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FDA says ROCKET AF trial results hold up
The US Food and Drug Administration (FDA) has concluded that results of the ROCKET AF trial were not significantly affected by accuracy issues with the Alere INRatio
Monitor System.
ROCKET AF was the trial used to support the 2011 approval of rivaroxaban (Xarelto) in patients with nonvalvular atrial fibrillation, and the Alere INRatio Monitor System was used to measure international normalized ratios (INRs) in the warfarin arm of the trial.
Critics have questioned the results of ROCKET AF because the INRatio system (INRatio Monitor or INRatio2 Monitor and INRatio Test Strips) has been shown to give falsely low test results.
If the system provided falsely low INR values for patients in the warfarin arm of ROCKET AF, investigators may have given those patients incorrect doses of warfarin. This could increase the risk of bleeding in those patients and give a false impression of the comparative safety of rivaroxaban.
In addition to increasing the risk of bleeding, over-anticoagulation in the warfarin arm might have reduced the rate of ischemic stroke for these patients. This might have distorted the study’s efficacy results in favor of warfarin.
Because the INRatio system was shown to be defective, it was recalled for certain patients in December 2014 and was withdrawn from the US market in July 2016.
Janssen Pharmaceuticals, Inc., the company developing rivaroxaban in cooperation with Bayer, informed the FDA of the issues with the INRatio system, and its possible impact on ROCKET AF, in September 2015.
In response, the FDA conducted a variety of analyses to assess the impact the INRatio system had on the results of ROCKET AF. Janssen also performed its own analyses.
The FDA said the results of these analyses, which are available on the FDA website, suggest the INRatio system had minimal effects on strokes and bleeding in ROCKET AF.
The FDA therefore concluded that rivaroxaban is a safe and effective alternative to warfarin for patients with nonvalvular atrial fibrillation, no changes in rivaroxaban labeling are warranted, and no other major regulatory action should be taken with respect to rivaroxaban.
This corresponds to the opinion of the European Medicine’s Agency, which released a statement earlier this year saying the defect with the INRatio system does not change the overall conclusions of ROCKET AF.
Still, the issues with rivaroxaban are not fully resolved, as a recent investigation published in The BMJ suggested that Janssen and Bayer knew about concerns regarding the accuracy of the INRatio system while ROCKET AF was underway but allowed the system to be used in the trial anyway.
The BMJ said the companies also neglected to mention these concerns to regulatory authorities prior to rivaroxaban’s approval and later failed to notify regulators about the recall of the INRatio system, and its potential impact on ROCKET AF, in a timely manner.
In addition, Janssen, which was responsible for conducting ROCKET AF, did not tell regulators about a safety program the company launched during the trial to address concerns about the INRatio system. 
The US Food and Drug Administration (FDA) has concluded that results of the ROCKET AF trial were not significantly affected by accuracy issues with the Alere INRatio
Monitor System.
ROCKET AF was the trial used to support the 2011 approval of rivaroxaban (Xarelto) in patients with nonvalvular atrial fibrillation, and the Alere INRatio Monitor System was used to measure international normalized ratios (INRs) in the warfarin arm of the trial.
Critics have questioned the results of ROCKET AF because the INRatio system (INRatio Monitor or INRatio2 Monitor and INRatio Test Strips) has been shown to give falsely low test results.
If the system provided falsely low INR values for patients in the warfarin arm of ROCKET AF, investigators may have given those patients incorrect doses of warfarin. This could increase the risk of bleeding in those patients and give a false impression of the comparative safety of rivaroxaban.
In addition to increasing the risk of bleeding, over-anticoagulation in the warfarin arm might have reduced the rate of ischemic stroke for these patients. This might have distorted the study’s efficacy results in favor of warfarin.
Because the INRatio system was shown to be defective, it was recalled for certain patients in December 2014 and was withdrawn from the US market in July 2016.
Janssen Pharmaceuticals, Inc., the company developing rivaroxaban in cooperation with Bayer, informed the FDA of the issues with the INRatio system, and its possible impact on ROCKET AF, in September 2015.
In response, the FDA conducted a variety of analyses to assess the impact the INRatio system had on the results of ROCKET AF. Janssen also performed its own analyses.
The FDA said the results of these analyses, which are available on the FDA website, suggest the INRatio system had minimal effects on strokes and bleeding in ROCKET AF.
The FDA therefore concluded that rivaroxaban is a safe and effective alternative to warfarin for patients with nonvalvular atrial fibrillation, no changes in rivaroxaban labeling are warranted, and no other major regulatory action should be taken with respect to rivaroxaban.
This corresponds to the opinion of the European Medicine’s Agency, which released a statement earlier this year saying the defect with the INRatio system does not change the overall conclusions of ROCKET AF.
Still, the issues with rivaroxaban are not fully resolved, as a recent investigation published in The BMJ suggested that Janssen and Bayer knew about concerns regarding the accuracy of the INRatio system while ROCKET AF was underway but allowed the system to be used in the trial anyway.
The BMJ said the companies also neglected to mention these concerns to regulatory authorities prior to rivaroxaban’s approval and later failed to notify regulators about the recall of the INRatio system, and its potential impact on ROCKET AF, in a timely manner.
In addition, Janssen, which was responsible for conducting ROCKET AF, did not tell regulators about a safety program the company launched during the trial to address concerns about the INRatio system.
The US Food and Drug Administration (FDA) has concluded that results of the ROCKET AF trial were not significantly affected by accuracy issues with the Alere INRatio
Monitor System.
ROCKET AF was the trial used to support the 2011 approval of rivaroxaban (Xarelto) in patients with nonvalvular atrial fibrillation, and the Alere INRatio Monitor System was used to measure international normalized ratios (INRs) in the warfarin arm of the trial.
Critics have questioned the results of ROCKET AF because the INRatio system (INRatio Monitor or INRatio2 Monitor and INRatio Test Strips) has been shown to give falsely low test results.
If the system provided falsely low INR values for patients in the warfarin arm of ROCKET AF, investigators may have given those patients incorrect doses of warfarin. This could increase the risk of bleeding in those patients and give a false impression of the comparative safety of rivaroxaban.
In addition to increasing the risk of bleeding, over-anticoagulation in the warfarin arm might have reduced the rate of ischemic stroke for these patients. This might have distorted the study’s efficacy results in favor of warfarin.
Because the INRatio system was shown to be defective, it was recalled for certain patients in December 2014 and was withdrawn from the US market in July 2016.
Janssen Pharmaceuticals, Inc., the company developing rivaroxaban in cooperation with Bayer, informed the FDA of the issues with the INRatio system, and its possible impact on ROCKET AF, in September 2015.
In response, the FDA conducted a variety of analyses to assess the impact the INRatio system had on the results of ROCKET AF. Janssen also performed its own analyses.
The FDA said the results of these analyses, which are available on the FDA website, suggest the INRatio system had minimal effects on strokes and bleeding in ROCKET AF.
The FDA therefore concluded that rivaroxaban is a safe and effective alternative to warfarin for patients with nonvalvular atrial fibrillation, no changes in rivaroxaban labeling are warranted, and no other major regulatory action should be taken with respect to rivaroxaban.
This corresponds to the opinion of the European Medicine’s Agency, which released a statement earlier this year saying the defect with the INRatio system does not change the overall conclusions of ROCKET AF.
Still, the issues with rivaroxaban are not fully resolved, as a recent investigation published in The BMJ suggested that Janssen and Bayer knew about concerns regarding the accuracy of the INRatio system while ROCKET AF was underway but allowed the system to be used in the trial anyway.
The BMJ said the companies also neglected to mention these concerns to regulatory authorities prior to rivaroxaban’s approval and later failed to notify regulators about the recall of the INRatio system, and its potential impact on ROCKET AF, in a timely manner.
In addition, Janssen, which was responsible for conducting ROCKET AF, did not tell regulators about a safety program the company launched during the trial to address concerns about the INRatio system.
Plasmapheresis system cleared by FDA
Photo from Business Wire
The US Food and Drug Administration (FDA) has granted 510(k) clearance for the Aurora™ Xi Plasmapheresis System.
The system collects plasma from donated blood and returns the remaining blood components to the donor.
The Aurora Xi Plasmapheresis System features a proprietary filtration-separation method that enables faster collection of source plasma, according to Fresenius Kabi, the company marketing the system.
“The system helps to improve plasma center efficiency and the overall experience for operators and donors,” said Dean Gregory, president, medical devices, Fresenius Kabi USA.
“Faster collection times mean more throughput for our customers, helping maximize the volumes of plasma they collect while assuring a good experience for plasma donors.”
Plasma collected via the Aurora Xi Plasmapheresis System can be used to treat bleeding disorders, burn victims, human immune deficiencies, and other chronic or genetic disorders.
The plasma can also be used to manufacture therapies such as albumin and intravenous immunoglobulin.
Photo from Business Wire
The US Food and Drug Administration (FDA) has granted 510(k) clearance for the Aurora™ Xi Plasmapheresis System.
The system collects plasma from donated blood and returns the remaining blood components to the donor.
The Aurora Xi Plasmapheresis System features a proprietary filtration-separation method that enables faster collection of source plasma, according to Fresenius Kabi, the company marketing the system.
“The system helps to improve plasma center efficiency and the overall experience for operators and donors,” said Dean Gregory, president, medical devices, Fresenius Kabi USA.
“Faster collection times mean more throughput for our customers, helping maximize the volumes of plasma they collect while assuring a good experience for plasma donors.”
Plasma collected via the Aurora Xi Plasmapheresis System can be used to treat bleeding disorders, burn victims, human immune deficiencies, and other chronic or genetic disorders.
The plasma can also be used to manufacture therapies such as albumin and intravenous immunoglobulin.
Photo from Business Wire
The US Food and Drug Administration (FDA) has granted 510(k) clearance for the Aurora™ Xi Plasmapheresis System.
The system collects plasma from donated blood and returns the remaining blood components to the donor.
The Aurora Xi Plasmapheresis System features a proprietary filtration-separation method that enables faster collection of source plasma, according to Fresenius Kabi, the company marketing the system.
“The system helps to improve plasma center efficiency and the overall experience for operators and donors,” said Dean Gregory, president, medical devices, Fresenius Kabi USA.
“Faster collection times mean more throughput for our customers, helping maximize the volumes of plasma they collect while assuring a good experience for plasma donors.”
Plasma collected via the Aurora Xi Plasmapheresis System can be used to treat bleeding disorders, burn victims, human immune deficiencies, and other chronic or genetic disorders.
The plasma can also be used to manufacture therapies such as albumin and intravenous immunoglobulin.
MF assessment and treatment an ‘evolution’ from the past
© ASCO/Zach Boyden-Holmes
NEW YORK—The 11th NCCN Congress: Hematologic Malignancies coincided with the release of the inaugural edition of the NCCN treatment guideline on myeloproliferative neoplasms (MPNs), and Ruben A. Mesa, MD, took the opportunity to discuss the framework of the document and the evolving management of MPNs.
Dr Mesa, of the Mayo Clinic Cancer Center in Arizona, is the chair of the MPN guideline committee.
This initial version of the guideline focuses on the workup and diagnosis of primary myelofibrosis (MF), post-polycythemia vera MF, and post-essential thrombocythemia MF, and treatment guidelines for MF.
The committee decided to first tackle the treatment guidelines in MF because, as Dr Mesa explained, MF is “the most severe of the MPNs with the most unmet needs in terms of guidance.”
Treatment guidelines for polycythemia vera (PV) and essential thrombocythemia (ET) will be forthcoming in 2017, he said, as well as diagnosis and treatment of atypical MPNs, such as hypereosinophilic syndrome and systemic mast cell disease.
Workup of an MPN
The guideline committee focused on information regarding diagnosis—the time and place to consider bone marrow biopsies, when to use cytogenetics, and when to perform next-generation sequencing.
They stressed the importance of quantifying disease burden and utilizing the now-validated symptom assessment tools, particularly in MF.
“Finally, we leveraged the many prognostic scoring systems that have been developed for these diseases, particularly IPSS for myelofibrosis at diagnosis or the DIPSS and DIPSS-plus at subsequent time points,” Dr Mesa said.
In addition to clinical-based prognostic scoring systems, information regarding molecular features and their impact is evolving, he said.
The guideline provides a table of mutations with prognostic significance. JAK2, MPL, or CALR mutations are “brighter mutations,” he said, while adverse prognostic markers include ASXL1, EZH2, IDH1/2, SRSF2, and TP53.
“All of these have some significant prognostic implications in primary myelofibrosis, specifically,” he said.
Assessing MPN burden
“When treating these patients, it’s important to be mindful of the overall burden of the disease,” Dr Mesa said.
He called this emphasis on disease burden “an evolution from the past, where therapy was either supportive or primarily focused on prevention of thrombosis with ET or PV.”
Practitioners need to be additionally mindful of the risk of vascular events, progression, the impact of cytopenias, splenomegaly, the burden of symptoms, and the baseline degree of comorbidities.
“[W]e encourage the use of validated symptom tools that have been used now in the majority of clinical trials in this setting,” Dr Mesa added.
The MPN-10 assessment tool, included in the guideline, evaluates 10 symptoms—early satiety, abdominal discomfort, inactivity, problems concentrating, numbness/tingling, night sweats, itching, bone pain, fever, and unintentional weight loss—on a scale of 0 to 10.
Patients with MF are the most symptomatic, Dr Mesa commented, although “it is notable how frequent symptoms are present in patients with PV and ET.”
Response criteria
For a complete response, individuals must have marked improvement to near normalization in both bone marrow and peripheral blood in addition to resolution of their disease symptoms.
Partial response is basically “just shy” of the complete response level, Dr Mesa said, with bone marrow resolution not being required.
The guideline also outlines response criteria for progressive, stable, and relapsed disease, clinical improvement, and anemia, spleen, and symptom response.
“But I’ll highlight that the majority of the responses that are received currently with medical therapy are in the area of clinical improvement,” Dr Mesa said.
Treatment guidance
Specific treatment guidelines for low-risk, intermediate-1 risk, intermediate-2- or high-risk MF from the new guideline have been described in an earlier article and will not be discussed here.
Of note, however, Dr Mesa explained that ruxolitinib is a very important part of the treatment guideline because it is the only therapy approved by the US Food and Drug Administration (FDA) to treat MF.
“Over time, it’s been shown that there is an improvement in survival [with ruxolitinib],” Dr Mesa said, perhaps because of a decrease with treatment in the morbidity and the debilitation of patients.
Investigators presented the 5-year update of this information at ASCO 2016 and reported that patients maintained reduction in splenomegaly up through 5 years, both in those randomized to ruxolitinib and those crossing over from placebo.
“Long-term, we clearly looked to see whether there was a signal of new onset or late onset toxicities,” Dr Mesa said, which largely was not the case. "Toxicities have been well described in earlier studies, primarily around anemia, thrombocytopenia, and mild constitutional symptoms.”
However, long-term therapy increases the rate of development of shingles and non-melanoma skin cancer. Rates of transformation to acute myeloid leukemia were consistent with those published for similar patient populations with MF.
“If I see a patient stable on ruxolitinib who has a marked drop in their counts later on in the course of their disease,” Dr Mesa added, “I’m certainly suspicious of progression.”
He also works them up for other causes of anemia if it evolves out of the blue.
Support in MF-related anemia
“With anemia, we’re mindful of iron stores, EPO level, and being certain there’s not the presence of hemolysis or other contributors,” Dr Mesa said.
The guideline recommends stratifying patients based on serum EPO levels—those with less than 500 mU/mL and those with 500 mU/mL and higher.
“If we lower the EPO level, the greater the likelihood of response,” Dr Mesa said. “In my experience, the lower the transfusion burden, the greater the likelihood of response.”
Other than erythropoiesis-stimulating agents for individuals with lower serum levels, androgens and immunomodulatory drugs for those with higher levels have some benefit.
But “they all have their limitations,” Dr Mesa said, and “they tend to range in benefit from 20% to 30%.”
The future
Dr Mesa discussed a few agents in the pipeline that “might impact these guidelines,” such as the JAK2/FLT3 inhibitor pacritinib and the JAK1/JAK2 inhibitor momelotinib.
Pacritinib had a positive phase 3 study, but the mortality rate was higher than expected, and it was put on an FDA hold.
Data from a second phase 3 study (PERSIST-1) will be reviewed in the aggregate to evaluate the benefit of pacritinib and whether the mortality rate was associated with drug-related side effects or adverse patient selection, “which we suspect might be the case,” Dr Mesa said.
“This agent may come off hold, depending upon the data of that second phase 3 study,” he added.
Momelotinib is also in an advanced phase 3 program with 2 trials underway. Both trials have completed accrual.
One is an upfront study of momelotinib versus ruxolitinib (NCT01969838). The goal is to reduce anemia without inferiority of splenomegaly and MPN symptoms.
The other phase 3 momelotinib trial is a second-line study versus best alternative therapy, including ruxoltinib (NCT02101268).
Combination studies are ongoing with a ruxolitinib base and a variety of secondary agents, including danazol, pomalidomide, PEG IFN α2a, 5-AZA, panobinostat, BKM-120, and LDE-225. All agents appear to achieve improvement in splenomegaly and symptoms.
But “incremental benefit over ruxolitinib alone is not yet clear,” Dr Mesa said. “I would say there’s not yet a recommended off-label combination which is widely being used.”
Dr Mesa also highlighted PRM-151, an antifibrosing drug that had a favorable early stage study with several doses, and the telomerase inhibitor imetelstat, which had a deep set of molecular responses in about a third of patients with MF. Imetelstat is currently being evaluated in the second-line setting (NCT02426086).
Regarding the possible positioning of new therapies, Dr Mesa believes “momelotinib and pacritinib may play a role in front-line, depending on the final data from those studies.”
“In second-line for MF—this is where most of the activity is in the trials,” he said. “Momelotinib, pacritinib, PRM-151, and imetelstat have possibilities.”
© ASCO/Zach Boyden-Holmes
NEW YORK—The 11th NCCN Congress: Hematologic Malignancies coincided with the release of the inaugural edition of the NCCN treatment guideline on myeloproliferative neoplasms (MPNs), and Ruben A. Mesa, MD, took the opportunity to discuss the framework of the document and the evolving management of MPNs.
Dr Mesa, of the Mayo Clinic Cancer Center in Arizona, is the chair of the MPN guideline committee.
This initial version of the guideline focuses on the workup and diagnosis of primary myelofibrosis (MF), post-polycythemia vera MF, and post-essential thrombocythemia MF, and treatment guidelines for MF.
The committee decided to first tackle the treatment guidelines in MF because, as Dr Mesa explained, MF is “the most severe of the MPNs with the most unmet needs in terms of guidance.”
Treatment guidelines for polycythemia vera (PV) and essential thrombocythemia (ET) will be forthcoming in 2017, he said, as well as diagnosis and treatment of atypical MPNs, such as hypereosinophilic syndrome and systemic mast cell disease.
Workup of an MPN
The guideline committee focused on information regarding diagnosis—the time and place to consider bone marrow biopsies, when to use cytogenetics, and when to perform next-generation sequencing.
They stressed the importance of quantifying disease burden and utilizing the now-validated symptom assessment tools, particularly in MF.
“Finally, we leveraged the many prognostic scoring systems that have been developed for these diseases, particularly IPSS for myelofibrosis at diagnosis or the DIPSS and DIPSS-plus at subsequent time points,” Dr Mesa said.
In addition to clinical-based prognostic scoring systems, information regarding molecular features and their impact is evolving, he said.
The guideline provides a table of mutations with prognostic significance. JAK2, MPL, or CALR mutations are “brighter mutations,” he said, while adverse prognostic markers include ASXL1, EZH2, IDH1/2, SRSF2, and TP53.
“All of these have some significant prognostic implications in primary myelofibrosis, specifically,” he said.
Assessing MPN burden
“When treating these patients, it’s important to be mindful of the overall burden of the disease,” Dr Mesa said.
He called this emphasis on disease burden “an evolution from the past, where therapy was either supportive or primarily focused on prevention of thrombosis with ET or PV.”
Practitioners need to be additionally mindful of the risk of vascular events, progression, the impact of cytopenias, splenomegaly, the burden of symptoms, and the baseline degree of comorbidities.
“[W]e encourage the use of validated symptom tools that have been used now in the majority of clinical trials in this setting,” Dr Mesa added.
The MPN-10 assessment tool, included in the guideline, evaluates 10 symptoms—early satiety, abdominal discomfort, inactivity, problems concentrating, numbness/tingling, night sweats, itching, bone pain, fever, and unintentional weight loss—on a scale of 0 to 10.
Patients with MF are the most symptomatic, Dr Mesa commented, although “it is notable how frequent symptoms are present in patients with PV and ET.”
Response criteria
For a complete response, individuals must have marked improvement to near normalization in both bone marrow and peripheral blood in addition to resolution of their disease symptoms.
Partial response is basically “just shy” of the complete response level, Dr Mesa said, with bone marrow resolution not being required.
The guideline also outlines response criteria for progressive, stable, and relapsed disease, clinical improvement, and anemia, spleen, and symptom response.
“But I’ll highlight that the majority of the responses that are received currently with medical therapy are in the area of clinical improvement,” Dr Mesa said.
Treatment guidance
Specific treatment guidelines for low-risk, intermediate-1 risk, intermediate-2- or high-risk MF from the new guideline have been described in an earlier article and will not be discussed here.
Of note, however, Dr Mesa explained that ruxolitinib is a very important part of the treatment guideline because it is the only therapy approved by the US Food and Drug Administration (FDA) to treat MF.
“Over time, it’s been shown that there is an improvement in survival [with ruxolitinib],” Dr Mesa said, perhaps because of a decrease with treatment in the morbidity and the debilitation of patients.
Investigators presented the 5-year update of this information at ASCO 2016 and reported that patients maintained reduction in splenomegaly up through 5 years, both in those randomized to ruxolitinib and those crossing over from placebo.
“Long-term, we clearly looked to see whether there was a signal of new onset or late onset toxicities,” Dr Mesa said, which largely was not the case. "Toxicities have been well described in earlier studies, primarily around anemia, thrombocytopenia, and mild constitutional symptoms.”
However, long-term therapy increases the rate of development of shingles and non-melanoma skin cancer. Rates of transformation to acute myeloid leukemia were consistent with those published for similar patient populations with MF.
“If I see a patient stable on ruxolitinib who has a marked drop in their counts later on in the course of their disease,” Dr Mesa added, “I’m certainly suspicious of progression.”
He also works them up for other causes of anemia if it evolves out of the blue.
Support in MF-related anemia
“With anemia, we’re mindful of iron stores, EPO level, and being certain there’s not the presence of hemolysis or other contributors,” Dr Mesa said.
The guideline recommends stratifying patients based on serum EPO levels—those with less than 500 mU/mL and those with 500 mU/mL and higher.
“If we lower the EPO level, the greater the likelihood of response,” Dr Mesa said. “In my experience, the lower the transfusion burden, the greater the likelihood of response.”
Other than erythropoiesis-stimulating agents for individuals with lower serum levels, androgens and immunomodulatory drugs for those with higher levels have some benefit.
But “they all have their limitations,” Dr Mesa said, and “they tend to range in benefit from 20% to 30%.”
The future
Dr Mesa discussed a few agents in the pipeline that “might impact these guidelines,” such as the JAK2/FLT3 inhibitor pacritinib and the JAK1/JAK2 inhibitor momelotinib.
Pacritinib had a positive phase 3 study, but the mortality rate was higher than expected, and it was put on an FDA hold.
Data from a second phase 3 study (PERSIST-1) will be reviewed in the aggregate to evaluate the benefit of pacritinib and whether the mortality rate was associated with drug-related side effects or adverse patient selection, “which we suspect might be the case,” Dr Mesa said.
“This agent may come off hold, depending upon the data of that second phase 3 study,” he added.
Momelotinib is also in an advanced phase 3 program with 2 trials underway. Both trials have completed accrual.
One is an upfront study of momelotinib versus ruxolitinib (NCT01969838). The goal is to reduce anemia without inferiority of splenomegaly and MPN symptoms.
The other phase 3 momelotinib trial is a second-line study versus best alternative therapy, including ruxoltinib (NCT02101268).
Combination studies are ongoing with a ruxolitinib base and a variety of secondary agents, including danazol, pomalidomide, PEG IFN α2a, 5-AZA, panobinostat, BKM-120, and LDE-225. All agents appear to achieve improvement in splenomegaly and symptoms.
But “incremental benefit over ruxolitinib alone is not yet clear,” Dr Mesa said. “I would say there’s not yet a recommended off-label combination which is widely being used.”
Dr Mesa also highlighted PRM-151, an antifibrosing drug that had a favorable early stage study with several doses, and the telomerase inhibitor imetelstat, which had a deep set of molecular responses in about a third of patients with MF. Imetelstat is currently being evaluated in the second-line setting (NCT02426086).
Regarding the possible positioning of new therapies, Dr Mesa believes “momelotinib and pacritinib may play a role in front-line, depending on the final data from those studies.”
“In second-line for MF—this is where most of the activity is in the trials,” he said. “Momelotinib, pacritinib, PRM-151, and imetelstat have possibilities.”
© ASCO/Zach Boyden-Holmes
NEW YORK—The 11th NCCN Congress: Hematologic Malignancies coincided with the release of the inaugural edition of the NCCN treatment guideline on myeloproliferative neoplasms (MPNs), and Ruben A. Mesa, MD, took the opportunity to discuss the framework of the document and the evolving management of MPNs.
Dr Mesa, of the Mayo Clinic Cancer Center in Arizona, is the chair of the MPN guideline committee.
This initial version of the guideline focuses on the workup and diagnosis of primary myelofibrosis (MF), post-polycythemia vera MF, and post-essential thrombocythemia MF, and treatment guidelines for MF.
The committee decided to first tackle the treatment guidelines in MF because, as Dr Mesa explained, MF is “the most severe of the MPNs with the most unmet needs in terms of guidance.”
Treatment guidelines for polycythemia vera (PV) and essential thrombocythemia (ET) will be forthcoming in 2017, he said, as well as diagnosis and treatment of atypical MPNs, such as hypereosinophilic syndrome and systemic mast cell disease.
Workup of an MPN
The guideline committee focused on information regarding diagnosis—the time and place to consider bone marrow biopsies, when to use cytogenetics, and when to perform next-generation sequencing.
They stressed the importance of quantifying disease burden and utilizing the now-validated symptom assessment tools, particularly in MF.
“Finally, we leveraged the many prognostic scoring systems that have been developed for these diseases, particularly IPSS for myelofibrosis at diagnosis or the DIPSS and DIPSS-plus at subsequent time points,” Dr Mesa said.
In addition to clinical-based prognostic scoring systems, information regarding molecular features and their impact is evolving, he said.
The guideline provides a table of mutations with prognostic significance. JAK2, MPL, or CALR mutations are “brighter mutations,” he said, while adverse prognostic markers include ASXL1, EZH2, IDH1/2, SRSF2, and TP53.
“All of these have some significant prognostic implications in primary myelofibrosis, specifically,” he said.
Assessing MPN burden
“When treating these patients, it’s important to be mindful of the overall burden of the disease,” Dr Mesa said.
He called this emphasis on disease burden “an evolution from the past, where therapy was either supportive or primarily focused on prevention of thrombosis with ET or PV.”
Practitioners need to be additionally mindful of the risk of vascular events, progression, the impact of cytopenias, splenomegaly, the burden of symptoms, and the baseline degree of comorbidities.
“[W]e encourage the use of validated symptom tools that have been used now in the majority of clinical trials in this setting,” Dr Mesa added.
The MPN-10 assessment tool, included in the guideline, evaluates 10 symptoms—early satiety, abdominal discomfort, inactivity, problems concentrating, numbness/tingling, night sweats, itching, bone pain, fever, and unintentional weight loss—on a scale of 0 to 10.
Patients with MF are the most symptomatic, Dr Mesa commented, although “it is notable how frequent symptoms are present in patients with PV and ET.”
Response criteria
For a complete response, individuals must have marked improvement to near normalization in both bone marrow and peripheral blood in addition to resolution of their disease symptoms.
Partial response is basically “just shy” of the complete response level, Dr Mesa said, with bone marrow resolution not being required.
The guideline also outlines response criteria for progressive, stable, and relapsed disease, clinical improvement, and anemia, spleen, and symptom response.
“But I’ll highlight that the majority of the responses that are received currently with medical therapy are in the area of clinical improvement,” Dr Mesa said.
Treatment guidance
Specific treatment guidelines for low-risk, intermediate-1 risk, intermediate-2- or high-risk MF from the new guideline have been described in an earlier article and will not be discussed here.
Of note, however, Dr Mesa explained that ruxolitinib is a very important part of the treatment guideline because it is the only therapy approved by the US Food and Drug Administration (FDA) to treat MF.
“Over time, it’s been shown that there is an improvement in survival [with ruxolitinib],” Dr Mesa said, perhaps because of a decrease with treatment in the morbidity and the debilitation of patients.
Investigators presented the 5-year update of this information at ASCO 2016 and reported that patients maintained reduction in splenomegaly up through 5 years, both in those randomized to ruxolitinib and those crossing over from placebo.
“Long-term, we clearly looked to see whether there was a signal of new onset or late onset toxicities,” Dr Mesa said, which largely was not the case. "Toxicities have been well described in earlier studies, primarily around anemia, thrombocytopenia, and mild constitutional symptoms.”
However, long-term therapy increases the rate of development of shingles and non-melanoma skin cancer. Rates of transformation to acute myeloid leukemia were consistent with those published for similar patient populations with MF.
“If I see a patient stable on ruxolitinib who has a marked drop in their counts later on in the course of their disease,” Dr Mesa added, “I’m certainly suspicious of progression.”
He also works them up for other causes of anemia if it evolves out of the blue.
Support in MF-related anemia
“With anemia, we’re mindful of iron stores, EPO level, and being certain there’s not the presence of hemolysis or other contributors,” Dr Mesa said.
The guideline recommends stratifying patients based on serum EPO levels—those with less than 500 mU/mL and those with 500 mU/mL and higher.
“If we lower the EPO level, the greater the likelihood of response,” Dr Mesa said. “In my experience, the lower the transfusion burden, the greater the likelihood of response.”
Other than erythropoiesis-stimulating agents for individuals with lower serum levels, androgens and immunomodulatory drugs for those with higher levels have some benefit.
But “they all have their limitations,” Dr Mesa said, and “they tend to range in benefit from 20% to 30%.”
The future
Dr Mesa discussed a few agents in the pipeline that “might impact these guidelines,” such as the JAK2/FLT3 inhibitor pacritinib and the JAK1/JAK2 inhibitor momelotinib.
Pacritinib had a positive phase 3 study, but the mortality rate was higher than expected, and it was put on an FDA hold.
Data from a second phase 3 study (PERSIST-1) will be reviewed in the aggregate to evaluate the benefit of pacritinib and whether the mortality rate was associated with drug-related side effects or adverse patient selection, “which we suspect might be the case,” Dr Mesa said.
“This agent may come off hold, depending upon the data of that second phase 3 study,” he added.
Momelotinib is also in an advanced phase 3 program with 2 trials underway. Both trials have completed accrual.
One is an upfront study of momelotinib versus ruxolitinib (NCT01969838). The goal is to reduce anemia without inferiority of splenomegaly and MPN symptoms.
The other phase 3 momelotinib trial is a second-line study versus best alternative therapy, including ruxoltinib (NCT02101268).
Combination studies are ongoing with a ruxolitinib base and a variety of secondary agents, including danazol, pomalidomide, PEG IFN α2a, 5-AZA, panobinostat, BKM-120, and LDE-225. All agents appear to achieve improvement in splenomegaly and symptoms.
But “incremental benefit over ruxolitinib alone is not yet clear,” Dr Mesa said. “I would say there’s not yet a recommended off-label combination which is widely being used.”
Dr Mesa also highlighted PRM-151, an antifibrosing drug that had a favorable early stage study with several doses, and the telomerase inhibitor imetelstat, which had a deep set of molecular responses in about a third of patients with MF. Imetelstat is currently being evaluated in the second-line setting (NCT02426086).
Regarding the possible positioning of new therapies, Dr Mesa believes “momelotinib and pacritinib may play a role in front-line, depending on the final data from those studies.”
“In second-line for MF—this is where most of the activity is in the trials,” he said. “Momelotinib, pacritinib, PRM-151, and imetelstat have possibilities.”
FDA grants priority review for MM drug
Photo courtesy of Janssen
The US Food and Drug Administration (FDA) has granted priority review for part of a supplemental biologics license application (sBLA) for daratumumab (Darzalex®).
The priority review pertains to the use of daratumumab in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone to treat patients with multiple myeloma (MM) who have received at least 1 prior therapy.
To grant an application priority review, the FDA must believe the drug would provide a significant improvement in the treatment, diagnosis, or prevention of a serious condition.
The priority review designation means the FDA’s goal is to take action on an application within 6 months, rather than the 10 months typically taken for a standard review.
The FDA has assigned a Prescription Drug User Fee Act target date of February 17, 2017, to make a decision on daratumumab in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone.
Standard review
The FDA has also granted a standard review period for part of the sBLA.
The standard review pertains to the use of daratumumab in combination with pomalidomide and dexamethasone to treat patients with relapsed or refractory MM who have received at least 2 prior therapies, including a proteasome inhibitor and an immunomodulatory agent.
The Prescription Drug User Fee Act date for the combination of daratumumab with pomalidomide and dexamethasone is June 17, 2017.
Trial data
The sBLA submission included data from a pair of phase 3 studies:
- The CASTOR study, in which researchers compared the combination of daratumumab, bortezomib, and dexamethasone to bortezomib and dexamethasone in patients with relapsed or refractory MM
- The POLLUX study, in which researchers compared daratumumab in combination with lenalidomide and dexamethasone to lenalidomide and dexamethasone in patients with relapsed or refractory MM.
The sBLA submission also included data from a phase 1 study of daratumumab in combination with pomalidomide and dexamethasone in patients with relapsed or refractory MM.
About daratumumab
Daratumumab is a human IgG1k monoclonal antibody that binds to CD38, which is highly expressed on the surface of MM cells.
Daratumumab already has accelerated approval in the US as monotherapy for MM patients who have received at least 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who are double-refractory to a proteasome inhibitor and an immunomodulatory agent.
Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license from Genmab to develop, manufacture, and commercialize daratumumab.
For more information on daratumumab, visit www.DARZALEX.com.
Photo courtesy of Janssen
The US Food and Drug Administration (FDA) has granted priority review for part of a supplemental biologics license application (sBLA) for daratumumab (Darzalex®).
The priority review pertains to the use of daratumumab in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone to treat patients with multiple myeloma (MM) who have received at least 1 prior therapy.
To grant an application priority review, the FDA must believe the drug would provide a significant improvement in the treatment, diagnosis, or prevention of a serious condition.
The priority review designation means the FDA’s goal is to take action on an application within 6 months, rather than the 10 months typically taken for a standard review.
The FDA has assigned a Prescription Drug User Fee Act target date of February 17, 2017, to make a decision on daratumumab in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone.
Standard review
The FDA has also granted a standard review period for part of the sBLA.
The standard review pertains to the use of daratumumab in combination with pomalidomide and dexamethasone to treat patients with relapsed or refractory MM who have received at least 2 prior therapies, including a proteasome inhibitor and an immunomodulatory agent.
The Prescription Drug User Fee Act date for the combination of daratumumab with pomalidomide and dexamethasone is June 17, 2017.
Trial data
The sBLA submission included data from a pair of phase 3 studies:
- The CASTOR study, in which researchers compared the combination of daratumumab, bortezomib, and dexamethasone to bortezomib and dexamethasone in patients with relapsed or refractory MM
- The POLLUX study, in which researchers compared daratumumab in combination with lenalidomide and dexamethasone to lenalidomide and dexamethasone in patients with relapsed or refractory MM.
The sBLA submission also included data from a phase 1 study of daratumumab in combination with pomalidomide and dexamethasone in patients with relapsed or refractory MM.
About daratumumab
Daratumumab is a human IgG1k monoclonal antibody that binds to CD38, which is highly expressed on the surface of MM cells.
Daratumumab already has accelerated approval in the US as monotherapy for MM patients who have received at least 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who are double-refractory to a proteasome inhibitor and an immunomodulatory agent.
Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license from Genmab to develop, manufacture, and commercialize daratumumab.
For more information on daratumumab, visit www.DARZALEX.com.
Photo courtesy of Janssen
The US Food and Drug Administration (FDA) has granted priority review for part of a supplemental biologics license application (sBLA) for daratumumab (Darzalex®).
The priority review pertains to the use of daratumumab in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone to treat patients with multiple myeloma (MM) who have received at least 1 prior therapy.
To grant an application priority review, the FDA must believe the drug would provide a significant improvement in the treatment, diagnosis, or prevention of a serious condition.
The priority review designation means the FDA’s goal is to take action on an application within 6 months, rather than the 10 months typically taken for a standard review.
The FDA has assigned a Prescription Drug User Fee Act target date of February 17, 2017, to make a decision on daratumumab in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone.
Standard review
The FDA has also granted a standard review period for part of the sBLA.
The standard review pertains to the use of daratumumab in combination with pomalidomide and dexamethasone to treat patients with relapsed or refractory MM who have received at least 2 prior therapies, including a proteasome inhibitor and an immunomodulatory agent.
The Prescription Drug User Fee Act date for the combination of daratumumab with pomalidomide and dexamethasone is June 17, 2017.
Trial data
The sBLA submission included data from a pair of phase 3 studies:
- The CASTOR study, in which researchers compared the combination of daratumumab, bortezomib, and dexamethasone to bortezomib and dexamethasone in patients with relapsed or refractory MM
- The POLLUX study, in which researchers compared daratumumab in combination with lenalidomide and dexamethasone to lenalidomide and dexamethasone in patients with relapsed or refractory MM.
The sBLA submission also included data from a phase 1 study of daratumumab in combination with pomalidomide and dexamethasone in patients with relapsed or refractory MM.
About daratumumab
Daratumumab is a human IgG1k monoclonal antibody that binds to CD38, which is highly expressed on the surface of MM cells.
Daratumumab already has accelerated approval in the US as monotherapy for MM patients who have received at least 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who are double-refractory to a proteasome inhibitor and an immunomodulatory agent.
Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license from Genmab to develop, manufacture, and commercialize daratumumab.
For more information on daratumumab, visit www.DARZALEX.com.
FDA clears use of coagulation analyzer
The US Food and Drug Administration (FDA) has granted 510(k) clearance for the Xprecia Stride Coagulation Analyzer from Siemens Healthcare Diagnostics.
This hand-held, portable coagulation analyzer is designed to deliver prothrombin time/international normalized ratio (PT/INR) testing for point-of-care (POC) monitoring and management of oral anticoagulation therapy with the vitamin K antagonist warfarin.
The Xprecia Stride Coagulation Analyzer is the first POC PT/INR device cleared by the FDA based on the new rules published in March 2016.
The analyzer uses fresh capillary whole blood, and results are expressed as INR. The Xprecia Stride Coagulation Analyzer utilizes the same Dade® Innovin® reagent used by Siemens Healthineers central lab analyzers to minimize any potential for variability.
Research has shown the performance of the Xprecia Stride Coagulation Analyzer to be equivalent to a reference laboratory hemostasis system,* with results available within minutes.
According to Siemens, the Xprecia Stride Coagulation Analyzer includes a number of innovations and features not found on most other POC analyzers.
The Xprecia Stride Coagulation Analyzer has a touchscreen interface with step-by-step instructions that help guide the user.
To further enhance usability, the analyzer features simple icons and animation in a color display more commonly found in mobile devices than medical instruments.
The Xprecia Stride Coagulation Analyzer is no bigger than a smartphone and weighs just 10.5 oz, so it can be held at virtually any angle and brought directly to the patient’s finger for blood sample collection.
The analyzer has an integrated barcode scanner intended to simplify data capture and improve patient workflow. The scanner offers patient and operator ID entry.
The Xprecia Stride Coagulation Analyzer has an operator lockout feature that restricts the analyzer’s use to trained staff only.
And the analyzer includes a first-of-its kind test strip eject button that allows the user to eject a used test strip and easily dispose of it without touching it, minimizing potential biohazard exposure.
For more information on the Xprecia Stride Coagulation Analyzer, visit www.siemens.com/xprecia.
The US Food and Drug Administration (FDA) has granted 510(k) clearance for the Xprecia Stride Coagulation Analyzer from Siemens Healthcare Diagnostics.
This hand-held, portable coagulation analyzer is designed to deliver prothrombin time/international normalized ratio (PT/INR) testing for point-of-care (POC) monitoring and management of oral anticoagulation therapy with the vitamin K antagonist warfarin.
The Xprecia Stride Coagulation Analyzer is the first POC PT/INR device cleared by the FDA based on the new rules published in March 2016.
The analyzer uses fresh capillary whole blood, and results are expressed as INR. The Xprecia Stride Coagulation Analyzer utilizes the same Dade® Innovin® reagent used by Siemens Healthineers central lab analyzers to minimize any potential for variability.
Research has shown the performance of the Xprecia Stride Coagulation Analyzer to be equivalent to a reference laboratory hemostasis system,* with results available within minutes.
According to Siemens, the Xprecia Stride Coagulation Analyzer includes a number of innovations and features not found on most other POC analyzers.
The Xprecia Stride Coagulation Analyzer has a touchscreen interface with step-by-step instructions that help guide the user.
To further enhance usability, the analyzer features simple icons and animation in a color display more commonly found in mobile devices than medical instruments.
The Xprecia Stride Coagulation Analyzer is no bigger than a smartphone and weighs just 10.5 oz, so it can be held at virtually any angle and brought directly to the patient’s finger for blood sample collection.
The analyzer has an integrated barcode scanner intended to simplify data capture and improve patient workflow. The scanner offers patient and operator ID entry.
The Xprecia Stride Coagulation Analyzer has an operator lockout feature that restricts the analyzer’s use to trained staff only.
And the analyzer includes a first-of-its kind test strip eject button that allows the user to eject a used test strip and easily dispose of it without touching it, minimizing potential biohazard exposure.
For more information on the Xprecia Stride Coagulation Analyzer, visit www.siemens.com/xprecia.
The US Food and Drug Administration (FDA) has granted 510(k) clearance for the Xprecia Stride Coagulation Analyzer from Siemens Healthcare Diagnostics.
This hand-held, portable coagulation analyzer is designed to deliver prothrombin time/international normalized ratio (PT/INR) testing for point-of-care (POC) monitoring and management of oral anticoagulation therapy with the vitamin K antagonist warfarin.
The Xprecia Stride Coagulation Analyzer is the first POC PT/INR device cleared by the FDA based on the new rules published in March 2016.
The analyzer uses fresh capillary whole blood, and results are expressed as INR. The Xprecia Stride Coagulation Analyzer utilizes the same Dade® Innovin® reagent used by Siemens Healthineers central lab analyzers to minimize any potential for variability.
Research has shown the performance of the Xprecia Stride Coagulation Analyzer to be equivalent to a reference laboratory hemostasis system,* with results available within minutes.
According to Siemens, the Xprecia Stride Coagulation Analyzer includes a number of innovations and features not found on most other POC analyzers.
The Xprecia Stride Coagulation Analyzer has a touchscreen interface with step-by-step instructions that help guide the user.
To further enhance usability, the analyzer features simple icons and animation in a color display more commonly found in mobile devices than medical instruments.
The Xprecia Stride Coagulation Analyzer is no bigger than a smartphone and weighs just 10.5 oz, so it can be held at virtually any angle and brought directly to the patient’s finger for blood sample collection.
The analyzer has an integrated barcode scanner intended to simplify data capture and improve patient workflow. The scanner offers patient and operator ID entry.
The Xprecia Stride Coagulation Analyzer has an operator lockout feature that restricts the analyzer’s use to trained staff only.
And the analyzer includes a first-of-its kind test strip eject button that allows the user to eject a used test strip and easily dispose of it without touching it, minimizing potential biohazard exposure.
For more information on the Xprecia Stride Coagulation Analyzer, visit www.siemens.com/xprecia.
Supportive care isn’t palliative care, speaker says
Photo courtesy of NCI
NEW YORK—Two presentations at the NCCN 11th Annual Congress: Hematologic Malignancies addressed the importance of supportive care in the treatment of patients with T-cell lymphomas and multiple myeloma.
Erin Kopp, ACNP-BC, of City of Hope Comprehensive Cancer Center in Duarte, California, reminded the audience that supportive care is not palliative care.
Supportive care “complements critical care so that the patient doesn’t have to stop treatment,” she said.
Kopp focused primarily on cutaneous T-cell lymphoma (CTCL) in her presentation, with some recommendations for managing tumor lysis syndrome in patients undergoing therapy for peripheral T-cell lymphoma (PTCL).
And Kathleen Colson, RN, of the Dana-Farber Cancer Institute in Boston, Massachusetts, discussed supportive care for patients with multiple myeloma (MM).
T-cell lymphomas
Most T-cell lymphoma patients will require multiple treatment regimens over their lifetimes, Kopp said. And each type of therapy brings different treatment-related toxicities, which in turn require distinct supportive care measures to manage them.
Topical steroids, for example, may cause skin-thinning, stretch marks, skin irritation, and may be absorbed systemically when a high-potency formulation is used. So the lowest potency steroid that provides the maximum efficacy should be utilized. Practitioners should assess systemic effects if high-potency steroids are utilized.
Topical nitrogen mustard can darken the skin, which often occurs as the lesions resolve, Kopp said. She cautioned that patients experiencing hyperpigmentation often stop treatment without telling their physicians.
So Kopp recommends appropriate patient education to go along with the treatment. With nitrogen mustard, this includes applying a thin layer only to the affected areas and refrigerating the topical ointment to increase soothing.
Topical retinoids may cause redness, itching, warmth, swelling, burning, scaling or other irritation. They also increase the patients’ sensitivity to light. Kopp indicated that for the first week, topical retinoids should be applied once every other day and then titrated as tolerated.
Phototherapy with PUVA or narrowband-UVB may also cause itching, in addition to skin burn, nausea, and other side effects.
“Do not underestimate emollients,” Kopp said, for relief of pruritus. And skin baths with bleach significantly decrease infections that may result from treatment.
Systemic therapy with retinoids, interferon, cytotoxic agents, monoclonal antibodies, and HDAC inhibitors may also cause distinct reactions. For example, the retinoid bexarotene may cause primary hypothyroidism and major lipid abnormalities. Therefore, TSH, free T4, and triglycerides should be monitored every 8 weeks.
Cytotoxic agents such as pralatrexate and methotrexate significantly increase the risk for infection.
Monoclonal antibodies can reactivate previous viral infection, induce tumor lysis syndrome (TLS), and cause progressive multifocal leukoencephalopathy.
HDAC inhibitors such as vorinostat and romidepsin may cause QT prolongation and myelosuppression, among other side effects.
Practitioners need to assess symptoms and side effects thoroughly and often and provide options for supportive care management.
PTCL is an under recognized risk for TLS, Kopp said.
“It should be addressed aggressively,” she added, with monitoring and correction of electrolyte imbalance.
Patients should be rigorously hydrated, and allopurinol should be administered 2-3 days prior to treatment and adjusted based on the patient response and uric acid level.
Multiple myeloma
Colson described supportive care as “keeping all the pieces together.” MM itself can result in a broad spectrum of clinical manifestations, including renal compromise, neuropathy, infection, hypercalcemia, bone pain, lytic lesions, and anemia.
To preserve renal health, patients should drink plenty of water and avoid certain medications, such as IV contrast and nonsteroidal anti-inflammatory drugs.
Peripheral neuropathy can be a side effect of treatment or be caused by the disease itself. Bortezomib-related neuropathy can be reduced with weekly instead of twice weekly dosing and with subcutaneous administration.
Duration of higher doses of thalidomide treatment also impacts neuropathy. Carfilzomib and pomalidomide have a lower incidence of neuropathy.
Myeloma patients have a 15-fold increased risk of recurrent infection because white blood cell production is decreased and the normal immune role of plasma cells is lost.
Supportive therapy includes antibiotics and IVIG therapy. In addition, Colson said pneumonia and influenza vaccines should be considered, as well as prophylaxis for Pneumocystis carinii, herpes zoster, and fungal infections.
Hypercalcemia results from increased bone deterioration. Symptoms include loss of appetite, fatigue, vomiting, muscle weakness, confusion, constipation, increased thirst, and increased urine output. Supportive measures are adequate hydration, furosemide, bisphosphonates, and steroids.
Supportive therapy for bone pain includes bisphosphonates, radiation, pain medication, kyphoplasty, and vertebroplasty. Bisphosphonates, such as pamidronate and zoledronic acid, inhibit bone destruction and are recommended for all myeloma patients with bone disease. However, patients should be monitored for renal dysfunction and osteonecrosis of the jaw when taking bisphosphonates.
And Colson advises, “Hold bisphosphonate therapy if the patient needs a root canal or extraction.” Additionally, dental implants are not recommended for MM patients.
Anemia is another common presenting symptom of myeloma and may also be a result of decreased kidney function. Colson said the use of red blood cell supplements may be used with caution to ameliorate the symptom. Red blood cell transfusion may be considered and a reduction in the medication dose may be required.
MM is a hypercoagulable disease, and measures should be taken to avoid deep vein thrombosis (DVT) and pulmonary embolism (PE). Patients should wear anti-embolism stockings, exercise regularly, take low-dose aspirin, and move about frequently instead of sitting for long periods. Immunomodulatory medications may be adjusted to reduce the risk of a blot clot forming.
Infusion-related reactions are also a risk of therapy, and symptoms of a reaction need to be managed immediately and appropriately, with antihistamines, corticosteroids, interruption of the infusion, slowing of the infusion rate after symptom resolution, and permanent discontinuation in the case of grade 4 reactions.
The potential for longer survival exists, Colson said, due to appropriate supportive care measures.
Photo courtesy of NCI
NEW YORK—Two presentations at the NCCN 11th Annual Congress: Hematologic Malignancies addressed the importance of supportive care in the treatment of patients with T-cell lymphomas and multiple myeloma.
Erin Kopp, ACNP-BC, of City of Hope Comprehensive Cancer Center in Duarte, California, reminded the audience that supportive care is not palliative care.
Supportive care “complements critical care so that the patient doesn’t have to stop treatment,” she said.
Kopp focused primarily on cutaneous T-cell lymphoma (CTCL) in her presentation, with some recommendations for managing tumor lysis syndrome in patients undergoing therapy for peripheral T-cell lymphoma (PTCL).
And Kathleen Colson, RN, of the Dana-Farber Cancer Institute in Boston, Massachusetts, discussed supportive care for patients with multiple myeloma (MM).
T-cell lymphomas
Most T-cell lymphoma patients will require multiple treatment regimens over their lifetimes, Kopp said. And each type of therapy brings different treatment-related toxicities, which in turn require distinct supportive care measures to manage them.
Topical steroids, for example, may cause skin-thinning, stretch marks, skin irritation, and may be absorbed systemically when a high-potency formulation is used. So the lowest potency steroid that provides the maximum efficacy should be utilized. Practitioners should assess systemic effects if high-potency steroids are utilized.
Topical nitrogen mustard can darken the skin, which often occurs as the lesions resolve, Kopp said. She cautioned that patients experiencing hyperpigmentation often stop treatment without telling their physicians.
So Kopp recommends appropriate patient education to go along with the treatment. With nitrogen mustard, this includes applying a thin layer only to the affected areas and refrigerating the topical ointment to increase soothing.
Topical retinoids may cause redness, itching, warmth, swelling, burning, scaling or other irritation. They also increase the patients’ sensitivity to light. Kopp indicated that for the first week, topical retinoids should be applied once every other day and then titrated as tolerated.
Phototherapy with PUVA or narrowband-UVB may also cause itching, in addition to skin burn, nausea, and other side effects.
“Do not underestimate emollients,” Kopp said, for relief of pruritus. And skin baths with bleach significantly decrease infections that may result from treatment.
Systemic therapy with retinoids, interferon, cytotoxic agents, monoclonal antibodies, and HDAC inhibitors may also cause distinct reactions. For example, the retinoid bexarotene may cause primary hypothyroidism and major lipid abnormalities. Therefore, TSH, free T4, and triglycerides should be monitored every 8 weeks.
Cytotoxic agents such as pralatrexate and methotrexate significantly increase the risk for infection.
Monoclonal antibodies can reactivate previous viral infection, induce tumor lysis syndrome (TLS), and cause progressive multifocal leukoencephalopathy.
HDAC inhibitors such as vorinostat and romidepsin may cause QT prolongation and myelosuppression, among other side effects.
Practitioners need to assess symptoms and side effects thoroughly and often and provide options for supportive care management.
PTCL is an under recognized risk for TLS, Kopp said.
“It should be addressed aggressively,” she added, with monitoring and correction of electrolyte imbalance.
Patients should be rigorously hydrated, and allopurinol should be administered 2-3 days prior to treatment and adjusted based on the patient response and uric acid level.
Multiple myeloma
Colson described supportive care as “keeping all the pieces together.” MM itself can result in a broad spectrum of clinical manifestations, including renal compromise, neuropathy, infection, hypercalcemia, bone pain, lytic lesions, and anemia.
To preserve renal health, patients should drink plenty of water and avoid certain medications, such as IV contrast and nonsteroidal anti-inflammatory drugs.
Peripheral neuropathy can be a side effect of treatment or be caused by the disease itself. Bortezomib-related neuropathy can be reduced with weekly instead of twice weekly dosing and with subcutaneous administration.
Duration of higher doses of thalidomide treatment also impacts neuropathy. Carfilzomib and pomalidomide have a lower incidence of neuropathy.
Myeloma patients have a 15-fold increased risk of recurrent infection because white blood cell production is decreased and the normal immune role of plasma cells is lost.
Supportive therapy includes antibiotics and IVIG therapy. In addition, Colson said pneumonia and influenza vaccines should be considered, as well as prophylaxis for Pneumocystis carinii, herpes zoster, and fungal infections.
Hypercalcemia results from increased bone deterioration. Symptoms include loss of appetite, fatigue, vomiting, muscle weakness, confusion, constipation, increased thirst, and increased urine output. Supportive measures are adequate hydration, furosemide, bisphosphonates, and steroids.
Supportive therapy for bone pain includes bisphosphonates, radiation, pain medication, kyphoplasty, and vertebroplasty. Bisphosphonates, such as pamidronate and zoledronic acid, inhibit bone destruction and are recommended for all myeloma patients with bone disease. However, patients should be monitored for renal dysfunction and osteonecrosis of the jaw when taking bisphosphonates.
And Colson advises, “Hold bisphosphonate therapy if the patient needs a root canal or extraction.” Additionally, dental implants are not recommended for MM patients.
Anemia is another common presenting symptom of myeloma and may also be a result of decreased kidney function. Colson said the use of red blood cell supplements may be used with caution to ameliorate the symptom. Red blood cell transfusion may be considered and a reduction in the medication dose may be required.
MM is a hypercoagulable disease, and measures should be taken to avoid deep vein thrombosis (DVT) and pulmonary embolism (PE). Patients should wear anti-embolism stockings, exercise regularly, take low-dose aspirin, and move about frequently instead of sitting for long periods. Immunomodulatory medications may be adjusted to reduce the risk of a blot clot forming.
Infusion-related reactions are also a risk of therapy, and symptoms of a reaction need to be managed immediately and appropriately, with antihistamines, corticosteroids, interruption of the infusion, slowing of the infusion rate after symptom resolution, and permanent discontinuation in the case of grade 4 reactions.
The potential for longer survival exists, Colson said, due to appropriate supportive care measures.
Photo courtesy of NCI
NEW YORK—Two presentations at the NCCN 11th Annual Congress: Hematologic Malignancies addressed the importance of supportive care in the treatment of patients with T-cell lymphomas and multiple myeloma.
Erin Kopp, ACNP-BC, of City of Hope Comprehensive Cancer Center in Duarte, California, reminded the audience that supportive care is not palliative care.
Supportive care “complements critical care so that the patient doesn’t have to stop treatment,” she said.
Kopp focused primarily on cutaneous T-cell lymphoma (CTCL) in her presentation, with some recommendations for managing tumor lysis syndrome in patients undergoing therapy for peripheral T-cell lymphoma (PTCL).
And Kathleen Colson, RN, of the Dana-Farber Cancer Institute in Boston, Massachusetts, discussed supportive care for patients with multiple myeloma (MM).
T-cell lymphomas
Most T-cell lymphoma patients will require multiple treatment regimens over their lifetimes, Kopp said. And each type of therapy brings different treatment-related toxicities, which in turn require distinct supportive care measures to manage them.
Topical steroids, for example, may cause skin-thinning, stretch marks, skin irritation, and may be absorbed systemically when a high-potency formulation is used. So the lowest potency steroid that provides the maximum efficacy should be utilized. Practitioners should assess systemic effects if high-potency steroids are utilized.
Topical nitrogen mustard can darken the skin, which often occurs as the lesions resolve, Kopp said. She cautioned that patients experiencing hyperpigmentation often stop treatment without telling their physicians.
So Kopp recommends appropriate patient education to go along with the treatment. With nitrogen mustard, this includes applying a thin layer only to the affected areas and refrigerating the topical ointment to increase soothing.
Topical retinoids may cause redness, itching, warmth, swelling, burning, scaling or other irritation. They also increase the patients’ sensitivity to light. Kopp indicated that for the first week, topical retinoids should be applied once every other day and then titrated as tolerated.
Phototherapy with PUVA or narrowband-UVB may also cause itching, in addition to skin burn, nausea, and other side effects.
“Do not underestimate emollients,” Kopp said, for relief of pruritus. And skin baths with bleach significantly decrease infections that may result from treatment.
Systemic therapy with retinoids, interferon, cytotoxic agents, monoclonal antibodies, and HDAC inhibitors may also cause distinct reactions. For example, the retinoid bexarotene may cause primary hypothyroidism and major lipid abnormalities. Therefore, TSH, free T4, and triglycerides should be monitored every 8 weeks.
Cytotoxic agents such as pralatrexate and methotrexate significantly increase the risk for infection.
Monoclonal antibodies can reactivate previous viral infection, induce tumor lysis syndrome (TLS), and cause progressive multifocal leukoencephalopathy.
HDAC inhibitors such as vorinostat and romidepsin may cause QT prolongation and myelosuppression, among other side effects.
Practitioners need to assess symptoms and side effects thoroughly and often and provide options for supportive care management.
PTCL is an under recognized risk for TLS, Kopp said.
“It should be addressed aggressively,” she added, with monitoring and correction of electrolyte imbalance.
Patients should be rigorously hydrated, and allopurinol should be administered 2-3 days prior to treatment and adjusted based on the patient response and uric acid level.
Multiple myeloma
Colson described supportive care as “keeping all the pieces together.” MM itself can result in a broad spectrum of clinical manifestations, including renal compromise, neuropathy, infection, hypercalcemia, bone pain, lytic lesions, and anemia.
To preserve renal health, patients should drink plenty of water and avoid certain medications, such as IV contrast and nonsteroidal anti-inflammatory drugs.
Peripheral neuropathy can be a side effect of treatment or be caused by the disease itself. Bortezomib-related neuropathy can be reduced with weekly instead of twice weekly dosing and with subcutaneous administration.
Duration of higher doses of thalidomide treatment also impacts neuropathy. Carfilzomib and pomalidomide have a lower incidence of neuropathy.
Myeloma patients have a 15-fold increased risk of recurrent infection because white blood cell production is decreased and the normal immune role of plasma cells is lost.
Supportive therapy includes antibiotics and IVIG therapy. In addition, Colson said pneumonia and influenza vaccines should be considered, as well as prophylaxis for Pneumocystis carinii, herpes zoster, and fungal infections.
Hypercalcemia results from increased bone deterioration. Symptoms include loss of appetite, fatigue, vomiting, muscle weakness, confusion, constipation, increased thirst, and increased urine output. Supportive measures are adequate hydration, furosemide, bisphosphonates, and steroids.
Supportive therapy for bone pain includes bisphosphonates, radiation, pain medication, kyphoplasty, and vertebroplasty. Bisphosphonates, such as pamidronate and zoledronic acid, inhibit bone destruction and are recommended for all myeloma patients with bone disease. However, patients should be monitored for renal dysfunction and osteonecrosis of the jaw when taking bisphosphonates.
And Colson advises, “Hold bisphosphonate therapy if the patient needs a root canal or extraction.” Additionally, dental implants are not recommended for MM patients.
Anemia is another common presenting symptom of myeloma and may also be a result of decreased kidney function. Colson said the use of red blood cell supplements may be used with caution to ameliorate the symptom. Red blood cell transfusion may be considered and a reduction in the medication dose may be required.
MM is a hypercoagulable disease, and measures should be taken to avoid deep vein thrombosis (DVT) and pulmonary embolism (PE). Patients should wear anti-embolism stockings, exercise regularly, take low-dose aspirin, and move about frequently instead of sitting for long periods. Immunomodulatory medications may be adjusted to reduce the risk of a blot clot forming.
Infusion-related reactions are also a risk of therapy, and symptoms of a reaction need to be managed immediately and appropriately, with antihistamines, corticosteroids, interruption of the infusion, slowing of the infusion rate after symptom resolution, and permanent discontinuation in the case of grade 4 reactions.
The potential for longer survival exists, Colson said, due to appropriate supportive care measures.
Immunotherapy produces CRs in kids with rel/ref ALL
The bispecific T-cell engager (BiTE®) antibody blinatumomab can produce complete responses (CRs) in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (ALL), according to a phase 1/2 study published in the Journal of Clinical Oncology.
Of the patients who received the recommended dosage of blinatumomab, 39% achieved a CR within the first 2 treatment cycles.
And 52% of these patients achieved a complete minimal residual disease (MRD) response.
“This study showed that [blinatumomab] can induce deep molecular remissions in children with highly refractory, multiply relapsed ALL,” said study author Lia Gore, MD, of University of Colorado Anschutz Medical Campus in Aurora, Colorado.
However, most of these remissions did not last. Although a few of the complete responders were still alive and in CR at the study’s 2-year follow-up, more than half had relapsed, and two-thirds had died.
This trial, known as Study ‘205, was supported by Amgen.
Study ‘205 included 93 pediatric patients with relapsed or refractory B-cell precursor ALL. Patients received blinatumomab as a continuous intravenous infusion—49 patients in the phase 1 portion of the trial and 44 in phase 2. The patients were followed for 2 years.
Toxicities and recommended dose
There were 4 dose-limiting toxicities during the phase 1 portion of the trial, and 2 of these events were fatal. One patient treated at 15 μg/m2/day developed grade 4 cytokine release syndrome (CRS), which was deemed related to grade 4 gastrointestinal hemorrhage.
Two patients treated at 30 μg/m2/day had grade 4 CRS. One case was attributed to grade 5 cardiac failure, and the other was treated successfully with tocilizumab.
One patient treated at 15 μg/m2/day had grade 5 respiratory failure with cardiac arrest after hypotonia and muscle weakness after 7 days of infusion with blinatumomab. This patient experienced febrile neutropenia and pneumonia shortly before the start of the infusion.
Based on these toxicities, the maximum-tolerated dose of blinatumomab was 15 μg/m2/day, but a step-wise dosage was recommended to reduce the risk of CRS.
So the recommended dose was 5 μg/m2/day on days 1-7 and 15 μg/m2/day on days 8-28 for cycle 1, and 15 μg/m2/day on days 1-28 for subsequent cycles.
Dose adjustment was possible in case of adverse events. Patients who responded to blinatumomab but later relapsed had the option to be retreated with blinatumomab.
Treatment at recommended dose
Seventy patients received at least 1 infusion of blinatumomab at the recommended dose. The median number of treatment cycles was 1 (range, 1 to 5).
The patients’ median age was 8 years (range, 7 months to 17 years). Forty patients (57%) had undergone allogeneic transplant prior to receiving blinatumomab, and 39 (56%) had refractory disease. Four patients had less than the 25% bone marrow blasts required for protocol entry but had more than 5% blasts.
Adverse events
The most common adverse events among the patients who received the recommended dose of blinatumomab were pyrexia (80%), anemia (41%), nausea (33%), and headache (30%).
The most frequent grade 3 or higher events were anemia (36%), thrombocytopenia (21%), febrile neutropenia (17%), hypokalemia (17%), and neutropenia (17%).
Eight patients developed CRS. Three had grade 3 and 1 had grade 4 CRS. Two of these patients had treatment interruptions, and 2 discontinued treatment permanently. All 4 patients achieved a CR.
Ten patients (14%) had treatment interruptions due to adverse events, and 4 (6%) discontinued treatment permanently because of adverse events.
Six patients had fatal adverse events. Three died after they went on to allogeneic transplant—1 of multiorgan failure, 1 of sepsis, and 1 of respiratory failure. The 3 other deaths were due to fungal infection, multiorgan failure, and thrombocytopenia.
Response and follow-up
Among the 70 patients who received the recommended dose of blinatumomab, 27 (39%) achieved a CR within the first 2 cycles. Fourteen of these patients (52%) achieved complete MRD response.
CRs were achieved across subgroups, and complete MRD response rates were similar across subgroups.
Thirteen of the 27 patients (48%) who achieved a CR went on to receive an allogeneic transplant.
At the end of the 2-year follow-up, 4 of the 27 complete responders were still in remission.
Two of the patients had relapsed but were still alive, 3 had withdrawn consent (1 in CR and 2 after relapse), 3 had died in CR after transplant, and 15 had relapsed and died.
Of the 43 patients who did not achieve a CR within the first 2 treatment cycles, 8 were still alive at the end of the 2-year follow-up.
The bispecific T-cell engager (BiTE®) antibody blinatumomab can produce complete responses (CRs) in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (ALL), according to a phase 1/2 study published in the Journal of Clinical Oncology.
Of the patients who received the recommended dosage of blinatumomab, 39% achieved a CR within the first 2 treatment cycles.
And 52% of these patients achieved a complete minimal residual disease (MRD) response.
“This study showed that [blinatumomab] can induce deep molecular remissions in children with highly refractory, multiply relapsed ALL,” said study author Lia Gore, MD, of University of Colorado Anschutz Medical Campus in Aurora, Colorado.
However, most of these remissions did not last. Although a few of the complete responders were still alive and in CR at the study’s 2-year follow-up, more than half had relapsed, and two-thirds had died.
This trial, known as Study ‘205, was supported by Amgen.
Study ‘205 included 93 pediatric patients with relapsed or refractory B-cell precursor ALL. Patients received blinatumomab as a continuous intravenous infusion—49 patients in the phase 1 portion of the trial and 44 in phase 2. The patients were followed for 2 years.
Toxicities and recommended dose
There were 4 dose-limiting toxicities during the phase 1 portion of the trial, and 2 of these events were fatal. One patient treated at 15 μg/m2/day developed grade 4 cytokine release syndrome (CRS), which was deemed related to grade 4 gastrointestinal hemorrhage.
Two patients treated at 30 μg/m2/day had grade 4 CRS. One case was attributed to grade 5 cardiac failure, and the other was treated successfully with tocilizumab.
One patient treated at 15 μg/m2/day had grade 5 respiratory failure with cardiac arrest after hypotonia and muscle weakness after 7 days of infusion with blinatumomab. This patient experienced febrile neutropenia and pneumonia shortly before the start of the infusion.
Based on these toxicities, the maximum-tolerated dose of blinatumomab was 15 μg/m2/day, but a step-wise dosage was recommended to reduce the risk of CRS.
So the recommended dose was 5 μg/m2/day on days 1-7 and 15 μg/m2/day on days 8-28 for cycle 1, and 15 μg/m2/day on days 1-28 for subsequent cycles.
Dose adjustment was possible in case of adverse events. Patients who responded to blinatumomab but later relapsed had the option to be retreated with blinatumomab.
Treatment at recommended dose
Seventy patients received at least 1 infusion of blinatumomab at the recommended dose. The median number of treatment cycles was 1 (range, 1 to 5).
The patients’ median age was 8 years (range, 7 months to 17 years). Forty patients (57%) had undergone allogeneic transplant prior to receiving blinatumomab, and 39 (56%) had refractory disease. Four patients had less than the 25% bone marrow blasts required for protocol entry but had more than 5% blasts.
Adverse events
The most common adverse events among the patients who received the recommended dose of blinatumomab were pyrexia (80%), anemia (41%), nausea (33%), and headache (30%).
The most frequent grade 3 or higher events were anemia (36%), thrombocytopenia (21%), febrile neutropenia (17%), hypokalemia (17%), and neutropenia (17%).
Eight patients developed CRS. Three had grade 3 and 1 had grade 4 CRS. Two of these patients had treatment interruptions, and 2 discontinued treatment permanently. All 4 patients achieved a CR.
Ten patients (14%) had treatment interruptions due to adverse events, and 4 (6%) discontinued treatment permanently because of adverse events.
Six patients had fatal adverse events. Three died after they went on to allogeneic transplant—1 of multiorgan failure, 1 of sepsis, and 1 of respiratory failure. The 3 other deaths were due to fungal infection, multiorgan failure, and thrombocytopenia.
Response and follow-up
Among the 70 patients who received the recommended dose of blinatumomab, 27 (39%) achieved a CR within the first 2 cycles. Fourteen of these patients (52%) achieved complete MRD response.
CRs were achieved across subgroups, and complete MRD response rates were similar across subgroups.
Thirteen of the 27 patients (48%) who achieved a CR went on to receive an allogeneic transplant.
At the end of the 2-year follow-up, 4 of the 27 complete responders were still in remission.
Two of the patients had relapsed but were still alive, 3 had withdrawn consent (1 in CR and 2 after relapse), 3 had died in CR after transplant, and 15 had relapsed and died.
Of the 43 patients who did not achieve a CR within the first 2 treatment cycles, 8 were still alive at the end of the 2-year follow-up.
The bispecific T-cell engager (BiTE®) antibody blinatumomab can produce complete responses (CRs) in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (ALL), according to a phase 1/2 study published in the Journal of Clinical Oncology.
Of the patients who received the recommended dosage of blinatumomab, 39% achieved a CR within the first 2 treatment cycles.
And 52% of these patients achieved a complete minimal residual disease (MRD) response.
“This study showed that [blinatumomab] can induce deep molecular remissions in children with highly refractory, multiply relapsed ALL,” said study author Lia Gore, MD, of University of Colorado Anschutz Medical Campus in Aurora, Colorado.
However, most of these remissions did not last. Although a few of the complete responders were still alive and in CR at the study’s 2-year follow-up, more than half had relapsed, and two-thirds had died.
This trial, known as Study ‘205, was supported by Amgen.
Study ‘205 included 93 pediatric patients with relapsed or refractory B-cell precursor ALL. Patients received blinatumomab as a continuous intravenous infusion—49 patients in the phase 1 portion of the trial and 44 in phase 2. The patients were followed for 2 years.
Toxicities and recommended dose
There were 4 dose-limiting toxicities during the phase 1 portion of the trial, and 2 of these events were fatal. One patient treated at 15 μg/m2/day developed grade 4 cytokine release syndrome (CRS), which was deemed related to grade 4 gastrointestinal hemorrhage.
Two patients treated at 30 μg/m2/day had grade 4 CRS. One case was attributed to grade 5 cardiac failure, and the other was treated successfully with tocilizumab.
One patient treated at 15 μg/m2/day had grade 5 respiratory failure with cardiac arrest after hypotonia and muscle weakness after 7 days of infusion with blinatumomab. This patient experienced febrile neutropenia and pneumonia shortly before the start of the infusion.
Based on these toxicities, the maximum-tolerated dose of blinatumomab was 15 μg/m2/day, but a step-wise dosage was recommended to reduce the risk of CRS.
So the recommended dose was 5 μg/m2/day on days 1-7 and 15 μg/m2/day on days 8-28 for cycle 1, and 15 μg/m2/day on days 1-28 for subsequent cycles.
Dose adjustment was possible in case of adverse events. Patients who responded to blinatumomab but later relapsed had the option to be retreated with blinatumomab.
Treatment at recommended dose
Seventy patients received at least 1 infusion of blinatumomab at the recommended dose. The median number of treatment cycles was 1 (range, 1 to 5).
The patients’ median age was 8 years (range, 7 months to 17 years). Forty patients (57%) had undergone allogeneic transplant prior to receiving blinatumomab, and 39 (56%) had refractory disease. Four patients had less than the 25% bone marrow blasts required for protocol entry but had more than 5% blasts.
Adverse events
The most common adverse events among the patients who received the recommended dose of blinatumomab were pyrexia (80%), anemia (41%), nausea (33%), and headache (30%).
The most frequent grade 3 or higher events were anemia (36%), thrombocytopenia (21%), febrile neutropenia (17%), hypokalemia (17%), and neutropenia (17%).
Eight patients developed CRS. Three had grade 3 and 1 had grade 4 CRS. Two of these patients had treatment interruptions, and 2 discontinued treatment permanently. All 4 patients achieved a CR.
Ten patients (14%) had treatment interruptions due to adverse events, and 4 (6%) discontinued treatment permanently because of adverse events.
Six patients had fatal adverse events. Three died after they went on to allogeneic transplant—1 of multiorgan failure, 1 of sepsis, and 1 of respiratory failure. The 3 other deaths were due to fungal infection, multiorgan failure, and thrombocytopenia.
Response and follow-up
Among the 70 patients who received the recommended dose of blinatumomab, 27 (39%) achieved a CR within the first 2 cycles. Fourteen of these patients (52%) achieved complete MRD response.
CRs were achieved across subgroups, and complete MRD response rates were similar across subgroups.
Thirteen of the 27 patients (48%) who achieved a CR went on to receive an allogeneic transplant.
At the end of the 2-year follow-up, 4 of the 27 complete responders were still in remission.
Two of the patients had relapsed but were still alive, 3 had withdrawn consent (1 in CR and 2 after relapse), 3 had died in CR after transplant, and 15 had relapsed and died.
Of the 43 patients who did not achieve a CR within the first 2 treatment cycles, 8 were still alive at the end of the 2-year follow-up.
Speaker outlines importance of cell of origin in DLBCL
NEW YORK—The importance of cell of origin in choosing a treatment for diffuse large B-cell lymphoma (DLBCL) is a topic “that has been kicking around for 16 years,” according to a speaker at the NCCN 11th Annual Congress: Hematologic Malignancies.
Cell of origin was first described in the year 2000 as a distinguishing factor in large-cell lymphoma, said the speaker, Andrew Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, New York.
The cell of origin in DLBCL—whether it’s germinal center B cell (GCB), activated B cell (ABC), or unclassified—contributes to biological and clinical heterogeneity of the disease.
“And more importantly, activated B-cell diffuse large B-cell lymphoma and germinal center diffuse large B-cell lymphoma are simply different diseases,” Dr Zelenetz said.
He then elaborated on the importance of cell of origin in treating DLBCL.
Biology
Dr Zelenetz noted that ABC and GCB lymphomas have different molecular pathways. ABC lymphomas are very dependent on the NF-kB pathway and have more active signaling through the B-cell receptor.
The GCB lymphomas tend to have more tonic regulation, and the PI3 kinase/mTOR pathway is more critical. GCB lymphomas have more genomic instability.
“So cell of origin determination identifies tumors with distinct biology, may provide prognostic information, and may be predictive for treatment selection,” Dr Zelenetz said. “Unfortunately, cell of origin is not the whole story.”
Gene mutations occur in large-cell lymphoma “just like every other cancer,” Dr Zelenetz said. And the vast majority occur in both lymphoma subtypes, he added, further complicating our understanding of the biology of these tumors.
Some of these mutations predict for sensitivity to treatment, while others predict for resistance. For example, CARD11 predicts for resistance to ibrutinib, while CD79b predicts for sensitivity.
Determining the cell of origin
Gene-expression profiling on fresh tissue is considered the gold standard, but “it is clearly not a clinical tool,” Dr Zelenetz said. It requires the Wright classifier, a statistical method based on Bayes’ rule, to make patient-level assignments to 1 of the 3 subgroups.
Immunohistochemistry is widely available, but reproducibility may be difficult. Many assays exist, such as the Hans, Choi, and Muris assays, but, in many studies, there may be a lack of correlation with gene-expression profiling.
In the last few years, gene-expression profiling of formalin‐fixed paraffin‐embedded (FFPE) tissue has emerged as a reliable method. The assay is reproducible between laboratories, and it’s reproducible between different sets of reagents.
“[T]here is tremendous correlation between the Lymph2Cx assay and the gold standard,” Dr Zelenetz added.
“So here we have a robust assay,” he said, which allows investigators to explore whether the cell of origin is prognostic in large-cell lymphoma.
Prognosis
In a data set of 339 patients with de novo DLBCL treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), the Lymph2Cx assay showing cell of origin was predictive of overall and progression-free survival.
However, the same exact assay applied to the RICOVER-60 data from the German High-Grade Non-Hodgkin Lymphoma Study group was not predictive, Dr Zelenetz reported, based on a personal communication from one of the investigators. There was a slight trend in favor of GCB tumors, but it was not statistically significant.
And the REMoDL-B study, using gene-expression profiling of FFPE tissue with the DASL assay, also didn’t show any difference in outcome between ABC or GCB tumors.
So gene-expression profiling of FFPE tissue does not universally show a prognostic difference, Dr Zelenetz said.
Influence of chemotherapy by cell of origin
CALGB 59910 showed that GCB tumors had a superior event-free, progression-free, and overall survival with dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) compared to ABC tumors.
“However, this is a phase 2, hypothesis-generating experiment,” Dr Zelenetz pointed out, and the results of the confirmatory study comparing dose-adjusted EPOCH-R and R-CHOP21 (CALGB 50303) will be presented later this year at the ASH Annual Meeting.
Sequential, non-cross-resistant chemotherapy
Data from the Memorial Sloan Kettering study (MSKCC 01-142/08-146; NCT00712582) of sequential therapy with R-CHOP followed by ICE (ifosfamide, carboplatin, and etoposide) demonstrate “excellent” progression-free and overall survival, Dr Zelenetz said.
“When we analyzed the outcome by cell of origin, there was a suggestion that the patients with the non-germinal center tumors were actually doing better than the germinal center tumors,” he added.
He pointed out one of the limitations of the study is that the cell of origin was determined by the Hans model. Nevertheless, the study raised another testable hypothesis: sequential therapy might overcome the adverse impact of the non-germinal center tumors.
Cell of origin analysis of the prospective, randomized study (LNH 03-2B) comparing R-ACVBP (rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone) to R-CHOP showed that whether patients with GCB tumors received CHOP or ACVBP didn’t make “a whit of difference,” Dr Zelenetz said, in terms of progression-free and overall survival.
However, patients with ABC tumors demonstrated an “enormous difference in favor of R-ACVBP,” he said.
“Again, evidence that you can overcome the adverse effect of the ABC tumors with chemotherapy.”
Dr Zelenetz pointed out that R-ACVBP and R-CHOP followed by ICE are “actually remarkably similar regimens.” Both are sequential, both include consolidation, and both incorporate high-dose ifosfamide and etoposide.
“[S]o they actually reinforce each other,” he said, “demonstrating a similar result.”
Lenalidomide
Lenalidomide in the relapsed/refractory setting has modest activity in DLBCL, with most of the benefit accruing to patients with non-germinal center tumors.
Two clinical studies evaluated the impact of adding lenalidomide to standard chemotherapy.
In an Italian series using lenalidomide (L) plus R-CHOP21 in elderly untreated patients, the combination produced outstanding progression-free and event-free survival, but with no significant differences between the subtypes.
A US study of RL-CHOP versus R-CHOP included 87 matched historical controls treated with R-CHOP and 64 patients treated with RL-CHOP. Patients with non-germinal center tumors treated with RL-CHOP fared much better than historical controls treated with R-CHOP.
However, among germinal center tumors, “there was not a hint of any difference,” Dr Zelenetz noted.
Two studies—E1412, using an unselected population, and the international ROBUST study, selecting for patients with ABC tumors—are underway to confirm that the benefit with lenalidomide is in patients with activated B-cell tumors.
Ibrutinib
Ibrutinib, a Bruton’s tyrosine kinase inhibitor, also has modest activity as a single agent in an unselected patient population with relapsed/refractory DLBCL. And most of the patients who demonstrated benefit had activated B-cell tumors.
Upon further analysis, investigators found that response was enhanced by the CD79b mutation, but it was not necessary for a response. And patients with CARD11 had no response.
MYD88 mutations seemed to cause resistance to ibrutinib, unless the mutation was associated with the CD79b mutation, and then patients had a “great” response, Dr Zelenetz explained.
In the upfront setting, a phase 1b study of R-CHOP plus ibrutinib demonstrated the safety of the combination, which had an overall survival rate of 100% and a complete response rate of 91%.
The prospective, randomized, phase 3 PHOENIX trial (NCT01855750) evaluating the combination in newly diagnosed non-germinal center DLBCL has completed accrual, but analysis is still pending.
Conclusion
“The prognostic significance of cell of origin is still controversial,” Dr Zelenetz wrapped up, “although I actually believe there is a prognostic difference in unselected registry patients.”
Sequential chemotherapy with ifosfamide and etoposide consolidation does very well in activated B-cell tumors, both in phase 2 and phase 3 studies.
“Importantly, small molecules seem to have differential effects totally predictable based on the biology of the difference between activated B-cell and germinal center tumors,” Dr Zelenetz said.
“But the big wild card here is somatic mutations further complicate things and will have to be incorporated into our understanding in the selection of patients.”
NEW YORK—The importance of cell of origin in choosing a treatment for diffuse large B-cell lymphoma (DLBCL) is a topic “that has been kicking around for 16 years,” according to a speaker at the NCCN 11th Annual Congress: Hematologic Malignancies.
Cell of origin was first described in the year 2000 as a distinguishing factor in large-cell lymphoma, said the speaker, Andrew Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, New York.
The cell of origin in DLBCL—whether it’s germinal center B cell (GCB), activated B cell (ABC), or unclassified—contributes to biological and clinical heterogeneity of the disease.
“And more importantly, activated B-cell diffuse large B-cell lymphoma and germinal center diffuse large B-cell lymphoma are simply different diseases,” Dr Zelenetz said.
He then elaborated on the importance of cell of origin in treating DLBCL.
Biology
Dr Zelenetz noted that ABC and GCB lymphomas have different molecular pathways. ABC lymphomas are very dependent on the NF-kB pathway and have more active signaling through the B-cell receptor.
The GCB lymphomas tend to have more tonic regulation, and the PI3 kinase/mTOR pathway is more critical. GCB lymphomas have more genomic instability.
“So cell of origin determination identifies tumors with distinct biology, may provide prognostic information, and may be predictive for treatment selection,” Dr Zelenetz said. “Unfortunately, cell of origin is not the whole story.”
Gene mutations occur in large-cell lymphoma “just like every other cancer,” Dr Zelenetz said. And the vast majority occur in both lymphoma subtypes, he added, further complicating our understanding of the biology of these tumors.
Some of these mutations predict for sensitivity to treatment, while others predict for resistance. For example, CARD11 predicts for resistance to ibrutinib, while CD79b predicts for sensitivity.
Determining the cell of origin
Gene-expression profiling on fresh tissue is considered the gold standard, but “it is clearly not a clinical tool,” Dr Zelenetz said. It requires the Wright classifier, a statistical method based on Bayes’ rule, to make patient-level assignments to 1 of the 3 subgroups.
Immunohistochemistry is widely available, but reproducibility may be difficult. Many assays exist, such as the Hans, Choi, and Muris assays, but, in many studies, there may be a lack of correlation with gene-expression profiling.
In the last few years, gene-expression profiling of formalin‐fixed paraffin‐embedded (FFPE) tissue has emerged as a reliable method. The assay is reproducible between laboratories, and it’s reproducible between different sets of reagents.
“[T]here is tremendous correlation between the Lymph2Cx assay and the gold standard,” Dr Zelenetz added.
“So here we have a robust assay,” he said, which allows investigators to explore whether the cell of origin is prognostic in large-cell lymphoma.
Prognosis
In a data set of 339 patients with de novo DLBCL treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), the Lymph2Cx assay showing cell of origin was predictive of overall and progression-free survival.
However, the same exact assay applied to the RICOVER-60 data from the German High-Grade Non-Hodgkin Lymphoma Study group was not predictive, Dr Zelenetz reported, based on a personal communication from one of the investigators. There was a slight trend in favor of GCB tumors, but it was not statistically significant.
And the REMoDL-B study, using gene-expression profiling of FFPE tissue with the DASL assay, also didn’t show any difference in outcome between ABC or GCB tumors.
So gene-expression profiling of FFPE tissue does not universally show a prognostic difference, Dr Zelenetz said.
Influence of chemotherapy by cell of origin
CALGB 59910 showed that GCB tumors had a superior event-free, progression-free, and overall survival with dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) compared to ABC tumors.
“However, this is a phase 2, hypothesis-generating experiment,” Dr Zelenetz pointed out, and the results of the confirmatory study comparing dose-adjusted EPOCH-R and R-CHOP21 (CALGB 50303) will be presented later this year at the ASH Annual Meeting.
Sequential, non-cross-resistant chemotherapy
Data from the Memorial Sloan Kettering study (MSKCC 01-142/08-146; NCT00712582) of sequential therapy with R-CHOP followed by ICE (ifosfamide, carboplatin, and etoposide) demonstrate “excellent” progression-free and overall survival, Dr Zelenetz said.
“When we analyzed the outcome by cell of origin, there was a suggestion that the patients with the non-germinal center tumors were actually doing better than the germinal center tumors,” he added.
He pointed out one of the limitations of the study is that the cell of origin was determined by the Hans model. Nevertheless, the study raised another testable hypothesis: sequential therapy might overcome the adverse impact of the non-germinal center tumors.
Cell of origin analysis of the prospective, randomized study (LNH 03-2B) comparing R-ACVBP (rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone) to R-CHOP showed that whether patients with GCB tumors received CHOP or ACVBP didn’t make “a whit of difference,” Dr Zelenetz said, in terms of progression-free and overall survival.
However, patients with ABC tumors demonstrated an “enormous difference in favor of R-ACVBP,” he said.
“Again, evidence that you can overcome the adverse effect of the ABC tumors with chemotherapy.”
Dr Zelenetz pointed out that R-ACVBP and R-CHOP followed by ICE are “actually remarkably similar regimens.” Both are sequential, both include consolidation, and both incorporate high-dose ifosfamide and etoposide.
“[S]o they actually reinforce each other,” he said, “demonstrating a similar result.”
Lenalidomide
Lenalidomide in the relapsed/refractory setting has modest activity in DLBCL, with most of the benefit accruing to patients with non-germinal center tumors.
Two clinical studies evaluated the impact of adding lenalidomide to standard chemotherapy.
In an Italian series using lenalidomide (L) plus R-CHOP21 in elderly untreated patients, the combination produced outstanding progression-free and event-free survival, but with no significant differences between the subtypes.
A US study of RL-CHOP versus R-CHOP included 87 matched historical controls treated with R-CHOP and 64 patients treated with RL-CHOP. Patients with non-germinal center tumors treated with RL-CHOP fared much better than historical controls treated with R-CHOP.
However, among germinal center tumors, “there was not a hint of any difference,” Dr Zelenetz noted.
Two studies—E1412, using an unselected population, and the international ROBUST study, selecting for patients with ABC tumors—are underway to confirm that the benefit with lenalidomide is in patients with activated B-cell tumors.
Ibrutinib
Ibrutinib, a Bruton’s tyrosine kinase inhibitor, also has modest activity as a single agent in an unselected patient population with relapsed/refractory DLBCL. And most of the patients who demonstrated benefit had activated B-cell tumors.
Upon further analysis, investigators found that response was enhanced by the CD79b mutation, but it was not necessary for a response. And patients with CARD11 had no response.
MYD88 mutations seemed to cause resistance to ibrutinib, unless the mutation was associated with the CD79b mutation, and then patients had a “great” response, Dr Zelenetz explained.
In the upfront setting, a phase 1b study of R-CHOP plus ibrutinib demonstrated the safety of the combination, which had an overall survival rate of 100% and a complete response rate of 91%.
The prospective, randomized, phase 3 PHOENIX trial (NCT01855750) evaluating the combination in newly diagnosed non-germinal center DLBCL has completed accrual, but analysis is still pending.
Conclusion
“The prognostic significance of cell of origin is still controversial,” Dr Zelenetz wrapped up, “although I actually believe there is a prognostic difference in unselected registry patients.”
Sequential chemotherapy with ifosfamide and etoposide consolidation does very well in activated B-cell tumors, both in phase 2 and phase 3 studies.
“Importantly, small molecules seem to have differential effects totally predictable based on the biology of the difference between activated B-cell and germinal center tumors,” Dr Zelenetz said.
“But the big wild card here is somatic mutations further complicate things and will have to be incorporated into our understanding in the selection of patients.”
NEW YORK—The importance of cell of origin in choosing a treatment for diffuse large B-cell lymphoma (DLBCL) is a topic “that has been kicking around for 16 years,” according to a speaker at the NCCN 11th Annual Congress: Hematologic Malignancies.
Cell of origin was first described in the year 2000 as a distinguishing factor in large-cell lymphoma, said the speaker, Andrew Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, New York.
The cell of origin in DLBCL—whether it’s germinal center B cell (GCB), activated B cell (ABC), or unclassified—contributes to biological and clinical heterogeneity of the disease.
“And more importantly, activated B-cell diffuse large B-cell lymphoma and germinal center diffuse large B-cell lymphoma are simply different diseases,” Dr Zelenetz said.
He then elaborated on the importance of cell of origin in treating DLBCL.
Biology
Dr Zelenetz noted that ABC and GCB lymphomas have different molecular pathways. ABC lymphomas are very dependent on the NF-kB pathway and have more active signaling through the B-cell receptor.
The GCB lymphomas tend to have more tonic regulation, and the PI3 kinase/mTOR pathway is more critical. GCB lymphomas have more genomic instability.
“So cell of origin determination identifies tumors with distinct biology, may provide prognostic information, and may be predictive for treatment selection,” Dr Zelenetz said. “Unfortunately, cell of origin is not the whole story.”
Gene mutations occur in large-cell lymphoma “just like every other cancer,” Dr Zelenetz said. And the vast majority occur in both lymphoma subtypes, he added, further complicating our understanding of the biology of these tumors.
Some of these mutations predict for sensitivity to treatment, while others predict for resistance. For example, CARD11 predicts for resistance to ibrutinib, while CD79b predicts for sensitivity.
Determining the cell of origin
Gene-expression profiling on fresh tissue is considered the gold standard, but “it is clearly not a clinical tool,” Dr Zelenetz said. It requires the Wright classifier, a statistical method based on Bayes’ rule, to make patient-level assignments to 1 of the 3 subgroups.
Immunohistochemistry is widely available, but reproducibility may be difficult. Many assays exist, such as the Hans, Choi, and Muris assays, but, in many studies, there may be a lack of correlation with gene-expression profiling.
In the last few years, gene-expression profiling of formalin‐fixed paraffin‐embedded (FFPE) tissue has emerged as a reliable method. The assay is reproducible between laboratories, and it’s reproducible between different sets of reagents.
“[T]here is tremendous correlation between the Lymph2Cx assay and the gold standard,” Dr Zelenetz added.
“So here we have a robust assay,” he said, which allows investigators to explore whether the cell of origin is prognostic in large-cell lymphoma.
Prognosis
In a data set of 339 patients with de novo DLBCL treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), the Lymph2Cx assay showing cell of origin was predictive of overall and progression-free survival.
However, the same exact assay applied to the RICOVER-60 data from the German High-Grade Non-Hodgkin Lymphoma Study group was not predictive, Dr Zelenetz reported, based on a personal communication from one of the investigators. There was a slight trend in favor of GCB tumors, but it was not statistically significant.
And the REMoDL-B study, using gene-expression profiling of FFPE tissue with the DASL assay, also didn’t show any difference in outcome between ABC or GCB tumors.
So gene-expression profiling of FFPE tissue does not universally show a prognostic difference, Dr Zelenetz said.
Influence of chemotherapy by cell of origin
CALGB 59910 showed that GCB tumors had a superior event-free, progression-free, and overall survival with dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) compared to ABC tumors.
“However, this is a phase 2, hypothesis-generating experiment,” Dr Zelenetz pointed out, and the results of the confirmatory study comparing dose-adjusted EPOCH-R and R-CHOP21 (CALGB 50303) will be presented later this year at the ASH Annual Meeting.
Sequential, non-cross-resistant chemotherapy
Data from the Memorial Sloan Kettering study (MSKCC 01-142/08-146; NCT00712582) of sequential therapy with R-CHOP followed by ICE (ifosfamide, carboplatin, and etoposide) demonstrate “excellent” progression-free and overall survival, Dr Zelenetz said.
“When we analyzed the outcome by cell of origin, there was a suggestion that the patients with the non-germinal center tumors were actually doing better than the germinal center tumors,” he added.
He pointed out one of the limitations of the study is that the cell of origin was determined by the Hans model. Nevertheless, the study raised another testable hypothesis: sequential therapy might overcome the adverse impact of the non-germinal center tumors.
Cell of origin analysis of the prospective, randomized study (LNH 03-2B) comparing R-ACVBP (rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone) to R-CHOP showed that whether patients with GCB tumors received CHOP or ACVBP didn’t make “a whit of difference,” Dr Zelenetz said, in terms of progression-free and overall survival.
However, patients with ABC tumors demonstrated an “enormous difference in favor of R-ACVBP,” he said.
“Again, evidence that you can overcome the adverse effect of the ABC tumors with chemotherapy.”
Dr Zelenetz pointed out that R-ACVBP and R-CHOP followed by ICE are “actually remarkably similar regimens.” Both are sequential, both include consolidation, and both incorporate high-dose ifosfamide and etoposide.
“[S]o they actually reinforce each other,” he said, “demonstrating a similar result.”
Lenalidomide
Lenalidomide in the relapsed/refractory setting has modest activity in DLBCL, with most of the benefit accruing to patients with non-germinal center tumors.
Two clinical studies evaluated the impact of adding lenalidomide to standard chemotherapy.
In an Italian series using lenalidomide (L) plus R-CHOP21 in elderly untreated patients, the combination produced outstanding progression-free and event-free survival, but with no significant differences between the subtypes.
A US study of RL-CHOP versus R-CHOP included 87 matched historical controls treated with R-CHOP and 64 patients treated with RL-CHOP. Patients with non-germinal center tumors treated with RL-CHOP fared much better than historical controls treated with R-CHOP.
However, among germinal center tumors, “there was not a hint of any difference,” Dr Zelenetz noted.
Two studies—E1412, using an unselected population, and the international ROBUST study, selecting for patients with ABC tumors—are underway to confirm that the benefit with lenalidomide is in patients with activated B-cell tumors.
Ibrutinib
Ibrutinib, a Bruton’s tyrosine kinase inhibitor, also has modest activity as a single agent in an unselected patient population with relapsed/refractory DLBCL. And most of the patients who demonstrated benefit had activated B-cell tumors.
Upon further analysis, investigators found that response was enhanced by the CD79b mutation, but it was not necessary for a response. And patients with CARD11 had no response.
MYD88 mutations seemed to cause resistance to ibrutinib, unless the mutation was associated with the CD79b mutation, and then patients had a “great” response, Dr Zelenetz explained.
In the upfront setting, a phase 1b study of R-CHOP plus ibrutinib demonstrated the safety of the combination, which had an overall survival rate of 100% and a complete response rate of 91%.
The prospective, randomized, phase 3 PHOENIX trial (NCT01855750) evaluating the combination in newly diagnosed non-germinal center DLBCL has completed accrual, but analysis is still pending.
Conclusion
“The prognostic significance of cell of origin is still controversial,” Dr Zelenetz wrapped up, “although I actually believe there is a prognostic difference in unselected registry patients.”
Sequential chemotherapy with ifosfamide and etoposide consolidation does very well in activated B-cell tumors, both in phase 2 and phase 3 studies.
“Importantly, small molecules seem to have differential effects totally predictable based on the biology of the difference between activated B-cell and germinal center tumors,” Dr Zelenetz said.
“But the big wild card here is somatic mutations further complicate things and will have to be incorporated into our understanding in the selection of patients.”
Study shows more bleeding with rivaroxaban than dabigatran
A large, retrospective study comparing first-time users of rivaroxaban and dabigatran suggests that rivaroxaban poses a higher risk of bleeding in elderly patients with nonvalvular atrial fibrillation (NVAF).
Treatment with rivaroxaban was associated with significant increases in intracranial hemorrhage (ICH) and major extracranial bleeding, a nonsignificant reduction in thromboembolic stroke, and a nonsignificant increase in mortality.
David J. Graham, MD, of the US Food and Drug Administration in Silver Spring, Maryland, and his colleagues reported these results in JAMA Internal Medicine.
The investigators analyzed 118,891 NVAF patients older than 65 who were enrolled in Medicare. The patients had started treatment with dabigatran (150 mg twice daily) or rivaroxaban (20 mg once daily) from November 4, 2011, through June 30, 2014.
There were 52,240 patients receiving dabigatran and 66,651 receiving rivaroxaban.
The study’s primary outcomes were thromboembolic stroke, ICH, major extracranial bleeding events (including major gastrointestinal bleeding), and mortality.
The investigators adjusted for differences in baseline characteristics and calculated hazard ratios (HRs) for the primary outcomes. They also calculated adjusted incidence rate differences.
The data showed that, compared to patients who received dabigatran, those who received rivaroxaban had:
- 1.8 fewer cases of thromboembolic stroke per 1000 person-years (HR=0.81; 95% CI, 0.65-1.01; P=0.07)
- 2.3 excess cases of ICH per 1000 person-years (HR=1.65; 95% CI, 1.20-2.26; P=0.002)
- 13.0 excess cases of major extracranial bleeding per 1000 person-years (HR=1.48; 95% CI, 1.32-1.67; P<0.001)
- 9.4 excess cases of major gastrointestinal bleeding per 1000 person-years (HR=1.40; 95% CI, 1.23-1.59; P<0.001)
- 3.1 excess deaths per 1000 person-years (HR=1.15; 95% CI, 1.00-1.32; P=0.051).
The investigators noted that this study had several limitations. The mean follow-up time was 4 months, which led to a smaller sample size at longer durations of use.
In addition, the study was restricted to patients age 65 and older. Although this age group accounts for 80% of patients with NVAF, the comparative effects of treatment with dabigatran and rivaroxaban could be different in younger populations.
Because the study was observational, it may also be subject to residual confounding by unmeasured factors.
And finally, the investigators examined warfarin-naïve, first-time users of dabigatran and rivaroxaban. Results could differ in patients switching from warfarin to a novel oral anticoagulant.
A large, retrospective study comparing first-time users of rivaroxaban and dabigatran suggests that rivaroxaban poses a higher risk of bleeding in elderly patients with nonvalvular atrial fibrillation (NVAF).
Treatment with rivaroxaban was associated with significant increases in intracranial hemorrhage (ICH) and major extracranial bleeding, a nonsignificant reduction in thromboembolic stroke, and a nonsignificant increase in mortality.
David J. Graham, MD, of the US Food and Drug Administration in Silver Spring, Maryland, and his colleagues reported these results in JAMA Internal Medicine.
The investigators analyzed 118,891 NVAF patients older than 65 who were enrolled in Medicare. The patients had started treatment with dabigatran (150 mg twice daily) or rivaroxaban (20 mg once daily) from November 4, 2011, through June 30, 2014.
There were 52,240 patients receiving dabigatran and 66,651 receiving rivaroxaban.
The study’s primary outcomes were thromboembolic stroke, ICH, major extracranial bleeding events (including major gastrointestinal bleeding), and mortality.
The investigators adjusted for differences in baseline characteristics and calculated hazard ratios (HRs) for the primary outcomes. They also calculated adjusted incidence rate differences.
The data showed that, compared to patients who received dabigatran, those who received rivaroxaban had:
- 1.8 fewer cases of thromboembolic stroke per 1000 person-years (HR=0.81; 95% CI, 0.65-1.01; P=0.07)
- 2.3 excess cases of ICH per 1000 person-years (HR=1.65; 95% CI, 1.20-2.26; P=0.002)
- 13.0 excess cases of major extracranial bleeding per 1000 person-years (HR=1.48; 95% CI, 1.32-1.67; P<0.001)
- 9.4 excess cases of major gastrointestinal bleeding per 1000 person-years (HR=1.40; 95% CI, 1.23-1.59; P<0.001)
- 3.1 excess deaths per 1000 person-years (HR=1.15; 95% CI, 1.00-1.32; P=0.051).
The investigators noted that this study had several limitations. The mean follow-up time was 4 months, which led to a smaller sample size at longer durations of use.
In addition, the study was restricted to patients age 65 and older. Although this age group accounts for 80% of patients with NVAF, the comparative effects of treatment with dabigatran and rivaroxaban could be different in younger populations.
Because the study was observational, it may also be subject to residual confounding by unmeasured factors.
And finally, the investigators examined warfarin-naïve, first-time users of dabigatran and rivaroxaban. Results could differ in patients switching from warfarin to a novel oral anticoagulant.
A large, retrospective study comparing first-time users of rivaroxaban and dabigatran suggests that rivaroxaban poses a higher risk of bleeding in elderly patients with nonvalvular atrial fibrillation (NVAF).
Treatment with rivaroxaban was associated with significant increases in intracranial hemorrhage (ICH) and major extracranial bleeding, a nonsignificant reduction in thromboembolic stroke, and a nonsignificant increase in mortality.
David J. Graham, MD, of the US Food and Drug Administration in Silver Spring, Maryland, and his colleagues reported these results in JAMA Internal Medicine.
The investigators analyzed 118,891 NVAF patients older than 65 who were enrolled in Medicare. The patients had started treatment with dabigatran (150 mg twice daily) or rivaroxaban (20 mg once daily) from November 4, 2011, through June 30, 2014.
There were 52,240 patients receiving dabigatran and 66,651 receiving rivaroxaban.
The study’s primary outcomes were thromboembolic stroke, ICH, major extracranial bleeding events (including major gastrointestinal bleeding), and mortality.
The investigators adjusted for differences in baseline characteristics and calculated hazard ratios (HRs) for the primary outcomes. They also calculated adjusted incidence rate differences.
The data showed that, compared to patients who received dabigatran, those who received rivaroxaban had:
- 1.8 fewer cases of thromboembolic stroke per 1000 person-years (HR=0.81; 95% CI, 0.65-1.01; P=0.07)
- 2.3 excess cases of ICH per 1000 person-years (HR=1.65; 95% CI, 1.20-2.26; P=0.002)
- 13.0 excess cases of major extracranial bleeding per 1000 person-years (HR=1.48; 95% CI, 1.32-1.67; P<0.001)
- 9.4 excess cases of major gastrointestinal bleeding per 1000 person-years (HR=1.40; 95% CI, 1.23-1.59; P<0.001)
- 3.1 excess deaths per 1000 person-years (HR=1.15; 95% CI, 1.00-1.32; P=0.051).
The investigators noted that this study had several limitations. The mean follow-up time was 4 months, which led to a smaller sample size at longer durations of use.
In addition, the study was restricted to patients age 65 and older. Although this age group accounts for 80% of patients with NVAF, the comparative effects of treatment with dabigatran and rivaroxaban could be different in younger populations.
Because the study was observational, it may also be subject to residual confounding by unmeasured factors.
And finally, the investigators examined warfarin-naïve, first-time users of dabigatran and rivaroxaban. Results could differ in patients switching from warfarin to a novel oral anticoagulant.
Triplet improves PFS in relapsed/refractory MM
Results of the phase 3 POLLUX trial suggest that adding daratumumab to treatment with lenalidomide and dexamethasone can improve progression-free survival (PFS) in patients with relapsed or refractory multiple myeloma (MM).
Compared to patients who received only lenalidomide and dexamethasone, those who received daratumumab as well had a significantly higher response rate and longer PFS.
Treatment with daratumumab was also associated with infusion-related reactions and a higher incidence of neutropenia.
These results were published in NEJM. They were previously presented at the 21st Congress of the European Hematology Association. The POLLUX trial was funded by Janssen Research and Development.
POLLUX enrolled 569 patients who had relapsed or refractory MM. The patients were randomized to receive either daratumumab, lenalidomide, and dexamethasone (DRd, n=286) or lenalidomide and dexamethasone alone (Rd, n=283).
Patient characteristics were similar between the treatment arms. The median age was 65 in both arms (overall range, 34-89). About half of patients in each arm had ISS stage I disease, about half had an ECOG performance score of 1 or 2, and patients were, roughly, a median of 4 years from diagnosis.
In both arms, patients had a median of 1 prior lines of therapy (overall range, 1-11).
More than 60% of patients in both arms (63%-64%) had received a prior transplant; 86% had received a proteasome inhibitor; 55% had received an immunomodulatory agent; 44% had received a proteasome inhibitor and an immunomodulatory agent; and 41%-43% had received a proteasome inhibitor, an immunomodulatory agent, and an alkylating agent.
Discontinuation
At the clinical cutoff date on March 7, 2016, 23.3% (n=66) of patients in the DRd arm and 47.0% (n=132) of those in the Rd arm discontinued treatment.
The most common reasons for discontinuation were progression (14.1% in the DRd arm and 34.2% in the Rd arm) and adverse events (6.7% and 8.2%, respectively).
Response
The overall response rate among evaluable patients (281 in the DRd arm and 276 in the Rd arm) was 92.9% in DRd arm and 76.4% in the Rd arm (P<0.001).
The rates of complete response or better were 43.1% and 19.2%, respectively. And the rates of stringent complete response were 18.1% and 7.2%, respectively.
In the DRd arm, 22.4% of patients had results below the threshold for minimal residual disease (1 tumor cell per 105 white cells). The same was true for 4.6% of patients in the Rd arm (P<0.001).
PFS and OS
At a median follow-up of 13.5 months, there were 169 events of disease progression or death. The incidence was 18.5% (53/286) in the DRd arm and 41% (116/283) in the Rd arm. The hazard ratio was 0.37 (P<0.001).
At 12 months, the rate of PFS was 83.2% in the DRd arm and 60.1% in the Rd arm. The median PFS has not been reached in the DRd arm but was 18.4 months for patients in the Rd arm.
The improvement in PFS for the DRd arm was seen across all patient subgroups, regardless of age, ISS stage, prior treatment, etc.
In addition, there was an overall survival (OS) advantage with DRd. The 12-month OS was 92.1% in the DRd arm and 86.8% in the Rd arm.
The median OS was not reached in the DRd arm and was 20.3 months in the Rd arm. The hazard ratio was 0.64 (P=0.0534). The researchers said follow-up for long-term survival is ongoing.
Safety
The most common hematologic adverse events (in the DRd and Rd arms, respectively) were neutropenia (59.4% and 43.1%), anemia (31.1% and 34.9%), thrombocytopenia (26.9% and 27.4%), lymphopenia (6.0% and 5.3%), and febrile neutropenia (5.7% and 2.5%). Deep vein thrombosis occurred in 1.8% and 3.9% of patients, respectively.
The most common non-hematologic adverse events (in the DRd and Rd arms, respectively) were diarrhea (42.8% and 24.6%), fatigue (35.3% and 27.8%), upper respiratory tract infection (31.8% and 20.6%), constipation (29.3% and 25.3%), cough (29.0% and 12.5%), muscle spasms (25.8% and 18.5%), and pneumonia (14.1% and 13.2%).
Patients in the DRd arm had a higher rate of several grade 3/4 events, including neutropenia (51.9% and 37.0%), diarrhea (5.3% and 3.2%), fatigue (6.4% and 2.5%), nausea (1.4% and 0%), dyspnea (3.2% and 0.7%), and infection (28.3% and 22.8%).
Serious adverse events occurred in 48.8% of patients in the DRd arm and 42.0% in the Rd arm. Pneumonia was the most common serious event, occurring in 8.1% and 8.5% of patients, respectively.
Daratumumab-infusion-related reactions occurred in 47.7% of patients, were mostly grade 1/2, and occurred predominantly during the first infusion.
The researchers also noted that daratumumab interferes with laboratory-based blood compatibility tests because the drug binds to CD38 on red cells.
Daratumumab development
Data from the phase 3 CASTOR trial—in which researchers compared daratumumab, bortezomib, and dexamethasone to bortezomib and dexamethasone alone—were also recently published in NEJM.
“Following the publication of the phase 3 CASTOR data, we are pleased that the positive data from the phase 3 POLLUX study has now also been published in the New England Journal of Medicine,” said Jan van de Winkel, PhD, chief executive officer of Genmab.
“The data from this study formed the basis, along with data from the CASTOR study, of 2 regulatory submissions in August—the supplemental Biologics License Application submitted to the US Food and Drug Administration and the submission of the variation to the Marketing Authorization to the European Medicines Agency.”
Both submissions seek to expand the current indication for daratumumab so the drug can be used in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone to treat MM patients who have received at least 1 prior therapy.
Daratumumab currently has conditional approval from the European Commission as monotherapy for adults with relapsed and refractory MM who progressed on their last therapy and have received treatment with a proteasome inhibitor and an immunomodulatory agent.
Daratumumab has accelerated approval in the US as monotherapy for MM patients who have received at least 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who are double-refractory to a proteasome inhibitor and an immunomodulatory agent.
Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license from Genmab to develop, manufacture, and commercialize daratumumab.
Results of the phase 3 POLLUX trial suggest that adding daratumumab to treatment with lenalidomide and dexamethasone can improve progression-free survival (PFS) in patients with relapsed or refractory multiple myeloma (MM).
Compared to patients who received only lenalidomide and dexamethasone, those who received daratumumab as well had a significantly higher response rate and longer PFS.
Treatment with daratumumab was also associated with infusion-related reactions and a higher incidence of neutropenia.
These results were published in NEJM. They were previously presented at the 21st Congress of the European Hematology Association. The POLLUX trial was funded by Janssen Research and Development.
POLLUX enrolled 569 patients who had relapsed or refractory MM. The patients were randomized to receive either daratumumab, lenalidomide, and dexamethasone (DRd, n=286) or lenalidomide and dexamethasone alone (Rd, n=283).
Patient characteristics were similar between the treatment arms. The median age was 65 in both arms (overall range, 34-89). About half of patients in each arm had ISS stage I disease, about half had an ECOG performance score of 1 or 2, and patients were, roughly, a median of 4 years from diagnosis.
In both arms, patients had a median of 1 prior lines of therapy (overall range, 1-11).
More than 60% of patients in both arms (63%-64%) had received a prior transplant; 86% had received a proteasome inhibitor; 55% had received an immunomodulatory agent; 44% had received a proteasome inhibitor and an immunomodulatory agent; and 41%-43% had received a proteasome inhibitor, an immunomodulatory agent, and an alkylating agent.
Discontinuation
At the clinical cutoff date on March 7, 2016, 23.3% (n=66) of patients in the DRd arm and 47.0% (n=132) of those in the Rd arm discontinued treatment.
The most common reasons for discontinuation were progression (14.1% in the DRd arm and 34.2% in the Rd arm) and adverse events (6.7% and 8.2%, respectively).
Response
The overall response rate among evaluable patients (281 in the DRd arm and 276 in the Rd arm) was 92.9% in DRd arm and 76.4% in the Rd arm (P<0.001).
The rates of complete response or better were 43.1% and 19.2%, respectively. And the rates of stringent complete response were 18.1% and 7.2%, respectively.
In the DRd arm, 22.4% of patients had results below the threshold for minimal residual disease (1 tumor cell per 105 white cells). The same was true for 4.6% of patients in the Rd arm (P<0.001).
PFS and OS
At a median follow-up of 13.5 months, there were 169 events of disease progression or death. The incidence was 18.5% (53/286) in the DRd arm and 41% (116/283) in the Rd arm. The hazard ratio was 0.37 (P<0.001).
At 12 months, the rate of PFS was 83.2% in the DRd arm and 60.1% in the Rd arm. The median PFS has not been reached in the DRd arm but was 18.4 months for patients in the Rd arm.
The improvement in PFS for the DRd arm was seen across all patient subgroups, regardless of age, ISS stage, prior treatment, etc.
In addition, there was an overall survival (OS) advantage with DRd. The 12-month OS was 92.1% in the DRd arm and 86.8% in the Rd arm.
The median OS was not reached in the DRd arm and was 20.3 months in the Rd arm. The hazard ratio was 0.64 (P=0.0534). The researchers said follow-up for long-term survival is ongoing.
Safety
The most common hematologic adverse events (in the DRd and Rd arms, respectively) were neutropenia (59.4% and 43.1%), anemia (31.1% and 34.9%), thrombocytopenia (26.9% and 27.4%), lymphopenia (6.0% and 5.3%), and febrile neutropenia (5.7% and 2.5%). Deep vein thrombosis occurred in 1.8% and 3.9% of patients, respectively.
The most common non-hematologic adverse events (in the DRd and Rd arms, respectively) were diarrhea (42.8% and 24.6%), fatigue (35.3% and 27.8%), upper respiratory tract infection (31.8% and 20.6%), constipation (29.3% and 25.3%), cough (29.0% and 12.5%), muscle spasms (25.8% and 18.5%), and pneumonia (14.1% and 13.2%).
Patients in the DRd arm had a higher rate of several grade 3/4 events, including neutropenia (51.9% and 37.0%), diarrhea (5.3% and 3.2%), fatigue (6.4% and 2.5%), nausea (1.4% and 0%), dyspnea (3.2% and 0.7%), and infection (28.3% and 22.8%).
Serious adverse events occurred in 48.8% of patients in the DRd arm and 42.0% in the Rd arm. Pneumonia was the most common serious event, occurring in 8.1% and 8.5% of patients, respectively.
Daratumumab-infusion-related reactions occurred in 47.7% of patients, were mostly grade 1/2, and occurred predominantly during the first infusion.
The researchers also noted that daratumumab interferes with laboratory-based blood compatibility tests because the drug binds to CD38 on red cells.
Daratumumab development
Data from the phase 3 CASTOR trial—in which researchers compared daratumumab, bortezomib, and dexamethasone to bortezomib and dexamethasone alone—were also recently published in NEJM.
“Following the publication of the phase 3 CASTOR data, we are pleased that the positive data from the phase 3 POLLUX study has now also been published in the New England Journal of Medicine,” said Jan van de Winkel, PhD, chief executive officer of Genmab.
“The data from this study formed the basis, along with data from the CASTOR study, of 2 regulatory submissions in August—the supplemental Biologics License Application submitted to the US Food and Drug Administration and the submission of the variation to the Marketing Authorization to the European Medicines Agency.”
Both submissions seek to expand the current indication for daratumumab so the drug can be used in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone to treat MM patients who have received at least 1 prior therapy.
Daratumumab currently has conditional approval from the European Commission as monotherapy for adults with relapsed and refractory MM who progressed on their last therapy and have received treatment with a proteasome inhibitor and an immunomodulatory agent.
Daratumumab has accelerated approval in the US as monotherapy for MM patients who have received at least 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who are double-refractory to a proteasome inhibitor and an immunomodulatory agent.
Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license from Genmab to develop, manufacture, and commercialize daratumumab.
Results of the phase 3 POLLUX trial suggest that adding daratumumab to treatment with lenalidomide and dexamethasone can improve progression-free survival (PFS) in patients with relapsed or refractory multiple myeloma (MM).
Compared to patients who received only lenalidomide and dexamethasone, those who received daratumumab as well had a significantly higher response rate and longer PFS.
Treatment with daratumumab was also associated with infusion-related reactions and a higher incidence of neutropenia.
These results were published in NEJM. They were previously presented at the 21st Congress of the European Hematology Association. The POLLUX trial was funded by Janssen Research and Development.
POLLUX enrolled 569 patients who had relapsed or refractory MM. The patients were randomized to receive either daratumumab, lenalidomide, and dexamethasone (DRd, n=286) or lenalidomide and dexamethasone alone (Rd, n=283).
Patient characteristics were similar between the treatment arms. The median age was 65 in both arms (overall range, 34-89). About half of patients in each arm had ISS stage I disease, about half had an ECOG performance score of 1 or 2, and patients were, roughly, a median of 4 years from diagnosis.
In both arms, patients had a median of 1 prior lines of therapy (overall range, 1-11).
More than 60% of patients in both arms (63%-64%) had received a prior transplant; 86% had received a proteasome inhibitor; 55% had received an immunomodulatory agent; 44% had received a proteasome inhibitor and an immunomodulatory agent; and 41%-43% had received a proteasome inhibitor, an immunomodulatory agent, and an alkylating agent.
Discontinuation
At the clinical cutoff date on March 7, 2016, 23.3% (n=66) of patients in the DRd arm and 47.0% (n=132) of those in the Rd arm discontinued treatment.
The most common reasons for discontinuation were progression (14.1% in the DRd arm and 34.2% in the Rd arm) and adverse events (6.7% and 8.2%, respectively).
Response
The overall response rate among evaluable patients (281 in the DRd arm and 276 in the Rd arm) was 92.9% in DRd arm and 76.4% in the Rd arm (P<0.001).
The rates of complete response or better were 43.1% and 19.2%, respectively. And the rates of stringent complete response were 18.1% and 7.2%, respectively.
In the DRd arm, 22.4% of patients had results below the threshold for minimal residual disease (1 tumor cell per 105 white cells). The same was true for 4.6% of patients in the Rd arm (P<0.001).
PFS and OS
At a median follow-up of 13.5 months, there were 169 events of disease progression or death. The incidence was 18.5% (53/286) in the DRd arm and 41% (116/283) in the Rd arm. The hazard ratio was 0.37 (P<0.001).
At 12 months, the rate of PFS was 83.2% in the DRd arm and 60.1% in the Rd arm. The median PFS has not been reached in the DRd arm but was 18.4 months for patients in the Rd arm.
The improvement in PFS for the DRd arm was seen across all patient subgroups, regardless of age, ISS stage, prior treatment, etc.
In addition, there was an overall survival (OS) advantage with DRd. The 12-month OS was 92.1% in the DRd arm and 86.8% in the Rd arm.
The median OS was not reached in the DRd arm and was 20.3 months in the Rd arm. The hazard ratio was 0.64 (P=0.0534). The researchers said follow-up for long-term survival is ongoing.
Safety
The most common hematologic adverse events (in the DRd and Rd arms, respectively) were neutropenia (59.4% and 43.1%), anemia (31.1% and 34.9%), thrombocytopenia (26.9% and 27.4%), lymphopenia (6.0% and 5.3%), and febrile neutropenia (5.7% and 2.5%). Deep vein thrombosis occurred in 1.8% and 3.9% of patients, respectively.
The most common non-hematologic adverse events (in the DRd and Rd arms, respectively) were diarrhea (42.8% and 24.6%), fatigue (35.3% and 27.8%), upper respiratory tract infection (31.8% and 20.6%), constipation (29.3% and 25.3%), cough (29.0% and 12.5%), muscle spasms (25.8% and 18.5%), and pneumonia (14.1% and 13.2%).
Patients in the DRd arm had a higher rate of several grade 3/4 events, including neutropenia (51.9% and 37.0%), diarrhea (5.3% and 3.2%), fatigue (6.4% and 2.5%), nausea (1.4% and 0%), dyspnea (3.2% and 0.7%), and infection (28.3% and 22.8%).
Serious adverse events occurred in 48.8% of patients in the DRd arm and 42.0% in the Rd arm. Pneumonia was the most common serious event, occurring in 8.1% and 8.5% of patients, respectively.
Daratumumab-infusion-related reactions occurred in 47.7% of patients, were mostly grade 1/2, and occurred predominantly during the first infusion.
The researchers also noted that daratumumab interferes with laboratory-based blood compatibility tests because the drug binds to CD38 on red cells.
Daratumumab development
Data from the phase 3 CASTOR trial—in which researchers compared daratumumab, bortezomib, and dexamethasone to bortezomib and dexamethasone alone—were also recently published in NEJM.
“Following the publication of the phase 3 CASTOR data, we are pleased that the positive data from the phase 3 POLLUX study has now also been published in the New England Journal of Medicine,” said Jan van de Winkel, PhD, chief executive officer of Genmab.
“The data from this study formed the basis, along with data from the CASTOR study, of 2 regulatory submissions in August—the supplemental Biologics License Application submitted to the US Food and Drug Administration and the submission of the variation to the Marketing Authorization to the European Medicines Agency.”
Both submissions seek to expand the current indication for daratumumab so the drug can be used in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone to treat MM patients who have received at least 1 prior therapy.
Daratumumab currently has conditional approval from the European Commission as monotherapy for adults with relapsed and refractory MM who progressed on their last therapy and have received treatment with a proteasome inhibitor and an immunomodulatory agent.
Daratumumab has accelerated approval in the US as monotherapy for MM patients who have received at least 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who are double-refractory to a proteasome inhibitor and an immunomodulatory agent.
Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license from Genmab to develop, manufacture, and commercialize daratumumab.