Leukemia, Myelodysplasia, Transplantation

Ofatumumab (Arzerra)

Photo courtesy of GSK

The US Food and Drug Administration (FDA) has approved the use of ofatumumab (Arzerra) as maintenance therapy for patients with chronic lymphocytic leukemia (CLL).

The drug can now be given for an extended period to patients who are in complete or partial response after receiving at least 2 lines of therapy for recurrent or progressive CLL.

Ofatumumab is also FDA-approved as a single agent to treat CLL that is refractory to fludarabine and alemtuzumab.

And the drug is approved for use in combination with chlorambucil to treat previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate.

The FDA granted the new approval for ofatumumab based on an interim analysis of the PROLONG study. The results suggested that ofatumumab maintenance can improve progression-free survival (PFS) in CLL patients when compared to observation.

Ofatumumab is marketed as Arzerra under a collaboration agreement between Genmab and Novartis. For more details on ofatumumab, see the full prescribing information.

PROLONG trial

The PROLONG trial was designed to compare ofatumumab maintenance to no further treatment in patients with a complete or partial response after second- or third-line treatment for CLL. Interim results of the study were presented at ASH 2014.

These results—in 474 patients—suggested that ofatumumab can significantly improve PFS. The median PFS was about 29 months in patients who received ofatumumab and about 15 months for patients who did not receive maintenance therapy (P<0.0001).

There was no significant difference in the median overall survival, which was not reached in either treatment arm.

The researchers said there were no unexpected safety findings. The most common adverse events (≥10%) were infusion reactions, neutropenia, and upper respiratory tract infection.

Ofatumumab (Arzerra)

Photo courtesy of GSK

The US Food and Drug Administration (FDA) has approved the use of ofatumumab (Arzerra) as maintenance therapy for patients with chronic lymphocytic leukemia (CLL).

The drug can now be given for an extended period to patients who are in complete or partial response after receiving at least 2 lines of therapy for recurrent or progressive CLL.

Ofatumumab is also FDA-approved as a single agent to treat CLL that is refractory to fludarabine and alemtuzumab.

And the drug is approved for use in combination with chlorambucil to treat previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate.

The FDA granted the new approval for ofatumumab based on an interim analysis of the PROLONG study. The results suggested that ofatumumab maintenance can improve progression-free survival (PFS) in CLL patients when compared to observation.

Ofatumumab is marketed as Arzerra under a collaboration agreement between Genmab and Novartis. For more details on ofatumumab, see the full prescribing information.

PROLONG trial

The PROLONG trial was designed to compare ofatumumab maintenance to no further treatment in patients with a complete or partial response after second- or third-line treatment for CLL. Interim results of the study were presented at ASH 2014.

These results—in 474 patients—suggested that ofatumumab can significantly improve PFS. The median PFS was about 29 months in patients who received ofatumumab and about 15 months for patients who did not receive maintenance therapy (P<0.0001).

There was no significant difference in the median overall survival, which was not reached in either treatment arm.

The researchers said there were no unexpected safety findings. The most common adverse events (≥10%) were infusion reactions, neutropenia, and upper respiratory tract infection.

Ofatumumab (Arzerra)

Photo courtesy of GSK

The US Food and Drug Administration (FDA) has approved the use of ofatumumab (Arzerra) as maintenance therapy for patients with chronic lymphocytic leukemia (CLL).

The drug can now be given for an extended period to patients who are in complete or partial response after receiving at least 2 lines of therapy for recurrent or progressive CLL.

Ofatumumab is also FDA-approved as a single agent to treat CLL that is refractory to fludarabine and alemtuzumab.

And the drug is approved for use in combination with chlorambucil to treat previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate.

The FDA granted the new approval for ofatumumab based on an interim analysis of the PROLONG study. The results suggested that ofatumumab maintenance can improve progression-free survival (PFS) in CLL patients when compared to observation.

Ofatumumab is marketed as Arzerra under a collaboration agreement between Genmab and Novartis. For more details on ofatumumab, see the full prescribing information.

PROLONG trial

The PROLONG trial was designed to compare ofatumumab maintenance to no further treatment in patients with a complete or partial response after second- or third-line treatment for CLL. Interim results of the study were presented at ASH 2014.

These results—in 474 patients—suggested that ofatumumab can significantly improve PFS. The median PFS was about 29 months in patients who received ofatumumab and about 15 months for patients who did not receive maintenance therapy (P<0.0001).

There was no significant difference in the median overall survival, which was not reached in either treatment arm.

The researchers said there were no unexpected safety findings. The most common adverse events (≥10%) were infusion reactions, neutropenia, and upper respiratory tract infection.

Micrograph showing ALL

The European Commission has granted marketing authorization for pegaspargase (Oncaspar) to be used as part of combination antineoplastic therapy for pediatric and adult patients with acute lymphoblastic leukemia (ALL).

The approval means the drug can be marketed for this indication in the 28 member countries of the European Union (EU), as well as Iceland, Liechtenstein, and Norway.

Pegaspargase was already approved for use in Argentina, Belarus, Germany, Kazakhstan, Poland, Russia, Ukraine, and the US.

“Oncaspar has been used as an integral component of the treatment regimen for pediatric and adult patients with ALL for many years, in Europe and worldwide,” said Martin Schrappe, of Schleswig-Holstein University Hospital in Kiel, Germany.

“Today’s marketing authorization will ensure that more patients across the EU will benefit from access to Oncaspar as part of a standard of care regimen.”

The drug is being developed by Baxalta Incorporated.

First-line ALL

Researchers have evaluated the safety and effectiveness of pegaspargase in a study of 118 pediatric patients (ages 1 to 9) with newly diagnosed ALL. The patients were randomized 1:1 to pegaspargase or native E coli L-asparaginase, both as part of combination therapy.

Asparagine depletion (magnitude and duration) was similar between the 2 treatment arms. Event-free survival rates were also similar (about 80% in both arms), but the study was not designed to evaluate differences in event-free survival.

Grade 3/4 adverse events occurring in the pegaspargase and native E coli L-asparaginase arms, respectively, were abnormal liver tests (5% and 8%), elevated transaminases (3% and 7%), hyperbilirubinemia (2% and 2%), hyperglycemia (5% and 3%), central nervous system thrombosis (3% and 3%), coagulopathy (2% and 5%), pancreatitis (2% and 2%), and clinical allergic reactions to asparaginase (2% and 0%).

Previously treated ALL

Researchers have evaluated the effectiveness of pegaspargase in 4 open-label studies of patients with a history of prior clinical allergic reaction to asparaginase. The studies enrolled a total of 42 patients with multiply relapsed acute leukemia (39 with ALL).

Patients received pegaspargase as a single agent or as part of multi-agent chemotherapy. The re-induction response rate was 50%—36% complete responses and 14% partial responses. Three responses occurred in patients who received single-agent pegaspargase.

Adverse event information on pegaspargase in relapsed ALL has been compiled from 5 clinical trials. The studies enrolled a total of 174 patients with relapsed ALL who received pegaspargase as a single agent or as part of combination therapy.

Sixty-two of the patients had prior hypersensitivity reactions to asparaginase, and 112 did not. Allergic reactions to pegaspargase occurred in 32% of previously hypersensitive patients and 10% of non-hypersensitive patients.

The most common adverse events observed in patients who received pegaspargase were clinical allergic reactions, elevated transaminases, hyperbilirubinemia, and coagulopathies.

The most common serious adverse events due to pegaspargase were thrombosis (4%), hyperglycemia requiring insulin therapy (3%), and pancreatitis (1%).

For more details on these trials and pegaspargase in general, see the product information.

Micrograph showing ALL

The European Commission has granted marketing authorization for pegaspargase (Oncaspar) to be used as part of combination antineoplastic therapy for pediatric and adult patients with acute lymphoblastic leukemia (ALL).

The approval means the drug can be marketed for this indication in the 28 member countries of the European Union (EU), as well as Iceland, Liechtenstein, and Norway.

Pegaspargase was already approved for use in Argentina, Belarus, Germany, Kazakhstan, Poland, Russia, Ukraine, and the US.

“Oncaspar has been used as an integral component of the treatment regimen for pediatric and adult patients with ALL for many years, in Europe and worldwide,” said Martin Schrappe, of Schleswig-Holstein University Hospital in Kiel, Germany.

“Today’s marketing authorization will ensure that more patients across the EU will benefit from access to Oncaspar as part of a standard of care regimen.”

The drug is being developed by Baxalta Incorporated.

First-line ALL

Researchers have evaluated the safety and effectiveness of pegaspargase in a study of 118 pediatric patients (ages 1 to 9) with newly diagnosed ALL. The patients were randomized 1:1 to pegaspargase or native E coli L-asparaginase, both as part of combination therapy.

Asparagine depletion (magnitude and duration) was similar between the 2 treatment arms. Event-free survival rates were also similar (about 80% in both arms), but the study was not designed to evaluate differences in event-free survival.

Grade 3/4 adverse events occurring in the pegaspargase and native E coli L-asparaginase arms, respectively, were abnormal liver tests (5% and 8%), elevated transaminases (3% and 7%), hyperbilirubinemia (2% and 2%), hyperglycemia (5% and 3%), central nervous system thrombosis (3% and 3%), coagulopathy (2% and 5%), pancreatitis (2% and 2%), and clinical allergic reactions to asparaginase (2% and 0%).

Previously treated ALL

Researchers have evaluated the effectiveness of pegaspargase in 4 open-label studies of patients with a history of prior clinical allergic reaction to asparaginase. The studies enrolled a total of 42 patients with multiply relapsed acute leukemia (39 with ALL).

Patients received pegaspargase as a single agent or as part of multi-agent chemotherapy. The re-induction response rate was 50%—36% complete responses and 14% partial responses. Three responses occurred in patients who received single-agent pegaspargase.

Adverse event information on pegaspargase in relapsed ALL has been compiled from 5 clinical trials. The studies enrolled a total of 174 patients with relapsed ALL who received pegaspargase as a single agent or as part of combination therapy.

Sixty-two of the patients had prior hypersensitivity reactions to asparaginase, and 112 did not. Allergic reactions to pegaspargase occurred in 32% of previously hypersensitive patients and 10% of non-hypersensitive patients.

The most common adverse events observed in patients who received pegaspargase were clinical allergic reactions, elevated transaminases, hyperbilirubinemia, and coagulopathies.

The most common serious adverse events due to pegaspargase were thrombosis (4%), hyperglycemia requiring insulin therapy (3%), and pancreatitis (1%).

For more details on these trials and pegaspargase in general, see the product information.

Micrograph showing ALL

The European Commission has granted marketing authorization for pegaspargase (Oncaspar) to be used as part of combination antineoplastic therapy for pediatric and adult patients with acute lymphoblastic leukemia (ALL).

The approval means the drug can be marketed for this indication in the 28 member countries of the European Union (EU), as well as Iceland, Liechtenstein, and Norway.

Pegaspargase was already approved for use in Argentina, Belarus, Germany, Kazakhstan, Poland, Russia, Ukraine, and the US.

“Oncaspar has been used as an integral component of the treatment regimen for pediatric and adult patients with ALL for many years, in Europe and worldwide,” said Martin Schrappe, of Schleswig-Holstein University Hospital in Kiel, Germany.

“Today’s marketing authorization will ensure that more patients across the EU will benefit from access to Oncaspar as part of a standard of care regimen.”

The drug is being developed by Baxalta Incorporated.

First-line ALL

Researchers have evaluated the safety and effectiveness of pegaspargase in a study of 118 pediatric patients (ages 1 to 9) with newly diagnosed ALL. The patients were randomized 1:1 to pegaspargase or native E coli L-asparaginase, both as part of combination therapy.

Asparagine depletion (magnitude and duration) was similar between the 2 treatment arms. Event-free survival rates were also similar (about 80% in both arms), but the study was not designed to evaluate differences in event-free survival.

Grade 3/4 adverse events occurring in the pegaspargase and native E coli L-asparaginase arms, respectively, were abnormal liver tests (5% and 8%), elevated transaminases (3% and 7%), hyperbilirubinemia (2% and 2%), hyperglycemia (5% and 3%), central nervous system thrombosis (3% and 3%), coagulopathy (2% and 5%), pancreatitis (2% and 2%), and clinical allergic reactions to asparaginase (2% and 0%).

Previously treated ALL

Researchers have evaluated the effectiveness of pegaspargase in 4 open-label studies of patients with a history of prior clinical allergic reaction to asparaginase. The studies enrolled a total of 42 patients with multiply relapsed acute leukemia (39 with ALL).

Patients received pegaspargase as a single agent or as part of multi-agent chemotherapy. The re-induction response rate was 50%—36% complete responses and 14% partial responses. Three responses occurred in patients who received single-agent pegaspargase.

Adverse event information on pegaspargase in relapsed ALL has been compiled from 5 clinical trials. The studies enrolled a total of 174 patients with relapsed ALL who received pegaspargase as a single agent or as part of combination therapy.

Sixty-two of the patients had prior hypersensitivity reactions to asparaginase, and 112 did not. Allergic reactions to pegaspargase occurred in 32% of previously hypersensitive patients and 10% of non-hypersensitive patients.

The most common adverse events observed in patients who received pegaspargase were clinical allergic reactions, elevated transaminases, hyperbilirubinemia, and coagulopathies.

The most common serious adverse events due to pegaspargase were thrombosis (4%), hyperglycemia requiring insulin therapy (3%), and pancreatitis (1%).

For more details on these trials and pegaspargase in general, see the product information.

Ofatumumab has been approved for extended treatment of patients who are in complete or partial response after at least two lines of therapy for recurrent or progressive chronic lymphocytic leukemia (CLL), the U.S. Food and Drug Administration announced on Jan. 19.

Ofatumumab (Arzerra Injection, Novartis Pharmaceuticals) was previously approved for treatment-naive patients with CLL for whom fludarabine-based therapy was considered inappropriate and for patients with CLL refractory to fludarabine and alemtuzumab.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

Approval of the new indication was based on the results of a randomized, open-label trial that found improved progression-free survival with ofatumumab as compared with observation in patients whose disease had a complete or partial response after at least two lines of prior therapy, the FDA said in a press release.

In the study, 238 patients were randomized to ofatumumab and 236 to observation. Patients in the ofatumumab arm had received a range of two to five prior therapies. The median progression-free survival was significantly longer with ofatumumab at 29.4 months (95% confidence interval, 26.2-34.2) than with observation at 15.2 months (95% CI, 11.8-18.8).

Of patients treated with ofatumumab, 33% reported serious adverse reactions. The most common were pneumonia, pyrexia, and neutropenia (including febrile neutropenia).

The recommended dose and schedule for ofatumumab therapy is 300 mg by intravenous infusion on day 1 followed by 1,000 mg on day 8, and then 7 weeks later, and then every 8 weeks thereafter for up to a maximum of 2 years.

Full prescribing information is available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125326s062lbl.pdf.

mdales@frontlinemedcom.com

Ofatumumab has been approved for extended treatment of patients who are in complete or partial response after at least two lines of therapy for recurrent or progressive chronic lymphocytic leukemia (CLL), the U.S. Food and Drug Administration announced on Jan. 19.

Ofatumumab (Arzerra Injection, Novartis Pharmaceuticals) was previously approved for treatment-naive patients with CLL for whom fludarabine-based therapy was considered inappropriate and for patients with CLL refractory to fludarabine and alemtuzumab.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

Approval of the new indication was based on the results of a randomized, open-label trial that found improved progression-free survival with ofatumumab as compared with observation in patients whose disease had a complete or partial response after at least two lines of prior therapy, the FDA said in a press release.

In the study, 238 patients were randomized to ofatumumab and 236 to observation. Patients in the ofatumumab arm had received a range of two to five prior therapies. The median progression-free survival was significantly longer with ofatumumab at 29.4 months (95% confidence interval, 26.2-34.2) than with observation at 15.2 months (95% CI, 11.8-18.8).

Of patients treated with ofatumumab, 33% reported serious adverse reactions. The most common were pneumonia, pyrexia, and neutropenia (including febrile neutropenia).

The recommended dose and schedule for ofatumumab therapy is 300 mg by intravenous infusion on day 1 followed by 1,000 mg on day 8, and then 7 weeks later, and then every 8 weeks thereafter for up to a maximum of 2 years.

Full prescribing information is available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125326s062lbl.pdf.

mdales@frontlinemedcom.com

Ofatumumab has been approved for extended treatment of patients who are in complete or partial response after at least two lines of therapy for recurrent or progressive chronic lymphocytic leukemia (CLL), the U.S. Food and Drug Administration announced on Jan. 19.

Ofatumumab (Arzerra Injection, Novartis Pharmaceuticals) was previously approved for treatment-naive patients with CLL for whom fludarabine-based therapy was considered inappropriate and for patients with CLL refractory to fludarabine and alemtuzumab.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

Approval of the new indication was based on the results of a randomized, open-label trial that found improved progression-free survival with ofatumumab as compared with observation in patients whose disease had a complete or partial response after at least two lines of prior therapy, the FDA said in a press release.

In the study, 238 patients were randomized to ofatumumab and 236 to observation. Patients in the ofatumumab arm had received a range of two to five prior therapies. The median progression-free survival was significantly longer with ofatumumab at 29.4 months (95% confidence interval, 26.2-34.2) than with observation at 15.2 months (95% CI, 11.8-18.8).

Of patients treated with ofatumumab, 33% reported serious adverse reactions. The most common were pneumonia, pyrexia, and neutropenia (including febrile neutropenia).

The recommended dose and schedule for ofatumumab therapy is 300 mg by intravenous infusion on day 1 followed by 1,000 mg on day 8, and then 7 weeks later, and then every 8 weeks thereafter for up to a maximum of 2 years.

Full prescribing information is available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125326s062lbl.pdf.

mdales@frontlinemedcom.com

Doctor and patient
Photo courtesy of NIH

SAN FRANCISCO—A study of female cancer survivors indicates that many still have chemotherapy-induced peripheral neuropathy (CIPN) symptoms years after completing cancer treatment.

In addition, CIPN was associated with worse physical functioning, poorer mobility, and a higher risk of falls.

Although more research is needed, investigators believe these findings may inform rehabilitation and fall prevention interventions for people with CIPN.

The findings were presented at the 2016 Cancer Survivorship Symposium (abstract 130*).

“We can’t dismiss neuropathy as a treatment side effect that goes away because symptoms persist for years in nearly half of women,” said Kerri M. Winters-Stone, PhD, of Oregon Health and Science University in Portland.

“While there are no effective treatments for this side effect, rehabilitative exercise programs may preserve physical functioning and mobility in the presence of neuropathy to help prevent falls and resulting injuries.”

For this study, Dr Winters-Stone and her colleagues assessed data from 512 women enrolled in exercise intervention trials designed to address fractures and falls in female cancer survivors. Most of the women had breast cancer, but there were also cases of lung, colorectal, ovarian, and hematologic cancers.

At an average of 6 years post-cancer diagnosis, 46% of the women (n=238) still reported some symptoms of CIPN, such as loss of feeling in their hands and feet.

The investigators noted significant relationships (P<0.01) between CIPN severity and gait speed, Physical Performance Battery score, self-reported physical functioning, and self-reported disability.

The team also compared measures of physical functioning in the women with CIPN to measures in women without CIPN (n=274). This analysis was adjusted for cancer type and time since diagnosis.

There was a significant difference (P<0.01) between the groups in one measure of lower-extremity fitness but not another. Namely, it took CIPN-positive women significantly longer to rise out of a chair (tested 5 times each). But women in both groups fared similarly on a test measuring maximal leg press strength.

The investigators also tested the women on mobility and physical functioning. The CIPN-positive women fared significantly worse than CIPN-negative women (P<0.01) when it came to walking speed, step number, stride length, percentage of gait cycle in double support, and Physical Performance Battery score. However, there was no significant difference between the groups with regard to base of support.

Finally, CIPN-positive women were significantly more likely than CIPN-negative women to report poor physical function and disability (P<0.01 for both). And CIPN-positive women had a higher rate of falls in the last year (P<0.01).

The investigators said women with CIPN have specific underlying impairments that put them at risk for falls, which may be different from the impairments that occur with other conditions or old age.

For example, CIPN does not cause muscle weakness, but it has a distinct effect on movement and gait patterns.

The team noted that the women with CIPN had difficulty rising from a chair, possibly because their brains do not get enough information from their feet about how quickly or forcefully to stand up.

Based on these findings, the investigators argued that commonly recommended exercise, such as walking, may be safer for women with CIPN when done on a treadmill with handrails because their altered gait puts them at an increased risk of falling.

The team also said that machine-based resistance training may not be beneficial because neuropathy does not appear to decrease leg strength. Instead, rehabilitation efforts should focus on improving balance during upright movement and specific gait training.

Furthermore, the investigators believe that, if the symptoms of CIPN are detected early, cancer treatments could potentially be changed to prevent these debilitating problems or early rehabilitation interventions could be started.

In addition, Dr Winters-Stone and her research team are developing a smartphone-driven device that patients can use to detect and quantify symptoms of neuropathy, such as gait and balance impairments.

*Data in the abstract differ from the presentation.

Doctor and patient
Photo courtesy of NIH

SAN FRANCISCO—A study of female cancer survivors indicates that many still have chemotherapy-induced peripheral neuropathy (CIPN) symptoms years after completing cancer treatment.

In addition, CIPN was associated with worse physical functioning, poorer mobility, and a higher risk of falls.

Although more research is needed, investigators believe these findings may inform rehabilitation and fall prevention interventions for people with CIPN.

The findings were presented at the 2016 Cancer Survivorship Symposium (abstract 130*).

“We can’t dismiss neuropathy as a treatment side effect that goes away because symptoms persist for years in nearly half of women,” said Kerri M. Winters-Stone, PhD, of Oregon Health and Science University in Portland.

“While there are no effective treatments for this side effect, rehabilitative exercise programs may preserve physical functioning and mobility in the presence of neuropathy to help prevent falls and resulting injuries.”

For this study, Dr Winters-Stone and her colleagues assessed data from 512 women enrolled in exercise intervention trials designed to address fractures and falls in female cancer survivors. Most of the women had breast cancer, but there were also cases of lung, colorectal, ovarian, and hematologic cancers.

At an average of 6 years post-cancer diagnosis, 46% of the women (n=238) still reported some symptoms of CIPN, such as loss of feeling in their hands and feet.

The investigators noted significant relationships (P<0.01) between CIPN severity and gait speed, Physical Performance Battery score, self-reported physical functioning, and self-reported disability.

The team also compared measures of physical functioning in the women with CIPN to measures in women without CIPN (n=274). This analysis was adjusted for cancer type and time since diagnosis.

There was a significant difference (P<0.01) between the groups in one measure of lower-extremity fitness but not another. Namely, it took CIPN-positive women significantly longer to rise out of a chair (tested 5 times each). But women in both groups fared similarly on a test measuring maximal leg press strength.

The investigators also tested the women on mobility and physical functioning. The CIPN-positive women fared significantly worse than CIPN-negative women (P<0.01) when it came to walking speed, step number, stride length, percentage of gait cycle in double support, and Physical Performance Battery score. However, there was no significant difference between the groups with regard to base of support.

Finally, CIPN-positive women were significantly more likely than CIPN-negative women to report poor physical function and disability (P<0.01 for both). And CIPN-positive women had a higher rate of falls in the last year (P<0.01).

The investigators said women with CIPN have specific underlying impairments that put them at risk for falls, which may be different from the impairments that occur with other conditions or old age.

For example, CIPN does not cause muscle weakness, but it has a distinct effect on movement and gait patterns.

The team noted that the women with CIPN had difficulty rising from a chair, possibly because their brains do not get enough information from their feet about how quickly or forcefully to stand up.

Based on these findings, the investigators argued that commonly recommended exercise, such as walking, may be safer for women with CIPN when done on a treadmill with handrails because their altered gait puts them at an increased risk of falling.

The team also said that machine-based resistance training may not be beneficial because neuropathy does not appear to decrease leg strength. Instead, rehabilitation efforts should focus on improving balance during upright movement and specific gait training.

Furthermore, the investigators believe that, if the symptoms of CIPN are detected early, cancer treatments could potentially be changed to prevent these debilitating problems or early rehabilitation interventions could be started.

In addition, Dr Winters-Stone and her research team are developing a smartphone-driven device that patients can use to detect and quantify symptoms of neuropathy, such as gait and balance impairments.

*Data in the abstract differ from the presentation.

Doctor and patient
Photo courtesy of NIH

SAN FRANCISCO—A study of female cancer survivors indicates that many still have chemotherapy-induced peripheral neuropathy (CIPN) symptoms years after completing cancer treatment.

In addition, CIPN was associated with worse physical functioning, poorer mobility, and a higher risk of falls.

Although more research is needed, investigators believe these findings may inform rehabilitation and fall prevention interventions for people with CIPN.

The findings were presented at the 2016 Cancer Survivorship Symposium (abstract 130*).

“We can’t dismiss neuropathy as a treatment side effect that goes away because symptoms persist for years in nearly half of women,” said Kerri M. Winters-Stone, PhD, of Oregon Health and Science University in Portland.

“While there are no effective treatments for this side effect, rehabilitative exercise programs may preserve physical functioning and mobility in the presence of neuropathy to help prevent falls and resulting injuries.”

For this study, Dr Winters-Stone and her colleagues assessed data from 512 women enrolled in exercise intervention trials designed to address fractures and falls in female cancer survivors. Most of the women had breast cancer, but there were also cases of lung, colorectal, ovarian, and hematologic cancers.

At an average of 6 years post-cancer diagnosis, 46% of the women (n=238) still reported some symptoms of CIPN, such as loss of feeling in their hands and feet.

The investigators noted significant relationships (P<0.01) between CIPN severity and gait speed, Physical Performance Battery score, self-reported physical functioning, and self-reported disability.

The team also compared measures of physical functioning in the women with CIPN to measures in women without CIPN (n=274). This analysis was adjusted for cancer type and time since diagnosis.

There was a significant difference (P<0.01) between the groups in one measure of lower-extremity fitness but not another. Namely, it took CIPN-positive women significantly longer to rise out of a chair (tested 5 times each). But women in both groups fared similarly on a test measuring maximal leg press strength.

The investigators also tested the women on mobility and physical functioning. The CIPN-positive women fared significantly worse than CIPN-negative women (P<0.01) when it came to walking speed, step number, stride length, percentage of gait cycle in double support, and Physical Performance Battery score. However, there was no significant difference between the groups with regard to base of support.

Finally, CIPN-positive women were significantly more likely than CIPN-negative women to report poor physical function and disability (P<0.01 for both). And CIPN-positive women had a higher rate of falls in the last year (P<0.01).

The investigators said women with CIPN have specific underlying impairments that put them at risk for falls, which may be different from the impairments that occur with other conditions or old age.

For example, CIPN does not cause muscle weakness, but it has a distinct effect on movement and gait patterns.

The team noted that the women with CIPN had difficulty rising from a chair, possibly because their brains do not get enough information from their feet about how quickly or forcefully to stand up.

Based on these findings, the investigators argued that commonly recommended exercise, such as walking, may be safer for women with CIPN when done on a treadmill with handrails because their altered gait puts them at an increased risk of falling.

The team also said that machine-based resistance training may not be beneficial because neuropathy does not appear to decrease leg strength. Instead, rehabilitation efforts should focus on improving balance during upright movement and specific gait training.

Furthermore, the investigators believe that, if the symptoms of CIPN are detected early, cancer treatments could potentially be changed to prevent these debilitating problems or early rehabilitation interventions could be started.

In addition, Dr Winters-Stone and her research team are developing a smartphone-driven device that patients can use to detect and quantify symptoms of neuropathy, such as gait and balance impairments.

*Data in the abstract differ from the presentation.

Child with cancer

Photo by Bill Branson

Results of a large study suggest that long-term survivors of childhood cancer are living longer, partly due to a reduction in the use of certain treatments.

The 15-year death rate among the more than 34,000 childhood cancer survivors studied decreased steadily from 1970 onward.

And this decline coincided with changes in pediatric cancer therapy, including reductions in the use and dose of radiation therapy and anthracyclines.

These therapies are known to put cancer survivors at increased risk for developing second malignancies, heart failure, and other serious health problems.

“This study is the first to show that younger survivors from more recent treatment eras are less likely to die from the late effects of cancer treatment and more likely to enjoy longer lives,” said study author Greg Armstrong, MD, of St. Jude Children's Research Hospital in Memphis, Tennessee.

He and his colleagues reported these results in NEJM.

The study included 34,033 subjects who had been diagnosed with cancer and received treatment between 1970 and 1999 when they were age 20 or younger. All patients lived at least 5 years after their cancers were discovered and were considered long-term survivors.

Changes in mortality

At a median follow-up of 21 years (range, 5 to 38), there were 3958 deaths. Forty-one percent of deaths (n=1618) were considered health-related. This included 746 deaths from subsequent neoplasms, 241 from cardiac causes, 137 from pulmonary causes, and 494 from other causes.

The 15-year death rate (death from any cause) fell from 12.4% in the early 1970s to 6% in the 1990s (P<0.001). During the same period, the rate of death from health-related causes fell from 3.5% to 2.1% (P<0.001).

The researchers said there were significant reductions across treatment eras in the rates of death from any health-related cause among patients with acute lymphoblastic leukemia (ALL), Hodgkin lymphoma (HL), Wilms’ tumor, and astrocytoma, but not among patients with other cancers.

The rate of health-related death among ALL patients fell from 3.2% in the early 1970s to 2.1% in the 1990s (P<0.001). The rate fell from 5.3% to 2.6% (P=0.006) for HL patients, from 2.6% to 0.4% (P=0.005) for Wilms’ tumor patients, and from 4.7% to 1.8% (P=0.02) for astrocytoma patients.

The researchers said these reductions in mortality were attributable to decreases in the rates of death from subsequent neoplasm (P<0.001), cardiac causes (P<0.001), and pulmonary causes (P=0.04).

Treatment changes

The overall use of anthracyclines fell from 73% in the 1970s to 42% in the 1990s. And the use of any radiation decreased from 77% to 41%.

The use of cranial radiotherapy for ALL fell from 85% to 19%. The use of abdominal radiotherapy for Wilms’ tumor decreased from 78% to 43%. And the use of chest radiotherapy for HL fell from 87% to 61%.

The researchers noted that temporal reductions in 15-year rates of death from health-related causes followed temporal reductions in therapeutic exposure for patients with ALL, HL, Wilms’ tumor, and astrocytoma.

However, when the team adjusted their analysis for therapy (eg, anthracycline dose), the effect of the treatment era on the relative rate of death from health-related causes was attenuated in ALL (unadjusted relative rate=0.88, adjusted relative rate=1.02) and Wilms’ tumor (0.68 and 0.80, respectively) but not in HL (0.79 in both models) and astrocytoma (0.81 and 0.82, respectively).

Still, the researchers said the results of this study suggest the strategy of lowering therapeutic exposure has contributed to the decline in late mortality among 5-year survivors of childhood cancer.

Child with cancer

Photo by Bill Branson

Results of a large study suggest that long-term survivors of childhood cancer are living longer, partly due to a reduction in the use of certain treatments.

The 15-year death rate among the more than 34,000 childhood cancer survivors studied decreased steadily from 1970 onward.

And this decline coincided with changes in pediatric cancer therapy, including reductions in the use and dose of radiation therapy and anthracyclines.

These therapies are known to put cancer survivors at increased risk for developing second malignancies, heart failure, and other serious health problems.

“This study is the first to show that younger survivors from more recent treatment eras are less likely to die from the late effects of cancer treatment and more likely to enjoy longer lives,” said study author Greg Armstrong, MD, of St. Jude Children's Research Hospital in Memphis, Tennessee.

He and his colleagues reported these results in NEJM.

The study included 34,033 subjects who had been diagnosed with cancer and received treatment between 1970 and 1999 when they were age 20 or younger. All patients lived at least 5 years after their cancers were discovered and were considered long-term survivors.

Changes in mortality

At a median follow-up of 21 years (range, 5 to 38), there were 3958 deaths. Forty-one percent of deaths (n=1618) were considered health-related. This included 746 deaths from subsequent neoplasms, 241 from cardiac causes, 137 from pulmonary causes, and 494 from other causes.

The 15-year death rate (death from any cause) fell from 12.4% in the early 1970s to 6% in the 1990s (P<0.001). During the same period, the rate of death from health-related causes fell from 3.5% to 2.1% (P<0.001).

The researchers said there were significant reductions across treatment eras in the rates of death from any health-related cause among patients with acute lymphoblastic leukemia (ALL), Hodgkin lymphoma (HL), Wilms’ tumor, and astrocytoma, but not among patients with other cancers.

The rate of health-related death among ALL patients fell from 3.2% in the early 1970s to 2.1% in the 1990s (P<0.001). The rate fell from 5.3% to 2.6% (P=0.006) for HL patients, from 2.6% to 0.4% (P=0.005) for Wilms’ tumor patients, and from 4.7% to 1.8% (P=0.02) for astrocytoma patients.

The researchers said these reductions in mortality were attributable to decreases in the rates of death from subsequent neoplasm (P<0.001), cardiac causes (P<0.001), and pulmonary causes (P=0.04).

Treatment changes

The overall use of anthracyclines fell from 73% in the 1970s to 42% in the 1990s. And the use of any radiation decreased from 77% to 41%.

The use of cranial radiotherapy for ALL fell from 85% to 19%. The use of abdominal radiotherapy for Wilms’ tumor decreased from 78% to 43%. And the use of chest radiotherapy for HL fell from 87% to 61%.

The researchers noted that temporal reductions in 15-year rates of death from health-related causes followed temporal reductions in therapeutic exposure for patients with ALL, HL, Wilms’ tumor, and astrocytoma.

However, when the team adjusted their analysis for therapy (eg, anthracycline dose), the effect of the treatment era on the relative rate of death from health-related causes was attenuated in ALL (unadjusted relative rate=0.88, adjusted relative rate=1.02) and Wilms’ tumor (0.68 and 0.80, respectively) but not in HL (0.79 in both models) and astrocytoma (0.81 and 0.82, respectively).

Still, the researchers said the results of this study suggest the strategy of lowering therapeutic exposure has contributed to the decline in late mortality among 5-year survivors of childhood cancer.

Child with cancer

Photo by Bill Branson

Results of a large study suggest that long-term survivors of childhood cancer are living longer, partly due to a reduction in the use of certain treatments.

The 15-year death rate among the more than 34,000 childhood cancer survivors studied decreased steadily from 1970 onward.

And this decline coincided with changes in pediatric cancer therapy, including reductions in the use and dose of radiation therapy and anthracyclines.

These therapies are known to put cancer survivors at increased risk for developing second malignancies, heart failure, and other serious health problems.

“This study is the first to show that younger survivors from more recent treatment eras are less likely to die from the late effects of cancer treatment and more likely to enjoy longer lives,” said study author Greg Armstrong, MD, of St. Jude Children's Research Hospital in Memphis, Tennessee.

He and his colleagues reported these results in NEJM.

The study included 34,033 subjects who had been diagnosed with cancer and received treatment between 1970 and 1999 when they were age 20 or younger. All patients lived at least 5 years after their cancers were discovered and were considered long-term survivors.

Changes in mortality

At a median follow-up of 21 years (range, 5 to 38), there were 3958 deaths. Forty-one percent of deaths (n=1618) were considered health-related. This included 746 deaths from subsequent neoplasms, 241 from cardiac causes, 137 from pulmonary causes, and 494 from other causes.

The 15-year death rate (death from any cause) fell from 12.4% in the early 1970s to 6% in the 1990s (P<0.001). During the same period, the rate of death from health-related causes fell from 3.5% to 2.1% (P<0.001).

The researchers said there were significant reductions across treatment eras in the rates of death from any health-related cause among patients with acute lymphoblastic leukemia (ALL), Hodgkin lymphoma (HL), Wilms’ tumor, and astrocytoma, but not among patients with other cancers.

The rate of health-related death among ALL patients fell from 3.2% in the early 1970s to 2.1% in the 1990s (P<0.001). The rate fell from 5.3% to 2.6% (P=0.006) for HL patients, from 2.6% to 0.4% (P=0.005) for Wilms’ tumor patients, and from 4.7% to 1.8% (P=0.02) for astrocytoma patients.

The researchers said these reductions in mortality were attributable to decreases in the rates of death from subsequent neoplasm (P<0.001), cardiac causes (P<0.001), and pulmonary causes (P=0.04).

Treatment changes

The overall use of anthracyclines fell from 73% in the 1970s to 42% in the 1990s. And the use of any radiation decreased from 77% to 41%.

The use of cranial radiotherapy for ALL fell from 85% to 19%. The use of abdominal radiotherapy for Wilms’ tumor decreased from 78% to 43%. And the use of chest radiotherapy for HL fell from 87% to 61%.

The researchers noted that temporal reductions in 15-year rates of death from health-related causes followed temporal reductions in therapeutic exposure for patients with ALL, HL, Wilms’ tumor, and astrocytoma.

However, when the team adjusted their analysis for therapy (eg, anthracycline dose), the effect of the treatment era on the relative rate of death from health-related causes was attenuated in ALL (unadjusted relative rate=0.88, adjusted relative rate=1.02) and Wilms’ tumor (0.68 and 0.80, respectively) but not in HL (0.79 in both models) and astrocytoma (0.81 and 0.82, respectively).

Still, the researchers said the results of this study suggest the strategy of lowering therapeutic exposure has contributed to the decline in late mortality among 5-year survivors of childhood cancer.

Mick Bhatia, PhD

Photo courtesy of

McMaster University

Research published in Cancer Cell suggests a molecular signature can be used to predict which patients with myelodysplastic syndromes (MDS) will develop acute myeloid leukemia (AML).

Investigators found that progressive removal of glycogen synthase kinase-3 (GSK-3) signaling via GSK-3β deletion in hematopoietic stem cells (HSCs) results in an MDS-like state.

And when both GSK-3β and GSK-3α are deleted, AML develops.

“We’ve found that the transition from healthy to cancerous blood stem cells happens in clear, compartmentalized steps,” said study author Mick Bhatia, PhD, of McMaster University in Hamilton, Ontario, Canada. “We’ve identified 2 steps in that staircase.”

Specifically, the investigators found that deleting GSK-3β in HSCs led to the generation of self-renewing cells dubbed MDS-initiating cells. These cells proved capable of sustaining MDS in vivo.

Next, the team found that GSK-3β deletion drives Wnt/Akt/mTOR signaling and can induce AML in the absence of GSK-3α.

They noted that GSK-3α has no biological impact on hematopoiesis, but GSK-3α deletion is necessary for the evolution of MDS to AML that occurs in the absence of GSK-3β.

The investigators then defined a molecular signature of GSK-3β-deficient HSCs that could predict transformation to AML in patients with MDS.

The team tested the utility of this 63-gene signature using blood samples that were previously collected from patients with MDS, some of whom ultimately developed AML. The results showed the signature could accurately predict which patients would develop AML and which would not.

“[O]ur next step is to go beyond better predictive measures for the development of a blood cancer and use this predictive gene expression as a target for drugs to prevent AML from developing altogether,” Dr Bhatia said. “This will be part of a new era of genetic-based drug discovery.”

Mick Bhatia, PhD

Photo courtesy of

McMaster University

Research published in Cancer Cell suggests a molecular signature can be used to predict which patients with myelodysplastic syndromes (MDS) will develop acute myeloid leukemia (AML).

Investigators found that progressive removal of glycogen synthase kinase-3 (GSK-3) signaling via GSK-3β deletion in hematopoietic stem cells (HSCs) results in an MDS-like state.

And when both GSK-3β and GSK-3α are deleted, AML develops.

“We’ve found that the transition from healthy to cancerous blood stem cells happens in clear, compartmentalized steps,” said study author Mick Bhatia, PhD, of McMaster University in Hamilton, Ontario, Canada. “We’ve identified 2 steps in that staircase.”

Specifically, the investigators found that deleting GSK-3β in HSCs led to the generation of self-renewing cells dubbed MDS-initiating cells. These cells proved capable of sustaining MDS in vivo.

Next, the team found that GSK-3β deletion drives Wnt/Akt/mTOR signaling and can induce AML in the absence of GSK-3α.

They noted that GSK-3α has no biological impact on hematopoiesis, but GSK-3α deletion is necessary for the evolution of MDS to AML that occurs in the absence of GSK-3β.

The investigators then defined a molecular signature of GSK-3β-deficient HSCs that could predict transformation to AML in patients with MDS.

The team tested the utility of this 63-gene signature using blood samples that were previously collected from patients with MDS, some of whom ultimately developed AML. The results showed the signature could accurately predict which patients would develop AML and which would not.

“[O]ur next step is to go beyond better predictive measures for the development of a blood cancer and use this predictive gene expression as a target for drugs to prevent AML from developing altogether,” Dr Bhatia said. “This will be part of a new era of genetic-based drug discovery.”

Mick Bhatia, PhD

Photo courtesy of

McMaster University

Research published in Cancer Cell suggests a molecular signature can be used to predict which patients with myelodysplastic syndromes (MDS) will develop acute myeloid leukemia (AML).

Investigators found that progressive removal of glycogen synthase kinase-3 (GSK-3) signaling via GSK-3β deletion in hematopoietic stem cells (HSCs) results in an MDS-like state.

And when both GSK-3β and GSK-3α are deleted, AML develops.

“We’ve found that the transition from healthy to cancerous blood stem cells happens in clear, compartmentalized steps,” said study author Mick Bhatia, PhD, of McMaster University in Hamilton, Ontario, Canada. “We’ve identified 2 steps in that staircase.”

Specifically, the investigators found that deleting GSK-3β in HSCs led to the generation of self-renewing cells dubbed MDS-initiating cells. These cells proved capable of sustaining MDS in vivo.

Next, the team found that GSK-3β deletion drives Wnt/Akt/mTOR signaling and can induce AML in the absence of GSK-3α.

They noted that GSK-3α has no biological impact on hematopoiesis, but GSK-3α deletion is necessary for the evolution of MDS to AML that occurs in the absence of GSK-3β.

The investigators then defined a molecular signature of GSK-3β-deficient HSCs that could predict transformation to AML in patients with MDS.

The team tested the utility of this 63-gene signature using blood samples that were previously collected from patients with MDS, some of whom ultimately developed AML. The results showed the signature could accurately predict which patients would develop AML and which would not.

“[O]ur next step is to go beyond better predictive measures for the development of a blood cancer and use this predictive gene expression as a target for drugs to prevent AML from developing altogether,” Dr Bhatia said. “This will be part of a new era of genetic-based drug discovery.”

ORLANDO – Venetoclax monotherapy achieved an overall response rate of 79% in a high-risk population of 107 patients with relapsed or refractory del(17p) chronic lymphocytic leukemia, Dr. Stephan Stilgenbauer reported in a late-breaking abstract at the annual meeting of the American Society of Hematology.

Of the 85 responders, the response was maintained at 1 year in 85%. Of the 45 patients assessed for minimal residual disease in the blood, 18 achieved MRD negativity. Ten of these 18 patients also had bone marrow assessments and six were MRD negative.

Dr. Stilgenbauer of the University of Ulm (Germany), discussed the implications of the phase II study findings in our exclusive interview at ASH, as well as phase III study plans and the use of venetoclax in combination therapies.

He receives honoraria or research funding from a wide range of companies, including AbbVie and Genentech, the companies collaborating on the development of venetoclax.

mdales@frontlinemedcom.com

On Twitter @maryjodales

ORLANDO – Venetoclax monotherapy achieved an overall response rate of 79% in a high-risk population of 107 patients with relapsed or refractory del(17p) chronic lymphocytic leukemia, Dr. Stephan Stilgenbauer reported in a late-breaking abstract at the annual meeting of the American Society of Hematology.

Of the 85 responders, the response was maintained at 1 year in 85%. Of the 45 patients assessed for minimal residual disease in the blood, 18 achieved MRD negativity. Ten of these 18 patients also had bone marrow assessments and six were MRD negative.

Dr. Stilgenbauer of the University of Ulm (Germany), discussed the implications of the phase II study findings in our exclusive interview at ASH, as well as phase III study plans and the use of venetoclax in combination therapies.

He receives honoraria or research funding from a wide range of companies, including AbbVie and Genentech, the companies collaborating on the development of venetoclax.

mdales@frontlinemedcom.com

On Twitter @maryjodales

ORLANDO – Venetoclax monotherapy achieved an overall response rate of 79% in a high-risk population of 107 patients with relapsed or refractory del(17p) chronic lymphocytic leukemia, Dr. Stephan Stilgenbauer reported in a late-breaking abstract at the annual meeting of the American Society of Hematology.

Of the 85 responders, the response was maintained at 1 year in 85%. Of the 45 patients assessed for minimal residual disease in the blood, 18 achieved MRD negativity. Ten of these 18 patients also had bone marrow assessments and six were MRD negative.

Dr. Stilgenbauer of the University of Ulm (Germany), discussed the implications of the phase II study findings in our exclusive interview at ASH, as well as phase III study plans and the use of venetoclax in combination therapies.

He receives honoraria or research funding from a wide range of companies, including AbbVie and Genentech, the companies collaborating on the development of venetoclax.

mdales@frontlinemedcom.com

On Twitter @maryjodales

Ibrutinib may prove useful for patients whose chronic lymphocytic leukemia (CLL) relapses after allogeneic stem cell transplantation, Dr. C. S. Link and colleagues reported.

Ibrutinib has shown efficacy in patients with high-risk CLL, but there are few data from patients who relapsed after allogeneic stem cell transplantation, wrote Dr. Link of the Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus and the DFG Research Center for Regenerative Therapies, both at the Technische Universität Dresden (Germany).

The researchers performed analyses on cytokine levels and direct measuring of CD4 Th1 and CD4 Th2 cells in a study of five CLL patients treated with ibrutinib for relapse after allogeneic transplants. All patients had partial responses to ibrutinib and one had a minimal residual disease–negative remission.

At 1 year, none of the patients had relapsed; however, one patient died of pneumonia while on ibrutinib treatment. No other unexpected adverse events were observed, the researchers reported in the study, which was published online on Jan. 11.

No substantial changes in T-cell distribution in favor of a CD4 Th1 T-cell shift were noted based on flow cytometry and analyses of T cell–mediated cytokine levels. No acute exacerbations of graft-versus-host disease occurred.

Click here to read the study (Bone Marrow Transplant. 2016 Jan 11. doi: 10.1038/bmt.2015.339).

mdales@frontlinemedcom.com

On Twitter @maryjodales

Ibrutinib may prove useful for patients whose chronic lymphocytic leukemia (CLL) relapses after allogeneic stem cell transplantation, Dr. C. S. Link and colleagues reported.

Ibrutinib has shown efficacy in patients with high-risk CLL, but there are few data from patients who relapsed after allogeneic stem cell transplantation, wrote Dr. Link of the Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus and the DFG Research Center for Regenerative Therapies, both at the Technische Universität Dresden (Germany).

The researchers performed analyses on cytokine levels and direct measuring of CD4 Th1 and CD4 Th2 cells in a study of five CLL patients treated with ibrutinib for relapse after allogeneic transplants. All patients had partial responses to ibrutinib and one had a minimal residual disease–negative remission.

At 1 year, none of the patients had relapsed; however, one patient died of pneumonia while on ibrutinib treatment. No other unexpected adverse events were observed, the researchers reported in the study, which was published online on Jan. 11.

No substantial changes in T-cell distribution in favor of a CD4 Th1 T-cell shift were noted based on flow cytometry and analyses of T cell–mediated cytokine levels. No acute exacerbations of graft-versus-host disease occurred.

Click here to read the study (Bone Marrow Transplant. 2016 Jan 11. doi: 10.1038/bmt.2015.339).

mdales@frontlinemedcom.com

On Twitter @maryjodales

Ibrutinib may prove useful for patients whose chronic lymphocytic leukemia (CLL) relapses after allogeneic stem cell transplantation, Dr. C. S. Link and colleagues reported.

Ibrutinib has shown efficacy in patients with high-risk CLL, but there are few data from patients who relapsed after allogeneic stem cell transplantation, wrote Dr. Link of the Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus and the DFG Research Center for Regenerative Therapies, both at the Technische Universität Dresden (Germany).

The researchers performed analyses on cytokine levels and direct measuring of CD4 Th1 and CD4 Th2 cells in a study of five CLL patients treated with ibrutinib for relapse after allogeneic transplants. All patients had partial responses to ibrutinib and one had a minimal residual disease–negative remission.

At 1 year, none of the patients had relapsed; however, one patient died of pneumonia while on ibrutinib treatment. No other unexpected adverse events were observed, the researchers reported in the study, which was published online on Jan. 11.

No substantial changes in T-cell distribution in favor of a CD4 Th1 T-cell shift were noted based on flow cytometry and analyses of T cell–mediated cytokine levels. No acute exacerbations of graft-versus-host disease occurred.

Click here to read the study (Bone Marrow Transplant. 2016 Jan 11. doi: 10.1038/bmt.2015.339).

mdales@frontlinemedcom.com

On Twitter @maryjodales

Micrograph showing CLL

Image by Mary Ann Thompson

Despite previous safety concerns, the US Food and Drug Administration (FDA) has granted priority review for the BCL-2 inhibitor venetoclax.

The FDA is reviewing the drug as a potential treatment for patients with chronic lymphocytic leukemia (CLL), including those with 17p deletion, who have received at least 1 prior therapy.

A priority review designation is granted to drugs thought to have the potential to provide significant improvements in the treatment, prevention, or diagnosis of a disease.

The designation means the FDA’s goal is to take action on a drug application within 6 months, compared to 10 months under standard review.

Venetoclax has proven active against CLL and other hematologic malignancies, but it is known to induce tumor lysis syndrome (TLS). In fact, TLS-related deaths temporarily halted enrollment in trials of venetoclax. But researchers discovered ways to reduce the risk of TLS, and the trials continued.

Venetoclax received breakthrough therapy designation from the FDA last year for the treatment of patients with relapsed or refractory CLL and 17p deletion. This designation is designed to expedite the development and review of medicines intended to treat serious or life-threatening diseases.

The new drug application for venetoclax is based, in part, on data from the phase 2 M13-982 study, which were just presented at the 2015 ASH Annual Meeting.

Phase 2 trial

M13-982 is an open-label, single-arm, multicenter study in which researchers are evaluating the efficacy and safety of venetoclax in patients with relapsed, refractory, or previously untreated CLL with 17p deletion.

The study included 107 patients with relapsed or refractory disease, and all but 1 had 17p deletion. An additional 50 patients with relapsed, refractory, or previously untreated disease have been enrolled in the safety expansion cohort.

The primary endpoint of the study is overall response rate as determined by an independent review committee, and secondary endpoints include complete response, partial response, duration of response, progression-free survival, and overall survival. The level of minimal residual disease (MRD) in peripheral blood and/or bone marrow was assessed in a subset of patients.

The study met its primary endpoint, with an overall response rate of 79.4% among the 107 patients with relapsed or refractory disease. In addition, 7.5% of patients achieved a complete response, with or without complete recovery of blood counts in the bone marrow.

Forty-five patients had an assessment for MRD in the blood. Of these, 18 patients achieved MRD-negativity. Ten of these 18 patients also had bone marrow assessments, and 6 were MRD-negative.

At 1 year, 84.7% of all responses and 94.4% of MRD-negative responses were maintained. The 1-year progression-free survival and overall survival rates were 72% and 86.7%, respectively.

The most common serious adverse events were pyrexia (7%), autoimmune hemolytic anemia (7%), pneumonia (6%), and febrile neutropenia (5%). The most common grade 3-4 adverse events were neutropenia (40%), infection (20%), anemia (18%), and thrombocytopenia (15%).

Laboratory TLS was reported in 5 patients. None had clinical consequences.

Venetoclax is under development by AbbVie and Genentech/Roche.

Micrograph showing CLL

Image by Mary Ann Thompson

Despite previous safety concerns, the US Food and Drug Administration (FDA) has granted priority review for the BCL-2 inhibitor venetoclax.

The FDA is reviewing the drug as a potential treatment for patients with chronic lymphocytic leukemia (CLL), including those with 17p deletion, who have received at least 1 prior therapy.

A priority review designation is granted to drugs thought to have the potential to provide significant improvements in the treatment, prevention, or diagnosis of a disease.

The designation means the FDA’s goal is to take action on a drug application within 6 months, compared to 10 months under standard review.

Venetoclax has proven active against CLL and other hematologic malignancies, but it is known to induce tumor lysis syndrome (TLS). In fact, TLS-related deaths temporarily halted enrollment in trials of venetoclax. But researchers discovered ways to reduce the risk of TLS, and the trials continued.

Venetoclax received breakthrough therapy designation from the FDA last year for the treatment of patients with relapsed or refractory CLL and 17p deletion. This designation is designed to expedite the development and review of medicines intended to treat serious or life-threatening diseases.

The new drug application for venetoclax is based, in part, on data from the phase 2 M13-982 study, which were just presented at the 2015 ASH Annual Meeting.

Phase 2 trial

M13-982 is an open-label, single-arm, multicenter study in which researchers are evaluating the efficacy and safety of venetoclax in patients with relapsed, refractory, or previously untreated CLL with 17p deletion.

The study included 107 patients with relapsed or refractory disease, and all but 1 had 17p deletion. An additional 50 patients with relapsed, refractory, or previously untreated disease have been enrolled in the safety expansion cohort.

The primary endpoint of the study is overall response rate as determined by an independent review committee, and secondary endpoints include complete response, partial response, duration of response, progression-free survival, and overall survival. The level of minimal residual disease (MRD) in peripheral blood and/or bone marrow was assessed in a subset of patients.

The study met its primary endpoint, with an overall response rate of 79.4% among the 107 patients with relapsed or refractory disease. In addition, 7.5% of patients achieved a complete response, with or without complete recovery of blood counts in the bone marrow.

Forty-five patients had an assessment for MRD in the blood. Of these, 18 patients achieved MRD-negativity. Ten of these 18 patients also had bone marrow assessments, and 6 were MRD-negative.

At 1 year, 84.7% of all responses and 94.4% of MRD-negative responses were maintained. The 1-year progression-free survival and overall survival rates were 72% and 86.7%, respectively.

The most common serious adverse events were pyrexia (7%), autoimmune hemolytic anemia (7%), pneumonia (6%), and febrile neutropenia (5%). The most common grade 3-4 adverse events were neutropenia (40%), infection (20%), anemia (18%), and thrombocytopenia (15%).

Laboratory TLS was reported in 5 patients. None had clinical consequences.

Venetoclax is under development by AbbVie and Genentech/Roche.

Micrograph showing CLL

Image by Mary Ann Thompson

Despite previous safety concerns, the US Food and Drug Administration (FDA) has granted priority review for the BCL-2 inhibitor venetoclax.

The FDA is reviewing the drug as a potential treatment for patients with chronic lymphocytic leukemia (CLL), including those with 17p deletion, who have received at least 1 prior therapy.

A priority review designation is granted to drugs thought to have the potential to provide significant improvements in the treatment, prevention, or diagnosis of a disease.

The designation means the FDA’s goal is to take action on a drug application within 6 months, compared to 10 months under standard review.

Venetoclax has proven active against CLL and other hematologic malignancies, but it is known to induce tumor lysis syndrome (TLS). In fact, TLS-related deaths temporarily halted enrollment in trials of venetoclax. But researchers discovered ways to reduce the risk of TLS, and the trials continued.

Venetoclax received breakthrough therapy designation from the FDA last year for the treatment of patients with relapsed or refractory CLL and 17p deletion. This designation is designed to expedite the development and review of medicines intended to treat serious or life-threatening diseases.

The new drug application for venetoclax is based, in part, on data from the phase 2 M13-982 study, which were just presented at the 2015 ASH Annual Meeting.

Phase 2 trial

M13-982 is an open-label, single-arm, multicenter study in which researchers are evaluating the efficacy and safety of venetoclax in patients with relapsed, refractory, or previously untreated CLL with 17p deletion.

The study included 107 patients with relapsed or refractory disease, and all but 1 had 17p deletion. An additional 50 patients with relapsed, refractory, or previously untreated disease have been enrolled in the safety expansion cohort.

The primary endpoint of the study is overall response rate as determined by an independent review committee, and secondary endpoints include complete response, partial response, duration of response, progression-free survival, and overall survival. The level of minimal residual disease (MRD) in peripheral blood and/or bone marrow was assessed in a subset of patients.

The study met its primary endpoint, with an overall response rate of 79.4% among the 107 patients with relapsed or refractory disease. In addition, 7.5% of patients achieved a complete response, with or without complete recovery of blood counts in the bone marrow.

Forty-five patients had an assessment for MRD in the blood. Of these, 18 patients achieved MRD-negativity. Ten of these 18 patients also had bone marrow assessments, and 6 were MRD-negative.

At 1 year, 84.7% of all responses and 94.4% of MRD-negative responses were maintained. The 1-year progression-free survival and overall survival rates were 72% and 86.7%, respectively.

The most common serious adverse events were pyrexia (7%), autoimmune hemolytic anemia (7%), pneumonia (6%), and febrile neutropenia (5%). The most common grade 3-4 adverse events were neutropenia (40%), infection (20%), anemia (18%), and thrombocytopenia (15%).

Laboratory TLS was reported in 5 patients. None had clinical consequences.

Venetoclax is under development by AbbVie and Genentech/Roche.

Megakaryocytes

in the bone marrow

Investigators have discovered a new mechanism of megakaryocyte differentiation, according to a paper published in eLife.

They found that overexpression of the methyltransferase enzyme PRMT1 in acute megakaryocytic leukemia blocks megakaryocyte differentiation by downregulating levels of the RNA-binding protein RBM15.

The team therefore believes that targeting PRMT1 could restore megakaryocyte differentiation in this malignancy.

They also think their findings could lead to new approaches for researching and treating other hematologic malignancies and solid tumors.

Xinyang Zhao, PhD, of the University of Alabama at Birmingham, and his colleagues began this study looking at PRMT1, which attaches a methyl group onto specific arginine amino acid residues of target proteins.

The investigators screened for proteins that were tagged with methyl groups by PRMT1 and selected one of them—RBM15—for further study. RBM15 was of interest because a mutant fusion of RBM15 and MKL1 proteins is associated with acute megakaryoblastic leukemia.

The team discovered that when a cell’s PRMT1 levels are high, a greater proportion of RBM15 is tagged with methyl groups on certain arginine residues. This tagging causes a ligase called CNOT4 to mark RBM15 with another tag, ubiquitin, which marks the protein for transport to the cell’s garbage removal machinery.

The methyl-tagged RBM15 proteins rapidly disappear, even though the amount of RBM15 messenger RNA does not change. Thus, the expression levels of PRMT1 inversely affect the amount of RBM15.

When the concentration of RBM15 is low, megakaryocytic progenitor cells cannot move forward to differentiation. But when the concentration of RBM15 is high enough, the progenitor cells differentiate into mature megakaryocytes.

The investigators also found that RBM15 binds to intron regions of the pre-messenger RNA for genes known to be important in megakaryocyte differentiation, including 3 transcription factors—RUNX1, GATA1, and TAL1—that are important for normal and abnormal hematopoiesis.

And RBM15 appears to recruit the splicing factor SF3B1 to correctly splice exons. When RBM15 is low, one or more exons are not correctly spliced.

The team said this is a new mechanism for cell differentiation, initiated by methylation of RNA-binding proteins.

“The regulation of alternative splicing by RBM15 through SF3B1 is an exciting and novel pathway that clearly participates in the decision of a megakaryocyte to grow or differentiate,” said John Crispino, PhD, of the Northwestern University Feinberg School of Medicine in Chicago, Illinois, who was not involved in this study.

“These findings suggest that modulation of RBM15 activity by suppressing PRMT1 activity may change the splicing pattern of megakaryocytic tumor cells and facilitate their differentiation.”

The investigators also believe RBM15 may have broader functions in cells. They found that RBM15 binds directly to the pre-messenger RNA of 1257 genes. Among them are genes involved in metabolic regulation.

In agreement with this finding, the team discovered that overexpression of PRMT1 or reduced expression of RBM15 enhances the creation of more mitochondria.

The investigators have further identified metabolic pathways regulated by PRMT1 in leukemia cells. They said these data, in a manuscript under preparation, will further link tumorigenesis to metabolic pathways.

The team also noted that SF3B1 contains mutations in more than 70% of myelodysplastic syndrome patients and 20% of chronic lymphocytic leukemia patients, and mutated SF3B1 appears in other hematologic malignancies as well.

So the investigators believe that understanding the PRMT1-RBM15 axis can shed new light on SF3B1-mutated hematologic malignancies and may lead to targeting PRMT1 as a novel therapy for myelodysplastic syndromes. The team is already testing PRMT1 inhibitors.

Megakaryocytes

in the bone marrow

Investigators have discovered a new mechanism of megakaryocyte differentiation, according to a paper published in eLife.

They found that overexpression of the methyltransferase enzyme PRMT1 in acute megakaryocytic leukemia blocks megakaryocyte differentiation by downregulating levels of the RNA-binding protein RBM15.

The team therefore believes that targeting PRMT1 could restore megakaryocyte differentiation in this malignancy.

They also think their findings could lead to new approaches for researching and treating other hematologic malignancies and solid tumors.

Xinyang Zhao, PhD, of the University of Alabama at Birmingham, and his colleagues began this study looking at PRMT1, which attaches a methyl group onto specific arginine amino acid residues of target proteins.

The investigators screened for proteins that were tagged with methyl groups by PRMT1 and selected one of them—RBM15—for further study. RBM15 was of interest because a mutant fusion of RBM15 and MKL1 proteins is associated with acute megakaryoblastic leukemia.

The team discovered that when a cell’s PRMT1 levels are high, a greater proportion of RBM15 is tagged with methyl groups on certain arginine residues. This tagging causes a ligase called CNOT4 to mark RBM15 with another tag, ubiquitin, which marks the protein for transport to the cell’s garbage removal machinery.

The methyl-tagged RBM15 proteins rapidly disappear, even though the amount of RBM15 messenger RNA does not change. Thus, the expression levels of PRMT1 inversely affect the amount of RBM15.

When the concentration of RBM15 is low, megakaryocytic progenitor cells cannot move forward to differentiation. But when the concentration of RBM15 is high enough, the progenitor cells differentiate into mature megakaryocytes.

The investigators also found that RBM15 binds to intron regions of the pre-messenger RNA for genes known to be important in megakaryocyte differentiation, including 3 transcription factors—RUNX1, GATA1, and TAL1—that are important for normal and abnormal hematopoiesis.

And RBM15 appears to recruit the splicing factor SF3B1 to correctly splice exons. When RBM15 is low, one or more exons are not correctly spliced.

The team said this is a new mechanism for cell differentiation, initiated by methylation of RNA-binding proteins.

“The regulation of alternative splicing by RBM15 through SF3B1 is an exciting and novel pathway that clearly participates in the decision of a megakaryocyte to grow or differentiate,” said John Crispino, PhD, of the Northwestern University Feinberg School of Medicine in Chicago, Illinois, who was not involved in this study.

“These findings suggest that modulation of RBM15 activity by suppressing PRMT1 activity may change the splicing pattern of megakaryocytic tumor cells and facilitate their differentiation.”

The investigators also believe RBM15 may have broader functions in cells. They found that RBM15 binds directly to the pre-messenger RNA of 1257 genes. Among them are genes involved in metabolic regulation.

In agreement with this finding, the team discovered that overexpression of PRMT1 or reduced expression of RBM15 enhances the creation of more mitochondria.

The investigators have further identified metabolic pathways regulated by PRMT1 in leukemia cells. They said these data, in a manuscript under preparation, will further link tumorigenesis to metabolic pathways.

The team also noted that SF3B1 contains mutations in more than 70% of myelodysplastic syndrome patients and 20% of chronic lymphocytic leukemia patients, and mutated SF3B1 appears in other hematologic malignancies as well.

So the investigators believe that understanding the PRMT1-RBM15 axis can shed new light on SF3B1-mutated hematologic malignancies and may lead to targeting PRMT1 as a novel therapy for myelodysplastic syndromes. The team is already testing PRMT1 inhibitors.

Megakaryocytes

in the bone marrow

Investigators have discovered a new mechanism of megakaryocyte differentiation, according to a paper published in eLife.

They found that overexpression of the methyltransferase enzyme PRMT1 in acute megakaryocytic leukemia blocks megakaryocyte differentiation by downregulating levels of the RNA-binding protein RBM15.

The team therefore believes that targeting PRMT1 could restore megakaryocyte differentiation in this malignancy.

They also think their findings could lead to new approaches for researching and treating other hematologic malignancies and solid tumors.

Xinyang Zhao, PhD, of the University of Alabama at Birmingham, and his colleagues began this study looking at PRMT1, which attaches a methyl group onto specific arginine amino acid residues of target proteins.

The investigators screened for proteins that were tagged with methyl groups by PRMT1 and selected one of them—RBM15—for further study. RBM15 was of interest because a mutant fusion of RBM15 and MKL1 proteins is associated with acute megakaryoblastic leukemia.

The team discovered that when a cell’s PRMT1 levels are high, a greater proportion of RBM15 is tagged with methyl groups on certain arginine residues. This tagging causes a ligase called CNOT4 to mark RBM15 with another tag, ubiquitin, which marks the protein for transport to the cell’s garbage removal machinery.

The methyl-tagged RBM15 proteins rapidly disappear, even though the amount of RBM15 messenger RNA does not change. Thus, the expression levels of PRMT1 inversely affect the amount of RBM15.

When the concentration of RBM15 is low, megakaryocytic progenitor cells cannot move forward to differentiation. But when the concentration of RBM15 is high enough, the progenitor cells differentiate into mature megakaryocytes.

The investigators also found that RBM15 binds to intron regions of the pre-messenger RNA for genes known to be important in megakaryocyte differentiation, including 3 transcription factors—RUNX1, GATA1, and TAL1—that are important for normal and abnormal hematopoiesis.

And RBM15 appears to recruit the splicing factor SF3B1 to correctly splice exons. When RBM15 is low, one or more exons are not correctly spliced.

The team said this is a new mechanism for cell differentiation, initiated by methylation of RNA-binding proteins.

“The regulation of alternative splicing by RBM15 through SF3B1 is an exciting and novel pathway that clearly participates in the decision of a megakaryocyte to grow or differentiate,” said John Crispino, PhD, of the Northwestern University Feinberg School of Medicine in Chicago, Illinois, who was not involved in this study.

“These findings suggest that modulation of RBM15 activity by suppressing PRMT1 activity may change the splicing pattern of megakaryocytic tumor cells and facilitate their differentiation.”

The investigators also believe RBM15 may have broader functions in cells. They found that RBM15 binds directly to the pre-messenger RNA of 1257 genes. Among them are genes involved in metabolic regulation.

In agreement with this finding, the team discovered that overexpression of PRMT1 or reduced expression of RBM15 enhances the creation of more mitochondria.

The investigators have further identified metabolic pathways regulated by PRMT1 in leukemia cells. They said these data, in a manuscript under preparation, will further link tumorigenesis to metabolic pathways.

The team also noted that SF3B1 contains mutations in more than 70% of myelodysplastic syndrome patients and 20% of chronic lymphocytic leukemia patients, and mutated SF3B1 appears in other hematologic malignancies as well.

So the investigators believe that understanding the PRMT1-RBM15 axis can shed new light on SF3B1-mutated hematologic malignancies and may lead to targeting PRMT1 as a novel therapy for myelodysplastic syndromes. The team is already testing PRMT1 inhibitors.