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ADAR1 linked to MM pathogenesis, outcomes
Overly zealous editing of messenger RNA in multiple myeloma (MM) cells contributes to MM pathogenesis and is associated with poor outcomes after certain treatments, investigators contend.
The team found evidence to suggest that overexpression of the RNA editing enzyme ADAR1 leads to hyperediting of the MM transcriptome that appears related to a drug-resistant disease phenotype and worse prognosis.
Phaik Ju Teoh, PhD, of the Cancer Science Institute of Singapore, and colleagues reported these findings in Blood.
The investigators implicate aberrant editing of adenosine (A) to inosine (I) in malignant plasma cells and its effects on NEIL1, a gene that encodes proteins involved in base-excision repair of DNA, as important mechanisms in MM pathogenesis.
A to I editing is the most prevalent form of RNA editing in humans, and aberrant editing mediated by ADAR1 has recently been linked to the development of several cancer types, the investigators noted.
To see whether this process may also be involved in MM, the investigators examined whole blood or bone marrow samples from healthy volunteers and MM patients.
The team found that ADAR1 was overexpressed in MM cells compared to nonmalignant plasma cells.
Furthermore, ADAR1 was expressed at higher levels in patients with newly diagnosed or relapsed MM compared to patients who had smoldering myeloma or monoclonal gammopathy of undetermined significance.
Response to treatment
The investigators also assessed ADAR1 expression in relation to MM patients’ responsiveness to treatment using data from the CoMMpass study.
The team found that patients with poor responses (stable or progressive disease) to bortezomib-based and immunomodulatory-based therapies had high ADAR1 mRNA.
There was no correlation between ADAR1 and responsiveness to carfilzomib-based treatments, but the investigators said this may be because of the relatively lower number of patients who received carfilzomib in this study.
The investigators also found that bortezomib was more effective in inhibiting the growth of MM cells with low ADAR1, and bortezomib-treated cells showed downregulation of ADAR1 expression in a dose- and time-dependent manner.
ADAR1-mediated editing
The investigators determined that ADAR1 directly regulates hyperediting of the MM transcriptome. This was evidenced by a significant increase in A to guanosine (G) editing in newly diagnosed and relapsed MM samples, compared with normal plasma cells.
The team confirmed this finding by observing the effects of ADAR1 levels on editing events across the transcriptome.
The investigators followed this observation with experiments to see whether ADAR1-mediated editing contributes to oncogenesis in MM cells. The MM growth rate slowed when the team silenced ADAR1, and introducing wild-type ADAR1 into cells promoted growth and proliferation.
The investigators also identified NEIL1 as an important ADAR1 editing target in MM. The editing compromised NEIL1’s ability to accurately repair DNA damage.
This study was supported by the National Research Foundation Singapore, the Singapore Ministry of Education, and the National University of Singapore. The investigators reported no competing financial interests.
Overly zealous editing of messenger RNA in multiple myeloma (MM) cells contributes to MM pathogenesis and is associated with poor outcomes after certain treatments, investigators contend.
The team found evidence to suggest that overexpression of the RNA editing enzyme ADAR1 leads to hyperediting of the MM transcriptome that appears related to a drug-resistant disease phenotype and worse prognosis.
Phaik Ju Teoh, PhD, of the Cancer Science Institute of Singapore, and colleagues reported these findings in Blood.
The investigators implicate aberrant editing of adenosine (A) to inosine (I) in malignant plasma cells and its effects on NEIL1, a gene that encodes proteins involved in base-excision repair of DNA, as important mechanisms in MM pathogenesis.
A to I editing is the most prevalent form of RNA editing in humans, and aberrant editing mediated by ADAR1 has recently been linked to the development of several cancer types, the investigators noted.
To see whether this process may also be involved in MM, the investigators examined whole blood or bone marrow samples from healthy volunteers and MM patients.
The team found that ADAR1 was overexpressed in MM cells compared to nonmalignant plasma cells.
Furthermore, ADAR1 was expressed at higher levels in patients with newly diagnosed or relapsed MM compared to patients who had smoldering myeloma or monoclonal gammopathy of undetermined significance.
Response to treatment
The investigators also assessed ADAR1 expression in relation to MM patients’ responsiveness to treatment using data from the CoMMpass study.
The team found that patients with poor responses (stable or progressive disease) to bortezomib-based and immunomodulatory-based therapies had high ADAR1 mRNA.
There was no correlation between ADAR1 and responsiveness to carfilzomib-based treatments, but the investigators said this may be because of the relatively lower number of patients who received carfilzomib in this study.
The investigators also found that bortezomib was more effective in inhibiting the growth of MM cells with low ADAR1, and bortezomib-treated cells showed downregulation of ADAR1 expression in a dose- and time-dependent manner.
ADAR1-mediated editing
The investigators determined that ADAR1 directly regulates hyperediting of the MM transcriptome. This was evidenced by a significant increase in A to guanosine (G) editing in newly diagnosed and relapsed MM samples, compared with normal plasma cells.
The team confirmed this finding by observing the effects of ADAR1 levels on editing events across the transcriptome.
The investigators followed this observation with experiments to see whether ADAR1-mediated editing contributes to oncogenesis in MM cells. The MM growth rate slowed when the team silenced ADAR1, and introducing wild-type ADAR1 into cells promoted growth and proliferation.
The investigators also identified NEIL1 as an important ADAR1 editing target in MM. The editing compromised NEIL1’s ability to accurately repair DNA damage.
This study was supported by the National Research Foundation Singapore, the Singapore Ministry of Education, and the National University of Singapore. The investigators reported no competing financial interests.
Overly zealous editing of messenger RNA in multiple myeloma (MM) cells contributes to MM pathogenesis and is associated with poor outcomes after certain treatments, investigators contend.
The team found evidence to suggest that overexpression of the RNA editing enzyme ADAR1 leads to hyperediting of the MM transcriptome that appears related to a drug-resistant disease phenotype and worse prognosis.
Phaik Ju Teoh, PhD, of the Cancer Science Institute of Singapore, and colleagues reported these findings in Blood.
The investigators implicate aberrant editing of adenosine (A) to inosine (I) in malignant plasma cells and its effects on NEIL1, a gene that encodes proteins involved in base-excision repair of DNA, as important mechanisms in MM pathogenesis.
A to I editing is the most prevalent form of RNA editing in humans, and aberrant editing mediated by ADAR1 has recently been linked to the development of several cancer types, the investigators noted.
To see whether this process may also be involved in MM, the investigators examined whole blood or bone marrow samples from healthy volunteers and MM patients.
The team found that ADAR1 was overexpressed in MM cells compared to nonmalignant plasma cells.
Furthermore, ADAR1 was expressed at higher levels in patients with newly diagnosed or relapsed MM compared to patients who had smoldering myeloma or monoclonal gammopathy of undetermined significance.
Response to treatment
The investigators also assessed ADAR1 expression in relation to MM patients’ responsiveness to treatment using data from the CoMMpass study.
The team found that patients with poor responses (stable or progressive disease) to bortezomib-based and immunomodulatory-based therapies had high ADAR1 mRNA.
There was no correlation between ADAR1 and responsiveness to carfilzomib-based treatments, but the investigators said this may be because of the relatively lower number of patients who received carfilzomib in this study.
The investigators also found that bortezomib was more effective in inhibiting the growth of MM cells with low ADAR1, and bortezomib-treated cells showed downregulation of ADAR1 expression in a dose- and time-dependent manner.
ADAR1-mediated editing
The investigators determined that ADAR1 directly regulates hyperediting of the MM transcriptome. This was evidenced by a significant increase in A to guanosine (G) editing in newly diagnosed and relapsed MM samples, compared with normal plasma cells.
The team confirmed this finding by observing the effects of ADAR1 levels on editing events across the transcriptome.
The investigators followed this observation with experiments to see whether ADAR1-mediated editing contributes to oncogenesis in MM cells. The MM growth rate slowed when the team silenced ADAR1, and introducing wild-type ADAR1 into cells promoted growth and proliferation.
The investigators also identified NEIL1 as an important ADAR1 editing target in MM. The editing compromised NEIL1’s ability to accurately repair DNA damage.
This study was supported by the National Research Foundation Singapore, the Singapore Ministry of Education, and the National University of Singapore. The investigators reported no competing financial interests.
Abiraterone also benefits low-risk metastatic prostate cancer patients
MUNICH – Men with metastatic hormone-naive prostate cancer may benefit from treatment with the combination of abiraterone (Zytiga), prednisolone, and androgen deprivation regardless of risk group or disease volume, STAMPEDE trialists contend.
Results of the STAMPEDE and LATITUDE trials, published in 2017 in the New England Journal of Medicine, showed significant improvements in overall survival with abiraterone, androgen deprivation therapy (ADT) and either prednisone (in LATITUDE) or prednisolone (in STAMPEDE) compared with ADT alone.
Data from the LATITUDE trial were used to support approval by both the Food and Drug Administration and European Medicines Agency of abiraterone in combination with ADT and a glucocorticoid for the new indication of treatment of men with metastatic high-risk castration-sensitive prostate cancer.
“So where we stand, at the minute, in terms of guidance: the EAU [European Urology Association] and the NCCN [National Comprehensive Cancer Network] have suggested that we consider treatment for men with hormone-naive metastatic prostatic cancer, but in 2018 the FDA and EMA licensed the drug for high-risk disease, so there’s therefore an evolving uncertainty about what we should be doing in low-risk disease,” Alex Hoyle, MBChB, of Christie NHS Foundation Trust, Manchester, England, said on behalf of colleagues in the STAMPEDE trial group.
The problem is that there is no international consensus on what constitutes low-risk disease, Dr. Hoyle said at the European Society for Medical Oncology Congress.
For example, in the CHAARTED trial, risk was defined by volume, with high-risk patients defined as those with visceral metastases and/or four or more bone metastases with one or more outside the vertebral column or pelvis. In contrast, the LATITUDE investigators defined high-risk patients as those with two or more high-risk features, including three or more bone metastases, visceral metastases, and/or a Gleason score of 8 or more.
To determine whether men with low-risk disease could also benefit from the combination, Dr. Hoyle and colleagues performed a retrospective analysis of the STAMPEDE trial, using staging scans to stratify patients with M1 disease into either high- or low-risk categories according to the LATITUDE risk criteria. The reviewers were blinded to the treatment arm for each patient. They also performed a secondary differential analysis by tumor volume according to the CHAARTED criteria.
The investigators then retrospectively reviewed outcomes for 901 evaluable patients, median age 67 years, with a median PSA of 96 ng/mL, followed for a median of 42 months. The sample included 428 patients determined to have low-risk disease, and 473 determined to have high-risk disease.
Overall survival (OS), the primary endpoint, was significantly better for patients treated with the combination vs. ADT alone in both high- and low-risk groups. The 3-year OS in high-risk patients treated with the abiraterone/prednisolone/ADT was 64.7% compared with 45% for patients treated with AD alone, an absolute difference of 19.7% that translated into a hazard ratio (HR) for death of 0.54 (P less than .001).
For patients in the low-risk group, 3-year OS was 82.4% with the combination vs. 78% with ADT alone, an absolute difference of 4.4%, translating into an HR of 0.66 (P = .041).
Three-year prostate cancer-specific survival, a secondary endpoint, was better with abiraterone in the high-risk (67% vs. 47.9%, HR 0.57, P less than .001) and low-risk (88.7% vs. 81.6%, HR 0.51, P = .008) populations.
The results were even more pronounced in favor of the abiraterone combination for the secondary endpoint of failure-free survival (FFS) in both groups, with 45.1% of high-risk patients on abiraterone having no biochemical failure at 3 years vs. 12.2% for those treated with ADT alone (HR 0.48, P less than .001). The respective FFS rates in the low-risk group were 80.8% vs. 56.4% (HR 0.66, P = .041).
ADT was superior in analyses of skeletal related event-free survival (HR 0.48 for high risk and 0.31 for low risk, P less than .001 for both comparisons), and metastasis progression-free survival (HR 0.54, P less than .001 for high risk, HR 0.66, P = .041 for low risk).
An exploratory analysis using the CHAARTED risk criteria showed similar results, with the combination significantly better in every category except prostate cancer–specific survival in patients with low-volume disease, although here, too, there was a clear trend favoring abiraterone.
“Abiraterone plus prednisolone in addition to ADT improves survival endpoints in metastatic hormone-naive prostate cancer,” Dr. Hoyle said.
Invited discussant Karim Fizazi, MD, PhD, of Gustave Roussy Cancer Institute at the University of Paris-Sud, France, said that the study, despite some limitations, was very important.
“For patients with high-risk de novo disease, until today we’ve had two standards of care: castration plus abiraterone or castration plus docetaxel. For patients with low risk, that was strongly debated – either castration alone or castration plus docetaxel. After this publication, I think it’s fair to say that for patients with high-risk disease the role of abiraterone is being strengthened, while for patients with low-risk disease, ADT plus abiraterone probably is going to become the new standard,” he said.
The STAMPEDE trial is supported by the Medical Research Council of the United Kingdom, the Salford Royal and the Christie NHS Foundation trusts, and Manchester Cancer Research Centre. Dr. Hoyle reported having no conflicts of interest. Dr. Fizazi reported advisory board participation and/or honoraria from Amgen, Astellas, AstraZeneca, Bayer, Clovis, CureVac, Essa, Genentech, Janssen, MSD, Orion, and Sanofi.
SOURCE: Hoyle AP et al. ESMO 2018. Abstract LBA4.
MUNICH – Men with metastatic hormone-naive prostate cancer may benefit from treatment with the combination of abiraterone (Zytiga), prednisolone, and androgen deprivation regardless of risk group or disease volume, STAMPEDE trialists contend.
Results of the STAMPEDE and LATITUDE trials, published in 2017 in the New England Journal of Medicine, showed significant improvements in overall survival with abiraterone, androgen deprivation therapy (ADT) and either prednisone (in LATITUDE) or prednisolone (in STAMPEDE) compared with ADT alone.
Data from the LATITUDE trial were used to support approval by both the Food and Drug Administration and European Medicines Agency of abiraterone in combination with ADT and a glucocorticoid for the new indication of treatment of men with metastatic high-risk castration-sensitive prostate cancer.
“So where we stand, at the minute, in terms of guidance: the EAU [European Urology Association] and the NCCN [National Comprehensive Cancer Network] have suggested that we consider treatment for men with hormone-naive metastatic prostatic cancer, but in 2018 the FDA and EMA licensed the drug for high-risk disease, so there’s therefore an evolving uncertainty about what we should be doing in low-risk disease,” Alex Hoyle, MBChB, of Christie NHS Foundation Trust, Manchester, England, said on behalf of colleagues in the STAMPEDE trial group.
The problem is that there is no international consensus on what constitutes low-risk disease, Dr. Hoyle said at the European Society for Medical Oncology Congress.
For example, in the CHAARTED trial, risk was defined by volume, with high-risk patients defined as those with visceral metastases and/or four or more bone metastases with one or more outside the vertebral column or pelvis. In contrast, the LATITUDE investigators defined high-risk patients as those with two or more high-risk features, including three or more bone metastases, visceral metastases, and/or a Gleason score of 8 or more.
To determine whether men with low-risk disease could also benefit from the combination, Dr. Hoyle and colleagues performed a retrospective analysis of the STAMPEDE trial, using staging scans to stratify patients with M1 disease into either high- or low-risk categories according to the LATITUDE risk criteria. The reviewers were blinded to the treatment arm for each patient. They also performed a secondary differential analysis by tumor volume according to the CHAARTED criteria.
The investigators then retrospectively reviewed outcomes for 901 evaluable patients, median age 67 years, with a median PSA of 96 ng/mL, followed for a median of 42 months. The sample included 428 patients determined to have low-risk disease, and 473 determined to have high-risk disease.
Overall survival (OS), the primary endpoint, was significantly better for patients treated with the combination vs. ADT alone in both high- and low-risk groups. The 3-year OS in high-risk patients treated with the abiraterone/prednisolone/ADT was 64.7% compared with 45% for patients treated with AD alone, an absolute difference of 19.7% that translated into a hazard ratio (HR) for death of 0.54 (P less than .001).
For patients in the low-risk group, 3-year OS was 82.4% with the combination vs. 78% with ADT alone, an absolute difference of 4.4%, translating into an HR of 0.66 (P = .041).
Three-year prostate cancer-specific survival, a secondary endpoint, was better with abiraterone in the high-risk (67% vs. 47.9%, HR 0.57, P less than .001) and low-risk (88.7% vs. 81.6%, HR 0.51, P = .008) populations.
The results were even more pronounced in favor of the abiraterone combination for the secondary endpoint of failure-free survival (FFS) in both groups, with 45.1% of high-risk patients on abiraterone having no biochemical failure at 3 years vs. 12.2% for those treated with ADT alone (HR 0.48, P less than .001). The respective FFS rates in the low-risk group were 80.8% vs. 56.4% (HR 0.66, P = .041).
ADT was superior in analyses of skeletal related event-free survival (HR 0.48 for high risk and 0.31 for low risk, P less than .001 for both comparisons), and metastasis progression-free survival (HR 0.54, P less than .001 for high risk, HR 0.66, P = .041 for low risk).
An exploratory analysis using the CHAARTED risk criteria showed similar results, with the combination significantly better in every category except prostate cancer–specific survival in patients with low-volume disease, although here, too, there was a clear trend favoring abiraterone.
“Abiraterone plus prednisolone in addition to ADT improves survival endpoints in metastatic hormone-naive prostate cancer,” Dr. Hoyle said.
Invited discussant Karim Fizazi, MD, PhD, of Gustave Roussy Cancer Institute at the University of Paris-Sud, France, said that the study, despite some limitations, was very important.
“For patients with high-risk de novo disease, until today we’ve had two standards of care: castration plus abiraterone or castration plus docetaxel. For patients with low risk, that was strongly debated – either castration alone or castration plus docetaxel. After this publication, I think it’s fair to say that for patients with high-risk disease the role of abiraterone is being strengthened, while for patients with low-risk disease, ADT plus abiraterone probably is going to become the new standard,” he said.
The STAMPEDE trial is supported by the Medical Research Council of the United Kingdom, the Salford Royal and the Christie NHS Foundation trusts, and Manchester Cancer Research Centre. Dr. Hoyle reported having no conflicts of interest. Dr. Fizazi reported advisory board participation and/or honoraria from Amgen, Astellas, AstraZeneca, Bayer, Clovis, CureVac, Essa, Genentech, Janssen, MSD, Orion, and Sanofi.
SOURCE: Hoyle AP et al. ESMO 2018. Abstract LBA4.
MUNICH – Men with metastatic hormone-naive prostate cancer may benefit from treatment with the combination of abiraterone (Zytiga), prednisolone, and androgen deprivation regardless of risk group or disease volume, STAMPEDE trialists contend.
Results of the STAMPEDE and LATITUDE trials, published in 2017 in the New England Journal of Medicine, showed significant improvements in overall survival with abiraterone, androgen deprivation therapy (ADT) and either prednisone (in LATITUDE) or prednisolone (in STAMPEDE) compared with ADT alone.
Data from the LATITUDE trial were used to support approval by both the Food and Drug Administration and European Medicines Agency of abiraterone in combination with ADT and a glucocorticoid for the new indication of treatment of men with metastatic high-risk castration-sensitive prostate cancer.
“So where we stand, at the minute, in terms of guidance: the EAU [European Urology Association] and the NCCN [National Comprehensive Cancer Network] have suggested that we consider treatment for men with hormone-naive metastatic prostatic cancer, but in 2018 the FDA and EMA licensed the drug for high-risk disease, so there’s therefore an evolving uncertainty about what we should be doing in low-risk disease,” Alex Hoyle, MBChB, of Christie NHS Foundation Trust, Manchester, England, said on behalf of colleagues in the STAMPEDE trial group.
The problem is that there is no international consensus on what constitutes low-risk disease, Dr. Hoyle said at the European Society for Medical Oncology Congress.
For example, in the CHAARTED trial, risk was defined by volume, with high-risk patients defined as those with visceral metastases and/or four or more bone metastases with one or more outside the vertebral column or pelvis. In contrast, the LATITUDE investigators defined high-risk patients as those with two or more high-risk features, including three or more bone metastases, visceral metastases, and/or a Gleason score of 8 or more.
To determine whether men with low-risk disease could also benefit from the combination, Dr. Hoyle and colleagues performed a retrospective analysis of the STAMPEDE trial, using staging scans to stratify patients with M1 disease into either high- or low-risk categories according to the LATITUDE risk criteria. The reviewers were blinded to the treatment arm for each patient. They also performed a secondary differential analysis by tumor volume according to the CHAARTED criteria.
The investigators then retrospectively reviewed outcomes for 901 evaluable patients, median age 67 years, with a median PSA of 96 ng/mL, followed for a median of 42 months. The sample included 428 patients determined to have low-risk disease, and 473 determined to have high-risk disease.
Overall survival (OS), the primary endpoint, was significantly better for patients treated with the combination vs. ADT alone in both high- and low-risk groups. The 3-year OS in high-risk patients treated with the abiraterone/prednisolone/ADT was 64.7% compared with 45% for patients treated with AD alone, an absolute difference of 19.7% that translated into a hazard ratio (HR) for death of 0.54 (P less than .001).
For patients in the low-risk group, 3-year OS was 82.4% with the combination vs. 78% with ADT alone, an absolute difference of 4.4%, translating into an HR of 0.66 (P = .041).
Three-year prostate cancer-specific survival, a secondary endpoint, was better with abiraterone in the high-risk (67% vs. 47.9%, HR 0.57, P less than .001) and low-risk (88.7% vs. 81.6%, HR 0.51, P = .008) populations.
The results were even more pronounced in favor of the abiraterone combination for the secondary endpoint of failure-free survival (FFS) in both groups, with 45.1% of high-risk patients on abiraterone having no biochemical failure at 3 years vs. 12.2% for those treated with ADT alone (HR 0.48, P less than .001). The respective FFS rates in the low-risk group were 80.8% vs. 56.4% (HR 0.66, P = .041).
ADT was superior in analyses of skeletal related event-free survival (HR 0.48 for high risk and 0.31 for low risk, P less than .001 for both comparisons), and metastasis progression-free survival (HR 0.54, P less than .001 for high risk, HR 0.66, P = .041 for low risk).
An exploratory analysis using the CHAARTED risk criteria showed similar results, with the combination significantly better in every category except prostate cancer–specific survival in patients with low-volume disease, although here, too, there was a clear trend favoring abiraterone.
“Abiraterone plus prednisolone in addition to ADT improves survival endpoints in metastatic hormone-naive prostate cancer,” Dr. Hoyle said.
Invited discussant Karim Fizazi, MD, PhD, of Gustave Roussy Cancer Institute at the University of Paris-Sud, France, said that the study, despite some limitations, was very important.
“For patients with high-risk de novo disease, until today we’ve had two standards of care: castration plus abiraterone or castration plus docetaxel. For patients with low risk, that was strongly debated – either castration alone or castration plus docetaxel. After this publication, I think it’s fair to say that for patients with high-risk disease the role of abiraterone is being strengthened, while for patients with low-risk disease, ADT plus abiraterone probably is going to become the new standard,” he said.
The STAMPEDE trial is supported by the Medical Research Council of the United Kingdom, the Salford Royal and the Christie NHS Foundation trusts, and Manchester Cancer Research Centre. Dr. Hoyle reported having no conflicts of interest. Dr. Fizazi reported advisory board participation and/or honoraria from Amgen, Astellas, AstraZeneca, Bayer, Clovis, CureVac, Essa, Genentech, Janssen, MSD, Orion, and Sanofi.
SOURCE: Hoyle AP et al. ESMO 2018. Abstract LBA4.
AT ESMO 2018
Key clinical point: Men with metastatic hormone-naive prostate cancer at both low and high risk have better outcomes with abiraterone plus androgen deprivation and prednisolone or prednisone.
Major finding: Patients with low-risk disease treated with the abiraterone combination had 3-year OS of 82.4% vs. 78% with ADT alone (HR 0.66, P = .041).
Study details: Retrospective analysis of data from the STAMPEDE trial using risk criteria from the LATITUDE and CHAARTED trials.
Disclosures: The STAMPEDE trial is supported by the Medical Research Council of the United Kingdom, the Salford Royal and the Christie NHS Foundation trusts, and Manchester Cancer Research Centre. Dr. Hoyle reported having no conflicts of interest. Dr. Fizazi reported advisory board participation and/or honoraria from Amgen, Astellas, AstraZeneca, Bayer, Clovis, CureVac, Essa, Genentech, Janssen, MSD, Orion, and Sanofi.
Source: Hoyle AP et al. ESMO 2018. Abstract LBA4.
Study supports PBM program for HSCT recipients
BOSTON—A blood management program for patients undergoing hematopoietic stem cell transplant (HSCT) can reduce inappropriate transfusions and costs without compromising patient outcomes, a new study suggests.
Researchers retrospectively compared outcomes before and after implementation of a patient blood management (PBM) program at a single institution.
After the program was implemented, the number of transfusions and the units transfused declined without affecting patient mortality, intensive care unit (ICU) admission rates, or other transfusion-related complications.
In addition, the program saved the hospital more than $600,000 over a year.
Nilesh Jambhekar, MD, of the Mayo Clinic in Rochester, Minnesota, reported these results in a presentation at AABB 2018 (abstract PBM3-ST4-22*).
Study design
Dr. Jambhekar and his colleagues looked at blood product use both before and after the Mayo Clinic started a PBM program that included emphasis on AABB best practice guidelines and electronic clinical-decision support for transfusion orders.
The researchers evaluated the frequency and proportion of red blood cell (RBC) and platelet transfusions, total transfusion quantities, transfusions that occurred outside of the clinical guidelines, and the activity-based costs of transfusions.
Dr. Jambhekar acknowledged that the study relied on rigid hemoglobin and platelet thresholds when considering transfusions conducted outside of the guidelines, defined as RBCs administered for hemoglobin values greater than 7 g/dL and platelet transfusions for platelet counts greater than 10 x 109/L.
He noted, however, that the researchers conducted sensitivity analyses to account for exceptions such as patients with coronary disease or neutropenic fever.
The patient-centered outcomes the researchers evaluated included mortality, hospital and ICU admission rates, transfusion reactions, cerebrovascular and coronary ischemic events, and infections.
The study included data on 360 adults older than 18 who underwent HSCT in 2013, before the PBM program was implemented, and 368 transplanted in 2015, after implementation.
In each cohort, patients were followed out to 90 days after transplant.
Results
The total number of platelet units transfused dropped from 1,660 pre-PBM program to 1,417 post-PBM implementation. The total number of RBC units dropped from 1,158 to 826.
The researchers also saw changes in the proportions of inappropriate (outside guidelines) transfusions between the two time periods.
In 2013, 94.2% of RBC transfusions occurred outside the guidelines, compared with 35.4% in 2015 (P<0.0001). Similarly, the proportion of inappropriate platelet transfusions declined from 73.4% to 48.7% over the same time period (P<0.0001).
In addition, all-cause mortality at 3 months was significantly lower after the PBM program was introduced. The 3-month mortality rate was 30.7% for the 2013 cohort and 20.2% for the 2015 cohort (P=0.001).
Dr. Jambhekar noted that, in a multivariable analysis accounting for baseline differences between the groups, mortality for patients treated before the PBM program remained significantly higher, with an odds ratio of 1.85 (P=0.0008).
Neither hospital nor ICU admission within 30 days differed significantly between the groups, and there were no significant between-group differences in hospital or ICU lengths of stay.
Likewise, there were no significant between-group differences in myocardial infarctions, cerebrovascular events, sepsis, and febrile or allergic transfusion reactions.
Dr. Jambhekar noted that this study was retrospective in design and therefore could not fully account for potential confounders. It’s also unclear whether the results could be generalized for adoption by other institutions.
“In general, PBM implementation is probably helpful in reducing both platelet and PRBC [packed red blood cell] utilization, but it’s not an easy thing to do,” Dr. Jambhekar said.
“It requires institutional buy-in and key players to make it happen. Ongoing PBM-related activities like surveillance, education, and clinical decision feedback are critical to maintaining success that we’ve had.”
This study was internally funded. Dr. Jambhekar reported having nothing to disclose.
*Data presented differ from the abstract.
BOSTON—A blood management program for patients undergoing hematopoietic stem cell transplant (HSCT) can reduce inappropriate transfusions and costs without compromising patient outcomes, a new study suggests.
Researchers retrospectively compared outcomes before and after implementation of a patient blood management (PBM) program at a single institution.
After the program was implemented, the number of transfusions and the units transfused declined without affecting patient mortality, intensive care unit (ICU) admission rates, or other transfusion-related complications.
In addition, the program saved the hospital more than $600,000 over a year.
Nilesh Jambhekar, MD, of the Mayo Clinic in Rochester, Minnesota, reported these results in a presentation at AABB 2018 (abstract PBM3-ST4-22*).
Study design
Dr. Jambhekar and his colleagues looked at blood product use both before and after the Mayo Clinic started a PBM program that included emphasis on AABB best practice guidelines and electronic clinical-decision support for transfusion orders.
The researchers evaluated the frequency and proportion of red blood cell (RBC) and platelet transfusions, total transfusion quantities, transfusions that occurred outside of the clinical guidelines, and the activity-based costs of transfusions.
Dr. Jambhekar acknowledged that the study relied on rigid hemoglobin and platelet thresholds when considering transfusions conducted outside of the guidelines, defined as RBCs administered for hemoglobin values greater than 7 g/dL and platelet transfusions for platelet counts greater than 10 x 109/L.
He noted, however, that the researchers conducted sensitivity analyses to account for exceptions such as patients with coronary disease or neutropenic fever.
The patient-centered outcomes the researchers evaluated included mortality, hospital and ICU admission rates, transfusion reactions, cerebrovascular and coronary ischemic events, and infections.
The study included data on 360 adults older than 18 who underwent HSCT in 2013, before the PBM program was implemented, and 368 transplanted in 2015, after implementation.
In each cohort, patients were followed out to 90 days after transplant.
Results
The total number of platelet units transfused dropped from 1,660 pre-PBM program to 1,417 post-PBM implementation. The total number of RBC units dropped from 1,158 to 826.
The researchers also saw changes in the proportions of inappropriate (outside guidelines) transfusions between the two time periods.
In 2013, 94.2% of RBC transfusions occurred outside the guidelines, compared with 35.4% in 2015 (P<0.0001). Similarly, the proportion of inappropriate platelet transfusions declined from 73.4% to 48.7% over the same time period (P<0.0001).
In addition, all-cause mortality at 3 months was significantly lower after the PBM program was introduced. The 3-month mortality rate was 30.7% for the 2013 cohort and 20.2% for the 2015 cohort (P=0.001).
Dr. Jambhekar noted that, in a multivariable analysis accounting for baseline differences between the groups, mortality for patients treated before the PBM program remained significantly higher, with an odds ratio of 1.85 (P=0.0008).
Neither hospital nor ICU admission within 30 days differed significantly between the groups, and there were no significant between-group differences in hospital or ICU lengths of stay.
Likewise, there were no significant between-group differences in myocardial infarctions, cerebrovascular events, sepsis, and febrile or allergic transfusion reactions.
Dr. Jambhekar noted that this study was retrospective in design and therefore could not fully account for potential confounders. It’s also unclear whether the results could be generalized for adoption by other institutions.
“In general, PBM implementation is probably helpful in reducing both platelet and PRBC [packed red blood cell] utilization, but it’s not an easy thing to do,” Dr. Jambhekar said.
“It requires institutional buy-in and key players to make it happen. Ongoing PBM-related activities like surveillance, education, and clinical decision feedback are critical to maintaining success that we’ve had.”
This study was internally funded. Dr. Jambhekar reported having nothing to disclose.
*Data presented differ from the abstract.
BOSTON—A blood management program for patients undergoing hematopoietic stem cell transplant (HSCT) can reduce inappropriate transfusions and costs without compromising patient outcomes, a new study suggests.
Researchers retrospectively compared outcomes before and after implementation of a patient blood management (PBM) program at a single institution.
After the program was implemented, the number of transfusions and the units transfused declined without affecting patient mortality, intensive care unit (ICU) admission rates, or other transfusion-related complications.
In addition, the program saved the hospital more than $600,000 over a year.
Nilesh Jambhekar, MD, of the Mayo Clinic in Rochester, Minnesota, reported these results in a presentation at AABB 2018 (abstract PBM3-ST4-22*).
Study design
Dr. Jambhekar and his colleagues looked at blood product use both before and after the Mayo Clinic started a PBM program that included emphasis on AABB best practice guidelines and electronic clinical-decision support for transfusion orders.
The researchers evaluated the frequency and proportion of red blood cell (RBC) and platelet transfusions, total transfusion quantities, transfusions that occurred outside of the clinical guidelines, and the activity-based costs of transfusions.
Dr. Jambhekar acknowledged that the study relied on rigid hemoglobin and platelet thresholds when considering transfusions conducted outside of the guidelines, defined as RBCs administered for hemoglobin values greater than 7 g/dL and platelet transfusions for platelet counts greater than 10 x 109/L.
He noted, however, that the researchers conducted sensitivity analyses to account for exceptions such as patients with coronary disease or neutropenic fever.
The patient-centered outcomes the researchers evaluated included mortality, hospital and ICU admission rates, transfusion reactions, cerebrovascular and coronary ischemic events, and infections.
The study included data on 360 adults older than 18 who underwent HSCT in 2013, before the PBM program was implemented, and 368 transplanted in 2015, after implementation.
In each cohort, patients were followed out to 90 days after transplant.
Results
The total number of platelet units transfused dropped from 1,660 pre-PBM program to 1,417 post-PBM implementation. The total number of RBC units dropped from 1,158 to 826.
The researchers also saw changes in the proportions of inappropriate (outside guidelines) transfusions between the two time periods.
In 2013, 94.2% of RBC transfusions occurred outside the guidelines, compared with 35.4% in 2015 (P<0.0001). Similarly, the proportion of inappropriate platelet transfusions declined from 73.4% to 48.7% over the same time period (P<0.0001).
In addition, all-cause mortality at 3 months was significantly lower after the PBM program was introduced. The 3-month mortality rate was 30.7% for the 2013 cohort and 20.2% for the 2015 cohort (P=0.001).
Dr. Jambhekar noted that, in a multivariable analysis accounting for baseline differences between the groups, mortality for patients treated before the PBM program remained significantly higher, with an odds ratio of 1.85 (P=0.0008).
Neither hospital nor ICU admission within 30 days differed significantly between the groups, and there were no significant between-group differences in hospital or ICU lengths of stay.
Likewise, there were no significant between-group differences in myocardial infarctions, cerebrovascular events, sepsis, and febrile or allergic transfusion reactions.
Dr. Jambhekar noted that this study was retrospective in design and therefore could not fully account for potential confounders. It’s also unclear whether the results could be generalized for adoption by other institutions.
“In general, PBM implementation is probably helpful in reducing both platelet and PRBC [packed red blood cell] utilization, but it’s not an easy thing to do,” Dr. Jambhekar said.
“It requires institutional buy-in and key players to make it happen. Ongoing PBM-related activities like surveillance, education, and clinical decision feedback are critical to maintaining success that we’ve had.”
This study was internally funded. Dr. Jambhekar reported having nothing to disclose.
*Data presented differ from the abstract.
PBM saves blood, costs in HSCT unit
BOSTON – Implementing a patient blood management (PBM) program for patients undergoing hematopoietic stem cell transplantation (HSCT) resulted in significant reductions in blood product use with an attendant reduction in costs, but without negative effects on patient-centered outcomes, investigators reported.
Since the PBM program began, the number of transfusions and the units transfused declined without affecting mortality, ICU admission rates, or other transfusion-related complications. The program saved the hospital more than $600,000 over 1 year, reported Nilesh Jambhekar, MD, an anesthesiology resident at the Mayo Clinic in Rochester, Minn.
“In general, PBM implementation is probably helpful in reducing both platelet and [packed red blood cell] utilization, but it’s not an easy thing to do. It requires institutional buy-in and key players to make it happen,” he said at AABB 2018, the annual meeting of the group formerly known as the American Association of Blood Banks.
“Ongoing PBM-related activities [such as] surveillance, education, and clinical decision feedback are critical to maintaining success that we’ve had,” he added.
The investigators looked at blood-product use both before and after the Mayo Clinic started a PBM program that included emphasis on AABB best practice guidelines and electronic clinical decision support for transfusion orders.
They analyzed the frequency and proportion of red blood cell (RBC) and platelet transfusions, total transfusion quantities, transfusions that occurred outside of the clinical guidelines, and the activity-based costs of transfusions.
Dr. Jambhekar acknowledged that the study relied on rigid hemoglobin and platelet thresholds when considering transfusions conducted outside of the guidelines, which they defined as RBCs administered for hemoglobin values greater than 7 g/dL and platelet transfusions for platelets counts greater than 10 x 109/L. He noted, however, that they conducted sensitivity analyses to account for exceptions, such as patients with coronary disease or neutropenic fever.
The patient-centered outcomes they evaluated included mortality, hospital and ICU admission rates, transfusion reactions, cerebrovascular and coronary ischemic events, and infections.
The study included data on 360 adults who underwent HSCT in 2013, before the PBM program was implemented, and 368 transplanted in 2015, after implementation. In each cohort, patients were followed out to 90 days after transplant.
The investigators found that the total number of units transfused dropped from 1,660 units of platelets and 1,158 U of RBCs before implementation, to 1,417 U and 826 U, respectively, after PBM implementation.
Significantly, in addition to an overall reduction in units transfused, the investigators saw substantial changes in the proportions of inappropriate (outside guidelines) transfusions of red blood cells between the two time periods, with 94.2% of RBC transfusions occurring outside the guidelines in 2013, compared with 35.4% in 2015 (P less than .0001). Similarly, the proportion of inappropriate platelet transfusions declined from 73.4% to 48.7% over the same time period (P less than .0001).
Also of note was the fact that all-cause mortality at 3 months was significantly lower after the PBM program was introduced. The 3-month mortality rate for the 2013 cohort was 30.7%, compared with 20.2% for the 2015 cohort (P = .001). Neither hospital or ICU admission with 30 days or hospital or ICU lengths of stay differed significantly between the groups.
Dr. Jambhekar noted that in a multivariable analysis accounting for baseline differences between the groups as a possible explanation for the higher mortality in the 2013 cohort, mortality for patients treated before the PBM program remained significantly higher, with an odds ratio of 1.85 (P = .0008).
There were also no significant differences in either MIs, cerebrovascular events, sepsis, and febrile or allergic transfusion reactions.
He noted that in addition to the rigid thresholds used, the study was retrospective in design – and therefore could not fully account for potential confounders – and that it is unclear whether the results could be generalized for adoption by other institutions.
The study was internally funded. Dr. Jambhekar reported having no financial disclosures.
SOURCE: Jambhekar N et al. AABB 2018, Abstract PBM3-ST4-22.
BOSTON – Implementing a patient blood management (PBM) program for patients undergoing hematopoietic stem cell transplantation (HSCT) resulted in significant reductions in blood product use with an attendant reduction in costs, but without negative effects on patient-centered outcomes, investigators reported.
Since the PBM program began, the number of transfusions and the units transfused declined without affecting mortality, ICU admission rates, or other transfusion-related complications. The program saved the hospital more than $600,000 over 1 year, reported Nilesh Jambhekar, MD, an anesthesiology resident at the Mayo Clinic in Rochester, Minn.
“In general, PBM implementation is probably helpful in reducing both platelet and [packed red blood cell] utilization, but it’s not an easy thing to do. It requires institutional buy-in and key players to make it happen,” he said at AABB 2018, the annual meeting of the group formerly known as the American Association of Blood Banks.
“Ongoing PBM-related activities [such as] surveillance, education, and clinical decision feedback are critical to maintaining success that we’ve had,” he added.
The investigators looked at blood-product use both before and after the Mayo Clinic started a PBM program that included emphasis on AABB best practice guidelines and electronic clinical decision support for transfusion orders.
They analyzed the frequency and proportion of red blood cell (RBC) and platelet transfusions, total transfusion quantities, transfusions that occurred outside of the clinical guidelines, and the activity-based costs of transfusions.
Dr. Jambhekar acknowledged that the study relied on rigid hemoglobin and platelet thresholds when considering transfusions conducted outside of the guidelines, which they defined as RBCs administered for hemoglobin values greater than 7 g/dL and platelet transfusions for platelets counts greater than 10 x 109/L. He noted, however, that they conducted sensitivity analyses to account for exceptions, such as patients with coronary disease or neutropenic fever.
The patient-centered outcomes they evaluated included mortality, hospital and ICU admission rates, transfusion reactions, cerebrovascular and coronary ischemic events, and infections.
The study included data on 360 adults who underwent HSCT in 2013, before the PBM program was implemented, and 368 transplanted in 2015, after implementation. In each cohort, patients were followed out to 90 days after transplant.
The investigators found that the total number of units transfused dropped from 1,660 units of platelets and 1,158 U of RBCs before implementation, to 1,417 U and 826 U, respectively, after PBM implementation.
Significantly, in addition to an overall reduction in units transfused, the investigators saw substantial changes in the proportions of inappropriate (outside guidelines) transfusions of red blood cells between the two time periods, with 94.2% of RBC transfusions occurring outside the guidelines in 2013, compared with 35.4% in 2015 (P less than .0001). Similarly, the proportion of inappropriate platelet transfusions declined from 73.4% to 48.7% over the same time period (P less than .0001).
Also of note was the fact that all-cause mortality at 3 months was significantly lower after the PBM program was introduced. The 3-month mortality rate for the 2013 cohort was 30.7%, compared with 20.2% for the 2015 cohort (P = .001). Neither hospital or ICU admission with 30 days or hospital or ICU lengths of stay differed significantly between the groups.
Dr. Jambhekar noted that in a multivariable analysis accounting for baseline differences between the groups as a possible explanation for the higher mortality in the 2013 cohort, mortality for patients treated before the PBM program remained significantly higher, with an odds ratio of 1.85 (P = .0008).
There were also no significant differences in either MIs, cerebrovascular events, sepsis, and febrile or allergic transfusion reactions.
He noted that in addition to the rigid thresholds used, the study was retrospective in design – and therefore could not fully account for potential confounders – and that it is unclear whether the results could be generalized for adoption by other institutions.
The study was internally funded. Dr. Jambhekar reported having no financial disclosures.
SOURCE: Jambhekar N et al. AABB 2018, Abstract PBM3-ST4-22.
BOSTON – Implementing a patient blood management (PBM) program for patients undergoing hematopoietic stem cell transplantation (HSCT) resulted in significant reductions in blood product use with an attendant reduction in costs, but without negative effects on patient-centered outcomes, investigators reported.
Since the PBM program began, the number of transfusions and the units transfused declined without affecting mortality, ICU admission rates, or other transfusion-related complications. The program saved the hospital more than $600,000 over 1 year, reported Nilesh Jambhekar, MD, an anesthesiology resident at the Mayo Clinic in Rochester, Minn.
“In general, PBM implementation is probably helpful in reducing both platelet and [packed red blood cell] utilization, but it’s not an easy thing to do. It requires institutional buy-in and key players to make it happen,” he said at AABB 2018, the annual meeting of the group formerly known as the American Association of Blood Banks.
“Ongoing PBM-related activities [such as] surveillance, education, and clinical decision feedback are critical to maintaining success that we’ve had,” he added.
The investigators looked at blood-product use both before and after the Mayo Clinic started a PBM program that included emphasis on AABB best practice guidelines and electronic clinical decision support for transfusion orders.
They analyzed the frequency and proportion of red blood cell (RBC) and platelet transfusions, total transfusion quantities, transfusions that occurred outside of the clinical guidelines, and the activity-based costs of transfusions.
Dr. Jambhekar acknowledged that the study relied on rigid hemoglobin and platelet thresholds when considering transfusions conducted outside of the guidelines, which they defined as RBCs administered for hemoglobin values greater than 7 g/dL and platelet transfusions for platelets counts greater than 10 x 109/L. He noted, however, that they conducted sensitivity analyses to account for exceptions, such as patients with coronary disease or neutropenic fever.
The patient-centered outcomes they evaluated included mortality, hospital and ICU admission rates, transfusion reactions, cerebrovascular and coronary ischemic events, and infections.
The study included data on 360 adults who underwent HSCT in 2013, before the PBM program was implemented, and 368 transplanted in 2015, after implementation. In each cohort, patients were followed out to 90 days after transplant.
The investigators found that the total number of units transfused dropped from 1,660 units of platelets and 1,158 U of RBCs before implementation, to 1,417 U and 826 U, respectively, after PBM implementation.
Significantly, in addition to an overall reduction in units transfused, the investigators saw substantial changes in the proportions of inappropriate (outside guidelines) transfusions of red blood cells between the two time periods, with 94.2% of RBC transfusions occurring outside the guidelines in 2013, compared with 35.4% in 2015 (P less than .0001). Similarly, the proportion of inappropriate platelet transfusions declined from 73.4% to 48.7% over the same time period (P less than .0001).
Also of note was the fact that all-cause mortality at 3 months was significantly lower after the PBM program was introduced. The 3-month mortality rate for the 2013 cohort was 30.7%, compared with 20.2% for the 2015 cohort (P = .001). Neither hospital or ICU admission with 30 days or hospital or ICU lengths of stay differed significantly between the groups.
Dr. Jambhekar noted that in a multivariable analysis accounting for baseline differences between the groups as a possible explanation for the higher mortality in the 2013 cohort, mortality for patients treated before the PBM program remained significantly higher, with an odds ratio of 1.85 (P = .0008).
There were also no significant differences in either MIs, cerebrovascular events, sepsis, and febrile or allergic transfusion reactions.
He noted that in addition to the rigid thresholds used, the study was retrospective in design – and therefore could not fully account for potential confounders – and that it is unclear whether the results could be generalized for adoption by other institutions.
The study was internally funded. Dr. Jambhekar reported having no financial disclosures.
SOURCE: Jambhekar N et al. AABB 2018, Abstract PBM3-ST4-22.
REPORTING FROM AABB 2018
Key clinical point:
Major finding: The program saved more than $600,000 in transfusion-related costs.
Study details: Retrospective study that compared clinical outcomes for 728 patients before and after implementation of a PBM program.
Disclosures: The study was internally funded. Dr. Jambhekar reported having no financial disclosures.
Source: Jambhekar N et al. AABB 2018, Abstract PBM3-ST4-22.
Capmatinib active against NSCLC with MET exon 14 mutations
MUNICH – The experimental agent capmatinib was associated with a high response rate when used in the first line for patients with advanced non–small cell lung cancers bearing MET exon 14–skipping mutations, said investigators in the Geometry MONO-1 trial.
Among a cohort of 25 patients with treatment-naive, MET exon 14–mutated non–small cell lung cancer (NSCLC), the primary endpoint of overall response rate (ORR) as determined by blinded, independent reviewers was 72%.
In contrast, the ORR among 69 patients who had received one or more prior lines of therapy was 39.1%, reported Juergen Wolf, MD, of University Hospital Cologne (Germany).
“The differential benefit observed between patients treated in the first line and relapsed [settings] highlights the need of early diagnosis of this aberration, and prompt targeted treatment of this challenging patient population,” he said at the European Society for Medical Oncology Congress.
MET exon14–skipping mutations occur in approximately 3%-4% of NSCLC cases. The mutation is thought to be an oncogenic driver and has been shown to be a poor prognostic factor for patients with advanced NSCLC. Patients with this mutation have poor responses to conventional therapy and immune checkpoint inhibitors, even when their tumors have high levels of programmed death–ligand 1 (PD-L1) and high mutational burden, Dr. Wolf said.
Capmatinib (INC280) is an oral, reversible inhibitor of the MET receptor tyrosine kinase and is highly selective for MET, with particular affinity for MET exon 14 mutations. It is also capable of crossing the blood-brain barrier and has shown activity in the brain in preliminary studies.
The Geometry MONO-1 trial is a phase 2 study of capmatinib in patients with stage IIIB/IV NSCLC with tumors that demonstrate MET amplification and/or carry the MET exon 14 mutation. Three study cohorts of patients with MET amplification were closed for futility. Dr. Wolf reported results from two cohorts of patients with MET exon 14–skipping mutations regardless of gene copy number: one with treatment-naive patients and the other with patients being treated in the second or third line.
As noted, the ORR in 25 patients in the treatment-naive cohort after a median follow-up of 5.6 months was 72%, including 18 partial responses and no complete responses. In addition, six patients (24%) had stable disease, for a disease control rate of 96%.
In the pretreated cohort, however, there were no complete responses among 69 patients, and 27 patients (39.1%) had partial responses. In this cohort, an additional 26 patients (37.7%) had stable disease, for an ORR of 39.1% and disease-control rate of 78.3%.
Dr. Wolf also highlighted preliminary evidence of capmatinib activity in the brain. He noted that one patient, an 80-year-old woman with multiple untreated brain metastases as well as lesions in dermal lymph nodes, liver, and pleura, had complete resolution of brain metastases at the first postbaseline CT scan, 42 days after starting capmatinib. The duration of response was 11.3 months, at which point the patient discontinued the drug because of extracranial progressive disease.
Among all patients in all study cohorts (302) the most common grade 3 or 4 adverse events were peripheral edema, dyspnea, fatigue, nausea, vomiting, and decreased appetite. Adverse drug-related events (grade 3 or 4) included peripheral edema, nausea, vomiting, fatigue, and decreased appetite. In all, 10.3% of patients discontinued for adverse events suspected to be related to capmatinib.
Invited discussant James Chih-Hsin Yang, MD, PhD, from the National Taiwan University Hospital in Taipei, said that the study shows that the MET exon 14–skipping mutation is an oncogenic driver and that capmatinib is an effective tyrosine kinase inhibitor (TKI) for patients with NSCLC harboring this mutation.
Questions that still need to be answered, he said, include whether patients with the mutation are heterogeneous and may have differing response to TKIs, how long the duration of response is, how long it will take for resistance to capmatinib to occur, how it compares with other MET inhibitors, and if there are additional biomarkers that could help select patients for treatment with the novel agent.
The study was funded by Novartis. Dr. Wolf reported advisory board participation, institutional research support, and lecture fees from Novartis and others. Dr. Yang reported honoraria from advisory board participation and/or speaking from Novartis and others. His institution participated in the Geometry MONO-1 study, but he was not personally involved.
MUNICH – The experimental agent capmatinib was associated with a high response rate when used in the first line for patients with advanced non–small cell lung cancers bearing MET exon 14–skipping mutations, said investigators in the Geometry MONO-1 trial.
Among a cohort of 25 patients with treatment-naive, MET exon 14–mutated non–small cell lung cancer (NSCLC), the primary endpoint of overall response rate (ORR) as determined by blinded, independent reviewers was 72%.
In contrast, the ORR among 69 patients who had received one or more prior lines of therapy was 39.1%, reported Juergen Wolf, MD, of University Hospital Cologne (Germany).
“The differential benefit observed between patients treated in the first line and relapsed [settings] highlights the need of early diagnosis of this aberration, and prompt targeted treatment of this challenging patient population,” he said at the European Society for Medical Oncology Congress.
MET exon14–skipping mutations occur in approximately 3%-4% of NSCLC cases. The mutation is thought to be an oncogenic driver and has been shown to be a poor prognostic factor for patients with advanced NSCLC. Patients with this mutation have poor responses to conventional therapy and immune checkpoint inhibitors, even when their tumors have high levels of programmed death–ligand 1 (PD-L1) and high mutational burden, Dr. Wolf said.
Capmatinib (INC280) is an oral, reversible inhibitor of the MET receptor tyrosine kinase and is highly selective for MET, with particular affinity for MET exon 14 mutations. It is also capable of crossing the blood-brain barrier and has shown activity in the brain in preliminary studies.
The Geometry MONO-1 trial is a phase 2 study of capmatinib in patients with stage IIIB/IV NSCLC with tumors that demonstrate MET amplification and/or carry the MET exon 14 mutation. Three study cohorts of patients with MET amplification were closed for futility. Dr. Wolf reported results from two cohorts of patients with MET exon 14–skipping mutations regardless of gene copy number: one with treatment-naive patients and the other with patients being treated in the second or third line.
As noted, the ORR in 25 patients in the treatment-naive cohort after a median follow-up of 5.6 months was 72%, including 18 partial responses and no complete responses. In addition, six patients (24%) had stable disease, for a disease control rate of 96%.
In the pretreated cohort, however, there were no complete responses among 69 patients, and 27 patients (39.1%) had partial responses. In this cohort, an additional 26 patients (37.7%) had stable disease, for an ORR of 39.1% and disease-control rate of 78.3%.
Dr. Wolf also highlighted preliminary evidence of capmatinib activity in the brain. He noted that one patient, an 80-year-old woman with multiple untreated brain metastases as well as lesions in dermal lymph nodes, liver, and pleura, had complete resolution of brain metastases at the first postbaseline CT scan, 42 days after starting capmatinib. The duration of response was 11.3 months, at which point the patient discontinued the drug because of extracranial progressive disease.
Among all patients in all study cohorts (302) the most common grade 3 or 4 adverse events were peripheral edema, dyspnea, fatigue, nausea, vomiting, and decreased appetite. Adverse drug-related events (grade 3 or 4) included peripheral edema, nausea, vomiting, fatigue, and decreased appetite. In all, 10.3% of patients discontinued for adverse events suspected to be related to capmatinib.
Invited discussant James Chih-Hsin Yang, MD, PhD, from the National Taiwan University Hospital in Taipei, said that the study shows that the MET exon 14–skipping mutation is an oncogenic driver and that capmatinib is an effective tyrosine kinase inhibitor (TKI) for patients with NSCLC harboring this mutation.
Questions that still need to be answered, he said, include whether patients with the mutation are heterogeneous and may have differing response to TKIs, how long the duration of response is, how long it will take for resistance to capmatinib to occur, how it compares with other MET inhibitors, and if there are additional biomarkers that could help select patients for treatment with the novel agent.
The study was funded by Novartis. Dr. Wolf reported advisory board participation, institutional research support, and lecture fees from Novartis and others. Dr. Yang reported honoraria from advisory board participation and/or speaking from Novartis and others. His institution participated in the Geometry MONO-1 study, but he was not personally involved.
MUNICH – The experimental agent capmatinib was associated with a high response rate when used in the first line for patients with advanced non–small cell lung cancers bearing MET exon 14–skipping mutations, said investigators in the Geometry MONO-1 trial.
Among a cohort of 25 patients with treatment-naive, MET exon 14–mutated non–small cell lung cancer (NSCLC), the primary endpoint of overall response rate (ORR) as determined by blinded, independent reviewers was 72%.
In contrast, the ORR among 69 patients who had received one or more prior lines of therapy was 39.1%, reported Juergen Wolf, MD, of University Hospital Cologne (Germany).
“The differential benefit observed between patients treated in the first line and relapsed [settings] highlights the need of early diagnosis of this aberration, and prompt targeted treatment of this challenging patient population,” he said at the European Society for Medical Oncology Congress.
MET exon14–skipping mutations occur in approximately 3%-4% of NSCLC cases. The mutation is thought to be an oncogenic driver and has been shown to be a poor prognostic factor for patients with advanced NSCLC. Patients with this mutation have poor responses to conventional therapy and immune checkpoint inhibitors, even when their tumors have high levels of programmed death–ligand 1 (PD-L1) and high mutational burden, Dr. Wolf said.
Capmatinib (INC280) is an oral, reversible inhibitor of the MET receptor tyrosine kinase and is highly selective for MET, with particular affinity for MET exon 14 mutations. It is also capable of crossing the blood-brain barrier and has shown activity in the brain in preliminary studies.
The Geometry MONO-1 trial is a phase 2 study of capmatinib in patients with stage IIIB/IV NSCLC with tumors that demonstrate MET amplification and/or carry the MET exon 14 mutation. Three study cohorts of patients with MET amplification were closed for futility. Dr. Wolf reported results from two cohorts of patients with MET exon 14–skipping mutations regardless of gene copy number: one with treatment-naive patients and the other with patients being treated in the second or third line.
As noted, the ORR in 25 patients in the treatment-naive cohort after a median follow-up of 5.6 months was 72%, including 18 partial responses and no complete responses. In addition, six patients (24%) had stable disease, for a disease control rate of 96%.
In the pretreated cohort, however, there were no complete responses among 69 patients, and 27 patients (39.1%) had partial responses. In this cohort, an additional 26 patients (37.7%) had stable disease, for an ORR of 39.1% and disease-control rate of 78.3%.
Dr. Wolf also highlighted preliminary evidence of capmatinib activity in the brain. He noted that one patient, an 80-year-old woman with multiple untreated brain metastases as well as lesions in dermal lymph nodes, liver, and pleura, had complete resolution of brain metastases at the first postbaseline CT scan, 42 days after starting capmatinib. The duration of response was 11.3 months, at which point the patient discontinued the drug because of extracranial progressive disease.
Among all patients in all study cohorts (302) the most common grade 3 or 4 adverse events were peripheral edema, dyspnea, fatigue, nausea, vomiting, and decreased appetite. Adverse drug-related events (grade 3 or 4) included peripheral edema, nausea, vomiting, fatigue, and decreased appetite. In all, 10.3% of patients discontinued for adverse events suspected to be related to capmatinib.
Invited discussant James Chih-Hsin Yang, MD, PhD, from the National Taiwan University Hospital in Taipei, said that the study shows that the MET exon 14–skipping mutation is an oncogenic driver and that capmatinib is an effective tyrosine kinase inhibitor (TKI) for patients with NSCLC harboring this mutation.
Questions that still need to be answered, he said, include whether patients with the mutation are heterogeneous and may have differing response to TKIs, how long the duration of response is, how long it will take for resistance to capmatinib to occur, how it compares with other MET inhibitors, and if there are additional biomarkers that could help select patients for treatment with the novel agent.
The study was funded by Novartis. Dr. Wolf reported advisory board participation, institutional research support, and lecture fees from Novartis and others. Dr. Yang reported honoraria from advisory board participation and/or speaking from Novartis and others. His institution participated in the Geometry MONO-1 study, but he was not personally involved.
REPORTING FROM ESMO 2018
Key clinical point: Patients with non–small cell lung cancer bearing a MET exon 14–skipping mutation had high overall response rates to the MET inhibitor capmatinib.
Major finding: The overall response rate in treatment-naive patients was 72%.
Study details: A phase 2 trial with previously treated and untreated patients with advanced non–small cell lung cancers bearing MET exon 14–skipping mutations.
Disclosures: The study was funded by Novartis. Dr. Wolf reported advisory board participation and lecture fees from Novartis and others and institutional research support from Novartis and others. Dr. Yang reported honoraria from advisory board participation and/or speaking from Novartis and others. His institution participated in the Geometry MONO-1 study, but he was not personally involved.
Aberrant RNA editing linked to aggressive myeloma
Overly zealous editing of messenger RNA in multiple myeloma cells appears to contribute to myeloma pathogenesis, and is prognostic of poor outcomes, investigators contend.
Over-expression of RNA editing enzymes in the adenosine deaminases acting on RNA (ADAR) family, specifically ADAR1, lead to hyperediting of the multiple myeloma (MM) transcriptome that in turn appears related to a drug-resistant disease phenotype and worse prognosis, reported Phaik Ju Teoh, PhD, of the Cancer Science Institute of Singapore, and colleagues.
The investigators implicate aberrant editing of adenosine to inosine (A-to-I) in malignant plasma cells, and its effects on NEIL1, a gene that encodes proteins involved in base excision repair of DNA, as important mechanisms in multiple myeloma pathogenesis.
“To the best of our knowledge, this is the first report of ADAR1-mediated hypereditome being an independent prognostic factor. The compromised integrity of MM transcriptome drives oncogenic phenotypes, likely contributing to the disease pathogenesis. Our current work, therefore, recognizes the clear biological and clinical importance of A-to-I editing at both the whole-transcriptome and gene-specific level (NEIL1) in MM,” they wrote in Blood.
A-to-I editing is the most prevalent form of RNA editing in humans, and aberrant editing mediated by ADAR1 has recently been linked to the development of several different cancer types, the investigators noted.
To see whether this process may also be involved in multiple myeloma, the investigators examined whole blood or bone marrow samples from healthy volunteers and patients with multiple myeloma.
They first looked at gene-expression profiling in the control and multiple myeloma samples and found that ADAR1 was overexpressed in the multiple myeloma cells, compared with nonmalignant plasma cells. Additionally, they saw that, at the protein level, ADAR1 was expressed at higher levels in patients with newly diagnosed or relapsed disease, compared with patients with smoldering myeloma or monoclonal gammopathy of undetermined significance.
They next determined that ADAR1 directly regulates hyperediting of the MM transcriptome, evidenced by the observation of a significant increase in A-to-G editing in the newly diagnosed and relapsed myeloma samples, compared with normal plasma cells. They confirmed this finding by observing the effects of ADAR1 levels on editing events across the transcriptome.
The authors followed this observation with experiments to see whether RNA editing by ADAR1 contributes to oncogenesis in myeloma cells. They silenced its expression and found that growth rate slowed and that ADAR1 wild-type protein introduced into cells promoted growth and proliferation.
“As the rescue with mutant ADAR1 is incomplete, we do not discount potential nonediting effects in ADAR1-induced oncogenesis in vivo. Nevertheless, taking into consideration the collective results from both the in vitro and in vivo studies, the RNA editing function of ADAR1 is important for its oncogenic effects in myeloma,” they wrote.
In the final steps, they identified NEIL1 as an important target for editing in multiple myeloma and observed that the editing compromised the ability of the proteins produced by the gene to accurately repair DNA damage.
“Further demonstrating its vital contribution to disease aggressiveness, patients with high ADAR1 expression showed less responsiveness toward standard and novel therapies. Therefore, our findings implied that a disturbed editome mediated by ADAR1 overexpression is both clinically and functionally crucial in our disease setting, and that ADAR1 confers oncogenic properties in myeloma in an editing-dependent manner,” they wrote.
The study was supported by the National Research Foundation Singapore, the Singapore Ministry of Education, and the National University of Singapore. The authors reported having no competing financial interests.
SOURCE: Teoh PJ et al. Blood. 2018;132(12):1304-17.
Overly zealous editing of messenger RNA in multiple myeloma cells appears to contribute to myeloma pathogenesis, and is prognostic of poor outcomes, investigators contend.
Over-expression of RNA editing enzymes in the adenosine deaminases acting on RNA (ADAR) family, specifically ADAR1, lead to hyperediting of the multiple myeloma (MM) transcriptome that in turn appears related to a drug-resistant disease phenotype and worse prognosis, reported Phaik Ju Teoh, PhD, of the Cancer Science Institute of Singapore, and colleagues.
The investigators implicate aberrant editing of adenosine to inosine (A-to-I) in malignant plasma cells, and its effects on NEIL1, a gene that encodes proteins involved in base excision repair of DNA, as important mechanisms in multiple myeloma pathogenesis.
“To the best of our knowledge, this is the first report of ADAR1-mediated hypereditome being an independent prognostic factor. The compromised integrity of MM transcriptome drives oncogenic phenotypes, likely contributing to the disease pathogenesis. Our current work, therefore, recognizes the clear biological and clinical importance of A-to-I editing at both the whole-transcriptome and gene-specific level (NEIL1) in MM,” they wrote in Blood.
A-to-I editing is the most prevalent form of RNA editing in humans, and aberrant editing mediated by ADAR1 has recently been linked to the development of several different cancer types, the investigators noted.
To see whether this process may also be involved in multiple myeloma, the investigators examined whole blood or bone marrow samples from healthy volunteers and patients with multiple myeloma.
They first looked at gene-expression profiling in the control and multiple myeloma samples and found that ADAR1 was overexpressed in the multiple myeloma cells, compared with nonmalignant plasma cells. Additionally, they saw that, at the protein level, ADAR1 was expressed at higher levels in patients with newly diagnosed or relapsed disease, compared with patients with smoldering myeloma or monoclonal gammopathy of undetermined significance.
They next determined that ADAR1 directly regulates hyperediting of the MM transcriptome, evidenced by the observation of a significant increase in A-to-G editing in the newly diagnosed and relapsed myeloma samples, compared with normal plasma cells. They confirmed this finding by observing the effects of ADAR1 levels on editing events across the transcriptome.
The authors followed this observation with experiments to see whether RNA editing by ADAR1 contributes to oncogenesis in myeloma cells. They silenced its expression and found that growth rate slowed and that ADAR1 wild-type protein introduced into cells promoted growth and proliferation.
“As the rescue with mutant ADAR1 is incomplete, we do not discount potential nonediting effects in ADAR1-induced oncogenesis in vivo. Nevertheless, taking into consideration the collective results from both the in vitro and in vivo studies, the RNA editing function of ADAR1 is important for its oncogenic effects in myeloma,” they wrote.
In the final steps, they identified NEIL1 as an important target for editing in multiple myeloma and observed that the editing compromised the ability of the proteins produced by the gene to accurately repair DNA damage.
“Further demonstrating its vital contribution to disease aggressiveness, patients with high ADAR1 expression showed less responsiveness toward standard and novel therapies. Therefore, our findings implied that a disturbed editome mediated by ADAR1 overexpression is both clinically and functionally crucial in our disease setting, and that ADAR1 confers oncogenic properties in myeloma in an editing-dependent manner,” they wrote.
The study was supported by the National Research Foundation Singapore, the Singapore Ministry of Education, and the National University of Singapore. The authors reported having no competing financial interests.
SOURCE: Teoh PJ et al. Blood. 2018;132(12):1304-17.
Overly zealous editing of messenger RNA in multiple myeloma cells appears to contribute to myeloma pathogenesis, and is prognostic of poor outcomes, investigators contend.
Over-expression of RNA editing enzymes in the adenosine deaminases acting on RNA (ADAR) family, specifically ADAR1, lead to hyperediting of the multiple myeloma (MM) transcriptome that in turn appears related to a drug-resistant disease phenotype and worse prognosis, reported Phaik Ju Teoh, PhD, of the Cancer Science Institute of Singapore, and colleagues.
The investigators implicate aberrant editing of adenosine to inosine (A-to-I) in malignant plasma cells, and its effects on NEIL1, a gene that encodes proteins involved in base excision repair of DNA, as important mechanisms in multiple myeloma pathogenesis.
“To the best of our knowledge, this is the first report of ADAR1-mediated hypereditome being an independent prognostic factor. The compromised integrity of MM transcriptome drives oncogenic phenotypes, likely contributing to the disease pathogenesis. Our current work, therefore, recognizes the clear biological and clinical importance of A-to-I editing at both the whole-transcriptome and gene-specific level (NEIL1) in MM,” they wrote in Blood.
A-to-I editing is the most prevalent form of RNA editing in humans, and aberrant editing mediated by ADAR1 has recently been linked to the development of several different cancer types, the investigators noted.
To see whether this process may also be involved in multiple myeloma, the investigators examined whole blood or bone marrow samples from healthy volunteers and patients with multiple myeloma.
They first looked at gene-expression profiling in the control and multiple myeloma samples and found that ADAR1 was overexpressed in the multiple myeloma cells, compared with nonmalignant plasma cells. Additionally, they saw that, at the protein level, ADAR1 was expressed at higher levels in patients with newly diagnosed or relapsed disease, compared with patients with smoldering myeloma or monoclonal gammopathy of undetermined significance.
They next determined that ADAR1 directly regulates hyperediting of the MM transcriptome, evidenced by the observation of a significant increase in A-to-G editing in the newly diagnosed and relapsed myeloma samples, compared with normal plasma cells. They confirmed this finding by observing the effects of ADAR1 levels on editing events across the transcriptome.
The authors followed this observation with experiments to see whether RNA editing by ADAR1 contributes to oncogenesis in myeloma cells. They silenced its expression and found that growth rate slowed and that ADAR1 wild-type protein introduced into cells promoted growth and proliferation.
“As the rescue with mutant ADAR1 is incomplete, we do not discount potential nonediting effects in ADAR1-induced oncogenesis in vivo. Nevertheless, taking into consideration the collective results from both the in vitro and in vivo studies, the RNA editing function of ADAR1 is important for its oncogenic effects in myeloma,” they wrote.
In the final steps, they identified NEIL1 as an important target for editing in multiple myeloma and observed that the editing compromised the ability of the proteins produced by the gene to accurately repair DNA damage.
“Further demonstrating its vital contribution to disease aggressiveness, patients with high ADAR1 expression showed less responsiveness toward standard and novel therapies. Therefore, our findings implied that a disturbed editome mediated by ADAR1 overexpression is both clinically and functionally crucial in our disease setting, and that ADAR1 confers oncogenic properties in myeloma in an editing-dependent manner,” they wrote.
The study was supported by the National Research Foundation Singapore, the Singapore Ministry of Education, and the National University of Singapore. The authors reported having no competing financial interests.
SOURCE: Teoh PJ et al. Blood. 2018;132(12):1304-17.
FROM BLOOD
Key clinical point:
Major finding: ADAR1-mediated editing of NEIL1 leads to a weakened DNA base excision repair mechanism.
Study details: Experimental series using plasma samples from healthy volunteers and patients with multiple myeloma.
Disclosures: The study was supported by the National Research Foundation Singapore, the Singapore Ministry of Education, and the National University of Singapore. The authors reported having no competing financial interests.
Source: Teoh PJ et al. Blood. 2018;132(12):1304-17.
Changes related to AML relapse may be reversible
New research suggests relapse of acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplant (HSCT) is related to changes in immune-related gene expression that may be reversible.
Researchers observed downregulation of major histocompatibility complex (MHC) class II genes in samples from patients who relapsed after HSCT.
However, interferon-gamma “rapidly reversed this phenotype” in vitro, according to the researchers.
Matthew J. Christopher, MD, PhD, of Washington University School of Medicine in St. Louis, Missouri, and his colleagues reported these findings in The New England Journal of Medicine.
The researchers set out to determine how genetic and epigenetic changes after HSCT may allow leukemic cells to avoid the graft-vs-leukemia effect and to see whether immune-related genes are affected by HSCT.
The team analyzed paired samples obtained at diagnosis and relapse from 15 AML patients who relapsed after HSCT and 20 AML patients who relapsed after chemotherapy. The team also analyzed additional samples from patients who relapsed after HSCT to validate initial findings.
Methods of analysis included enhanced exome sequencing, RNA sequencing, flow cytometry, and immunohistochemical analysis.
Findings
The researchers first looked for relapse-specific mutations but found no driver mutations associated with relapse after HSCT.
The mutations seen post-HSCT relapse were generally similar to those seen both before treatment and after relapse in patients who had undergone chemotherapy, and the researchers could not identify any patterns of mutations related to relapse.
They then looked for, but did not find, relapse-specific mutations in genes involved in modulation of immune checkpoints, antigen presentation, or cytokine signaling.
The researchers did, however, find evidence of epigenetic changes that were more common in the samples from patients with post-transplant relapses.
RNA sequencing showed that MHC class II genes (HLA-DPA1, HLA-DPB1, HLA-DQB1, and HLA-DRB1) were downregulated three- to 12-fold after transplant.
Flow cytometry and immunohistochemical analysis confirmed that MHC class II expression was decreased at relapse after HSCT in 17 of 34 samples evaluated.
The researchers said there was no association between the downregulation of MHC class II and donor type or use of immunosuppression.
To see whether the downregulation of MHC class II genes was reversible, the researchers treated three post-HSCT relapse samples with interferon-gamma, which is known to upregulate MHC class II on certain cells.
Culturing patient cells with interferon-gamma “rapidly induced MHC class II protein expression on leukemic blasts,” the researchers said. They observed “essentially full restoration of MHC class II protein expression in nearly all AML blasts after 72 hours.”
This study was supported by the National Institutes of Health, Leukemia and Lymphoma Society, and the Barnes-Jewish Hospital Foundation.
Several study authors reported personal fees and/or research support from industry outside the submitted work.
New research suggests relapse of acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplant (HSCT) is related to changes in immune-related gene expression that may be reversible.
Researchers observed downregulation of major histocompatibility complex (MHC) class II genes in samples from patients who relapsed after HSCT.
However, interferon-gamma “rapidly reversed this phenotype” in vitro, according to the researchers.
Matthew J. Christopher, MD, PhD, of Washington University School of Medicine in St. Louis, Missouri, and his colleagues reported these findings in The New England Journal of Medicine.
The researchers set out to determine how genetic and epigenetic changes after HSCT may allow leukemic cells to avoid the graft-vs-leukemia effect and to see whether immune-related genes are affected by HSCT.
The team analyzed paired samples obtained at diagnosis and relapse from 15 AML patients who relapsed after HSCT and 20 AML patients who relapsed after chemotherapy. The team also analyzed additional samples from patients who relapsed after HSCT to validate initial findings.
Methods of analysis included enhanced exome sequencing, RNA sequencing, flow cytometry, and immunohistochemical analysis.
Findings
The researchers first looked for relapse-specific mutations but found no driver mutations associated with relapse after HSCT.
The mutations seen post-HSCT relapse were generally similar to those seen both before treatment and after relapse in patients who had undergone chemotherapy, and the researchers could not identify any patterns of mutations related to relapse.
They then looked for, but did not find, relapse-specific mutations in genes involved in modulation of immune checkpoints, antigen presentation, or cytokine signaling.
The researchers did, however, find evidence of epigenetic changes that were more common in the samples from patients with post-transplant relapses.
RNA sequencing showed that MHC class II genes (HLA-DPA1, HLA-DPB1, HLA-DQB1, and HLA-DRB1) were downregulated three- to 12-fold after transplant.
Flow cytometry and immunohistochemical analysis confirmed that MHC class II expression was decreased at relapse after HSCT in 17 of 34 samples evaluated.
The researchers said there was no association between the downregulation of MHC class II and donor type or use of immunosuppression.
To see whether the downregulation of MHC class II genes was reversible, the researchers treated three post-HSCT relapse samples with interferon-gamma, which is known to upregulate MHC class II on certain cells.
Culturing patient cells with interferon-gamma “rapidly induced MHC class II protein expression on leukemic blasts,” the researchers said. They observed “essentially full restoration of MHC class II protein expression in nearly all AML blasts after 72 hours.”
This study was supported by the National Institutes of Health, Leukemia and Lymphoma Society, and the Barnes-Jewish Hospital Foundation.
Several study authors reported personal fees and/or research support from industry outside the submitted work.
New research suggests relapse of acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplant (HSCT) is related to changes in immune-related gene expression that may be reversible.
Researchers observed downregulation of major histocompatibility complex (MHC) class II genes in samples from patients who relapsed after HSCT.
However, interferon-gamma “rapidly reversed this phenotype” in vitro, according to the researchers.
Matthew J. Christopher, MD, PhD, of Washington University School of Medicine in St. Louis, Missouri, and his colleagues reported these findings in The New England Journal of Medicine.
The researchers set out to determine how genetic and epigenetic changes after HSCT may allow leukemic cells to avoid the graft-vs-leukemia effect and to see whether immune-related genes are affected by HSCT.
The team analyzed paired samples obtained at diagnosis and relapse from 15 AML patients who relapsed after HSCT and 20 AML patients who relapsed after chemotherapy. The team also analyzed additional samples from patients who relapsed after HSCT to validate initial findings.
Methods of analysis included enhanced exome sequencing, RNA sequencing, flow cytometry, and immunohistochemical analysis.
Findings
The researchers first looked for relapse-specific mutations but found no driver mutations associated with relapse after HSCT.
The mutations seen post-HSCT relapse were generally similar to those seen both before treatment and after relapse in patients who had undergone chemotherapy, and the researchers could not identify any patterns of mutations related to relapse.
They then looked for, but did not find, relapse-specific mutations in genes involved in modulation of immune checkpoints, antigen presentation, or cytokine signaling.
The researchers did, however, find evidence of epigenetic changes that were more common in the samples from patients with post-transplant relapses.
RNA sequencing showed that MHC class II genes (HLA-DPA1, HLA-DPB1, HLA-DQB1, and HLA-DRB1) were downregulated three- to 12-fold after transplant.
Flow cytometry and immunohistochemical analysis confirmed that MHC class II expression was decreased at relapse after HSCT in 17 of 34 samples evaluated.
The researchers said there was no association between the downregulation of MHC class II and donor type or use of immunosuppression.
To see whether the downregulation of MHC class II genes was reversible, the researchers treated three post-HSCT relapse samples with interferon-gamma, which is known to upregulate MHC class II on certain cells.
Culturing patient cells with interferon-gamma “rapidly induced MHC class II protein expression on leukemic blasts,” the researchers said. They observed “essentially full restoration of MHC class II protein expression in nearly all AML blasts after 72 hours.”
This study was supported by the National Institutes of Health, Leukemia and Lymphoma Society, and the Barnes-Jewish Hospital Foundation.
Several study authors reported personal fees and/or research support from industry outside the submitted work.
Venetoclax/HMA combo still safe, effective for elderly with AML
In patients aged 65 years and older with acute myeloid leukemia (AML), the combination of venetoclax (Venclexta) and a hypomethylating agent had good efficacy and was well tolerated, according to updated results from a phase 1b dose-escalation and expansion trial.
At a median of 8.9 months of study, the overall response rate (ORR) among all treated patients was 68%, with a median duration of complete remission (CR) plus CR with incomplete count recovery (CRi) of 11.3 months, reported Courtney DiNardo, MD, from the University of Texas MD Anderson Center in Houston and her colleagues.
“Venetoclax in combination with azacitidine or decitabine was well tolerated, with similar safety profiles within all arms of the dose escalation and expansion phases in elderly patients with previously untreated AML ineligible for standard induction therapy,” they wrote in a paper published in Blood.
At the 2017 European Hematology Association Congress, the investigators reported that the combined rate of complete remission CR and CRi was 60% among patients with poor-risk cytogenetics and 78% among patients with intermediate-risk disease. In addition, the drug combination was effective among patients with both primary de novo AML (68%) and secondary AML (related to myelodysplasia or myeloproliferative neoplasms or previous therapy; 73%).
In this, the most recent analysis, Dr. DiNardo and her colleagues reported on follow-up of 145 patients aged 65 and older with treatment-naive AML who were not eligible for intensive chemotherapy regimens used for younger adults. The median age was 74 years. Approximately half of all patients (49%) had poor-risk cytogenetics.
The patients were treated with either decitabine or azacitidine plus venetoclax at a dose of either 400 mg or 800 mg. Decitabine was dosed at 20 mg/m2 intravenously on days 1-5 of a 28-day cycle. Azacitidine was dosed at 75 mg/m2 subcutaneously on days 1-7 of every cycle.
The median time on study was 8.9 months. Among all patients treated at all doses, 67% had either a CR or CRi. The combined CR/CRi rate in patients treated at the 400 mg dose of venetoclax was 73%.
The CR/CRi rate for patients with poor-risk cytogenetics was 60%, and the rate for patients aged 75 years and older was 65%.
Among all patients, the median duration of CR/CRi was 11.3 months, and median overall survival was 17.5 months. In the 400 mg venetoclax cohort, the median duration of CR/CRi was 12.5 months, with the median OS not reached at the time of data cutoff.
Adverse events occurring in 30% or more of patients included constipation, diarrhea, vomiting, nausea, fatigue, febrile neutropenia, hypokalemia, decreased appetite, and decreased white blood cell count. There were no reported cases of the tumor lysis syndrome, a known complication of venetoclax therapy.
Venetoclax plus decitabine or azacitidine was effective in high-risk subgroups, including patients aged 75 years and older, those with poor cytogenetic risk, and those with secondary AML, the investigators noted.
“Though these observations are drawn from a relatively small subset of patients, the remission rates achieved by our low-intensity regimen are encouraging in light of the traditionally lower remission rates in the elderly AML population (40%-50%) compared with young patients receiving chemotherapy (60%-70%) and the relatively short duration of these remissions,” Dr. DiNardo and her colleagues wrote.
A phase 3 trial is currently underway comparing venetoclax at the 400 mg dose plus azacitidine with azacitidine alone in treatment-naive patients with AML who are ineligible for standard induction therapy.
The trial was supported by AbbVie and Genentech. Dr. DiNardo and multiple coauthors disclosed relationships with AbbVie, Genentech, and other companies.
SOURCE: DiNardo C et al. Blood. 2018 Oct 25. doi: 10.1182/blood-2018-08-868752.
In patients aged 65 years and older with acute myeloid leukemia (AML), the combination of venetoclax (Venclexta) and a hypomethylating agent had good efficacy and was well tolerated, according to updated results from a phase 1b dose-escalation and expansion trial.
At a median of 8.9 months of study, the overall response rate (ORR) among all treated patients was 68%, with a median duration of complete remission (CR) plus CR with incomplete count recovery (CRi) of 11.3 months, reported Courtney DiNardo, MD, from the University of Texas MD Anderson Center in Houston and her colleagues.
“Venetoclax in combination with azacitidine or decitabine was well tolerated, with similar safety profiles within all arms of the dose escalation and expansion phases in elderly patients with previously untreated AML ineligible for standard induction therapy,” they wrote in a paper published in Blood.
At the 2017 European Hematology Association Congress, the investigators reported that the combined rate of complete remission CR and CRi was 60% among patients with poor-risk cytogenetics and 78% among patients with intermediate-risk disease. In addition, the drug combination was effective among patients with both primary de novo AML (68%) and secondary AML (related to myelodysplasia or myeloproliferative neoplasms or previous therapy; 73%).
In this, the most recent analysis, Dr. DiNardo and her colleagues reported on follow-up of 145 patients aged 65 and older with treatment-naive AML who were not eligible for intensive chemotherapy regimens used for younger adults. The median age was 74 years. Approximately half of all patients (49%) had poor-risk cytogenetics.
The patients were treated with either decitabine or azacitidine plus venetoclax at a dose of either 400 mg or 800 mg. Decitabine was dosed at 20 mg/m2 intravenously on days 1-5 of a 28-day cycle. Azacitidine was dosed at 75 mg/m2 subcutaneously on days 1-7 of every cycle.
The median time on study was 8.9 months. Among all patients treated at all doses, 67% had either a CR or CRi. The combined CR/CRi rate in patients treated at the 400 mg dose of venetoclax was 73%.
The CR/CRi rate for patients with poor-risk cytogenetics was 60%, and the rate for patients aged 75 years and older was 65%.
Among all patients, the median duration of CR/CRi was 11.3 months, and median overall survival was 17.5 months. In the 400 mg venetoclax cohort, the median duration of CR/CRi was 12.5 months, with the median OS not reached at the time of data cutoff.
Adverse events occurring in 30% or more of patients included constipation, diarrhea, vomiting, nausea, fatigue, febrile neutropenia, hypokalemia, decreased appetite, and decreased white blood cell count. There were no reported cases of the tumor lysis syndrome, a known complication of venetoclax therapy.
Venetoclax plus decitabine or azacitidine was effective in high-risk subgroups, including patients aged 75 years and older, those with poor cytogenetic risk, and those with secondary AML, the investigators noted.
“Though these observations are drawn from a relatively small subset of patients, the remission rates achieved by our low-intensity regimen are encouraging in light of the traditionally lower remission rates in the elderly AML population (40%-50%) compared with young patients receiving chemotherapy (60%-70%) and the relatively short duration of these remissions,” Dr. DiNardo and her colleagues wrote.
A phase 3 trial is currently underway comparing venetoclax at the 400 mg dose plus azacitidine with azacitidine alone in treatment-naive patients with AML who are ineligible for standard induction therapy.
The trial was supported by AbbVie and Genentech. Dr. DiNardo and multiple coauthors disclosed relationships with AbbVie, Genentech, and other companies.
SOURCE: DiNardo C et al. Blood. 2018 Oct 25. doi: 10.1182/blood-2018-08-868752.
In patients aged 65 years and older with acute myeloid leukemia (AML), the combination of venetoclax (Venclexta) and a hypomethylating agent had good efficacy and was well tolerated, according to updated results from a phase 1b dose-escalation and expansion trial.
At a median of 8.9 months of study, the overall response rate (ORR) among all treated patients was 68%, with a median duration of complete remission (CR) plus CR with incomplete count recovery (CRi) of 11.3 months, reported Courtney DiNardo, MD, from the University of Texas MD Anderson Center in Houston and her colleagues.
“Venetoclax in combination with azacitidine or decitabine was well tolerated, with similar safety profiles within all arms of the dose escalation and expansion phases in elderly patients with previously untreated AML ineligible for standard induction therapy,” they wrote in a paper published in Blood.
At the 2017 European Hematology Association Congress, the investigators reported that the combined rate of complete remission CR and CRi was 60% among patients with poor-risk cytogenetics and 78% among patients with intermediate-risk disease. In addition, the drug combination was effective among patients with both primary de novo AML (68%) and secondary AML (related to myelodysplasia or myeloproliferative neoplasms or previous therapy; 73%).
In this, the most recent analysis, Dr. DiNardo and her colleagues reported on follow-up of 145 patients aged 65 and older with treatment-naive AML who were not eligible for intensive chemotherapy regimens used for younger adults. The median age was 74 years. Approximately half of all patients (49%) had poor-risk cytogenetics.
The patients were treated with either decitabine or azacitidine plus venetoclax at a dose of either 400 mg or 800 mg. Decitabine was dosed at 20 mg/m2 intravenously on days 1-5 of a 28-day cycle. Azacitidine was dosed at 75 mg/m2 subcutaneously on days 1-7 of every cycle.
The median time on study was 8.9 months. Among all patients treated at all doses, 67% had either a CR or CRi. The combined CR/CRi rate in patients treated at the 400 mg dose of venetoclax was 73%.
The CR/CRi rate for patients with poor-risk cytogenetics was 60%, and the rate for patients aged 75 years and older was 65%.
Among all patients, the median duration of CR/CRi was 11.3 months, and median overall survival was 17.5 months. In the 400 mg venetoclax cohort, the median duration of CR/CRi was 12.5 months, with the median OS not reached at the time of data cutoff.
Adverse events occurring in 30% or more of patients included constipation, diarrhea, vomiting, nausea, fatigue, febrile neutropenia, hypokalemia, decreased appetite, and decreased white blood cell count. There were no reported cases of the tumor lysis syndrome, a known complication of venetoclax therapy.
Venetoclax plus decitabine or azacitidine was effective in high-risk subgroups, including patients aged 75 years and older, those with poor cytogenetic risk, and those with secondary AML, the investigators noted.
“Though these observations are drawn from a relatively small subset of patients, the remission rates achieved by our low-intensity regimen are encouraging in light of the traditionally lower remission rates in the elderly AML population (40%-50%) compared with young patients receiving chemotherapy (60%-70%) and the relatively short duration of these remissions,” Dr. DiNardo and her colleagues wrote.
A phase 3 trial is currently underway comparing venetoclax at the 400 mg dose plus azacitidine with azacitidine alone in treatment-naive patients with AML who are ineligible for standard induction therapy.
The trial was supported by AbbVie and Genentech. Dr. DiNardo and multiple coauthors disclosed relationships with AbbVie, Genentech, and other companies.
SOURCE: DiNardo C et al. Blood. 2018 Oct 25. doi: 10.1182/blood-2018-08-868752.
FROM BLOOD
Key clinical point:
Major finding: At a median time of study of 8.9 months, the overall response rate among all treated patients was 68%.
Study details: Follow-up of a phase 1b dose-escalation and expansion cohort of 145 patients aged 65 years and older with treatment-naive AML.
Disclosures: The trial was supported by AbbVie and Genentech. Dr. DiNardo and multiple coauthors disclosed relationships with AbbVie, Genentech, and other companies.
Source: DiNardo C et al. Blood. 2018 Oct 25. doi: 10.1182/blood-2018-08-868752.
AML relapse after HSCT linked to potentially reversible immune changes
Relapse of acute myeloid leukemia after hematopoietic stem cell transplantation appears to be related to posttransplant changes in immune function that may be reversible with interferon-gamma therapy, investigators said.
Researchers performed a comparison of acute myeloid leukemia (AML) samples taken from patients before hematopoietic stem cell transplantation (HSCT) and at the time of relapse. They found that, while the general genomic changes seen at relapse resembled changes seen when patients experience relapse after chemotherapy, HSCT was associated with changes in genes believed to control both adaptive and innate immunity.
The findings suggest that transplantation results in a dampening of immune surveillance that could potentially be reversed with interferon gamma, an immunostimulatory cytokine, reported Matthew J. Christopher, MD, PhD, from Washington University, St. Louis, and his colleagues.
“These changes appeared to be epigenetic in nature in at least some cases, which suggests that therapeutic strategies to resensitize AML cells to the graft-versus-leukemia effect may be feasible,” they wrote in the New England Journal of Medicine.
The researchers noted that, while the presence of certain AML mutations may predict risk for relapse following HSCT, “the mechanisms by which these mutations promote relapse remain unclear.”
To get a better sense of how genetic and epigenetic changes after transplantation may allow leukemic cells to avoid the graft-versus-leukemia effect – and to see whether immune-related genes are affected by HSCT – they performed enhanced exome sequencing, flow cytometry, and immunohistochemical analyses on samples from 15 patients with AML who had a relapse after receiving transplants from HLA-matched siblings, matched unrelated donors, or HLA-mismatched unrelated donors, and on paired samples from 20 patients who experienced relapses after chemotherapy.
To validate their findings, they also evaluated samples from 28 other patients with AML who had a relapse after transplantation.
They first looked for relapse-specific mutations, but found no driver mutations associated with relapse after transplantation. The mutations seen during relapse after transplantation were generally similar to those seen both before treatment and after relapse in patients who had undergone chemotherapy. The researchers could not identify any patterns of mutations related to relapse.
They then looked for, but did not find, relapse-specific mutations in genes involved in either modulation of immune checkpoints, antigen presentation, or cytokine signaling.
The researchers did, however, find evidence of epigenetic changes that were more common in the samples of patients with posttransplant relapses, compared with postchemotherapy relapses. Specifically, they found that major histocompatibility (MHC) class II genes were down-regulated 200%-1100% after transplant, compared with the pretransplant samples.
In samples from 17 of 34 patients who experienced a relapse after transplantation, both flow cytometry and immunohistochemical analyses confirmed that expression of MHC class II molecules were decreased at relapse.
To see whether this down-regulation was reversible, the researchers treated samples from three patients with posttransplant relapse with interferon gamma, which is known to up-regulate MHC class II protein on myeloid cells and other cell types.
“Culture of these cells with interferon-gamma rapidly induced MHC class II protein expression on leukemic blasts, with essentially full restoration of MHC class II protein expression in nearly all AML blasts after 72 hours,” they wrote, adding that the reversibility of down-regulation of MHC class II in these blasts “strongly suggests that this phenomenon is mediated by an epigenetic mechanism.”
The study was supported by grants to investigators from the National Institutes of Health, Leukemia & Lymphoma Society, and the Barnes-Jewish Hospital Foundation. Dr. Christopher and several coauthors reported receiving grants from the study funders but no other relevant conflicts of interest. Several coauthors reported receiving personal fees and/or research support from industry outside the submitted work.
SOURCE: Christopher MJ et al. N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1808777.
Relapse of acute myeloid leukemia after hematopoietic stem cell transplantation appears to be related to posttransplant changes in immune function that may be reversible with interferon-gamma therapy, investigators said.
Researchers performed a comparison of acute myeloid leukemia (AML) samples taken from patients before hematopoietic stem cell transplantation (HSCT) and at the time of relapse. They found that, while the general genomic changes seen at relapse resembled changes seen when patients experience relapse after chemotherapy, HSCT was associated with changes in genes believed to control both adaptive and innate immunity.
The findings suggest that transplantation results in a dampening of immune surveillance that could potentially be reversed with interferon gamma, an immunostimulatory cytokine, reported Matthew J. Christopher, MD, PhD, from Washington University, St. Louis, and his colleagues.
“These changes appeared to be epigenetic in nature in at least some cases, which suggests that therapeutic strategies to resensitize AML cells to the graft-versus-leukemia effect may be feasible,” they wrote in the New England Journal of Medicine.
The researchers noted that, while the presence of certain AML mutations may predict risk for relapse following HSCT, “the mechanisms by which these mutations promote relapse remain unclear.”
To get a better sense of how genetic and epigenetic changes after transplantation may allow leukemic cells to avoid the graft-versus-leukemia effect – and to see whether immune-related genes are affected by HSCT – they performed enhanced exome sequencing, flow cytometry, and immunohistochemical analyses on samples from 15 patients with AML who had a relapse after receiving transplants from HLA-matched siblings, matched unrelated donors, or HLA-mismatched unrelated donors, and on paired samples from 20 patients who experienced relapses after chemotherapy.
To validate their findings, they also evaluated samples from 28 other patients with AML who had a relapse after transplantation.
They first looked for relapse-specific mutations, but found no driver mutations associated with relapse after transplantation. The mutations seen during relapse after transplantation were generally similar to those seen both before treatment and after relapse in patients who had undergone chemotherapy. The researchers could not identify any patterns of mutations related to relapse.
They then looked for, but did not find, relapse-specific mutations in genes involved in either modulation of immune checkpoints, antigen presentation, or cytokine signaling.
The researchers did, however, find evidence of epigenetic changes that were more common in the samples of patients with posttransplant relapses, compared with postchemotherapy relapses. Specifically, they found that major histocompatibility (MHC) class II genes were down-regulated 200%-1100% after transplant, compared with the pretransplant samples.
In samples from 17 of 34 patients who experienced a relapse after transplantation, both flow cytometry and immunohistochemical analyses confirmed that expression of MHC class II molecules were decreased at relapse.
To see whether this down-regulation was reversible, the researchers treated samples from three patients with posttransplant relapse with interferon gamma, which is known to up-regulate MHC class II protein on myeloid cells and other cell types.
“Culture of these cells with interferon-gamma rapidly induced MHC class II protein expression on leukemic blasts, with essentially full restoration of MHC class II protein expression in nearly all AML blasts after 72 hours,” they wrote, adding that the reversibility of down-regulation of MHC class II in these blasts “strongly suggests that this phenomenon is mediated by an epigenetic mechanism.”
The study was supported by grants to investigators from the National Institutes of Health, Leukemia & Lymphoma Society, and the Barnes-Jewish Hospital Foundation. Dr. Christopher and several coauthors reported receiving grants from the study funders but no other relevant conflicts of interest. Several coauthors reported receiving personal fees and/or research support from industry outside the submitted work.
SOURCE: Christopher MJ et al. N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1808777.
Relapse of acute myeloid leukemia after hematopoietic stem cell transplantation appears to be related to posttransplant changes in immune function that may be reversible with interferon-gamma therapy, investigators said.
Researchers performed a comparison of acute myeloid leukemia (AML) samples taken from patients before hematopoietic stem cell transplantation (HSCT) and at the time of relapse. They found that, while the general genomic changes seen at relapse resembled changes seen when patients experience relapse after chemotherapy, HSCT was associated with changes in genes believed to control both adaptive and innate immunity.
The findings suggest that transplantation results in a dampening of immune surveillance that could potentially be reversed with interferon gamma, an immunostimulatory cytokine, reported Matthew J. Christopher, MD, PhD, from Washington University, St. Louis, and his colleagues.
“These changes appeared to be epigenetic in nature in at least some cases, which suggests that therapeutic strategies to resensitize AML cells to the graft-versus-leukemia effect may be feasible,” they wrote in the New England Journal of Medicine.
The researchers noted that, while the presence of certain AML mutations may predict risk for relapse following HSCT, “the mechanisms by which these mutations promote relapse remain unclear.”
To get a better sense of how genetic and epigenetic changes after transplantation may allow leukemic cells to avoid the graft-versus-leukemia effect – and to see whether immune-related genes are affected by HSCT – they performed enhanced exome sequencing, flow cytometry, and immunohistochemical analyses on samples from 15 patients with AML who had a relapse after receiving transplants from HLA-matched siblings, matched unrelated donors, or HLA-mismatched unrelated donors, and on paired samples from 20 patients who experienced relapses after chemotherapy.
To validate their findings, they also evaluated samples from 28 other patients with AML who had a relapse after transplantation.
They first looked for relapse-specific mutations, but found no driver mutations associated with relapse after transplantation. The mutations seen during relapse after transplantation were generally similar to those seen both before treatment and after relapse in patients who had undergone chemotherapy. The researchers could not identify any patterns of mutations related to relapse.
They then looked for, but did not find, relapse-specific mutations in genes involved in either modulation of immune checkpoints, antigen presentation, or cytokine signaling.
The researchers did, however, find evidence of epigenetic changes that were more common in the samples of patients with posttransplant relapses, compared with postchemotherapy relapses. Specifically, they found that major histocompatibility (MHC) class II genes were down-regulated 200%-1100% after transplant, compared with the pretransplant samples.
In samples from 17 of 34 patients who experienced a relapse after transplantation, both flow cytometry and immunohistochemical analyses confirmed that expression of MHC class II molecules were decreased at relapse.
To see whether this down-regulation was reversible, the researchers treated samples from three patients with posttransplant relapse with interferon gamma, which is known to up-regulate MHC class II protein on myeloid cells and other cell types.
“Culture of these cells with interferon-gamma rapidly induced MHC class II protein expression on leukemic blasts, with essentially full restoration of MHC class II protein expression in nearly all AML blasts after 72 hours,” they wrote, adding that the reversibility of down-regulation of MHC class II in these blasts “strongly suggests that this phenomenon is mediated by an epigenetic mechanism.”
The study was supported by grants to investigators from the National Institutes of Health, Leukemia & Lymphoma Society, and the Barnes-Jewish Hospital Foundation. Dr. Christopher and several coauthors reported receiving grants from the study funders but no other relevant conflicts of interest. Several coauthors reported receiving personal fees and/or research support from industry outside the submitted work.
SOURCE: Christopher MJ et al. N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1808777.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point:
Major finding: MHC class II genes were down-regulated 200%-1100% after transplant, compared with pretransplant samples.
Study details: Analysis of genetic changes pre- and posttransplant in 15 patients with AML relapse after transplant, 20 patients with relapse after chemotherapy, and 28 patients in a validation sample.
Disclosures: The study was supported by grants to investigators from the National Institutes of Health, Leukemia & Lymphoma Society, and the Barnes-Jewish Hospital Foundation. Dr. Christopher and several coauthors reported receiving grants from the study funders but no other relevant conflicts of interest. Several coauthors reported receiving personal fees and/or research support from industry outside the submitted work.
Source: Christopher MJ et al. N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1808777.
Pembrolizumab extends survival of head and neck cancer
MUNICH – In patients with recurrent or metastatic head and neck squamous cell carcinoma expressing programmed death ligand-1 (PDL-1), the immune checkpoint inhibitor pembrolizumab alone or in combination with chemotherapy improved overall survival, compared with the EXTREME chemotherapy regimen, reported investigators in the Keynote 048 trial. 
Overall survival (OS) among patients with a PD-L1 combined positive score (CPS) of 20 or greater treated with pembrolizumab (Keytruda) monotherapy was 14.9 months compared with 10.7 months for patients treated with the EXTREME regimen, a combination of cetuximab (Erbitux), carboplatin or cisplatin, and 5-fluorouracil.
A similar overall survival benefit was seen in patients with a CPS of 1 or greater, and in the total population of patients treated with pembrolizumab plus chemotherapy followed by pembrolizumab maintenance compared with EXTREME chemotherapy, Barbara Burtness, MD, of Yale Cancer Center, New Haven, Conn.
There were no differences in response rates between either pembrolizumab monotherapy or in combination compared with chemotherapy alone, but responses were more durable with the checkpoint inhibitor than with chemotherapy.
“Pembrolizumab alone and pembrolizumab given with platinum and 5-fluorouracil should represent new standards of care for the first-line treatment of metastatic head and neck carcinoma. Immune checkpoint monotherapy with pembrolizumab allows patients to live longer and has a better safety profile than the previous standard for those patients whose tumors express PD-L1,” she said at a briefing prior to her presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.
“This is the first time since 10 years that we show an improvement in survival for this group of patients,” said Jean-Pascal Machiels, MD, of University Clinic Saint-Luc, Brussels, the invited discussant for the briefing and the symposium.
The CPS is a ratio of PD-L1-positive tumor cells, lymphocytes, and macrophages to the total numbers of cells counted multiplied by 100. The investigators looked at progression-free survival (PFS) and OS in three cohorts of patients with squamous cell carcinomas of the oropharynx, oral cavity, hypopharynx, or larynx that were recurrent or metastatic and were incurable by local therapies. They compared pembrolizumab monotherapy with the EXTREME regimen, and pembrolizumab plus chemotherapy (as described in the following paragraph) with EXTREME.
A total of 882 patients were enrolled and stratified by PD-L1 expression (on 50% or greater of tumor cells, or less than 50%), p16 positive or negative status in the oropharynx, and Eastern Cooperative Oncology Group performance status of 0 or 1. The patients were then randomly assigned on a 1:1:1 basis to either pembrolizumab monotherapy at 200 mg every 3 weeks for up to 35 cycles, pembrolizumab plus a standard chemotherapy regimen (carboplatin to an area-under-the curve [AUC] of 5 or cisplatin 100 mg/m2 plus 5-FU 1000 mg/m2 per day for 4 days for six cycles, followed by pembrolizumab maintenance for up to 35 cycles or EXTREME (cetuximab at a loading dose of 400 mg/m2 followed by 250 mg/m2 once weekly plus the chemotherapy regimen described above, followed by maintenance cetuximab).
Pembrolizumab monotherapy vs. EXTREME
For the coprimary endpoint of OS in the CPS 20 or greater population, pembrolizumab was associated with significantly better survival than EXTREME at both the 12- and 24-month time points (56.9% vs. 44.9%, and 38.3% vs. 22,1%, respectively). After a minimum follow-up of 17 months, the median OS was 14.9 months with pembrolizumab, vs. 10.7 months for EXTREME. The hazard ratio (HR) for death with pembrolizumab was 0.61 (P = .0007).
The median OS in the CPS 1 or greater population was 12.3 months and 10.3 months, respectively (HR 0.78, P = .0086).
There were no differences between the arms in PFS, however, either in the CPS 20 or greater or CPS 1 or greater populations.
Although, as noted, response rates did not differ between the groups, the median duration of response was 20.9 months with pembrolizumab in both the CPS 20 and CPS 1 populations, compared with 4.2 and 4.5 months, respectively, for EXTREME.
Treatment-related adverse events of any grade occurred in 58% of patients in the monotherapy arm, vs. 96.9% in the EXTREME arm. Fatal adverse events occurred in 1% vs. 2.8%, and events leading to drug discontinuation occurred in 4.7% vs. 19.9%, respectively. There were more immune-mediated events in the pembrolizumab arm, including one death (from pneumonitis) vs. no deaths from immune-related causes in the EXTREME arm.
Pembrolizumab plus chemo vs. EXTREME
The combination of pembrolizumab was also superior to EXTREME in the total population, with 12- and 24-month OS rates of 53% vs. 43.9%, and 29% vs. 18.7%, respectively. The median OS was 13 months with the pembrolizumab/chemo combination, vs. 10.7 months for EXTREME, translating into an HR of 0.77 (P = .0034). In this analysis as well as in the pembrolizumab monotherapy combination, there was no difference in PFS or response rates, but responses in the pembrolizumab arm were more durable.
In this comparison, treatment-related adverse events were generally similar between the groups, although there were 10 treatment-related deaths with pembrolizumab, compared with eight in the EXTREME arm.
There was one immune-related death, from pneumonitis, in the pembrolizumab arm, vs. none in the EXTREME arm. Hypothyroidism, pneumonitis, hyperthyroidism and colitis were more frequent with pembrolizumab, whereas infusion reactions and severe skin reactions were more frequent with EXTREME.
“There are further analyses of biomarker and clinical predictors that will be forthcoming from this study, and these may eventually optimally guide the choice of whether to administer pembrolizumab alone or in the novel combination, Dr. Burtness said at the briefing.
“What’s extremely important also is that for a subgroup of patients with high expression of PD-L1, we can probably remove the cisplatin and have a good outcome with immunotherapy alone,” Dr. Machiels said.
He said that more work needs to be done to determine which patients are most likely to benefit from immunotherapy in the recurrent/metastatic setting, and “we have to see how we can now bring this active drug to the curative treatment of the patient, in combination with chemoradiation.”
The study was funded by Merck Sharp & Dohme. Dr. Burtness disclosed being and advisory board member and receiving travel expenses from MSD and others. Dr. Machiels disclosed speaker honoraria, travel expenses, and an uncompensated advisory role with MSD.
SOURCE: Burtness B et al. ESMO 2018. Abstract LBA8_PR.
MUNICH – In patients with recurrent or metastatic head and neck squamous cell carcinoma expressing programmed death ligand-1 (PDL-1), the immune checkpoint inhibitor pembrolizumab alone or in combination with chemotherapy improved overall survival, compared with the EXTREME chemotherapy regimen, reported investigators in the Keynote 048 trial.
Overall survival (OS) among patients with a PD-L1 combined positive score (CPS) of 20 or greater treated with pembrolizumab (Keytruda) monotherapy was 14.9 months compared with 10.7 months for patients treated with the EXTREME regimen, a combination of cetuximab (Erbitux), carboplatin or cisplatin, and 5-fluorouracil.
A similar overall survival benefit was seen in patients with a CPS of 1 or greater, and in the total population of patients treated with pembrolizumab plus chemotherapy followed by pembrolizumab maintenance compared with EXTREME chemotherapy, Barbara Burtness, MD, of Yale Cancer Center, New Haven, Conn.
There were no differences in response rates between either pembrolizumab monotherapy or in combination compared with chemotherapy alone, but responses were more durable with the checkpoint inhibitor than with chemotherapy.
“Pembrolizumab alone and pembrolizumab given with platinum and 5-fluorouracil should represent new standards of care for the first-line treatment of metastatic head and neck carcinoma. Immune checkpoint monotherapy with pembrolizumab allows patients to live longer and has a better safety profile than the previous standard for those patients whose tumors express PD-L1,” she said at a briefing prior to her presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.
“This is the first time since 10 years that we show an improvement in survival for this group of patients,” said Jean-Pascal Machiels, MD, of University Clinic Saint-Luc, Brussels, the invited discussant for the briefing and the symposium.
The CPS is a ratio of PD-L1-positive tumor cells, lymphocytes, and macrophages to the total numbers of cells counted multiplied by 100. The investigators looked at progression-free survival (PFS) and OS in three cohorts of patients with squamous cell carcinomas of the oropharynx, oral cavity, hypopharynx, or larynx that were recurrent or metastatic and were incurable by local therapies. They compared pembrolizumab monotherapy with the EXTREME regimen, and pembrolizumab plus chemotherapy (as described in the following paragraph) with EXTREME.
A total of 882 patients were enrolled and stratified by PD-L1 expression (on 50% or greater of tumor cells, or less than 50%), p16 positive or negative status in the oropharynx, and Eastern Cooperative Oncology Group performance status of 0 or 1. The patients were then randomly assigned on a 1:1:1 basis to either pembrolizumab monotherapy at 200 mg every 3 weeks for up to 35 cycles, pembrolizumab plus a standard chemotherapy regimen (carboplatin to an area-under-the curve [AUC] of 5 or cisplatin 100 mg/m2 plus 5-FU 1000 mg/m2 per day for 4 days for six cycles, followed by pembrolizumab maintenance for up to 35 cycles or EXTREME (cetuximab at a loading dose of 400 mg/m2 followed by 250 mg/m2 once weekly plus the chemotherapy regimen described above, followed by maintenance cetuximab).
Pembrolizumab monotherapy vs. EXTREME
For the coprimary endpoint of OS in the CPS 20 or greater population, pembrolizumab was associated with significantly better survival than EXTREME at both the 12- and 24-month time points (56.9% vs. 44.9%, and 38.3% vs. 22,1%, respectively). After a minimum follow-up of 17 months, the median OS was 14.9 months with pembrolizumab, vs. 10.7 months for EXTREME. The hazard ratio (HR) for death with pembrolizumab was 0.61 (P = .0007).
The median OS in the CPS 1 or greater population was 12.3 months and 10.3 months, respectively (HR 0.78, P = .0086).
There were no differences between the arms in PFS, however, either in the CPS 20 or greater or CPS 1 or greater populations.
Although, as noted, response rates did not differ between the groups, the median duration of response was 20.9 months with pembrolizumab in both the CPS 20 and CPS 1 populations, compared with 4.2 and 4.5 months, respectively, for EXTREME.
Treatment-related adverse events of any grade occurred in 58% of patients in the monotherapy arm, vs. 96.9% in the EXTREME arm. Fatal adverse events occurred in 1% vs. 2.8%, and events leading to drug discontinuation occurred in 4.7% vs. 19.9%, respectively. There were more immune-mediated events in the pembrolizumab arm, including one death (from pneumonitis) vs. no deaths from immune-related causes in the EXTREME arm.
Pembrolizumab plus chemo vs. EXTREME
The combination of pembrolizumab was also superior to EXTREME in the total population, with 12- and 24-month OS rates of 53% vs. 43.9%, and 29% vs. 18.7%, respectively. The median OS was 13 months with the pembrolizumab/chemo combination, vs. 10.7 months for EXTREME, translating into an HR of 0.77 (P = .0034). In this analysis as well as in the pembrolizumab monotherapy combination, there was no difference in PFS or response rates, but responses in the pembrolizumab arm were more durable.
In this comparison, treatment-related adverse events were generally similar between the groups, although there were 10 treatment-related deaths with pembrolizumab, compared with eight in the EXTREME arm.
There was one immune-related death, from pneumonitis, in the pembrolizumab arm, vs. none in the EXTREME arm. Hypothyroidism, pneumonitis, hyperthyroidism and colitis were more frequent with pembrolizumab, whereas infusion reactions and severe skin reactions were more frequent with EXTREME.
“There are further analyses of biomarker and clinical predictors that will be forthcoming from this study, and these may eventually optimally guide the choice of whether to administer pembrolizumab alone or in the novel combination, Dr. Burtness said at the briefing.
“What’s extremely important also is that for a subgroup of patients with high expression of PD-L1, we can probably remove the cisplatin and have a good outcome with immunotherapy alone,” Dr. Machiels said.
He said that more work needs to be done to determine which patients are most likely to benefit from immunotherapy in the recurrent/metastatic setting, and “we have to see how we can now bring this active drug to the curative treatment of the patient, in combination with chemoradiation.”
The study was funded by Merck Sharp & Dohme. Dr. Burtness disclosed being and advisory board member and receiving travel expenses from MSD and others. Dr. Machiels disclosed speaker honoraria, travel expenses, and an uncompensated advisory role with MSD.
SOURCE: Burtness B et al. ESMO 2018. Abstract LBA8_PR.
MUNICH – In patients with recurrent or metastatic head and neck squamous cell carcinoma expressing programmed death ligand-1 (PDL-1), the immune checkpoint inhibitor pembrolizumab alone or in combination with chemotherapy improved overall survival, compared with the EXTREME chemotherapy regimen, reported investigators in the Keynote 048 trial.
Overall survival (OS) among patients with a PD-L1 combined positive score (CPS) of 20 or greater treated with pembrolizumab (Keytruda) monotherapy was 14.9 months compared with 10.7 months for patients treated with the EXTREME regimen, a combination of cetuximab (Erbitux), carboplatin or cisplatin, and 5-fluorouracil.
A similar overall survival benefit was seen in patients with a CPS of 1 or greater, and in the total population of patients treated with pembrolizumab plus chemotherapy followed by pembrolizumab maintenance compared with EXTREME chemotherapy, Barbara Burtness, MD, of Yale Cancer Center, New Haven, Conn.
There were no differences in response rates between either pembrolizumab monotherapy or in combination compared with chemotherapy alone, but responses were more durable with the checkpoint inhibitor than with chemotherapy.
“Pembrolizumab alone and pembrolizumab given with platinum and 5-fluorouracil should represent new standards of care for the first-line treatment of metastatic head and neck carcinoma. Immune checkpoint monotherapy with pembrolizumab allows patients to live longer and has a better safety profile than the previous standard for those patients whose tumors express PD-L1,” she said at a briefing prior to her presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.
“This is the first time since 10 years that we show an improvement in survival for this group of patients,” said Jean-Pascal Machiels, MD, of University Clinic Saint-Luc, Brussels, the invited discussant for the briefing and the symposium.
The CPS is a ratio of PD-L1-positive tumor cells, lymphocytes, and macrophages to the total numbers of cells counted multiplied by 100. The investigators looked at progression-free survival (PFS) and OS in three cohorts of patients with squamous cell carcinomas of the oropharynx, oral cavity, hypopharynx, or larynx that were recurrent or metastatic and were incurable by local therapies. They compared pembrolizumab monotherapy with the EXTREME regimen, and pembrolizumab plus chemotherapy (as described in the following paragraph) with EXTREME.
A total of 882 patients were enrolled and stratified by PD-L1 expression (on 50% or greater of tumor cells, or less than 50%), p16 positive or negative status in the oropharynx, and Eastern Cooperative Oncology Group performance status of 0 or 1. The patients were then randomly assigned on a 1:1:1 basis to either pembrolizumab monotherapy at 200 mg every 3 weeks for up to 35 cycles, pembrolizumab plus a standard chemotherapy regimen (carboplatin to an area-under-the curve [AUC] of 5 or cisplatin 100 mg/m2 plus 5-FU 1000 mg/m2 per day for 4 days for six cycles, followed by pembrolizumab maintenance for up to 35 cycles or EXTREME (cetuximab at a loading dose of 400 mg/m2 followed by 250 mg/m2 once weekly plus the chemotherapy regimen described above, followed by maintenance cetuximab).
Pembrolizumab monotherapy vs. EXTREME
For the coprimary endpoint of OS in the CPS 20 or greater population, pembrolizumab was associated with significantly better survival than EXTREME at both the 12- and 24-month time points (56.9% vs. 44.9%, and 38.3% vs. 22,1%, respectively). After a minimum follow-up of 17 months, the median OS was 14.9 months with pembrolizumab, vs. 10.7 months for EXTREME. The hazard ratio (HR) for death with pembrolizumab was 0.61 (P = .0007).
The median OS in the CPS 1 or greater population was 12.3 months and 10.3 months, respectively (HR 0.78, P = .0086).
There were no differences between the arms in PFS, however, either in the CPS 20 or greater or CPS 1 or greater populations.
Although, as noted, response rates did not differ between the groups, the median duration of response was 20.9 months with pembrolizumab in both the CPS 20 and CPS 1 populations, compared with 4.2 and 4.5 months, respectively, for EXTREME.
Treatment-related adverse events of any grade occurred in 58% of patients in the monotherapy arm, vs. 96.9% in the EXTREME arm. Fatal adverse events occurred in 1% vs. 2.8%, and events leading to drug discontinuation occurred in 4.7% vs. 19.9%, respectively. There were more immune-mediated events in the pembrolizumab arm, including one death (from pneumonitis) vs. no deaths from immune-related causes in the EXTREME arm.
Pembrolizumab plus chemo vs. EXTREME
The combination of pembrolizumab was also superior to EXTREME in the total population, with 12- and 24-month OS rates of 53% vs. 43.9%, and 29% vs. 18.7%, respectively. The median OS was 13 months with the pembrolizumab/chemo combination, vs. 10.7 months for EXTREME, translating into an HR of 0.77 (P = .0034). In this analysis as well as in the pembrolizumab monotherapy combination, there was no difference in PFS or response rates, but responses in the pembrolizumab arm were more durable.
In this comparison, treatment-related adverse events were generally similar between the groups, although there were 10 treatment-related deaths with pembrolizumab, compared with eight in the EXTREME arm.
There was one immune-related death, from pneumonitis, in the pembrolizumab arm, vs. none in the EXTREME arm. Hypothyroidism, pneumonitis, hyperthyroidism and colitis were more frequent with pembrolizumab, whereas infusion reactions and severe skin reactions were more frequent with EXTREME.
“There are further analyses of biomarker and clinical predictors that will be forthcoming from this study, and these may eventually optimally guide the choice of whether to administer pembrolizumab alone or in the novel combination, Dr. Burtness said at the briefing.
“What’s extremely important also is that for a subgroup of patients with high expression of PD-L1, we can probably remove the cisplatin and have a good outcome with immunotherapy alone,” Dr. Machiels said.
He said that more work needs to be done to determine which patients are most likely to benefit from immunotherapy in the recurrent/metastatic setting, and “we have to see how we can now bring this active drug to the curative treatment of the patient, in combination with chemoradiation.”
The study was funded by Merck Sharp & Dohme. Dr. Burtness disclosed being and advisory board member and receiving travel expenses from MSD and others. Dr. Machiels disclosed speaker honoraria, travel expenses, and an uncompensated advisory role with MSD.
SOURCE: Burtness B et al. ESMO 2018. Abstract LBA8_PR.
REPORTING FROM ESMO 2018
Key clinical point: Pembrolizumab alone or in combination with chemotherapy was associated with better overall survival of squamous cell head and neck cancer, compared with the EXTREME chemotherapy regimen.
Major finding: Overall survival among patients with a PD-L1 combined positive score of 20 or greater treated with pembrolizumab (Keytruda) monotherapy was 14.9 compared with 10.7 months for patients treated with the EXTREME regimen.
Study details: Randomized phase 3 trial of 882 patients with recurrent or metastatic squamous cell carcinoma of the head and neck.
Disclosures: The study was funded by Merck Sharp & Dohme. Dr. Burtness disclosed being and advisory board member and receiving travel expenses from MSD and others. Dr. Machiels disclosed speaker honoraria, travel expenses, and an uncompensated advisory role with MSD.
Source: Burtness B et al. ESMO 2018. Abstract LBA8_PR.