trial included 125 patients with IDH2-mutant-positive AML who were in second or later relapse, refractory to second-line induction or reinduction treatment, or  relapsed after allogeneic transplant.

The data reported at ASH were from patients receiving enasidenib administered from 50-mg to 650-mg total daily doses in the dose-escalation arm and 100 mg once daily in the first 4 expansion arms, as of September 1, 2015.

The median age of these patients was 69 (range, 19-100). Patients with relapsed or refractory AML received a median of 2 prior lines of therapy (range, 1-6).

Safety data

A safety analysis was conducted for all 231 treated patients. As of the ASH presentation, a maximum tolerated dose of enasidenib had not been reached.

The majority of adverse events were mild to moderate, with the most common being nausea, diarrhea, fatigue, and febrile neutropenia.

Twenty-three percent of patients had treatment-related serious adverse events—notably, differentiation syndrome (4%), leukocytosis (4%), and nausea (2%).

Drug-related grade 5 serious adverse events include atrial flutter (n=1), cardiac tamponade (n=1), pericardial effusion (n=1), and respiratory failure (n=1).

Efficacy Data

Seventy-nine of the 209 response-evaluable patients achieved investigator-assessed objective responses, for an overall response rate of 38%.

There were 37 (18%) complete remissions (CR), 3 CRs with incomplete platelet recovery (CRp), 14 marrow CRs (mCR), 3 CRs with incomplete hematologic recovery (CRi), and 22 partial remissions (PR).

Of the 159 patients with relapsed or refractory AML, 59 (37%) achieved an objective response, including 29 (18%) CRs, 1 CRp, 9 mCRs, 3 CRis, and 17 PRs.

Of the 24 patients with AML who declined standard of care chemotherapy, 10 achieved an objective response, including 4 CRs, 1 CRp, 1 mCR, and 4 PRs.

The median duration of response was 6.9 months in patients with relapsed or refractory AML.

Responding relapsed/refractory AML patients were on study treatment for up to 18 months. The median duration of treatment was 6.8 months (range, 1.8 to 18 months).

Photo by Diane Reid

Hospital room floors may be an overlooked source of infection, according to a study published in the American Journal of Infection Control.

Researchers surveyed 5 hospitals and found that floors in patient rooms were often contaminated with pathogens.

Certain objects, such as personal items and medical devices and supplies, were in contact with the floor, and touching these objects resulted in the transfer of pathogens to bare and gloved hands.

Abhishek Deshpande, MD, PhD, of Case Western Reserve University School of Medicine in Cleveland, Ohio, and his colleagues conducted this research.

The team cultured 318 floor sites from 159 patient rooms (2 sites per room) in 5 hospitals in the Cleveland area. The rooms included both Clostridium difficile infection (CDI) isolation rooms and non-CDI rooms.

The researchers also cultured hands (gloved and bare) as well as other “high-touch” surfaces such as clothing and medical devices/supplies.

The team found that floors in patient rooms were often contaminated with Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and C difficile.

C difficile was recovered in 55% of CDI rooms and 47% of non-CDI rooms. MRSA was recovered in 32% of CDI rooms and 8% of non-CDI rooms. VRE was recovered in 30% of CDI rooms and 13% of non-CDI rooms.

The researchers said the frequency of contamination was similar for each of the 5 hospitals and from room and bathroom floor sites.

Of the 100 occupied rooms surveyed, 41% had one or more high-touch objects that were in contact with the floor. These included personal items (eg, clothing, canes, and cellular phone chargers), medical devices and supplies (eg, pulse oximeter, call button, heating pad, urinal, blood pressure cuff, wash basin, and heel protector), and bed linens or towels.

The findings indicate that handling such items resulted in the transfer of pathogens. All 3 pathogens were recovered from bare or gloved hand cultures—MRSA in 6 (18%), VRE in 2 (6%), and C difficile in 1 (3%).

The researchers said these results suggest hospital floors could be an underappreciated source for dissemination of pathogens and are an important area for additional research.

“Understanding gaps in infection prevention is critically important for institutions seeking to improve the quality of care offered to patients,” said Linda Greene, RN, current president of the Association for Professionals in Infection Control and Epidemiology.

“Even though most facilities believe they are taking the proper precautions, this study points out the importance of ensuring cleanliness of the hospital environment and the need for education of both staff and patients on this issue.”

Photo by Diane Reid

Hospital room floors may be an overlooked source of infection, according to a study published in the American Journal of Infection Control.

Researchers surveyed 5 hospitals and found that floors in patient rooms were often contaminated with pathogens.

Certain objects, such as personal items and medical devices and supplies, were in contact with the floor, and touching these objects resulted in the transfer of pathogens to bare and gloved hands.

Abhishek Deshpande, MD, PhD, of Case Western Reserve University School of Medicine in Cleveland, Ohio, and his colleagues conducted this research.

The team cultured 318 floor sites from 159 patient rooms (2 sites per room) in 5 hospitals in the Cleveland area. The rooms included both Clostridium difficile infection (CDI) isolation rooms and non-CDI rooms.

The researchers also cultured hands (gloved and bare) as well as other “high-touch” surfaces such as clothing and medical devices/supplies.

The team found that floors in patient rooms were often contaminated with Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and C difficile.

C difficile was recovered in 55% of CDI rooms and 47% of non-CDI rooms. MRSA was recovered in 32% of CDI rooms and 8% of non-CDI rooms. VRE was recovered in 30% of CDI rooms and 13% of non-CDI rooms.

The researchers said the frequency of contamination was similar for each of the 5 hospitals and from room and bathroom floor sites.

Of the 100 occupied rooms surveyed, 41% had one or more high-touch objects that were in contact with the floor. These included personal items (eg, clothing, canes, and cellular phone chargers), medical devices and supplies (eg, pulse oximeter, call button, heating pad, urinal, blood pressure cuff, wash basin, and heel protector), and bed linens or towels.

The findings indicate that handling such items resulted in the transfer of pathogens. All 3 pathogens were recovered from bare or gloved hand cultures—MRSA in 6 (18%), VRE in 2 (6%), and C difficile in 1 (3%).

The researchers said these results suggest hospital floors could be an underappreciated source for dissemination of pathogens and are an important area for additional research.

“Understanding gaps in infection prevention is critically important for institutions seeking to improve the quality of care offered to patients,” said Linda Greene, RN, current president of the Association for Professionals in Infection Control and Epidemiology.

“Even though most facilities believe they are taking the proper precautions, this study points out the importance of ensuring cleanliness of the hospital environment and the need for education of both staff and patients on this issue.”

Photo by Diane Reid

Hospital room floors may be an overlooked source of infection, according to a study published in the American Journal of Infection Control.

Researchers surveyed 5 hospitals and found that floors in patient rooms were often contaminated with pathogens.

Certain objects, such as personal items and medical devices and supplies, were in contact with the floor, and touching these objects resulted in the transfer of pathogens to bare and gloved hands.

Abhishek Deshpande, MD, PhD, of Case Western Reserve University School of Medicine in Cleveland, Ohio, and his colleagues conducted this research.

The team cultured 318 floor sites from 159 patient rooms (2 sites per room) in 5 hospitals in the Cleveland area. The rooms included both Clostridium difficile infection (CDI) isolation rooms and non-CDI rooms.

The researchers also cultured hands (gloved and bare) as well as other “high-touch” surfaces such as clothing and medical devices/supplies.

The team found that floors in patient rooms were often contaminated with Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and C difficile.

C difficile was recovered in 55% of CDI rooms and 47% of non-CDI rooms. MRSA was recovered in 32% of CDI rooms and 8% of non-CDI rooms. VRE was recovered in 30% of CDI rooms and 13% of non-CDI rooms.

The researchers said the frequency of contamination was similar for each of the 5 hospitals and from room and bathroom floor sites.

Of the 100 occupied rooms surveyed, 41% had one or more high-touch objects that were in contact with the floor. These included personal items (eg, clothing, canes, and cellular phone chargers), medical devices and supplies (eg, pulse oximeter, call button, heating pad, urinal, blood pressure cuff, wash basin, and heel protector), and bed linens or towels.

The findings indicate that handling such items resulted in the transfer of pathogens. All 3 pathogens were recovered from bare or gloved hand cultures—MRSA in 6 (18%), VRE in 2 (6%), and C difficile in 1 (3%).

The researchers said these results suggest hospital floors could be an underappreciated source for dissemination of pathogens and are an important area for additional research.

“Understanding gaps in infection prevention is critically important for institutions seeking to improve the quality of care offered to patients,” said Linda Greene, RN, current president of the Association for Professionals in Infection Control and Epidemiology.

“Even though most facilities believe they are taking the proper precautions, this study points out the importance of ensuring cleanliness of the hospital environment and the need for education of both staff and patients on this issue.”

Photo by Steven Fruitsmaak

ORLANDO, FL—A single, 4 mg-dose of the bisphosphonate zoledronic acid (ZA) prior to allogeneic hematopoietic stem cell transplant (HSCT) prevents femoral neck (FN) bone loss at day 100 in patients with lymphoid or myeloid malignancies, according to new research.

The study also suggests that patients who receive risk-adapted ZA therapy after transplant can experience significant reductions in bone loss between days 100 and 365.

However, patients with acute and chronic graft-versus-host disease (GVHD) continue to be at risk of bone loss.

Eric Wong, of the Royal Melbourne Hospital in Parkville, Australia, presented these findings at the 2017 BMT Tandem Meetings (abstract 53) on behalf of the Australasian Leukaemia and Lymphoma Group.

“Previous studies have demonstrated that efforts to prevent bone loss through calcium and vitamin D supplementation as well as hormone-replacement therapy alone have been ineffective in preventing bone loss,” Wong explained.

And monthly pamidronate begun prior to HSCT reduces, but does not prevent, FN bone density loss.

So Wong and his colleagues began a trial of ZA, which is approximately 100-fold more potent than pamidronate.

Study design

The researchers enrolled 82 patients into the phase 2 ALLG BM07 trial. All patients received a single shot of ZA prior to HSCT conditioning.

All patients also received vitamin D and calcium supplements, and pre-menopausal women received hormone replacement therapy.

Depending on their risk of bone loss, patients received individualized ZA therapy after transplant. Researchers assessed the patients’ bone density at days 100, 180, 270, and 365 post-HSCT. Patients at high risk of bone loss received additional doses of ZA.

Risks for bone loss included bone mineral density (BMD) reduction of 5% or greater compared to baseline, prednisolone exposure of 1 mg/kg/d or greater for 2 weeks, or prednisolone exposure of 10 mg/d or more for 6 weeks

The primary endpoint of the study was the change in FN BMD at days 100 and 365 after HSCT compared to baseline.

The researchers also compared patients’ FN BMD with 35 untreated historical controls assessed at the same time points.

Patient characteristics

Seventy patients were alive and had not relapsed at day 100. Most (87%) were 60 years or younger, 60% were male, 53% had myeloid disease, 43% lymphoid, and 4% other disease.

“The most common indications for transplant were acute myeloid leukemia and acute lymphoblastic leukemia,” Wong said, “which, together, formed over 50% of the entire cohort.”

Seventy percent of patients were ECOG status 0 or 1, and 30% were 2 or greater.

Most (59%) had received myeloablative conditioning, the predominant regimens being busulfan/cyclophosphamide or cyclophosphamide/total-body irradiation. And the most common reduced-intensity conditioning regimen was fludarabine/melphalan.

Fifty-six percent of patients had a sibling donor, and 43% had a matched unrelated donor.

Thirty-eight percent of patients developed acute GVHD—19% grade 1, and 19% grade 2 to 3.

“Of note,” Wong said, “no patient developed grade 4 acute GVHD.”

Patients received a median of 2 ZA doses (range, 1–4), including the pre-transplant dose.

Sixty patients received at least 1 dose of ZA between day 100 and day 365, including 33% who received multiple doses.

At day 100, 33 patients received additional ZA. At day 180, 27 patients received additional ZA, including 8 patients who did not have it at day 100. And at day 270, 18 patients had additional ZA, including 1 patient who had no additional ZA at earlier time points.

Results

At day 100, there was no statistically significant change in FN bone density compared with baseline. The mean change was -2.6% (range, -6.6% to 1.4%).

For patients with acute GVHD, however, the change in bone density was significant (P=0.03). Patients with grade 1-2 GVHD had a mean change of -1.6% ± 3.7%, and patients with grade 3-4 GVHD had a mean change of -8.5% ± 11.2%.

Sixty-five patients were available for the day 365 efficacy analysis.

Bone density did not change significantly between day 100 and 365 for the entire group.

“By day 365,” Wong noted, “there was a net loss of bone density of -2.9%.”

But by day 365, patients with extensive chronic GVHD had significantly more bone loss compared with patients who had no chronic GVHD (P=0.03).

Age, sex, duration of cyclosporine, and mean steroid dose were not associated with a change in bone density at day 100 or 365, although there was a trend for an association between high steroid exposure and increased bone loss (P=0.07).

When the researchers compared the patients to untreated historical controls, patients who received ZA had significantly less bone loss at day 100  (P=0.001) and day 365 (P<0.0001).

The researchers observed no serious adverse events with ZA.

Wong concluded that patients with extensive GVHD are a “high-risk cohort that needs augmented therapies.”

Photo by Steven Fruitsmaak

ORLANDO, FL—A single, 4 mg-dose of the bisphosphonate zoledronic acid (ZA) prior to allogeneic hematopoietic stem cell transplant (HSCT) prevents femoral neck (FN) bone loss at day 100 in patients with lymphoid or myeloid malignancies, according to new research.

The study also suggests that patients who receive risk-adapted ZA therapy after transplant can experience significant reductions in bone loss between days 100 and 365.

However, patients with acute and chronic graft-versus-host disease (GVHD) continue to be at risk of bone loss.

Eric Wong, of the Royal Melbourne Hospital in Parkville, Australia, presented these findings at the 2017 BMT Tandem Meetings (abstract 53) on behalf of the Australasian Leukaemia and Lymphoma Group.

“Previous studies have demonstrated that efforts to prevent bone loss through calcium and vitamin D supplementation as well as hormone-replacement therapy alone have been ineffective in preventing bone loss,” Wong explained.

And monthly pamidronate begun prior to HSCT reduces, but does not prevent, FN bone density loss.

So Wong and his colleagues began a trial of ZA, which is approximately 100-fold more potent than pamidronate.

Study design

The researchers enrolled 82 patients into the phase 2 ALLG BM07 trial. All patients received a single shot of ZA prior to HSCT conditioning.

All patients also received vitamin D and calcium supplements, and pre-menopausal women received hormone replacement therapy.

Depending on their risk of bone loss, patients received individualized ZA therapy after transplant. Researchers assessed the patients’ bone density at days 100, 180, 270, and 365 post-HSCT. Patients at high risk of bone loss received additional doses of ZA.

Risks for bone loss included bone mineral density (BMD) reduction of 5% or greater compared to baseline, prednisolone exposure of 1 mg/kg/d or greater for 2 weeks, or prednisolone exposure of 10 mg/d or more for 6 weeks

The primary endpoint of the study was the change in FN BMD at days 100 and 365 after HSCT compared to baseline.

The researchers also compared patients’ FN BMD with 35 untreated historical controls assessed at the same time points.

Patient characteristics

Seventy patients were alive and had not relapsed at day 100. Most (87%) were 60 years or younger, 60% were male, 53% had myeloid disease, 43% lymphoid, and 4% other disease.

“The most common indications for transplant were acute myeloid leukemia and acute lymphoblastic leukemia,” Wong said, “which, together, formed over 50% of the entire cohort.”

Seventy percent of patients were ECOG status 0 or 1, and 30% were 2 or greater.

Most (59%) had received myeloablative conditioning, the predominant regimens being busulfan/cyclophosphamide or cyclophosphamide/total-body irradiation. And the most common reduced-intensity conditioning regimen was fludarabine/melphalan.

Fifty-six percent of patients had a sibling donor, and 43% had a matched unrelated donor.

Thirty-eight percent of patients developed acute GVHD—19% grade 1, and 19% grade 2 to 3.

“Of note,” Wong said, “no patient developed grade 4 acute GVHD.”

Patients received a median of 2 ZA doses (range, 1–4), including the pre-transplant dose.

Sixty patients received at least 1 dose of ZA between day 100 and day 365, including 33% who received multiple doses.

At day 100, 33 patients received additional ZA. At day 180, 27 patients received additional ZA, including 8 patients who did not have it at day 100. And at day 270, 18 patients had additional ZA, including 1 patient who had no additional ZA at earlier time points.

Results

At day 100, there was no statistically significant change in FN bone density compared with baseline. The mean change was -2.6% (range, -6.6% to 1.4%).

For patients with acute GVHD, however, the change in bone density was significant (P=0.03). Patients with grade 1-2 GVHD had a mean change of -1.6% ± 3.7%, and patients with grade 3-4 GVHD had a mean change of -8.5% ± 11.2%.

Sixty-five patients were available for the day 365 efficacy analysis.

Bone density did not change significantly between day 100 and 365 for the entire group.

“By day 365,” Wong noted, “there was a net loss of bone density of -2.9%.”

But by day 365, patients with extensive chronic GVHD had significantly more bone loss compared with patients who had no chronic GVHD (P=0.03).

Age, sex, duration of cyclosporine, and mean steroid dose were not associated with a change in bone density at day 100 or 365, although there was a trend for an association between high steroid exposure and increased bone loss (P=0.07).

When the researchers compared the patients to untreated historical controls, patients who received ZA had significantly less bone loss at day 100  (P=0.001) and day 365 (P<0.0001).

The researchers observed no serious adverse events with ZA.

Wong concluded that patients with extensive GVHD are a “high-risk cohort that needs augmented therapies.”

Photo by Steven Fruitsmaak

ORLANDO, FL—A single, 4 mg-dose of the bisphosphonate zoledronic acid (ZA) prior to allogeneic hematopoietic stem cell transplant (HSCT) prevents femoral neck (FN) bone loss at day 100 in patients with lymphoid or myeloid malignancies, according to new research.

The study also suggests that patients who receive risk-adapted ZA therapy after transplant can experience significant reductions in bone loss between days 100 and 365.

However, patients with acute and chronic graft-versus-host disease (GVHD) continue to be at risk of bone loss.

Eric Wong, of the Royal Melbourne Hospital in Parkville, Australia, presented these findings at the 2017 BMT Tandem Meetings (abstract 53) on behalf of the Australasian Leukaemia and Lymphoma Group.

“Previous studies have demonstrated that efforts to prevent bone loss through calcium and vitamin D supplementation as well as hormone-replacement therapy alone have been ineffective in preventing bone loss,” Wong explained.

And monthly pamidronate begun prior to HSCT reduces, but does not prevent, FN bone density loss.

So Wong and his colleagues began a trial of ZA, which is approximately 100-fold more potent than pamidronate.

Study design

The researchers enrolled 82 patients into the phase 2 ALLG BM07 trial. All patients received a single shot of ZA prior to HSCT conditioning.

All patients also received vitamin D and calcium supplements, and pre-menopausal women received hormone replacement therapy.

Depending on their risk of bone loss, patients received individualized ZA therapy after transplant. Researchers assessed the patients’ bone density at days 100, 180, 270, and 365 post-HSCT. Patients at high risk of bone loss received additional doses of ZA.

Risks for bone loss included bone mineral density (BMD) reduction of 5% or greater compared to baseline, prednisolone exposure of 1 mg/kg/d or greater for 2 weeks, or prednisolone exposure of 10 mg/d or more for 6 weeks

The primary endpoint of the study was the change in FN BMD at days 100 and 365 after HSCT compared to baseline.

The researchers also compared patients’ FN BMD with 35 untreated historical controls assessed at the same time points.

Patient characteristics

Seventy patients were alive and had not relapsed at day 100. Most (87%) were 60 years or younger, 60% were male, 53% had myeloid disease, 43% lymphoid, and 4% other disease.

“The most common indications for transplant were acute myeloid leukemia and acute lymphoblastic leukemia,” Wong said, “which, together, formed over 50% of the entire cohort.”

Seventy percent of patients were ECOG status 0 or 1, and 30% were 2 or greater.

Most (59%) had received myeloablative conditioning, the predominant regimens being busulfan/cyclophosphamide or cyclophosphamide/total-body irradiation. And the most common reduced-intensity conditioning regimen was fludarabine/melphalan.

Fifty-six percent of patients had a sibling donor, and 43% had a matched unrelated donor.

Thirty-eight percent of patients developed acute GVHD—19% grade 1, and 19% grade 2 to 3.

“Of note,” Wong said, “no patient developed grade 4 acute GVHD.”

Patients received a median of 2 ZA doses (range, 1–4), including the pre-transplant dose.

Sixty patients received at least 1 dose of ZA between day 100 and day 365, including 33% who received multiple doses.

At day 100, 33 patients received additional ZA. At day 180, 27 patients received additional ZA, including 8 patients who did not have it at day 100. And at day 270, 18 patients had additional ZA, including 1 patient who had no additional ZA at earlier time points.

Results

At day 100, there was no statistically significant change in FN bone density compared with baseline. The mean change was -2.6% (range, -6.6% to 1.4%).

For patients with acute GVHD, however, the change in bone density was significant (P=0.03). Patients with grade 1-2 GVHD had a mean change of -1.6% ± 3.7%, and patients with grade 3-4 GVHD had a mean change of -8.5% ± 11.2%.

Sixty-five patients were available for the day 365 efficacy analysis.

Bone density did not change significantly between day 100 and 365 for the entire group.

“By day 365,” Wong noted, “there was a net loss of bone density of -2.9%.”

But by day 365, patients with extensive chronic GVHD had significantly more bone loss compared with patients who had no chronic GVHD (P=0.03).

Age, sex, duration of cyclosporine, and mean steroid dose were not associated with a change in bone density at day 100 or 365, although there was a trend for an association between high steroid exposure and increased bone loss (P=0.07).

When the researchers compared the patients to untreated historical controls, patients who received ZA had significantly less bone loss at day 100  (P=0.001) and day 365 (P<0.0001).

The researchers observed no serious adverse events with ZA.

Wong concluded that patients with extensive GVHD are a “high-risk cohort that needs augmented therapies.”

Warfarin tablets

Use of antithrombotic drugs is associated with a higher risk of subdural hematoma, according to a case-control study of more than 400,000 individuals in Denmark.

The highest risk of subdural hematoma was observed in patients who were taking both a vitamin K antagonist (VKA) and clopidogrel.

The study also showed that the incidence of subdural hematoma increased from 2000 to 2015, which appeared to be associated with the increased use of antithrombotic drugs over that time period.

David Gaist, MD, PhD, of Odense University Hospital and the University of Southern Denmark, and his colleagues conducted this research and reported the results in JAMA.

The researchers evaluated 10,010 patients, ages 20 to 89, with a first-ever subdural hematoma diagnosis from 2000 to 2015. The patients were matched to 400,380 individuals from the general population.

Among the patients with subdural hematoma (average age, 69), 47% were taking antithrombotic medications.

The researchers used conditional logistic regression models to estimate the association between antithrombotic drugs and subdural hematoma risk, adjusting for a range of factors. With the following data, they adjusted for age, sex, calendar period, comorbidity, education level, and income level.

The team found that current low-dose aspirin use was associated with a low risk of subdural hematoma (adjusted odds ratio [OR]=1.24).

Current clopidogrel (OR=1.80) and direct oral anticoagulant (OR=1.55) use were both associated with a moderate risk.

And current VKA use was associated with the highest risk of all the agents when given alone (OR=3.69).

Concurrent use of more than one antithrombotic drug was also associated with a high subdural hematoma risk:

• Low-dose aspirin and clopidogrel (OR=2.45)
• Low-dose aspirin and direct oral anticoagulant (OR=2.52)
• Low-dose aspirin and VKA (OR=4.00)
• Clopidogrel and VKA (OR=7.93).

There was one exception to this. Low-dose aspirin combined with the antiplatelet drug dipyridamole was associated with a risk similar to that of low-dose aspirin alone (OR=1.17).

The researchers noted that the prevalence of antithrombotic drug use increased in the general population over the time period studied, from 31.0 per 1000 individuals in 2000 to 76.9 per 1000 individuals in 2015 (P<0.001 for trend).

The overall subdural hematoma incidence rate increased as well, from 10.9 per 100,000 person-years in 2000 to 19.0 per 100,000 person-years in 2015 (P<0.001 for trend).

The largest increase in subdural hematoma incidence was among patients older than 75 years of age—from 55.1 per 100,000 person-years to 99.7 per 100,000 person-years (P<0.001 for trend).

Warfarin tablets

Use of antithrombotic drugs is associated with a higher risk of subdural hematoma, according to a case-control study of more than 400,000 individuals in Denmark.

The highest risk of subdural hematoma was observed in patients who were taking both a vitamin K antagonist (VKA) and clopidogrel.

The study also showed that the incidence of subdural hematoma increased from 2000 to 2015, which appeared to be associated with the increased use of antithrombotic drugs over that time period.

David Gaist, MD, PhD, of Odense University Hospital and the University of Southern Denmark, and his colleagues conducted this research and reported the results in JAMA.

The researchers evaluated 10,010 patients, ages 20 to 89, with a first-ever subdural hematoma diagnosis from 2000 to 2015. The patients were matched to 400,380 individuals from the general population.

Among the patients with subdural hematoma (average age, 69), 47% were taking antithrombotic medications.

The researchers used conditional logistic regression models to estimate the association between antithrombotic drugs and subdural hematoma risk, adjusting for a range of factors. With the following data, they adjusted for age, sex, calendar period, comorbidity, education level, and income level.

The team found that current low-dose aspirin use was associated with a low risk of subdural hematoma (adjusted odds ratio [OR]=1.24).

Current clopidogrel (OR=1.80) and direct oral anticoagulant (OR=1.55) use were both associated with a moderate risk.

And current VKA use was associated with the highest risk of all the agents when given alone (OR=3.69).

Concurrent use of more than one antithrombotic drug was also associated with a high subdural hematoma risk:

• Low-dose aspirin and clopidogrel (OR=2.45)
• Low-dose aspirin and direct oral anticoagulant (OR=2.52)
• Low-dose aspirin and VKA (OR=4.00)
• Clopidogrel and VKA (OR=7.93).

There was one exception to this. Low-dose aspirin combined with the antiplatelet drug dipyridamole was associated with a risk similar to that of low-dose aspirin alone (OR=1.17).

The researchers noted that the prevalence of antithrombotic drug use increased in the general population over the time period studied, from 31.0 per 1000 individuals in 2000 to 76.9 per 1000 individuals in 2015 (P<0.001 for trend).

The overall subdural hematoma incidence rate increased as well, from 10.9 per 100,000 person-years in 2000 to 19.0 per 100,000 person-years in 2015 (P<0.001 for trend).

The largest increase in subdural hematoma incidence was among patients older than 75 years of age—from 55.1 per 100,000 person-years to 99.7 per 100,000 person-years (P<0.001 for trend).

Warfarin tablets

Use of antithrombotic drugs is associated with a higher risk of subdural hematoma, according to a case-control study of more than 400,000 individuals in Denmark.

The highest risk of subdural hematoma was observed in patients who were taking both a vitamin K antagonist (VKA) and clopidogrel.

The study also showed that the incidence of subdural hematoma increased from 2000 to 2015, which appeared to be associated with the increased use of antithrombotic drugs over that time period.

David Gaist, MD, PhD, of Odense University Hospital and the University of Southern Denmark, and his colleagues conducted this research and reported the results in JAMA.

The researchers evaluated 10,010 patients, ages 20 to 89, with a first-ever subdural hematoma diagnosis from 2000 to 2015. The patients were matched to 400,380 individuals from the general population.

Among the patients with subdural hematoma (average age, 69), 47% were taking antithrombotic medications.

The researchers used conditional logistic regression models to estimate the association between antithrombotic drugs and subdural hematoma risk, adjusting for a range of factors. With the following data, they adjusted for age, sex, calendar period, comorbidity, education level, and income level.

The team found that current low-dose aspirin use was associated with a low risk of subdural hematoma (adjusted odds ratio [OR]=1.24).

Current clopidogrel (OR=1.80) and direct oral anticoagulant (OR=1.55) use were both associated with a moderate risk.

And current VKA use was associated with the highest risk of all the agents when given alone (OR=3.69).

Concurrent use of more than one antithrombotic drug was also associated with a high subdural hematoma risk:

• Low-dose aspirin and clopidogrel (OR=2.45)
• Low-dose aspirin and direct oral anticoagulant (OR=2.52)
• Low-dose aspirin and VKA (OR=4.00)
• Clopidogrel and VKA (OR=7.93).

There was one exception to this. Low-dose aspirin combined with the antiplatelet drug dipyridamole was associated with a risk similar to that of low-dose aspirin alone (OR=1.17).

The researchers noted that the prevalence of antithrombotic drug use increased in the general population over the time period studied, from 31.0 per 1000 individuals in 2000 to 76.9 per 1000 individuals in 2015 (P<0.001 for trend).

The overall subdural hematoma incidence rate increased as well, from 10.9 per 100,000 person-years in 2000 to 19.0 per 100,000 person-years in 2015 (P<0.001 for trend).

The largest increase in subdural hematoma incidence was among patients older than 75 years of age—from 55.1 per 100,000 person-years to 99.7 per 100,000 person-years (P<0.001 for trend).

Photo by Darren Baker

A new resource has been made available for US-based scientists studying hemophilia A and B.

The resource—known as the My Life, Our Future Research Repository—is a collection of genetic data and blood samples that are linked to phenotypic data from more than 5000 hemophilia patients in the US.

Academic and industry scientists within the US can now access the repository but must apply to do so.

Scientists outside of the US should have access to the repository in 2018.

My Life, Our Future is a program founded by the American Thrombosis and Hemostasis Network, Bloodworks Northwest, the National Hemophilia Foundation, and Bioverativ.

My Life, Our Future was launched in 2012 to increase genotyping among individuals with hemophilia A and B, as well as potential and confirmed carriers of the disorder. The program will be available at participating hemophilia treatment centers through the end of 2017.

My Life, Our Future provides hemophilia patients (and potential/confirmed carriers) with free genotyping, and patients can then consent to add their de-identified genetic data and blood sample to the My Life, Our Future Research Repository.

Eighty-three percent of genotyped patients have contributed their data and blood samples. This is more than 5000 individuals representing more than 25% of the US hemophilia population.

The information provided by these individuals has led to the discovery of more than 600 new genetic variants that cause hemophilia.

“Hemophilia is a complex disorder, and, prior to today, there was no genetic and phenotypic database of this scale aiding scientific innovation,” said Barbara Konkle, MD, associate chief scientific officer of Bloodworks Northwest and principal investigator for My Life, Our Future.

“With this new resource, researchers now have one source for the genetic data, repository samples, and clinical data needed to investigate the many unanswered questions about hemophilia.”

Accessing the repository

To access the samples and data in the repository, scientists must first submit a letter of intent to the  American Thrombosis and Hemostasis Network.

Scientists may then be asked to submit a full research proposal, which will be evaluated by a research review committee—a group of experts including a molecular pathologist, genetic counselor, research scientist, molecular biologist, genetic epidemiologist, molecular epidemiologist, geneticist, patient representative, and hematologists.

Approved scientists will be selected based on the scientific merit of their proposals and level of benefit to those with bleeding disorders.

For details on how to apply, visit ATHN.org/MLOF.

Photo by Darren Baker

A new resource has been made available for US-based scientists studying hemophilia A and B.

The resource—known as the My Life, Our Future Research Repository—is a collection of genetic data and blood samples that are linked to phenotypic data from more than 5000 hemophilia patients in the US.

Academic and industry scientists within the US can now access the repository but must apply to do so.

Scientists outside of the US should have access to the repository in 2018.

My Life, Our Future is a program founded by the American Thrombosis and Hemostasis Network, Bloodworks Northwest, the National Hemophilia Foundation, and Bioverativ.

My Life, Our Future was launched in 2012 to increase genotyping among individuals with hemophilia A and B, as well as potential and confirmed carriers of the disorder. The program will be available at participating hemophilia treatment centers through the end of 2017.

My Life, Our Future provides hemophilia patients (and potential/confirmed carriers) with free genotyping, and patients can then consent to add their de-identified genetic data and blood sample to the My Life, Our Future Research Repository.

Eighty-three percent of genotyped patients have contributed their data and blood samples. This is more than 5000 individuals representing more than 25% of the US hemophilia population.

The information provided by these individuals has led to the discovery of more than 600 new genetic variants that cause hemophilia.

“Hemophilia is a complex disorder, and, prior to today, there was no genetic and phenotypic database of this scale aiding scientific innovation,” said Barbara Konkle, MD, associate chief scientific officer of Bloodworks Northwest and principal investigator for My Life, Our Future.

“With this new resource, researchers now have one source for the genetic data, repository samples, and clinical data needed to investigate the many unanswered questions about hemophilia.”

Accessing the repository

To access the samples and data in the repository, scientists must first submit a letter of intent to the  American Thrombosis and Hemostasis Network.

Scientists may then be asked to submit a full research proposal, which will be evaluated by a research review committee—a group of experts including a molecular pathologist, genetic counselor, research scientist, molecular biologist, genetic epidemiologist, molecular epidemiologist, geneticist, patient representative, and hematologists.

Approved scientists will be selected based on the scientific merit of their proposals and level of benefit to those with bleeding disorders.

For details on how to apply, visit ATHN.org/MLOF.

Photo by Darren Baker

A new resource has been made available for US-based scientists studying hemophilia A and B.

The resource—known as the My Life, Our Future Research Repository—is a collection of genetic data and blood samples that are linked to phenotypic data from more than 5000 hemophilia patients in the US.

Academic and industry scientists within the US can now access the repository but must apply to do so.

Scientists outside of the US should have access to the repository in 2018.

My Life, Our Future is a program founded by the American Thrombosis and Hemostasis Network, Bloodworks Northwest, the National Hemophilia Foundation, and Bioverativ.

My Life, Our Future was launched in 2012 to increase genotyping among individuals with hemophilia A and B, as well as potential and confirmed carriers of the disorder. The program will be available at participating hemophilia treatment centers through the end of 2017.

My Life, Our Future provides hemophilia patients (and potential/confirmed carriers) with free genotyping, and patients can then consent to add their de-identified genetic data and blood sample to the My Life, Our Future Research Repository.

Eighty-three percent of genotyped patients have contributed their data and blood samples. This is more than 5000 individuals representing more than 25% of the US hemophilia population.

The information provided by these individuals has led to the discovery of more than 600 new genetic variants that cause hemophilia.

“Hemophilia is a complex disorder, and, prior to today, there was no genetic and phenotypic database of this scale aiding scientific innovation,” said Barbara Konkle, MD, associate chief scientific officer of Bloodworks Northwest and principal investigator for My Life, Our Future.

“With this new resource, researchers now have one source for the genetic data, repository samples, and clinical data needed to investigate the many unanswered questions about hemophilia.”

Accessing the repository

To access the samples and data in the repository, scientists must first submit a letter of intent to the  American Thrombosis and Hemostasis Network.

Scientists may then be asked to submit a full research proposal, which will be evaluated by a research review committee—a group of experts including a molecular pathologist, genetic counselor, research scientist, molecular biologist, genetic epidemiologist, molecular epidemiologist, geneticist, patient representative, and hematologists.

Approved scientists will be selected based on the scientific merit of their proposals and level of benefit to those with bleeding disorders.

For details on how to apply, visit ATHN.org/MLOF.

Photo by Bill Branson

Childhood cancer survivors (CCSs) who were diagnosed in the 1990s have a lower risk of subsequent malignancies than CCSs diagnosed in the 1970s, according to research published in JAMA.

The data suggest this outcome is associated with a reduction in the overall use and median dose of therapeutic radiation over time.

Past research has shown an association between therapeutic radiation and the development of subsequent neoplasms in CCSs. Studies have also linked specific chemotherapeutic agents to subsequent neoplasms.

This information has been used to modify childhood cancer treatment over time, with the hope of reducing the risk of subsequent neoplasms while maintaining or improving 5-year survival.

To assess the effects of these treatment modifications, Gregory Armstrong, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted a study of CCSs.

The researchers evaluated 23,603 five-year CCSs (mean age at diagnosis, 7.7 years) treated at pediatric hospitals in the US and Canada from 1970 through 1999, with follow-up through December 2015.

The most common initial diagnoses were acute lymphoblastic leukemia (35.1%), Hodgkin lymphoma (11.1%), and astrocytoma (9.6%).

Subsequent neoplasms, malignancies

At a mean follow-up of 20.5 years, 1639 CCSs had experienced 3115 subsequent neoplasms, including 1026 malignancies, 233 benign meningiomas, and 1856 non-melanoma skin cancers. The most common neoplasms were breast and thyroid cancers.

The 15-year cumulative incidence of subsequent neoplasms decreased by decade of diagnosis. The incidence was 2.9% for patients diagnosed in the 1970s, 2.4% for those diagnosed in the ’80s, and 1.5% for those diagnosed in the ’90s. For the 1970s vs 1980s, the P value was 0.02. For the 1970s vs 1990s and for the 1980s vs 1990s, the P value was <0.001.

The 15-year cumulative incidence of subsequent malignancies also decreased by decade of diagnosis—2.1% for the ’70s, 1.7% for the ’80s, and 1.3% for the ’90s. The P value was <0.001 for the ’70s vs the ’90s and the ’80s vs the ’90s.

Risk factors

In multivariable analyses, female CCSs had a higher rate of subsequent neoplasms (including malignancies) than males.

In addition, high doses of alkylating agents and platinum agents were associated with increased rates of subsequent malignancies.

The researchers noted that, although there was a decrease in the median cumulative dose of alkylating agents over time, the proportion of CCSs receiving these agents increased. And both the median cumulative dose of platinum agents and the proportion of CCSs receiving these agents increased from the ’70s to the ’90s.

Finally, therapeutic radiation was associated with increased rates of subsequent malignant neoplasms, meningiomas, and non-melanoma skin cancers.

This corresponded with the researchers’ findings that the proportion of individuals receiving radiation and the median dose of radiation both decreased over time.

The proportion of individuals receiving any radiation therapy was 77.7% in the ’70s, 56.7% in the ’80s, and 36.8% in the ’90s. The median dose of radiation was 30.0 Gy in the ’70s, 24.0 Gy in the ’80s, and 26.0 Gy in the ’90s.

“The most ominous late effect of pediatric cancer treatment is a second malignancy,” Dr Armstrong said. “This study shows efforts to reduce the late effects of treatment are paying off. The risk of second cancers for survivors increases with age, so it is good to see the reduction emerging early in survivorship while survivors are still young.”

Photo by Bill Branson

Childhood cancer survivors (CCSs) who were diagnosed in the 1990s have a lower risk of subsequent malignancies than CCSs diagnosed in the 1970s, according to research published in JAMA.

The data suggest this outcome is associated with a reduction in the overall use and median dose of therapeutic radiation over time.

Past research has shown an association between therapeutic radiation and the development of subsequent neoplasms in CCSs. Studies have also linked specific chemotherapeutic agents to subsequent neoplasms.

This information has been used to modify childhood cancer treatment over time, with the hope of reducing the risk of subsequent neoplasms while maintaining or improving 5-year survival.

To assess the effects of these treatment modifications, Gregory Armstrong, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted a study of CCSs.

The researchers evaluated 23,603 five-year CCSs (mean age at diagnosis, 7.7 years) treated at pediatric hospitals in the US and Canada from 1970 through 1999, with follow-up through December 2015.

The most common initial diagnoses were acute lymphoblastic leukemia (35.1%), Hodgkin lymphoma (11.1%), and astrocytoma (9.6%).

Subsequent neoplasms, malignancies

At a mean follow-up of 20.5 years, 1639 CCSs had experienced 3115 subsequent neoplasms, including 1026 malignancies, 233 benign meningiomas, and 1856 non-melanoma skin cancers. The most common neoplasms were breast and thyroid cancers.

The 15-year cumulative incidence of subsequent neoplasms decreased by decade of diagnosis. The incidence was 2.9% for patients diagnosed in the 1970s, 2.4% for those diagnosed in the ’80s, and 1.5% for those diagnosed in the ’90s. For the 1970s vs 1980s, the P value was 0.02. For the 1970s vs 1990s and for the 1980s vs 1990s, the P value was <0.001.

The 15-year cumulative incidence of subsequent malignancies also decreased by decade of diagnosis—2.1% for the ’70s, 1.7% for the ’80s, and 1.3% for the ’90s. The P value was <0.001 for the ’70s vs the ’90s and the ’80s vs the ’90s.

Risk factors

In multivariable analyses, female CCSs had a higher rate of subsequent neoplasms (including malignancies) than males.

In addition, high doses of alkylating agents and platinum agents were associated with increased rates of subsequent malignancies.

The researchers noted that, although there was a decrease in the median cumulative dose of alkylating agents over time, the proportion of CCSs receiving these agents increased. And both the median cumulative dose of platinum agents and the proportion of CCSs receiving these agents increased from the ’70s to the ’90s.

Finally, therapeutic radiation was associated with increased rates of subsequent malignant neoplasms, meningiomas, and non-melanoma skin cancers.

This corresponded with the researchers’ findings that the proportion of individuals receiving radiation and the median dose of radiation both decreased over time.

The proportion of individuals receiving any radiation therapy was 77.7% in the ’70s, 56.7% in the ’80s, and 36.8% in the ’90s. The median dose of radiation was 30.0 Gy in the ’70s, 24.0 Gy in the ’80s, and 26.0 Gy in the ’90s.

“The most ominous late effect of pediatric cancer treatment is a second malignancy,” Dr Armstrong said. “This study shows efforts to reduce the late effects of treatment are paying off. The risk of second cancers for survivors increases with age, so it is good to see the reduction emerging early in survivorship while survivors are still young.”

Photo by Bill Branson

Childhood cancer survivors (CCSs) who were diagnosed in the 1990s have a lower risk of subsequent malignancies than CCSs diagnosed in the 1970s, according to research published in JAMA.

The data suggest this outcome is associated with a reduction in the overall use and median dose of therapeutic radiation over time.

Past research has shown an association between therapeutic radiation and the development of subsequent neoplasms in CCSs. Studies have also linked specific chemotherapeutic agents to subsequent neoplasms.

This information has been used to modify childhood cancer treatment over time, with the hope of reducing the risk of subsequent neoplasms while maintaining or improving 5-year survival.

To assess the effects of these treatment modifications, Gregory Armstrong, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted a study of CCSs.

The researchers evaluated 23,603 five-year CCSs (mean age at diagnosis, 7.7 years) treated at pediatric hospitals in the US and Canada from 1970 through 1999, with follow-up through December 2015.

The most common initial diagnoses were acute lymphoblastic leukemia (35.1%), Hodgkin lymphoma (11.1%), and astrocytoma (9.6%).

Subsequent neoplasms, malignancies

At a mean follow-up of 20.5 years, 1639 CCSs had experienced 3115 subsequent neoplasms, including 1026 malignancies, 233 benign meningiomas, and 1856 non-melanoma skin cancers. The most common neoplasms were breast and thyroid cancers.

The 15-year cumulative incidence of subsequent neoplasms decreased by decade of diagnosis. The incidence was 2.9% for patients diagnosed in the 1970s, 2.4% for those diagnosed in the ’80s, and 1.5% for those diagnosed in the ’90s. For the 1970s vs 1980s, the P value was 0.02. For the 1970s vs 1990s and for the 1980s vs 1990s, the P value was <0.001.

The 15-year cumulative incidence of subsequent malignancies also decreased by decade of diagnosis—2.1% for the ’70s, 1.7% for the ’80s, and 1.3% for the ’90s. The P value was <0.001 for the ’70s vs the ’90s and the ’80s vs the ’90s.

Risk factors

In multivariable analyses, female CCSs had a higher rate of subsequent neoplasms (including malignancies) than males.

In addition, high doses of alkylating agents and platinum agents were associated with increased rates of subsequent malignancies.

The researchers noted that, although there was a decrease in the median cumulative dose of alkylating agents over time, the proportion of CCSs receiving these agents increased. And both the median cumulative dose of platinum agents and the proportion of CCSs receiving these agents increased from the ’70s to the ’90s.

Finally, therapeutic radiation was associated with increased rates of subsequent malignant neoplasms, meningiomas, and non-melanoma skin cancers.

This corresponded with the researchers’ findings that the proportion of individuals receiving radiation and the median dose of radiation both decreased over time.

The proportion of individuals receiving any radiation therapy was 77.7% in the ’70s, 56.7% in the ’80s, and 36.8% in the ’90s. The median dose of radiation was 30.0 Gy in the ’70s, 24.0 Gy in the ’80s, and 26.0 Gy in the ’90s.

“The most ominous late effect of pediatric cancer treatment is a second malignancy,” Dr Armstrong said. “This study shows efforts to reduce the late effects of treatment are paying off. The risk of second cancers for survivors increases with age, so it is good to see the reduction emerging early in survivorship while survivors are still young.”

Photo courtesy of Celgene

The US Food and Drug Administration (FDA) has approved a new indication for lenalidomide (Revlimid).

The drug is now approved for use as maintenance therapy after autologous hematopoietic stem cell transplant (auto-HSCT) in patients with multiple myeloma (MM).

The expanded indication makes lenalidomide the first treatment to receive FDA approval for maintenance following auto-HSCT.

The drug was previously FDA-approved for use in combination with dexamethasone to treat patients with MM.

Lenalidomide is also FDA-approved to treat patients with transfusion-dependent anemia due to low-or intermediate-1-risk myelodysplastic syndromes associated with deletion 5q, with or without additional cytogenetic abnormalities.

And lenalidomide is FDA-approved to treat patients with mantle cell lymphoma who have relapsed or progressed after 2 prior therapies, one of which included bortezomib.

Lenalidomide is a product of Celgene.

Studies: Lenalidomide maintenance

The latest approval for lenalidomide was based on results of 2 cooperative group-led studies, CALGB 10010410 and IFM 2005-0211.

Results from both studies were published in NEJM in May 2012 (CALGB 100104, IFM 2005-02). The updated data reported here are included in the prescribing information for lenalidomide.

CALGB 100104 was a phase 3, double-blind study of 460 patients with newly diagnosed MM undergoing auto-HSCT. The patients received continuous daily treatment with lenalidomide or placebo until relapse.

IFM 2005-02 was a phase 3, double-blind study of 614 patients newly diagnosed with MM. The patients were randomized to receive a 2-month consolidation regimen after auto-HSCT, which consisted of lenalidomide monotherapy followed by continuous daily treatment with lenalidomide or placebo until relapse.

Survival

In both studies, the primary efficacy endpoint was progression-free survival (PFS). The PFS data for both studies were updated to reflect results as of March 2015.

In the CALGB study, the median PFS was 5.7 years in the lenalidomide arm and 1.9 years in the placebo arm (hazard ratio [HR]=0.38 [95% CI: 0.28-0.50]).

In the IFM study, the median PFS was 3.9 years in the lenalidomide arm and 2 years in the placebo arm (HR=0.53 [95% CI: 0.44-0.64]).

These studies were not powered for an overall survival (OS) endpoint. However, OS was recorded, and the OS data for both studies were updated to reflect results as of February 2016.

The median OS in the CALGB study was 9.3 years in the lenalidomide arm and 7 years in the placebo arm (HR=0.59 [95% CI: 0.44-0.78]).

In the IFM study, the median OS was 8.8 years in the lenalidomide arm and 7.3 years in the placebo arm (HR=0.90 [95% CI: 0.72-1.13]).

Adverse events

The most frequently reported adverse events in ≥20% of patients in the lenalidomide arm across both  studies (CALGB and IFM, respectively) were neutropenia (79%, 61%), thrombocytopenia (72%, 24%), leukopenia (23%, 32%), anemia (21%, 9%), upper respiratory tract infection (27%, 11%), bronchitis (5%, 47%), nasopharyngitis (2%, 35%), cough (10%, 27%), gastroenteritis (0%, 23%), diarrhea (55%, 39%), rash (32%, 8%), fatigue (23%, 11%), asthenia (0%, 30%), muscle spasm (0%, 33%), and pyrexia (8%, 21%).

The most frequently reported grade 3/4 events (more than 20% in the lenalidomide arm) were neutropenia, thrombocytopenia, and leukopenia.

Hematologic second primary malignancies (SPM) occurred in 7.5% of patients receiving lenalidomide maintenance and 3.3% of controls.

The incidence of hematologic plus solid tumor SPM (excluding squamous cell carcinoma and basal cell carcinoma) was 14.9% in the lenalidomide group and 8.8% in the control group, with a median follow-up of 91.5 months.

Non-melanoma skin cancer SPM, including squamous cell carcinoma and basal cell carcinoma, occurred in 3.9% of patients receiving lenalidomide maintenance and 2.6% of controls.

Photo courtesy of Celgene

The US Food and Drug Administration (FDA) has approved a new indication for lenalidomide (Revlimid).

The drug is now approved for use as maintenance therapy after autologous hematopoietic stem cell transplant (auto-HSCT) in patients with multiple myeloma (MM).

The expanded indication makes lenalidomide the first treatment to receive FDA approval for maintenance following auto-HSCT.

The drug was previously FDA-approved for use in combination with dexamethasone to treat patients with MM.

Lenalidomide is also FDA-approved to treat patients with transfusion-dependent anemia due to low-or intermediate-1-risk myelodysplastic syndromes associated with deletion 5q, with or without additional cytogenetic abnormalities.

And lenalidomide is FDA-approved to treat patients with mantle cell lymphoma who have relapsed or progressed after 2 prior therapies, one of which included bortezomib.

Lenalidomide is a product of Celgene.

Studies: Lenalidomide maintenance

The latest approval for lenalidomide was based on results of 2 cooperative group-led studies, CALGB 10010410 and IFM 2005-0211.

Results from both studies were published in NEJM in May 2012 (CALGB 100104, IFM 2005-02). The updated data reported here are included in the prescribing information for lenalidomide.

CALGB 100104 was a phase 3, double-blind study of 460 patients with newly diagnosed MM undergoing auto-HSCT. The patients received continuous daily treatment with lenalidomide or placebo until relapse.

IFM 2005-02 was a phase 3, double-blind study of 614 patients newly diagnosed with MM. The patients were randomized to receive a 2-month consolidation regimen after auto-HSCT, which consisted of lenalidomide monotherapy followed by continuous daily treatment with lenalidomide or placebo until relapse.

Survival

In both studies, the primary efficacy endpoint was progression-free survival (PFS). The PFS data for both studies were updated to reflect results as of March 2015.

In the CALGB study, the median PFS was 5.7 years in the lenalidomide arm and 1.9 years in the placebo arm (hazard ratio [HR]=0.38 [95% CI: 0.28-0.50]).

In the IFM study, the median PFS was 3.9 years in the lenalidomide arm and 2 years in the placebo arm (HR=0.53 [95% CI: 0.44-0.64]).

These studies were not powered for an overall survival (OS) endpoint. However, OS was recorded, and the OS data for both studies were updated to reflect results as of February 2016.

The median OS in the CALGB study was 9.3 years in the lenalidomide arm and 7 years in the placebo arm (HR=0.59 [95% CI: 0.44-0.78]).

In the IFM study, the median OS was 8.8 years in the lenalidomide arm and 7.3 years in the placebo arm (HR=0.90 [95% CI: 0.72-1.13]).

Adverse events

The most frequently reported adverse events in ≥20% of patients in the lenalidomide arm across both  studies (CALGB and IFM, respectively) were neutropenia (79%, 61%), thrombocytopenia (72%, 24%), leukopenia (23%, 32%), anemia (21%, 9%), upper respiratory tract infection (27%, 11%), bronchitis (5%, 47%), nasopharyngitis (2%, 35%), cough (10%, 27%), gastroenteritis (0%, 23%), diarrhea (55%, 39%), rash (32%, 8%), fatigue (23%, 11%), asthenia (0%, 30%), muscle spasm (0%, 33%), and pyrexia (8%, 21%).

The most frequently reported grade 3/4 events (more than 20% in the lenalidomide arm) were neutropenia, thrombocytopenia, and leukopenia.

Hematologic second primary malignancies (SPM) occurred in 7.5% of patients receiving lenalidomide maintenance and 3.3% of controls.

The incidence of hematologic plus solid tumor SPM (excluding squamous cell carcinoma and basal cell carcinoma) was 14.9% in the lenalidomide group and 8.8% in the control group, with a median follow-up of 91.5 months.

Non-melanoma skin cancer SPM, including squamous cell carcinoma and basal cell carcinoma, occurred in 3.9% of patients receiving lenalidomide maintenance and 2.6% of controls.

Photo courtesy of Celgene

The US Food and Drug Administration (FDA) has approved a new indication for lenalidomide (Revlimid).

The drug is now approved for use as maintenance therapy after autologous hematopoietic stem cell transplant (auto-HSCT) in patients with multiple myeloma (MM).

The expanded indication makes lenalidomide the first treatment to receive FDA approval for maintenance following auto-HSCT.

The drug was previously FDA-approved for use in combination with dexamethasone to treat patients with MM.

Lenalidomide is also FDA-approved to treat patients with transfusion-dependent anemia due to low-or intermediate-1-risk myelodysplastic syndromes associated with deletion 5q, with or without additional cytogenetic abnormalities.

And lenalidomide is FDA-approved to treat patients with mantle cell lymphoma who have relapsed or progressed after 2 prior therapies, one of which included bortezomib.

Lenalidomide is a product of Celgene.

Studies: Lenalidomide maintenance

The latest approval for lenalidomide was based on results of 2 cooperative group-led studies, CALGB 10010410 and IFM 2005-0211.

Results from both studies were published in NEJM in May 2012 (CALGB 100104, IFM 2005-02). The updated data reported here are included in the prescribing information for lenalidomide.

CALGB 100104 was a phase 3, double-blind study of 460 patients with newly diagnosed MM undergoing auto-HSCT. The patients received continuous daily treatment with lenalidomide or placebo until relapse.

IFM 2005-02 was a phase 3, double-blind study of 614 patients newly diagnosed with MM. The patients were randomized to receive a 2-month consolidation regimen after auto-HSCT, which consisted of lenalidomide monotherapy followed by continuous daily treatment with lenalidomide or placebo until relapse.

Survival

In both studies, the primary efficacy endpoint was progression-free survival (PFS). The PFS data for both studies were updated to reflect results as of March 2015.

In the CALGB study, the median PFS was 5.7 years in the lenalidomide arm and 1.9 years in the placebo arm (hazard ratio [HR]=0.38 [95% CI: 0.28-0.50]).

In the IFM study, the median PFS was 3.9 years in the lenalidomide arm and 2 years in the placebo arm (HR=0.53 [95% CI: 0.44-0.64]).

These studies were not powered for an overall survival (OS) endpoint. However, OS was recorded, and the OS data for both studies were updated to reflect results as of February 2016.

The median OS in the CALGB study was 9.3 years in the lenalidomide arm and 7 years in the placebo arm (HR=0.59 [95% CI: 0.44-0.78]).

In the IFM study, the median OS was 8.8 years in the lenalidomide arm and 7.3 years in the placebo arm (HR=0.90 [95% CI: 0.72-1.13]).

Adverse events

The most frequently reported adverse events in ≥20% of patients in the lenalidomide arm across both  studies (CALGB and IFM, respectively) were neutropenia (79%, 61%), thrombocytopenia (72%, 24%), leukopenia (23%, 32%), anemia (21%, 9%), upper respiratory tract infection (27%, 11%), bronchitis (5%, 47%), nasopharyngitis (2%, 35%), cough (10%, 27%), gastroenteritis (0%, 23%), diarrhea (55%, 39%), rash (32%, 8%), fatigue (23%, 11%), asthenia (0%, 30%), muscle spasm (0%, 33%), and pyrexia (8%, 21%).

The most frequently reported grade 3/4 events (more than 20% in the lenalidomide arm) were neutropenia, thrombocytopenia, and leukopenia.

Hematologic second primary malignancies (SPM) occurred in 7.5% of patients receiving lenalidomide maintenance and 3.3% of controls.

The incidence of hematologic plus solid tumor SPM (excluding squamous cell carcinoma and basal cell carcinoma) was 14.9% in the lenalidomide group and 8.8% in the control group, with a median follow-up of 91.5 months.

Non-melanoma skin cancer SPM, including squamous cell carcinoma and basal cell carcinoma, occurred in 3.9% of patients receiving lenalidomide maintenance and 2.6% of controls.

Photo by Bill Branson

ORLANDO, FL—Results of a phase 3 trial suggest an inactivated varicella zoster virus (VZV) vaccine known as V212 can reduce the risk of herpes zoster (HZ) in patients who have undergone autologous hematopoietic stem cell transplant (HSCT).

V212 reduced the hazard rate of HZ by an estimated 64% compared to placebo.

The vaccine also reduced the incidence of moderate-to-severe HZ pain and other HZ-related complications, such as hospitalization.

The overall incidence of adverse events (AEs) and the incidence of serious AEs were similar among vaccinated patients and those who received placebo.

Drew J. Winston, MD, of the University of California Los Angeles Medical Center, presented these results as one of the “Best Abstracts” at the 2017 BMT Tandem Meetings (abstract 6). The trial was sponsored by Merck, the company developing V212.

Treatment

This randomized, double-blind trial enrolled 1230 patients age 18 and older who were undergoing HSCT for any indication and had a history of varicella infection and/or were seropositive for VZV antibody.

The patients were randomized to receive:

• A 4-dose regimen of V212 (n=560) from a consistency lot (a lot having a targeted potency as required by regulators in order to demonstrate that the vaccine can be manufactured consistently)
• A 4-dose regimen of V212 (n=106) from a high-antigen lot (a lot having a higher antigen potency added to assess the safety profile of V212)
• Placebo (n=564).

Randomization was stratified by age (< 50 years vs ≥ 50 years) and by intended duration of post-transplant antiviral prophylaxis (≤3 months vs >3 to 6 months).

Dose 1 of V212 or placebo was given within approximately 30 days before HSCT, and doses 2, 3, and 4 were given approximately 30, 60, and 90 days after HSCT.

Patient characteristics

The median patient age was 57 (range, 19-76) for the consistency lot group, 56 (range, 21-75) for the high-antigen lot group, and 56 (range, 19-79) for the placebo group.

Underlying diseases were non-Hodgkin lymphoma (42%, 40%, and 44%, respectively), Hodgkin lymphoma (10%, 9%, and 9%, respectively), multiple myeloma (44%, 47% and 41%, respectively), acute leukemia (2%, 1%, and 2%, respectively), and “other” diseases (2%, 3% and 4%, respectively).

Roughly 30% of patients in each group received anti-viral agents for 3 months or less after HSCT. Twenty percent to 25% received antiviral therapy for more than 3 months to 6 months.

Thirty-seven percent to 40% received antiviral agents for more than 6 months. And 7% to 12% of patients did not receive any antiviral therapy.

HZ incidence

The average follow-up time for HZ surveillance was approximately 2.3 years (median: 2.6 years) post-vaccination.

Confirmed HZ occurred in 42 of the 538 patients who received V212 from a consistency lot and 113 of the 535 patients who received placebo. (Patients receiving V212 from a high-antigen lot were only included in the safety analysis.)

The estimated efficacy of V212 was 63.8% after adjustment for patient age and the duration of antiviral prophylaxis. Vaccine efficacy against HZ was defined as the relative reduction of hazard rate of HZ in vaccine recipients compared with placebo recipients.

The vaccine met the pre-specified criterion for success, as the lower bound of the 95% confidence interval (CI) was greater than 25%. The 95% CI was 48.4% to 74.6% (P<0.0001).

“The study demonstrates that the inactivated varicella vaccine is very effective for preventing herpes zoster after autologous stem cell transplantation,” Dr Winston said.

Pain, PHN, and other complications

V212 also reduced the incidence of moderate-to-severe HZ pain—according to the Zoster Brief Pain Inventory (ZBPI) score—by an estimated 69.5% (95% CI, 0.490-0.818).

Nineteen patients in the V212 consistency lot group had moderate-to-severe pain, as did 61 placebo-treated patients.

V212 conferred an estimated 83.7% (95% CI, 0.446-0.952) reduction in the incidence of post-herpetic neuralgia (PHN). Three patients in the V212 consistency lot group and 18 patients in the placebo group had PHN.

PHN was defined as pain in the area of the HZ rash with a “worst pain in the last 24 hours” score of 3 or greater (on a 0-10 scale) on the ZBPI that persists or appears 90 days or beyond after HZ rash onset following HSCT.

Patients who received V212 also saw an estimated 73.5% (95% CI, 0.498-0.860) reduction in “other” HZ complications. Twelve patients in the V212 consistency group and 44 in the placebo group had such complications.

“Other” complications included hospitalization or prolongation of hospitalization due to HZ, disseminated HZ (including disseminated HZ rash or VZV viremia), visceral HZ, ophthalmic HZ, neurological impairment due to HZ, and the administration of intravenous acyclovir therapy for the treatment of HZ post-HSCT.

Safety

All patients who received at least 1 dose of the vaccine or placebo and had follow-up data were included in the safety analysis. Patients were followed for AEs up to 28 days after the fourth vaccination dose.

AEs occurred in 97% of patients who received the vaccine (consistency and high-antigen groups assessed together) and 96.9% of placebo-treated patients. Vaccine-related AEs occurred in 32.6% and 12.6%, respectively.

“Of course, in this population of autologous stem cell transplant patients, adverse events of any type were very common in almost all patients,” Dr Winston said. “However, vaccine-related adverse events were greater in the vaccine recipients compared to the placebo patients, but this was primarily due to an increased incidence of injection-site adverse events in the vaccine recipients.”

Injection-site reactions occurred in 191 vaccinated patients and 36 placebo-treated patients.

The most common systemic AEs—in vaccinated and placebo-treated patients, respectively—were diarrhea (60.1% and 61.9%), nausea (56.5% and 57.8%), pyrexia (49.8% and 46.9%), mucosal inflammation (39.7% and 41.7%), thrombocytopenia (36.4% and 38.4%), febrile neutropenia (33.9% and 28.3%), vomiting (32.6% and 36.6%), anemia (26.6% and 24.4%), neutropenia (25.1% and 23.5%), decreased appetite (23.1% and 23.8%), fatigue (21.8% and 20.7%), hypokalemia (21.3% and 19.9%), and constipation (16.1% and 18.4%).

The incidence of serious AEs was 32.9% in vaccinated patients and 32.7% in the placebo group. The incidence of serious vaccine-related AEs was 0.8% and 0.9%, respectively.

The most common serious AEs—in vaccinated and placebo-treated patients, respectively—were infection (12.3% and 11.9%), relapsed malignancy (7.8% for both), febrile neutropenia (5.3% and 4.9%), pyrexia (3.2% and 4.0%), gastrointestinal disorders (3.2% and 3.6%), respiratory failure (2.7% and 2.2%), cardiac disorders (1.7% and 1.6%), and mucositis (1.2% and 0.9%).

Death occurred in 6.2% of vaccinated patients and 6.3% of placebo-treated patients. Three percent and 3.1%, respectively, discontinued the study due to AEs.

Photo by Bill Branson

ORLANDO, FL—Results of a phase 3 trial suggest an inactivated varicella zoster virus (VZV) vaccine known as V212 can reduce the risk of herpes zoster (HZ) in patients who have undergone autologous hematopoietic stem cell transplant (HSCT).

V212 reduced the hazard rate of HZ by an estimated 64% compared to placebo.

The vaccine also reduced the incidence of moderate-to-severe HZ pain and other HZ-related complications, such as hospitalization.

The overall incidence of adverse events (AEs) and the incidence of serious AEs were similar among vaccinated patients and those who received placebo.

Drew J. Winston, MD, of the University of California Los Angeles Medical Center, presented these results as one of the “Best Abstracts” at the 2017 BMT Tandem Meetings (abstract 6). The trial was sponsored by Merck, the company developing V212.

Treatment

This randomized, double-blind trial enrolled 1230 patients age 18 and older who were undergoing HSCT for any indication and had a history of varicella infection and/or were seropositive for VZV antibody.

The patients were randomized to receive:

• A 4-dose regimen of V212 (n=560) from a consistency lot (a lot having a targeted potency as required by regulators in order to demonstrate that the vaccine can be manufactured consistently)
• A 4-dose regimen of V212 (n=106) from a high-antigen lot (a lot having a higher antigen potency added to assess the safety profile of V212)
• Placebo (n=564).

Randomization was stratified by age (< 50 years vs ≥ 50 years) and by intended duration of post-transplant antiviral prophylaxis (≤3 months vs >3 to 6 months).

Dose 1 of V212 or placebo was given within approximately 30 days before HSCT, and doses 2, 3, and 4 were given approximately 30, 60, and 90 days after HSCT.

Patient characteristics

The median patient age was 57 (range, 19-76) for the consistency lot group, 56 (range, 21-75) for the high-antigen lot group, and 56 (range, 19-79) for the placebo group.

Underlying diseases were non-Hodgkin lymphoma (42%, 40%, and 44%, respectively), Hodgkin lymphoma (10%, 9%, and 9%, respectively), multiple myeloma (44%, 47% and 41%, respectively), acute leukemia (2%, 1%, and 2%, respectively), and “other” diseases (2%, 3% and 4%, respectively).

Roughly 30% of patients in each group received anti-viral agents for 3 months or less after HSCT. Twenty percent to 25% received antiviral therapy for more than 3 months to 6 months.

Thirty-seven percent to 40% received antiviral agents for more than 6 months. And 7% to 12% of patients did not receive any antiviral therapy.

HZ incidence

The average follow-up time for HZ surveillance was approximately 2.3 years (median: 2.6 years) post-vaccination.

Confirmed HZ occurred in 42 of the 538 patients who received V212 from a consistency lot and 113 of the 535 patients who received placebo. (Patients receiving V212 from a high-antigen lot were only included in the safety analysis.)

The estimated efficacy of V212 was 63.8% after adjustment for patient age and the duration of antiviral prophylaxis. Vaccine efficacy against HZ was defined as the relative reduction of hazard rate of HZ in vaccine recipients compared with placebo recipients.

The vaccine met the pre-specified criterion for success, as the lower bound of the 95% confidence interval (CI) was greater than 25%. The 95% CI was 48.4% to 74.6% (P<0.0001).

“The study demonstrates that the inactivated varicella vaccine is very effective for preventing herpes zoster after autologous stem cell transplantation,” Dr Winston said.

Pain, PHN, and other complications

V212 also reduced the incidence of moderate-to-severe HZ pain—according to the Zoster Brief Pain Inventory (ZBPI) score—by an estimated 69.5% (95% CI, 0.490-0.818).

Nineteen patients in the V212 consistency lot group had moderate-to-severe pain, as did 61 placebo-treated patients.

V212 conferred an estimated 83.7% (95% CI, 0.446-0.952) reduction in the incidence of post-herpetic neuralgia (PHN). Three patients in the V212 consistency lot group and 18 patients in the placebo group had PHN.

PHN was defined as pain in the area of the HZ rash with a “worst pain in the last 24 hours” score of 3 or greater (on a 0-10 scale) on the ZBPI that persists or appears 90 days or beyond after HZ rash onset following HSCT.

Patients who received V212 also saw an estimated 73.5% (95% CI, 0.498-0.860) reduction in “other” HZ complications. Twelve patients in the V212 consistency group and 44 in the placebo group had such complications.

“Other” complications included hospitalization or prolongation of hospitalization due to HZ, disseminated HZ (including disseminated HZ rash or VZV viremia), visceral HZ, ophthalmic HZ, neurological impairment due to HZ, and the administration of intravenous acyclovir therapy for the treatment of HZ post-HSCT.

Safety

All patients who received at least 1 dose of the vaccine or placebo and had follow-up data were included in the safety analysis. Patients were followed for AEs up to 28 days after the fourth vaccination dose.

AEs occurred in 97% of patients who received the vaccine (consistency and high-antigen groups assessed together) and 96.9% of placebo-treated patients. Vaccine-related AEs occurred in 32.6% and 12.6%, respectively.

“Of course, in this population of autologous stem cell transplant patients, adverse events of any type were very common in almost all patients,” Dr Winston said. “However, vaccine-related adverse events were greater in the vaccine recipients compared to the placebo patients, but this was primarily due to an increased incidence of injection-site adverse events in the vaccine recipients.”

Injection-site reactions occurred in 191 vaccinated patients and 36 placebo-treated patients.

The most common systemic AEs—in vaccinated and placebo-treated patients, respectively—were diarrhea (60.1% and 61.9%), nausea (56.5% and 57.8%), pyrexia (49.8% and 46.9%), mucosal inflammation (39.7% and 41.7%), thrombocytopenia (36.4% and 38.4%), febrile neutropenia (33.9% and 28.3%), vomiting (32.6% and 36.6%), anemia (26.6% and 24.4%), neutropenia (25.1% and 23.5%), decreased appetite (23.1% and 23.8%), fatigue (21.8% and 20.7%), hypokalemia (21.3% and 19.9%), and constipation (16.1% and 18.4%).

The incidence of serious AEs was 32.9% in vaccinated patients and 32.7% in the placebo group. The incidence of serious vaccine-related AEs was 0.8% and 0.9%, respectively.

The most common serious AEs—in vaccinated and placebo-treated patients, respectively—were infection (12.3% and 11.9%), relapsed malignancy (7.8% for both), febrile neutropenia (5.3% and 4.9%), pyrexia (3.2% and 4.0%), gastrointestinal disorders (3.2% and 3.6%), respiratory failure (2.7% and 2.2%), cardiac disorders (1.7% and 1.6%), and mucositis (1.2% and 0.9%).

Death occurred in 6.2% of vaccinated patients and 6.3% of placebo-treated patients. Three percent and 3.1%, respectively, discontinued the study due to AEs.

Photo by Bill Branson

ORLANDO, FL—Results of a phase 3 trial suggest an inactivated varicella zoster virus (VZV) vaccine known as V212 can reduce the risk of herpes zoster (HZ) in patients who have undergone autologous hematopoietic stem cell transplant (HSCT).

V212 reduced the hazard rate of HZ by an estimated 64% compared to placebo.

The vaccine also reduced the incidence of moderate-to-severe HZ pain and other HZ-related complications, such as hospitalization.

The overall incidence of adverse events (AEs) and the incidence of serious AEs were similar among vaccinated patients and those who received placebo.

Drew J. Winston, MD, of the University of California Los Angeles Medical Center, presented these results as one of the “Best Abstracts” at the 2017 BMT Tandem Meetings (abstract 6). The trial was sponsored by Merck, the company developing V212.

Treatment

This randomized, double-blind trial enrolled 1230 patients age 18 and older who were undergoing HSCT for any indication and had a history of varicella infection and/or were seropositive for VZV antibody.

The patients were randomized to receive:

• A 4-dose regimen of V212 (n=560) from a consistency lot (a lot having a targeted potency as required by regulators in order to demonstrate that the vaccine can be manufactured consistently)
• A 4-dose regimen of V212 (n=106) from a high-antigen lot (a lot having a higher antigen potency added to assess the safety profile of V212)
• Placebo (n=564).

Randomization was stratified by age (< 50 years vs ≥ 50 years) and by intended duration of post-transplant antiviral prophylaxis (≤3 months vs >3 to 6 months).

Dose 1 of V212 or placebo was given within approximately 30 days before HSCT, and doses 2, 3, and 4 were given approximately 30, 60, and 90 days after HSCT.

Patient characteristics

The median patient age was 57 (range, 19-76) for the consistency lot group, 56 (range, 21-75) for the high-antigen lot group, and 56 (range, 19-79) for the placebo group.

Underlying diseases were non-Hodgkin lymphoma (42%, 40%, and 44%, respectively), Hodgkin lymphoma (10%, 9%, and 9%, respectively), multiple myeloma (44%, 47% and 41%, respectively), acute leukemia (2%, 1%, and 2%, respectively), and “other” diseases (2%, 3% and 4%, respectively).

Roughly 30% of patients in each group received anti-viral agents for 3 months or less after HSCT. Twenty percent to 25% received antiviral therapy for more than 3 months to 6 months.

Thirty-seven percent to 40% received antiviral agents for more than 6 months. And 7% to 12% of patients did not receive any antiviral therapy.

HZ incidence

The average follow-up time for HZ surveillance was approximately 2.3 years (median: 2.6 years) post-vaccination.

Confirmed HZ occurred in 42 of the 538 patients who received V212 from a consistency lot and 113 of the 535 patients who received placebo. (Patients receiving V212 from a high-antigen lot were only included in the safety analysis.)

The estimated efficacy of V212 was 63.8% after adjustment for patient age and the duration of antiviral prophylaxis. Vaccine efficacy against HZ was defined as the relative reduction of hazard rate of HZ in vaccine recipients compared with placebo recipients.

The vaccine met the pre-specified criterion for success, as the lower bound of the 95% confidence interval (CI) was greater than 25%. The 95% CI was 48.4% to 74.6% (P<0.0001).

“The study demonstrates that the inactivated varicella vaccine is very effective for preventing herpes zoster after autologous stem cell transplantation,” Dr Winston said.

Pain, PHN, and other complications

V212 also reduced the incidence of moderate-to-severe HZ pain—according to the Zoster Brief Pain Inventory (ZBPI) score—by an estimated 69.5% (95% CI, 0.490-0.818).

Nineteen patients in the V212 consistency lot group had moderate-to-severe pain, as did 61 placebo-treated patients.

V212 conferred an estimated 83.7% (95% CI, 0.446-0.952) reduction in the incidence of post-herpetic neuralgia (PHN). Three patients in the V212 consistency lot group and 18 patients in the placebo group had PHN.

PHN was defined as pain in the area of the HZ rash with a “worst pain in the last 24 hours” score of 3 or greater (on a 0-10 scale) on the ZBPI that persists or appears 90 days or beyond after HZ rash onset following HSCT.

Patients who received V212 also saw an estimated 73.5% (95% CI, 0.498-0.860) reduction in “other” HZ complications. Twelve patients in the V212 consistency group and 44 in the placebo group had such complications.

“Other” complications included hospitalization or prolongation of hospitalization due to HZ, disseminated HZ (including disseminated HZ rash or VZV viremia), visceral HZ, ophthalmic HZ, neurological impairment due to HZ, and the administration of intravenous acyclovir therapy for the treatment of HZ post-HSCT.

Safety

All patients who received at least 1 dose of the vaccine or placebo and had follow-up data were included in the safety analysis. Patients were followed for AEs up to 28 days after the fourth vaccination dose.

AEs occurred in 97% of patients who received the vaccine (consistency and high-antigen groups assessed together) and 96.9% of placebo-treated patients. Vaccine-related AEs occurred in 32.6% and 12.6%, respectively.

“Of course, in this population of autologous stem cell transplant patients, adverse events of any type were very common in almost all patients,” Dr Winston said. “However, vaccine-related adverse events were greater in the vaccine recipients compared to the placebo patients, but this was primarily due to an increased incidence of injection-site adverse events in the vaccine recipients.”

Injection-site reactions occurred in 191 vaccinated patients and 36 placebo-treated patients.

The most common systemic AEs—in vaccinated and placebo-treated patients, respectively—were diarrhea (60.1% and 61.9%), nausea (56.5% and 57.8%), pyrexia (49.8% and 46.9%), mucosal inflammation (39.7% and 41.7%), thrombocytopenia (36.4% and 38.4%), febrile neutropenia (33.9% and 28.3%), vomiting (32.6% and 36.6%), anemia (26.6% and 24.4%), neutropenia (25.1% and 23.5%), decreased appetite (23.1% and 23.8%), fatigue (21.8% and 20.7%), hypokalemia (21.3% and 19.9%), and constipation (16.1% and 18.4%).

The incidence of serious AEs was 32.9% in vaccinated patients and 32.7% in the placebo group. The incidence of serious vaccine-related AEs was 0.8% and 0.9%, respectively.

The most common serious AEs—in vaccinated and placebo-treated patients, respectively—were infection (12.3% and 11.9%), relapsed malignancy (7.8% for both), febrile neutropenia (5.3% and 4.9%), pyrexia (3.2% and 4.0%), gastrointestinal disorders (3.2% and 3.6%), respiratory failure (2.7% and 2.2%), cardiac disorders (1.7% and 1.6%), and mucositis (1.2% and 0.9%).

Death occurred in 6.2% of vaccinated patients and 6.3% of placebo-treated patients. Three percent and 3.1%, respectively, discontinued the study due to AEs.

Kristyna Wentz-Graff

A newly discovered issue with the Ba/F3 transformation assay could “jeopardize attempts to characterize the signaling mechanisms and drug sensitivities of leukemic oncogenes,” researchers reported in Oncotarget.

The researchers said the assay “remains an invaluable tool” for validating activating mutations in primary leukemias.

However, the assay is prone to a previously unreported flaw, where Ba/F3 cells can acquire additional mutations.

This issue was discovered by Kevin Watanabe-Smith, PhD, of Oregon Health & Science University in Portland.

He identified the problem while studying a growth-activating mutation in a patient with T-cell leukemia. (The results of that research were published in Leukemia in April 2016).

“When I was sequencing the patient’s DNA to make sure the original, known mutation is there, I was finding additional, unexpected mutations in the gene that I didn’t put there,” Dr Watanabe-Smith said. “And I was getting different mutations every time.”

“After we saw this in several cases, we knew it was worth further study,” added Cristina Tognon, PhD, of Oregon Health & Science University.

So the researchers decided to study Ba/F3 cell lines with and without 4 mutations (found in 3 cytokine receptors) that have “known transformative capacity,” including:

• CSF2RB R461C, a germline mutation found in a patient with T-cell acute lymphoblastic leukemia (ALL)
• CSF3R T618I, a mutation found in chronic neutrophilic leukemia (CNL) and atypical chronic myelogenous leukemia (aCML)
• CSF3R W791X, also found in CNL and aCML
• IL7R 243InsPPCL, which was found in a patient with B-cell ALL.

The researchers said they observed acquired mutations in 1 of 3 CSF2RB wild-type cell lines that transformed and all 4 CSF3R wild-type cell lines, which all transformed.

Furthermore, most CSF2RB R461C lines (4/5) and CSF3R W791X lines (3/4) had additional acquired mutations. However, the CSF3R T618I lines and the IL7R 243InsPPCL lines did not contain acquired mutations.

The researchers said acquired mutations were observed only in weakly transforming oncogenes, which were defined as mutations with a weaker ability to transform cells (less than 1 in every 200 cells) or a slower time to outgrowth (5 days or longer to reach a 5-fold increase over the initial cell number).

The team also said their findings indicate that the majority of the acquired mutations likely exist before IL-3 withdrawal but only expand to levels detectable by Sanger sequencing in the absence of IL-3.

“The potential impact [of these acquired mutations] is that a non-functional mutation could appear functional, and a researcher could publish results that would not be reproducible,” Dr Watanabe-Smith said.

To overcome this problem, Dr Watanabe-Smith and his colleagues recommended taking an additional step when using the Ba/F3 assay—sequencing outgrown cell lines. They also said additional research is needed to devise methods that reduce the incidence of acquired mutations in such assays. 

Kristyna Wentz-Graff

A newly discovered issue with the Ba/F3 transformation assay could “jeopardize attempts to characterize the signaling mechanisms and drug sensitivities of leukemic oncogenes,” researchers reported in Oncotarget.

The researchers said the assay “remains an invaluable tool” for validating activating mutations in primary leukemias.

However, the assay is prone to a previously unreported flaw, where Ba/F3 cells can acquire additional mutations.

This issue was discovered by Kevin Watanabe-Smith, PhD, of Oregon Health & Science University in Portland.

He identified the problem while studying a growth-activating mutation in a patient with T-cell leukemia. (The results of that research were published in Leukemia in April 2016).

“When I was sequencing the patient’s DNA to make sure the original, known mutation is there, I was finding additional, unexpected mutations in the gene that I didn’t put there,” Dr Watanabe-Smith said. “And I was getting different mutations every time.”

“After we saw this in several cases, we knew it was worth further study,” added Cristina Tognon, PhD, of Oregon Health & Science University.

So the researchers decided to study Ba/F3 cell lines with and without 4 mutations (found in 3 cytokine receptors) that have “known transformative capacity,” including:

• CSF2RB R461C, a germline mutation found in a patient with T-cell acute lymphoblastic leukemia (ALL)
• CSF3R T618I, a mutation found in chronic neutrophilic leukemia (CNL) and atypical chronic myelogenous leukemia (aCML)
• CSF3R W791X, also found in CNL and aCML
• IL7R 243InsPPCL, which was found in a patient with B-cell ALL.

The researchers said they observed acquired mutations in 1 of 3 CSF2RB wild-type cell lines that transformed and all 4 CSF3R wild-type cell lines, which all transformed.

Furthermore, most CSF2RB R461C lines (4/5) and CSF3R W791X lines (3/4) had additional acquired mutations. However, the CSF3R T618I lines and the IL7R 243InsPPCL lines did not contain acquired mutations.

The researchers said acquired mutations were observed only in weakly transforming oncogenes, which were defined as mutations with a weaker ability to transform cells (less than 1 in every 200 cells) or a slower time to outgrowth (5 days or longer to reach a 5-fold increase over the initial cell number).

The team also said their findings indicate that the majority of the acquired mutations likely exist before IL-3 withdrawal but only expand to levels detectable by Sanger sequencing in the absence of IL-3.

“The potential impact [of these acquired mutations] is that a non-functional mutation could appear functional, and a researcher could publish results that would not be reproducible,” Dr Watanabe-Smith said.

To overcome this problem, Dr Watanabe-Smith and his colleagues recommended taking an additional step when using the Ba/F3 assay—sequencing outgrown cell lines. They also said additional research is needed to devise methods that reduce the incidence of acquired mutations in such assays. 

Kristyna Wentz-Graff

A newly discovered issue with the Ba/F3 transformation assay could “jeopardize attempts to characterize the signaling mechanisms and drug sensitivities of leukemic oncogenes,” researchers reported in Oncotarget.

The researchers said the assay “remains an invaluable tool” for validating activating mutations in primary leukemias.

However, the assay is prone to a previously unreported flaw, where Ba/F3 cells can acquire additional mutations.

This issue was discovered by Kevin Watanabe-Smith, PhD, of Oregon Health & Science University in Portland.

He identified the problem while studying a growth-activating mutation in a patient with T-cell leukemia. (The results of that research were published in Leukemia in April 2016).

“When I was sequencing the patient’s DNA to make sure the original, known mutation is there, I was finding additional, unexpected mutations in the gene that I didn’t put there,” Dr Watanabe-Smith said. “And I was getting different mutations every time.”

“After we saw this in several cases, we knew it was worth further study,” added Cristina Tognon, PhD, of Oregon Health & Science University.

So the researchers decided to study Ba/F3 cell lines with and without 4 mutations (found in 3 cytokine receptors) that have “known transformative capacity,” including:

• CSF2RB R461C, a germline mutation found in a patient with T-cell acute lymphoblastic leukemia (ALL)
• CSF3R T618I, a mutation found in chronic neutrophilic leukemia (CNL) and atypical chronic myelogenous leukemia (aCML)
• CSF3R W791X, also found in CNL and aCML
• IL7R 243InsPPCL, which was found in a patient with B-cell ALL.

The researchers said they observed acquired mutations in 1 of 3 CSF2RB wild-type cell lines that transformed and all 4 CSF3R wild-type cell lines, which all transformed.

Furthermore, most CSF2RB R461C lines (4/5) and CSF3R W791X lines (3/4) had additional acquired mutations. However, the CSF3R T618I lines and the IL7R 243InsPPCL lines did not contain acquired mutations.

The researchers said acquired mutations were observed only in weakly transforming oncogenes, which were defined as mutations with a weaker ability to transform cells (less than 1 in every 200 cells) or a slower time to outgrowth (5 days or longer to reach a 5-fold increase over the initial cell number).

The team also said their findings indicate that the majority of the acquired mutations likely exist before IL-3 withdrawal but only expand to levels detectable by Sanger sequencing in the absence of IL-3.

“The potential impact [of these acquired mutations] is that a non-functional mutation could appear functional, and a researcher could publish results that would not be reproducible,” Dr Watanabe-Smith said.

To overcome this problem, Dr Watanabe-Smith and his colleagues recommended taking an additional step when using the Ba/F3 assay—sequencing outgrown cell lines. They also said additional research is needed to devise methods that reduce the incidence of acquired mutations in such assays.