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Azathioprine may increase risk of MDS, AML
Results of a large, retrospective study suggest that taking azathioprine, a drug commonly used to treat autoimmune disease, may increase a person’s risk of developing myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).
Researchers analyzed data on more than 40,000 patients with 27 common autoimmune diseases and found that azathioprine use was significantly associated with an increased risk of MDS and AML.
“Similar associations were already documented in case reports and case series but have never been evaluated in a broad spectrum of autoimmune diseases in that many patients and in context of individual medications,” said study author Raoul Tibes, MD, PhD, of the Mayo Clinic in Phoenix, Arizona.
“Interestingly, there was no association with length of time on therapy and resulting myeloid neoplasm.”
Dr Tibes and his colleagues reported these findings in JAMA Oncology.
The researchers reviewed data on 40,011 patients with primary autoimmune disorders, such as lupus and rheumatoid arthritis, who were seen at 2 centers from January 1, 2004, to December 31, 2014.
There were 311 patients with MDS or AML, but only 86 met strict inclusion criteria. Fifty-five patients had MDS, 21 had de novo AML, and 10 had AML and a history of MDS.
The researchers collected detailed data on each patient’s drug exposures, treatment duration, and disease characteristics and compared this information to data from patients with autoimmune disorders who did not have MDS or AML.
This revealed that use of azathioprine sodium was more frequent in cases than controls, and azathioprine was significantly associated with an increased risk of MDS and AML. The odds ratio was 7.05 (P<0.001).
Other agents used showed a similar trend, but the results were not statistically significant. The odds ratios were 3.58 for cyclophosphamide and 2.73 for mitoxantrone hydrochloride.
The researchers said that, while these results are intriguing, they should not change or replace the clinical judgments, monitoring, and current standard treatments for patients with autoimmune diseases.
Despite its large size, this study had limitations, including its retrospective nature, the fact that many different autoimmune diseases were analyzed, and that the researchers only looked at cases of MDS and AML.
No definitive causal association was made between taking a particular drug and MDS or AML. The number of patients with autoimmune disease developing MDS or AML is still low overall, and no prediction for individual patients can be concluded from the study.
The researchers plan to perform molecular investigations into the genetic susceptibility for therapy-related myeloid neoplasms as the next phase of this research. 
Results of a large, retrospective study suggest that taking azathioprine, a drug commonly used to treat autoimmune disease, may increase a person’s risk of developing myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).
Researchers analyzed data on more than 40,000 patients with 27 common autoimmune diseases and found that azathioprine use was significantly associated with an increased risk of MDS and AML.
“Similar associations were already documented in case reports and case series but have never been evaluated in a broad spectrum of autoimmune diseases in that many patients and in context of individual medications,” said study author Raoul Tibes, MD, PhD, of the Mayo Clinic in Phoenix, Arizona.
“Interestingly, there was no association with length of time on therapy and resulting myeloid neoplasm.”
Dr Tibes and his colleagues reported these findings in JAMA Oncology.
The researchers reviewed data on 40,011 patients with primary autoimmune disorders, such as lupus and rheumatoid arthritis, who were seen at 2 centers from January 1, 2004, to December 31, 2014.
There were 311 patients with MDS or AML, but only 86 met strict inclusion criteria. Fifty-five patients had MDS, 21 had de novo AML, and 10 had AML and a history of MDS.
The researchers collected detailed data on each patient’s drug exposures, treatment duration, and disease characteristics and compared this information to data from patients with autoimmune disorders who did not have MDS or AML.
This revealed that use of azathioprine sodium was more frequent in cases than controls, and azathioprine was significantly associated with an increased risk of MDS and AML. The odds ratio was 7.05 (P<0.001).
Other agents used showed a similar trend, but the results were not statistically significant. The odds ratios were 3.58 for cyclophosphamide and 2.73 for mitoxantrone hydrochloride.
The researchers said that, while these results are intriguing, they should not change or replace the clinical judgments, monitoring, and current standard treatments for patients with autoimmune diseases.
Despite its large size, this study had limitations, including its retrospective nature, the fact that many different autoimmune diseases were analyzed, and that the researchers only looked at cases of MDS and AML.
No definitive causal association was made between taking a particular drug and MDS or AML. The number of patients with autoimmune disease developing MDS or AML is still low overall, and no prediction for individual patients can be concluded from the study.
The researchers plan to perform molecular investigations into the genetic susceptibility for therapy-related myeloid neoplasms as the next phase of this research.
Results of a large, retrospective study suggest that taking azathioprine, a drug commonly used to treat autoimmune disease, may increase a person’s risk of developing myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).
Researchers analyzed data on more than 40,000 patients with 27 common autoimmune diseases and found that azathioprine use was significantly associated with an increased risk of MDS and AML.
“Similar associations were already documented in case reports and case series but have never been evaluated in a broad spectrum of autoimmune diseases in that many patients and in context of individual medications,” said study author Raoul Tibes, MD, PhD, of the Mayo Clinic in Phoenix, Arizona.
“Interestingly, there was no association with length of time on therapy and resulting myeloid neoplasm.”
Dr Tibes and his colleagues reported these findings in JAMA Oncology.
The researchers reviewed data on 40,011 patients with primary autoimmune disorders, such as lupus and rheumatoid arthritis, who were seen at 2 centers from January 1, 2004, to December 31, 2014.
There were 311 patients with MDS or AML, but only 86 met strict inclusion criteria. Fifty-five patients had MDS, 21 had de novo AML, and 10 had AML and a history of MDS.
The researchers collected detailed data on each patient’s drug exposures, treatment duration, and disease characteristics and compared this information to data from patients with autoimmune disorders who did not have MDS or AML.
This revealed that use of azathioprine sodium was more frequent in cases than controls, and azathioprine was significantly associated with an increased risk of MDS and AML. The odds ratio was 7.05 (P<0.001).
Other agents used showed a similar trend, but the results were not statistically significant. The odds ratios were 3.58 for cyclophosphamide and 2.73 for mitoxantrone hydrochloride.
The researchers said that, while these results are intriguing, they should not change or replace the clinical judgments, monitoring, and current standard treatments for patients with autoimmune diseases.
Despite its large size, this study had limitations, including its retrospective nature, the fact that many different autoimmune diseases were analyzed, and that the researchers only looked at cases of MDS and AML.
No definitive causal association was made between taking a particular drug and MDS or AML. The number of patients with autoimmune disease developing MDS or AML is still low overall, and no prediction for individual patients can be concluded from the study.
The researchers plan to perform molecular investigations into the genetic susceptibility for therapy-related myeloid neoplasms as the next phase of this research.
Targeting disease stem cells in AML, MDS
Image by Robert Paulson
The cell surface molecule CD99 occurs more frequently than normal on stem cells responsible for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to research published in Science Translational Medicine.
Building on this discovery, researchers designed anti-CD99 monoclonal antibodies (mAbs).
In vitro and in vivo experiments
showed that these mAbs can recognize
and destroy AML and MDS stem/progenitor cells.
“Our findings not only identify a new molecule expressed on stem cells that drive these human malignancies, but we show that antibodies against this target can directly kill human AML stem cells,” said study author Christopher Y. Park, MD, PhD, of NYU Langone Medical Center in New York, New York.
“While we still have important details to work out, CD99 is likely to be an exploitable therapeutic target for most AML and MDS patients, and we are working urgently to finalize a therapy for human testing.”
Dr Park and his colleagues first examined stem cell populations from 79 patients with AML and 24 with MDS. More than 80% of stem cells in both groups expressed high levels of CD99.
The levels were so high that leukemia stem cells could be cleanly separated from normal hematopoietic stem cells in AML samples.
Upon confirming that CD99 was abundant on AML and MDS stem cells, the researchers made several anti-CD99 mAbs and tested them in vitro and in mouse models.
The mAbs destroyed AML and MDS stem cells by causing a sudden spike in the activity of SRC family kinases—a group of proteins that are implicated in invasion, tumor progression, and metastasis in a variety of cancers.
However, the mAbs had minimal effects on normal hematopoietic stem cells.
“With the appropriate support, we believe we can rapidly determine the best antibodies for use in patients, produce them at the quality needed to verify our results, and apply for permission to begin clinical trials,” Dr Park said.
Image by Robert Paulson
The cell surface molecule CD99 occurs more frequently than normal on stem cells responsible for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to research published in Science Translational Medicine.
Building on this discovery, researchers designed anti-CD99 monoclonal antibodies (mAbs).
In vitro and in vivo experiments
showed that these mAbs can recognize
and destroy AML and MDS stem/progenitor cells.
“Our findings not only identify a new molecule expressed on stem cells that drive these human malignancies, but we show that antibodies against this target can directly kill human AML stem cells,” said study author Christopher Y. Park, MD, PhD, of NYU Langone Medical Center in New York, New York.
“While we still have important details to work out, CD99 is likely to be an exploitable therapeutic target for most AML and MDS patients, and we are working urgently to finalize a therapy for human testing.”
Dr Park and his colleagues first examined stem cell populations from 79 patients with AML and 24 with MDS. More than 80% of stem cells in both groups expressed high levels of CD99.
The levels were so high that leukemia stem cells could be cleanly separated from normal hematopoietic stem cells in AML samples.
Upon confirming that CD99 was abundant on AML and MDS stem cells, the researchers made several anti-CD99 mAbs and tested them in vitro and in mouse models.
The mAbs destroyed AML and MDS stem cells by causing a sudden spike in the activity of SRC family kinases—a group of proteins that are implicated in invasion, tumor progression, and metastasis in a variety of cancers.
However, the mAbs had minimal effects on normal hematopoietic stem cells.
“With the appropriate support, we believe we can rapidly determine the best antibodies for use in patients, produce them at the quality needed to verify our results, and apply for permission to begin clinical trials,” Dr Park said.
Image by Robert Paulson
The cell surface molecule CD99 occurs more frequently than normal on stem cells responsible for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to research published in Science Translational Medicine.
Building on this discovery, researchers designed anti-CD99 monoclonal antibodies (mAbs).
In vitro and in vivo experiments
showed that these mAbs can recognize
and destroy AML and MDS stem/progenitor cells.
“Our findings not only identify a new molecule expressed on stem cells that drive these human malignancies, but we show that antibodies against this target can directly kill human AML stem cells,” said study author Christopher Y. Park, MD, PhD, of NYU Langone Medical Center in New York, New York.
“While we still have important details to work out, CD99 is likely to be an exploitable therapeutic target for most AML and MDS patients, and we are working urgently to finalize a therapy for human testing.”
Dr Park and his colleagues first examined stem cell populations from 79 patients with AML and 24 with MDS. More than 80% of stem cells in both groups expressed high levels of CD99.
The levels were so high that leukemia stem cells could be cleanly separated from normal hematopoietic stem cells in AML samples.
Upon confirming that CD99 was abundant on AML and MDS stem cells, the researchers made several anti-CD99 mAbs and tested them in vitro and in mouse models.
The mAbs destroyed AML and MDS stem cells by causing a sudden spike in the activity of SRC family kinases—a group of proteins that are implicated in invasion, tumor progression, and metastasis in a variety of cancers.
However, the mAbs had minimal effects on normal hematopoietic stem cells.
“With the appropriate support, we believe we can rapidly determine the best antibodies for use in patients, produce them at the quality needed to verify our results, and apply for permission to begin clinical trials,” Dr Park said.
Clonal hematopoiesis increases risk for therapy-related cancers
Small pre-leukemic clones left behind after treatment for non-myeloid malignancies appear to increase the risk for therapy-related myelodysplasia or leukemia, report investigators in two studies.
An analysis of peripheral blood samples taken from patients at the time of their primary cancer diagnosis and bone marrow samples taken at the time of a later therapy-related myeloid neoplasm diagnosis showed that 10 of 14 patients (71%) had clonal hematopoiesis before starting on cytotoxic chemotherapy. In contrast, clonal hematopoiesis was detected in pre-treatment samples of only 17 of 54 controls (31%), reported Koichi Takahashi, MD, and colleagues from the University of Texas MD Anderson Cancer Center in Houston.
“Preleukemic clonal hematopoiesis is common in patients with therapy-related myeloid neoplasms at the time of their primary cancer diagnosis and before they have been exposed to treatment. Our results suggest that clonal hematopoiesis could be used as a predictive marker to identify patients with cancer who are at risk of developing therapy-related myeloid neoplasms,” they wrote (Lancet Oncol 2017; 18: 100–11).
In a separate study, investigators from the Moffitt Cancer Center in Tampa, Florida, found in a nested case-control study that patients with therapy-related myeloid neoplasms were more likely than controls to have clonal hematopoiesis of indeterminate potential (CHIP), and that the CHIP was often present before exposure to chemotherapy.
“We recorded a significantly higher prevalence of CHIP in individuals who developed therapy-related myeloid neoplasms (cases) than in those who did not (controls); however, around 27% of individuals with CHIP did not develop therapy-related myeloid neoplasms, suggesting that this feature alone should not be used to determine a patient’s suitability for chemotherapy,” wrote Nancy K. Gillis, PharmD, and colleagues (Lancet Oncol 2017; 18:112-21).
Risk factors examined
Dr. Takahashi and colleagues noted that previous studies have identified several treatment-related risk factors as being associated with therapy-related myeloid dysplasia or leukemia, including the use of alkylating agents, topoisomerase II inhibitors, and high-dose chemotherapy with autologous stem-cell transplantation.
“By contrast, little is known about patient-specific risk factors. Older age was shown to increase the risk of therapy-related myeloid neoplasms. Several germline polymorphisms have also been associated with this risk, but none have been validated. As such, no predictive biomarkers exist for therapy-related myeloid neoplasms,” they wrote.
They performed a retrospective case-control study comparing patients treated for a primary cancer at their center from 1997 through 2015 who subsequently developed a myeloid neoplasm with controls treated during the same period. Controls were age-matched patients treated with combination chemotherapy for lymphoma who did not develop a therapy-related myeloid malignancy after at least 5 years of follow-up.
In addition, the investigators further explored the association between clonal hematopoiesis and therapy-related cancers in an external cohort of patients with lymphoma treated in a randomized trial at their center from 1999 through 2001. That trial compared the CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisone) with and without melatonin.
To detect clonal hematopoiesis in pre-treatment peripheral blood, the investigators used molecular barcode sequencing of 32 genes. They also used targeted gene sequencing on bone marrow samples from cases to investigate clonal evolution from clonal hematopoiesis to the development of therapy-related myeloid neoplasms.
As noted before, 10 of 14 cases had evidence of pre-treatment clonal hematopoiesis, compared with 17 of 54 controls. For both cases and controls, the cumulative incidence of therapy-related myeloid cancers after 5 years was significantly higher among those with baseline clonal hematopoiesis, at 30% vs. 7% for patients without it (P = .016).
Five of 74 patients in the external cohort (7%) went on to develop therapy-related myeloid neoplasms, and of this group, four (80%) had clonal hematopoiesis at baseline. In contrast, of the 69 patients who did not develop therapy-related cancers, 11 (16%) had baseline clonal hematopoiesis.
In a multivariate model using data from the external cohort, clonal hematopoiesis was significantly associated with risk for therapy-related myeloid neoplasms, with a hazard ratio of 13.7 (P = .013).
Elderly patient study
Dr. Gillis and her colleagues conducted a nested, case-control, proof-of-concept study to compare the prevalence of CHIP between patients with cancer who later developed therapy-related myeloid neoplasms (cases) and patients who did not (controls).
The cases were identified from an internal biobank of 123,357 patients, and included all patients who were diagnosed with a primary cancer, treated with chemotherapy, and subsequently developed a therapy-related myeloid neoplasm. The patients had to be 70 or older at the time of either primary or therapy-related cancer diagnosis with peripheral blood or mononuclear samples collected before the diagnosis of the second cancer.
Controls were patients diagnosed with a primary malignancy at age 70 or older who had chemotherapy but did not develop therapy-related myeloid neoplasms. Every case was matched with at least four controls selected for sex, primary tumor type, age at diagnosis, smoking status, chemotherapy drug class, and duration of follow up.
They used sequential targeted and whole-exome sequencing to assess clonal evolution in cases for whom paired CHIP and therapy-related myeloid neoplasm samples were available.
They identified a total of 13 cases and 56 controls. Among all patients, CHIP was seen in 23 (33%). In contrast, previous studies have shown a prevalence of CHIP among older patients without cancer of about 10%, the authors note in their article.
The prevalence of CHIP was significantly higher among cases than among controls, occurring in 8 of 13 cases (62%) vs 15 of 56 controls (27%; P = .024). The odds ratio for therapy-related neoplasms with CHIP was 5.75 (P = .013).
The most commonly mutated genes were TET2 and TP53 among cases, and TET2 among controls.
“The distribution of CHIP-related gene mutations differs between individuals with therapy-related myeloid neoplasm and those without, suggesting that mutation-specific differences might exist in therapy-related myeloid neoplasm risk,” the investigators write.
Dr. Takahashi’s study was supported by the Cancer Prevention Research Institute of Texas, Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer, The National Institutes of Health through MD Anderson Cancer Center Support Grant, and the MD Anderson MDS & AML Moon Shots Program. Dr. Gillis’ study was internally funded. Dr. Takahasi and colleagues reported no competing financial interests. Two of Dr. Gillis’ colleagues reported grants or fees from several drug companies.
The real importance of the work reported by Gillis and colleagues and Takahashi and colleagues will come when therapies exist that can effectively eradicate nascent clonal hematopoiesis, thereby preventing therapy-related myeloid neoplasm evolution in at-risk patients.
Although high-intensity treatments, such as anthracycline-based induction chemotherapy, can eradicate myeloid clones, their effectiveness in clearing TP53-mutant cells is limited, and it is difficult to imagine intense approaches having a favorable risk–benefit balance in patients whose clonal hematopoiesis might never become a problem. Existing lower-intensity therapies for myeloid neoplasms such as DNA hypomethylating agents are not curative and often do not result in the reduction of VAF [variant allele frequencies] even when hematopoietic improvement occurs during therapy, so such agents would not be expected to eliminate pre-therapy-related myeloid neoplasm clones (although this hypothesis might still be worth testing, given that the emergence of therapy-related myeloid neoplasm could at least be delayed – even if not entirely prevented – with azacitidine or decitabine).
More promising are strategies that change the bone marrow microenvironment or break the immune tolerance of abnormal clones, although the use of these approaches for myeloid neoplasia is still in the very early stages. Although no method yet exists to reliably eliminate the preleukemic clones that can give rise to therapy-related myeloid neoplasms, identification of higher risk patients could still affect monitoring practices, such as the frequency of clinical assessments. Molecular genetic panels are expensive at present but are becoming less so. Because VAF assessment by next-generation sequencing is quantitative and proportional to clone size, serial assessment could identify patients whose mutant clones are large and expanding and who therefore warrant closer monitoring or enrollment in so-called preventive hematology trials.
David P. Steensma, MD, is with the Dana-Farber Cancer Institute, Harvard Medical School, Boston. His remarks were excerpted from an accompanying editorial.
The real importance of the work reported by Gillis and colleagues and Takahashi and colleagues will come when therapies exist that can effectively eradicate nascent clonal hematopoiesis, thereby preventing therapy-related myeloid neoplasm evolution in at-risk patients.
Although high-intensity treatments, such as anthracycline-based induction chemotherapy, can eradicate myeloid clones, their effectiveness in clearing TP53-mutant cells is limited, and it is difficult to imagine intense approaches having a favorable risk–benefit balance in patients whose clonal hematopoiesis might never become a problem. Existing lower-intensity therapies for myeloid neoplasms such as DNA hypomethylating agents are not curative and often do not result in the reduction of VAF [variant allele frequencies] even when hematopoietic improvement occurs during therapy, so such agents would not be expected to eliminate pre-therapy-related myeloid neoplasm clones (although this hypothesis might still be worth testing, given that the emergence of therapy-related myeloid neoplasm could at least be delayed – even if not entirely prevented – with azacitidine or decitabine).
More promising are strategies that change the bone marrow microenvironment or break the immune tolerance of abnormal clones, although the use of these approaches for myeloid neoplasia is still in the very early stages. Although no method yet exists to reliably eliminate the preleukemic clones that can give rise to therapy-related myeloid neoplasms, identification of higher risk patients could still affect monitoring practices, such as the frequency of clinical assessments. Molecular genetic panels are expensive at present but are becoming less so. Because VAF assessment by next-generation sequencing is quantitative and proportional to clone size, serial assessment could identify patients whose mutant clones are large and expanding and who therefore warrant closer monitoring or enrollment in so-called preventive hematology trials.
David P. Steensma, MD, is with the Dana-Farber Cancer Institute, Harvard Medical School, Boston. His remarks were excerpted from an accompanying editorial.
The real importance of the work reported by Gillis and colleagues and Takahashi and colleagues will come when therapies exist that can effectively eradicate nascent clonal hematopoiesis, thereby preventing therapy-related myeloid neoplasm evolution in at-risk patients.
Although high-intensity treatments, such as anthracycline-based induction chemotherapy, can eradicate myeloid clones, their effectiveness in clearing TP53-mutant cells is limited, and it is difficult to imagine intense approaches having a favorable risk–benefit balance in patients whose clonal hematopoiesis might never become a problem. Existing lower-intensity therapies for myeloid neoplasms such as DNA hypomethylating agents are not curative and often do not result in the reduction of VAF [variant allele frequencies] even when hematopoietic improvement occurs during therapy, so such agents would not be expected to eliminate pre-therapy-related myeloid neoplasm clones (although this hypothesis might still be worth testing, given that the emergence of therapy-related myeloid neoplasm could at least be delayed – even if not entirely prevented – with azacitidine or decitabine).
More promising are strategies that change the bone marrow microenvironment or break the immune tolerance of abnormal clones, although the use of these approaches for myeloid neoplasia is still in the very early stages. Although no method yet exists to reliably eliminate the preleukemic clones that can give rise to therapy-related myeloid neoplasms, identification of higher risk patients could still affect monitoring practices, such as the frequency of clinical assessments. Molecular genetic panels are expensive at present but are becoming less so. Because VAF assessment by next-generation sequencing is quantitative and proportional to clone size, serial assessment could identify patients whose mutant clones are large and expanding and who therefore warrant closer monitoring or enrollment in so-called preventive hematology trials.
David P. Steensma, MD, is with the Dana-Farber Cancer Institute, Harvard Medical School, Boston. His remarks were excerpted from an accompanying editorial.
Small pre-leukemic clones left behind after treatment for non-myeloid malignancies appear to increase the risk for therapy-related myelodysplasia or leukemia, report investigators in two studies.
An analysis of peripheral blood samples taken from patients at the time of their primary cancer diagnosis and bone marrow samples taken at the time of a later therapy-related myeloid neoplasm diagnosis showed that 10 of 14 patients (71%) had clonal hematopoiesis before starting on cytotoxic chemotherapy. In contrast, clonal hematopoiesis was detected in pre-treatment samples of only 17 of 54 controls (31%), reported Koichi Takahashi, MD, and colleagues from the University of Texas MD Anderson Cancer Center in Houston.
“Preleukemic clonal hematopoiesis is common in patients with therapy-related myeloid neoplasms at the time of their primary cancer diagnosis and before they have been exposed to treatment. Our results suggest that clonal hematopoiesis could be used as a predictive marker to identify patients with cancer who are at risk of developing therapy-related myeloid neoplasms,” they wrote (Lancet Oncol 2017; 18: 100–11).
In a separate study, investigators from the Moffitt Cancer Center in Tampa, Florida, found in a nested case-control study that patients with therapy-related myeloid neoplasms were more likely than controls to have clonal hematopoiesis of indeterminate potential (CHIP), and that the CHIP was often present before exposure to chemotherapy.
“We recorded a significantly higher prevalence of CHIP in individuals who developed therapy-related myeloid neoplasms (cases) than in those who did not (controls); however, around 27% of individuals with CHIP did not develop therapy-related myeloid neoplasms, suggesting that this feature alone should not be used to determine a patient’s suitability for chemotherapy,” wrote Nancy K. Gillis, PharmD, and colleagues (Lancet Oncol 2017; 18:112-21).
Risk factors examined
Dr. Takahashi and colleagues noted that previous studies have identified several treatment-related risk factors as being associated with therapy-related myeloid dysplasia or leukemia, including the use of alkylating agents, topoisomerase II inhibitors, and high-dose chemotherapy with autologous stem-cell transplantation.
“By contrast, little is known about patient-specific risk factors. Older age was shown to increase the risk of therapy-related myeloid neoplasms. Several germline polymorphisms have also been associated with this risk, but none have been validated. As such, no predictive biomarkers exist for therapy-related myeloid neoplasms,” they wrote.
They performed a retrospective case-control study comparing patients treated for a primary cancer at their center from 1997 through 2015 who subsequently developed a myeloid neoplasm with controls treated during the same period. Controls were age-matched patients treated with combination chemotherapy for lymphoma who did not develop a therapy-related myeloid malignancy after at least 5 years of follow-up.
In addition, the investigators further explored the association between clonal hematopoiesis and therapy-related cancers in an external cohort of patients with lymphoma treated in a randomized trial at their center from 1999 through 2001. That trial compared the CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisone) with and without melatonin.
To detect clonal hematopoiesis in pre-treatment peripheral blood, the investigators used molecular barcode sequencing of 32 genes. They also used targeted gene sequencing on bone marrow samples from cases to investigate clonal evolution from clonal hematopoiesis to the development of therapy-related myeloid neoplasms.
As noted before, 10 of 14 cases had evidence of pre-treatment clonal hematopoiesis, compared with 17 of 54 controls. For both cases and controls, the cumulative incidence of therapy-related myeloid cancers after 5 years was significantly higher among those with baseline clonal hematopoiesis, at 30% vs. 7% for patients without it (P = .016).
Five of 74 patients in the external cohort (7%) went on to develop therapy-related myeloid neoplasms, and of this group, four (80%) had clonal hematopoiesis at baseline. In contrast, of the 69 patients who did not develop therapy-related cancers, 11 (16%) had baseline clonal hematopoiesis.
In a multivariate model using data from the external cohort, clonal hematopoiesis was significantly associated with risk for therapy-related myeloid neoplasms, with a hazard ratio of 13.7 (P = .013).
Elderly patient study
Dr. Gillis and her colleagues conducted a nested, case-control, proof-of-concept study to compare the prevalence of CHIP between patients with cancer who later developed therapy-related myeloid neoplasms (cases) and patients who did not (controls).
The cases were identified from an internal biobank of 123,357 patients, and included all patients who were diagnosed with a primary cancer, treated with chemotherapy, and subsequently developed a therapy-related myeloid neoplasm. The patients had to be 70 or older at the time of either primary or therapy-related cancer diagnosis with peripheral blood or mononuclear samples collected before the diagnosis of the second cancer.
Controls were patients diagnosed with a primary malignancy at age 70 or older who had chemotherapy but did not develop therapy-related myeloid neoplasms. Every case was matched with at least four controls selected for sex, primary tumor type, age at diagnosis, smoking status, chemotherapy drug class, and duration of follow up.
They used sequential targeted and whole-exome sequencing to assess clonal evolution in cases for whom paired CHIP and therapy-related myeloid neoplasm samples were available.
They identified a total of 13 cases and 56 controls. Among all patients, CHIP was seen in 23 (33%). In contrast, previous studies have shown a prevalence of CHIP among older patients without cancer of about 10%, the authors note in their article.
The prevalence of CHIP was significantly higher among cases than among controls, occurring in 8 of 13 cases (62%) vs 15 of 56 controls (27%; P = .024). The odds ratio for therapy-related neoplasms with CHIP was 5.75 (P = .013).
The most commonly mutated genes were TET2 and TP53 among cases, and TET2 among controls.
“The distribution of CHIP-related gene mutations differs between individuals with therapy-related myeloid neoplasm and those without, suggesting that mutation-specific differences might exist in therapy-related myeloid neoplasm risk,” the investigators write.
Dr. Takahashi’s study was supported by the Cancer Prevention Research Institute of Texas, Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer, The National Institutes of Health through MD Anderson Cancer Center Support Grant, and the MD Anderson MDS & AML Moon Shots Program. Dr. Gillis’ study was internally funded. Dr. Takahasi and colleagues reported no competing financial interests. Two of Dr. Gillis’ colleagues reported grants or fees from several drug companies.
Small pre-leukemic clones left behind after treatment for non-myeloid malignancies appear to increase the risk for therapy-related myelodysplasia or leukemia, report investigators in two studies.
An analysis of peripheral blood samples taken from patients at the time of their primary cancer diagnosis and bone marrow samples taken at the time of a later therapy-related myeloid neoplasm diagnosis showed that 10 of 14 patients (71%) had clonal hematopoiesis before starting on cytotoxic chemotherapy. In contrast, clonal hematopoiesis was detected in pre-treatment samples of only 17 of 54 controls (31%), reported Koichi Takahashi, MD, and colleagues from the University of Texas MD Anderson Cancer Center in Houston.
“Preleukemic clonal hematopoiesis is common in patients with therapy-related myeloid neoplasms at the time of their primary cancer diagnosis and before they have been exposed to treatment. Our results suggest that clonal hematopoiesis could be used as a predictive marker to identify patients with cancer who are at risk of developing therapy-related myeloid neoplasms,” they wrote (Lancet Oncol 2017; 18: 100–11).
In a separate study, investigators from the Moffitt Cancer Center in Tampa, Florida, found in a nested case-control study that patients with therapy-related myeloid neoplasms were more likely than controls to have clonal hematopoiesis of indeterminate potential (CHIP), and that the CHIP was often present before exposure to chemotherapy.
“We recorded a significantly higher prevalence of CHIP in individuals who developed therapy-related myeloid neoplasms (cases) than in those who did not (controls); however, around 27% of individuals with CHIP did not develop therapy-related myeloid neoplasms, suggesting that this feature alone should not be used to determine a patient’s suitability for chemotherapy,” wrote Nancy K. Gillis, PharmD, and colleagues (Lancet Oncol 2017; 18:112-21).
Risk factors examined
Dr. Takahashi and colleagues noted that previous studies have identified several treatment-related risk factors as being associated with therapy-related myeloid dysplasia or leukemia, including the use of alkylating agents, topoisomerase II inhibitors, and high-dose chemotherapy with autologous stem-cell transplantation.
“By contrast, little is known about patient-specific risk factors. Older age was shown to increase the risk of therapy-related myeloid neoplasms. Several germline polymorphisms have also been associated with this risk, but none have been validated. As such, no predictive biomarkers exist for therapy-related myeloid neoplasms,” they wrote.
They performed a retrospective case-control study comparing patients treated for a primary cancer at their center from 1997 through 2015 who subsequently developed a myeloid neoplasm with controls treated during the same period. Controls were age-matched patients treated with combination chemotherapy for lymphoma who did not develop a therapy-related myeloid malignancy after at least 5 years of follow-up.
In addition, the investigators further explored the association between clonal hematopoiesis and therapy-related cancers in an external cohort of patients with lymphoma treated in a randomized trial at their center from 1999 through 2001. That trial compared the CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisone) with and without melatonin.
To detect clonal hematopoiesis in pre-treatment peripheral blood, the investigators used molecular barcode sequencing of 32 genes. They also used targeted gene sequencing on bone marrow samples from cases to investigate clonal evolution from clonal hematopoiesis to the development of therapy-related myeloid neoplasms.
As noted before, 10 of 14 cases had evidence of pre-treatment clonal hematopoiesis, compared with 17 of 54 controls. For both cases and controls, the cumulative incidence of therapy-related myeloid cancers after 5 years was significantly higher among those with baseline clonal hematopoiesis, at 30% vs. 7% for patients without it (P = .016).
Five of 74 patients in the external cohort (7%) went on to develop therapy-related myeloid neoplasms, and of this group, four (80%) had clonal hematopoiesis at baseline. In contrast, of the 69 patients who did not develop therapy-related cancers, 11 (16%) had baseline clonal hematopoiesis.
In a multivariate model using data from the external cohort, clonal hematopoiesis was significantly associated with risk for therapy-related myeloid neoplasms, with a hazard ratio of 13.7 (P = .013).
Elderly patient study
Dr. Gillis and her colleagues conducted a nested, case-control, proof-of-concept study to compare the prevalence of CHIP between patients with cancer who later developed therapy-related myeloid neoplasms (cases) and patients who did not (controls).
The cases were identified from an internal biobank of 123,357 patients, and included all patients who were diagnosed with a primary cancer, treated with chemotherapy, and subsequently developed a therapy-related myeloid neoplasm. The patients had to be 70 or older at the time of either primary or therapy-related cancer diagnosis with peripheral blood or mononuclear samples collected before the diagnosis of the second cancer.
Controls were patients diagnosed with a primary malignancy at age 70 or older who had chemotherapy but did not develop therapy-related myeloid neoplasms. Every case was matched with at least four controls selected for sex, primary tumor type, age at diagnosis, smoking status, chemotherapy drug class, and duration of follow up.
They used sequential targeted and whole-exome sequencing to assess clonal evolution in cases for whom paired CHIP and therapy-related myeloid neoplasm samples were available.
They identified a total of 13 cases and 56 controls. Among all patients, CHIP was seen in 23 (33%). In contrast, previous studies have shown a prevalence of CHIP among older patients without cancer of about 10%, the authors note in their article.
The prevalence of CHIP was significantly higher among cases than among controls, occurring in 8 of 13 cases (62%) vs 15 of 56 controls (27%; P = .024). The odds ratio for therapy-related neoplasms with CHIP was 5.75 (P = .013).
The most commonly mutated genes were TET2 and TP53 among cases, and TET2 among controls.
“The distribution of CHIP-related gene mutations differs between individuals with therapy-related myeloid neoplasm and those without, suggesting that mutation-specific differences might exist in therapy-related myeloid neoplasm risk,” the investigators write.
Dr. Takahashi’s study was supported by the Cancer Prevention Research Institute of Texas, Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer, The National Institutes of Health through MD Anderson Cancer Center Support Grant, and the MD Anderson MDS & AML Moon Shots Program. Dr. Gillis’ study was internally funded. Dr. Takahasi and colleagues reported no competing financial interests. Two of Dr. Gillis’ colleagues reported grants or fees from several drug companies.
FROM LANCET ONCOLOGY
Key clinical point: Pre-therapy clonal hematopoiesis is associated with increased risk for therapy-related myeloid neoplasms.
Major finding: In two studies, the incidence of therapy-related myeloid neoplasms was higher among patients with clonal hematopoiesis at baseline.
Data source: Retrospective case-control studies.
Disclosures: Dr. Takahashi’s study was supported by the Cancer Prevention Research Institute of Texas, Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer, The National Institutes of Health through MD Anderson Cancer Center Support Grant, and the MD Anderson MDS & AML Moon Shots Program. Dr. Gillis’ study was internally funded. Dr. Takahasi and colleagues reported no competing financial interests. Two of Dr. Gillis’ colleagues reported grants or fees from several drug companies.
PERSIST-2 might allay some concerns about pacritinib in myelofibrosis
SAN DIEGO – Late-breaking results from the phase III PERSIST-2 trial may ease at least some safety concerns surrounding the use of pacritinib in patients with myelofibrosis, investigators said at the annual meeting of the American Society of Hematology.
In February 2016, the Food and Drug Administration imposed a clinical hold on studies of pacritinib in the wake of concerns about excess deaths, cardiotoxicities, and hemorrhage. But in the final data analysis presented at ASH, rates of these outcomes were low and similar among patients randomized to pacritinib once daily, pacritinib twice daily, or best available treatment for myelofibrosis, including ruxolitinib, lead investigator John Mascarenhas, MD, said.
Indeed, more patients died of progressive disease after stopping pacritinib than died of treatment-associated adverse events, said Dr. Mascarenhas of Icahn School of Medicine at Mount Sinai, New York.
Pacritinib is an oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CFS1R. In the previous phase III PERSIST-1 trial, patients who received pacritinib had a fourfold greater probability of experiencing at least a 35% decrease in splenic volume than did patients who received best available treatment (P = .003).
PERSIST-2 also yielded clear efficacy signals, particularly when patients took pacritinib twice daily, said Dr. Mascarenhas. Between baseline and week 24, splenic volume dropped by at least 35% in 22% of these patients (95% confidence interval, 13%-33%), compared with 3% of patients on best available treatment (95% CI, 0.3%-10%; P = .001). Patients who took pacritinib twice daily also had a 32% (95% CI, 22%-44%) chance of experiencing at least a 50% drop in symptoms such as fatigue, bone pain, itching, and abdominal pain, compared with 14% (95% CI, 7%-24%) of patients on best available treatment (P = .01).
Demographic and disease risk characteristics did not significantly affect the chances of reaching these coprimary endpoints, Dr. Mascarenhas noted. “My humble opinion as a clinical investigator is that [pacritinib] is an effective drug, with a favorable benefit-to-risk ratio,” he said.
Several hematologists who were not involved in this trial agreed. “I don’t see why you are nervous [about presenting these results],” noted hematologist Kanti Rai, MD, of the Feinstein Institute for Medical Research in Manhasset, N.Y., told Dr. Mascarenhas during the discussion after the data were presented, prompting laughter from the audience.
It remains to be seen whether the FDA will find the data convincing enough to lift the clinical hold on pacritinib. Ruxolitinib (Jakafi) is approved to treat splenomegaly and symptom burden in myelofibrosis but is associated with dose-limiting cytopenias and cannot be used in patients with platelet counts of less than 50,000/mcL.
PERSIST-2 compared pacritinib 400 mg once daily with pacritinib 200 mg twice daily and best available treatment, including ruxolitinib, in patients with primary or secondary myelofibrosis and less than 100,000 platelets/mcL. About half of the study patients had less than 50,000 platelets/mcL, and more than 40% had previously received ruxolitinib.
When the clinical hold on pacritinib went into effect, 221 patients had reached the 24-week designated study endpoint and were included in the intention-to-treat analysis, Dr. Mascarenhas reported. Censored Kaplan-Meier curves of overall survival favored pacritinib over best available treatment, although the difference in survival rates did not reach statistical significance (hazard ratio, 0.68; 95% CI, 0.3-1.5). A total of 9% of patients in the twice-daily pacritinib group died, compared with 14% of patients receiving pacritinib once daily or best available treatment.
Twice-daily pacritinib most often led to diarrhea (48% of patients), nausea (32%), thrombocytopenia (34%), and anemia (24%). Overall rates of serious treatment-emergent adverse events were seen in 47% of the two pacritinib groups and in 31% of patients receiving best available treatment. The most common serious treatment-emergent adverse event with twice daily pacritinib was anemia (8% of patients), followed by thrombocytopenia and pneumonia (6%). Heart failure, atrial fibrillation, and cardiac arrest were rare and similar across all three treatment groups, as were epistaxis and subdural hematoma.
This is the first randomized, controlled trial of patients with myelofibrosis and thrombocytopenia, according to Dr. Mascarenhas. “This was a patient population with low platelets and at risk of poor outcomes, and they did pretty well,” he said. “There really is no therapeutic option for patients with myelofibrosis and low platelets, and [pacritinib] offers patients in this vulnerable situation an opportunity for symptom relief. I hope to see it move forward.”
CTI Biopharma sponsored the study. Dr. Mascarenhas disclosed research funding from CTI Biopharma.
SAN DIEGO – Late-breaking results from the phase III PERSIST-2 trial may ease at least some safety concerns surrounding the use of pacritinib in patients with myelofibrosis, investigators said at the annual meeting of the American Society of Hematology.
In February 2016, the Food and Drug Administration imposed a clinical hold on studies of pacritinib in the wake of concerns about excess deaths, cardiotoxicities, and hemorrhage. But in the final data analysis presented at ASH, rates of these outcomes were low and similar among patients randomized to pacritinib once daily, pacritinib twice daily, or best available treatment for myelofibrosis, including ruxolitinib, lead investigator John Mascarenhas, MD, said.
Indeed, more patients died of progressive disease after stopping pacritinib than died of treatment-associated adverse events, said Dr. Mascarenhas of Icahn School of Medicine at Mount Sinai, New York.
Pacritinib is an oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CFS1R. In the previous phase III PERSIST-1 trial, patients who received pacritinib had a fourfold greater probability of experiencing at least a 35% decrease in splenic volume than did patients who received best available treatment (P = .003).
PERSIST-2 also yielded clear efficacy signals, particularly when patients took pacritinib twice daily, said Dr. Mascarenhas. Between baseline and week 24, splenic volume dropped by at least 35% in 22% of these patients (95% confidence interval, 13%-33%), compared with 3% of patients on best available treatment (95% CI, 0.3%-10%; P = .001). Patients who took pacritinib twice daily also had a 32% (95% CI, 22%-44%) chance of experiencing at least a 50% drop in symptoms such as fatigue, bone pain, itching, and abdominal pain, compared with 14% (95% CI, 7%-24%) of patients on best available treatment (P = .01).
Demographic and disease risk characteristics did not significantly affect the chances of reaching these coprimary endpoints, Dr. Mascarenhas noted. “My humble opinion as a clinical investigator is that [pacritinib] is an effective drug, with a favorable benefit-to-risk ratio,” he said.
Several hematologists who were not involved in this trial agreed. “I don’t see why you are nervous [about presenting these results],” noted hematologist Kanti Rai, MD, of the Feinstein Institute for Medical Research in Manhasset, N.Y., told Dr. Mascarenhas during the discussion after the data were presented, prompting laughter from the audience.
It remains to be seen whether the FDA will find the data convincing enough to lift the clinical hold on pacritinib. Ruxolitinib (Jakafi) is approved to treat splenomegaly and symptom burden in myelofibrosis but is associated with dose-limiting cytopenias and cannot be used in patients with platelet counts of less than 50,000/mcL.
PERSIST-2 compared pacritinib 400 mg once daily with pacritinib 200 mg twice daily and best available treatment, including ruxolitinib, in patients with primary or secondary myelofibrosis and less than 100,000 platelets/mcL. About half of the study patients had less than 50,000 platelets/mcL, and more than 40% had previously received ruxolitinib.
When the clinical hold on pacritinib went into effect, 221 patients had reached the 24-week designated study endpoint and were included in the intention-to-treat analysis, Dr. Mascarenhas reported. Censored Kaplan-Meier curves of overall survival favored pacritinib over best available treatment, although the difference in survival rates did not reach statistical significance (hazard ratio, 0.68; 95% CI, 0.3-1.5). A total of 9% of patients in the twice-daily pacritinib group died, compared with 14% of patients receiving pacritinib once daily or best available treatment.
Twice-daily pacritinib most often led to diarrhea (48% of patients), nausea (32%), thrombocytopenia (34%), and anemia (24%). Overall rates of serious treatment-emergent adverse events were seen in 47% of the two pacritinib groups and in 31% of patients receiving best available treatment. The most common serious treatment-emergent adverse event with twice daily pacritinib was anemia (8% of patients), followed by thrombocytopenia and pneumonia (6%). Heart failure, atrial fibrillation, and cardiac arrest were rare and similar across all three treatment groups, as were epistaxis and subdural hematoma.
This is the first randomized, controlled trial of patients with myelofibrosis and thrombocytopenia, according to Dr. Mascarenhas. “This was a patient population with low platelets and at risk of poor outcomes, and they did pretty well,” he said. “There really is no therapeutic option for patients with myelofibrosis and low platelets, and [pacritinib] offers patients in this vulnerable situation an opportunity for symptom relief. I hope to see it move forward.”
CTI Biopharma sponsored the study. Dr. Mascarenhas disclosed research funding from CTI Biopharma.
SAN DIEGO – Late-breaking results from the phase III PERSIST-2 trial may ease at least some safety concerns surrounding the use of pacritinib in patients with myelofibrosis, investigators said at the annual meeting of the American Society of Hematology.
In February 2016, the Food and Drug Administration imposed a clinical hold on studies of pacritinib in the wake of concerns about excess deaths, cardiotoxicities, and hemorrhage. But in the final data analysis presented at ASH, rates of these outcomes were low and similar among patients randomized to pacritinib once daily, pacritinib twice daily, or best available treatment for myelofibrosis, including ruxolitinib, lead investigator John Mascarenhas, MD, said.
Indeed, more patients died of progressive disease after stopping pacritinib than died of treatment-associated adverse events, said Dr. Mascarenhas of Icahn School of Medicine at Mount Sinai, New York.
Pacritinib is an oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CFS1R. In the previous phase III PERSIST-1 trial, patients who received pacritinib had a fourfold greater probability of experiencing at least a 35% decrease in splenic volume than did patients who received best available treatment (P = .003).
PERSIST-2 also yielded clear efficacy signals, particularly when patients took pacritinib twice daily, said Dr. Mascarenhas. Between baseline and week 24, splenic volume dropped by at least 35% in 22% of these patients (95% confidence interval, 13%-33%), compared with 3% of patients on best available treatment (95% CI, 0.3%-10%; P = .001). Patients who took pacritinib twice daily also had a 32% (95% CI, 22%-44%) chance of experiencing at least a 50% drop in symptoms such as fatigue, bone pain, itching, and abdominal pain, compared with 14% (95% CI, 7%-24%) of patients on best available treatment (P = .01).
Demographic and disease risk characteristics did not significantly affect the chances of reaching these coprimary endpoints, Dr. Mascarenhas noted. “My humble opinion as a clinical investigator is that [pacritinib] is an effective drug, with a favorable benefit-to-risk ratio,” he said.
Several hematologists who were not involved in this trial agreed. “I don’t see why you are nervous [about presenting these results],” noted hematologist Kanti Rai, MD, of the Feinstein Institute for Medical Research in Manhasset, N.Y., told Dr. Mascarenhas during the discussion after the data were presented, prompting laughter from the audience.
It remains to be seen whether the FDA will find the data convincing enough to lift the clinical hold on pacritinib. Ruxolitinib (Jakafi) is approved to treat splenomegaly and symptom burden in myelofibrosis but is associated with dose-limiting cytopenias and cannot be used in patients with platelet counts of less than 50,000/mcL.
PERSIST-2 compared pacritinib 400 mg once daily with pacritinib 200 mg twice daily and best available treatment, including ruxolitinib, in patients with primary or secondary myelofibrosis and less than 100,000 platelets/mcL. About half of the study patients had less than 50,000 platelets/mcL, and more than 40% had previously received ruxolitinib.
When the clinical hold on pacritinib went into effect, 221 patients had reached the 24-week designated study endpoint and were included in the intention-to-treat analysis, Dr. Mascarenhas reported. Censored Kaplan-Meier curves of overall survival favored pacritinib over best available treatment, although the difference in survival rates did not reach statistical significance (hazard ratio, 0.68; 95% CI, 0.3-1.5). A total of 9% of patients in the twice-daily pacritinib group died, compared with 14% of patients receiving pacritinib once daily or best available treatment.
Twice-daily pacritinib most often led to diarrhea (48% of patients), nausea (32%), thrombocytopenia (34%), and anemia (24%). Overall rates of serious treatment-emergent adverse events were seen in 47% of the two pacritinib groups and in 31% of patients receiving best available treatment. The most common serious treatment-emergent adverse event with twice daily pacritinib was anemia (8% of patients), followed by thrombocytopenia and pneumonia (6%). Heart failure, atrial fibrillation, and cardiac arrest were rare and similar across all three treatment groups, as were epistaxis and subdural hematoma.
This is the first randomized, controlled trial of patients with myelofibrosis and thrombocytopenia, according to Dr. Mascarenhas. “This was a patient population with low platelets and at risk of poor outcomes, and they did pretty well,” he said. “There really is no therapeutic option for patients with myelofibrosis and low platelets, and [pacritinib] offers patients in this vulnerable situation an opportunity for symptom relief. I hope to see it move forward.”
CTI Biopharma sponsored the study. Dr. Mascarenhas disclosed research funding from CTI Biopharma.
AT ASH 2016
Key clinical point: Pacritinib topped best available treatments for myelofibrosis and was not associated with increased risk of death or cardiac or bleeding events.
Major finding: Rates of death, cardiac events, and bleeding events were low and similar among groups. Splenic volume dropped by at least 35% in 22% of patients receiving twice daily pacritinib, compared with 3% of patients on best available treatment, including ruxolitinib (P = .001). Total symptom scores fell by at least 50% in 32% of patients receiving twice daily pacritinib and 14% of patients on best available treatment (P = .01).
Data source: A randomized phase III trial comparing pacritinib 400 mg once daily, pacritinib 200 mg twice daily, and best available treatment, including ruxolitinib, for 24 weeks in 221 patients with primary or secondary myelofibrosis and less than 100,000 platelets/mcL.
Disclosures: CTI Biopharma sponsored the study. Dr. Mascarenhas disclosed research funding from CTI Biopharma.
Adding epoetin alfa to lenalidomide boosted myelodysplastic syndrome responses
SAN DIEGO – Dual therapy with lenalidomide and epoetin alfa was safe and led to freedom from transfusion significantly more often than lenalidomide alone in patients with erythropoietin-refractory, lower-risk, non-del(5q) myelodysplastic syndromes, according to a randomized phase III head-to-head trial.
After 16 weeks of treatment, 33% of patients who received both lenalidomide and epoetin alfa met International Working Group 2000 criteria for major erythroid response, compared with only 14% of patients receiving lenalidomide monotherapy (P = .03), Alan F. List, MD, reported at the annual meeting of the American Society of Hematology.
Recombinant human erythropoietin improves anemia in some cases of MDS, but salvage options are limited. “Cytokine therapy is generally ineffective in patients with high transfusion burden or elevated serum erythropoietin level,” Dr. List said.
Lenalidomide (Revlimid) promotes the in vitro expansion of primitive erythroid precursors, and in a recent phase III, placebo-controlled trial, the immunomodulator improved erythropoiesis in about 25% of lower-risk, non-del(5q) MDS patients who were azanucleoside-naïve and transfusion-dependent, with effects lasting about 8 months. In another pilot study, adding epoetin alfa to lenalidomide induced erythroid responses in 28% of MDS patients who were not responding to lenalidomide alone. “This suggests that lenalidomide overcomes resistance and augments response to recombinant human erythropoietin,” Dr. List explained.
For their phase III trial, he and his associates randomly assigned erythropoietin-refractory, lower-risk, non-del(5q) MDS patients with hemoglobin levels under 9.5 g/dL to receive lenalidomide (10 mg per day for 21 days every 28 days) with or without epoetin alfa (weekly dose, 60,000 units subcutaneously). A total of 14% of patients had previously received azanucleoside therapy, about 92% had received erythropoietic stimulating agents, and median serum erythropoietin levels were 167 and 143 mU per mL in the monotherapy and dual therapy arms, respectively.
In accordance with International Working Group 2000 criteria, the researchers defined major erythroid response as transfusion independence for least 8 consecutive weeks, with at least a 1 g/dL increase in hemoglobin levels if patients were transfusion-dependent at baseline, and at least a 2 g/dL rise in hemoglobin if they were transfusion-independent.
In an interim analysis of 163 patients, 26% of the dual therapy group and 11% of lenalidomide-only patients met this primary endpoint (P = .02). These results met predefined criteria for stopping the study, after which 34 lenalidomide nonresponders crossed over to dual therapy. In all, 21% of these patients also had a major erythroid response, Dr. List said.
A multivariable analysis that included disease duration, International Prognostic Scoring System low versus intermediate-1 risk status, baseline erythropoietin level, and prior azanucleoside exposure showed that only dual lenalidomide–epoetin alfa therapy predicted major erythroid response. Specifically, dual therapy increased the odds of this outcome by about 63% when compared with lenalidomide monotherapy (P = .03).
Secondary analyses linked major erythroid response to having more low than high molecular weight CD45 isoform. In fact, the median ratio of high to low molecular weight CD45 was 1.5 among responders and 4.2 among nonresponders (P = .04) This finding fits the hypothesis that larger CD45 isoforms keep lenalidomide from enhancing erythropoietin receptor signaling, Dr. List said. Indeed, rates of major erythroid response to lenalidomide–epoetin alfa therapy were 73% when patients had a low isoform ratio, but were only 18% when they had a high isoform ratio (P = .03). The CD45 isoform ratio distinguished responders from nonresponders with a sensitivity and specificity of 80% and 75%, respectively, Dr. List said.
Grade 3 or higher nonhematologic events affected about a quarter of patients in each arm, and rates of individual events were similar. The most common serious adverse event was fatigue (5% of patients), followed by elevated serum creatinine (3.7%). About 10% of patients in each arm died while on study.
The National Institutes of Health supported the study. Dr. List had no relevant financial disclosures.
SAN DIEGO – Dual therapy with lenalidomide and epoetin alfa was safe and led to freedom from transfusion significantly more often than lenalidomide alone in patients with erythropoietin-refractory, lower-risk, non-del(5q) myelodysplastic syndromes, according to a randomized phase III head-to-head trial.
After 16 weeks of treatment, 33% of patients who received both lenalidomide and epoetin alfa met International Working Group 2000 criteria for major erythroid response, compared with only 14% of patients receiving lenalidomide monotherapy (P = .03), Alan F. List, MD, reported at the annual meeting of the American Society of Hematology.
Recombinant human erythropoietin improves anemia in some cases of MDS, but salvage options are limited. “Cytokine therapy is generally ineffective in patients with high transfusion burden or elevated serum erythropoietin level,” Dr. List said.
Lenalidomide (Revlimid) promotes the in vitro expansion of primitive erythroid precursors, and in a recent phase III, placebo-controlled trial, the immunomodulator improved erythropoiesis in about 25% of lower-risk, non-del(5q) MDS patients who were azanucleoside-naïve and transfusion-dependent, with effects lasting about 8 months. In another pilot study, adding epoetin alfa to lenalidomide induced erythroid responses in 28% of MDS patients who were not responding to lenalidomide alone. “This suggests that lenalidomide overcomes resistance and augments response to recombinant human erythropoietin,” Dr. List explained.
For their phase III trial, he and his associates randomly assigned erythropoietin-refractory, lower-risk, non-del(5q) MDS patients with hemoglobin levels under 9.5 g/dL to receive lenalidomide (10 mg per day for 21 days every 28 days) with or without epoetin alfa (weekly dose, 60,000 units subcutaneously). A total of 14% of patients had previously received azanucleoside therapy, about 92% had received erythropoietic stimulating agents, and median serum erythropoietin levels were 167 and 143 mU per mL in the monotherapy and dual therapy arms, respectively.
In accordance with International Working Group 2000 criteria, the researchers defined major erythroid response as transfusion independence for least 8 consecutive weeks, with at least a 1 g/dL increase in hemoglobin levels if patients were transfusion-dependent at baseline, and at least a 2 g/dL rise in hemoglobin if they were transfusion-independent.
In an interim analysis of 163 patients, 26% of the dual therapy group and 11% of lenalidomide-only patients met this primary endpoint (P = .02). These results met predefined criteria for stopping the study, after which 34 lenalidomide nonresponders crossed over to dual therapy. In all, 21% of these patients also had a major erythroid response, Dr. List said.
A multivariable analysis that included disease duration, International Prognostic Scoring System low versus intermediate-1 risk status, baseline erythropoietin level, and prior azanucleoside exposure showed that only dual lenalidomide–epoetin alfa therapy predicted major erythroid response. Specifically, dual therapy increased the odds of this outcome by about 63% when compared with lenalidomide monotherapy (P = .03).
Secondary analyses linked major erythroid response to having more low than high molecular weight CD45 isoform. In fact, the median ratio of high to low molecular weight CD45 was 1.5 among responders and 4.2 among nonresponders (P = .04) This finding fits the hypothesis that larger CD45 isoforms keep lenalidomide from enhancing erythropoietin receptor signaling, Dr. List said. Indeed, rates of major erythroid response to lenalidomide–epoetin alfa therapy were 73% when patients had a low isoform ratio, but were only 18% when they had a high isoform ratio (P = .03). The CD45 isoform ratio distinguished responders from nonresponders with a sensitivity and specificity of 80% and 75%, respectively, Dr. List said.
Grade 3 or higher nonhematologic events affected about a quarter of patients in each arm, and rates of individual events were similar. The most common serious adverse event was fatigue (5% of patients), followed by elevated serum creatinine (3.7%). About 10% of patients in each arm died while on study.
The National Institutes of Health supported the study. Dr. List had no relevant financial disclosures.
SAN DIEGO – Dual therapy with lenalidomide and epoetin alfa was safe and led to freedom from transfusion significantly more often than lenalidomide alone in patients with erythropoietin-refractory, lower-risk, non-del(5q) myelodysplastic syndromes, according to a randomized phase III head-to-head trial.
After 16 weeks of treatment, 33% of patients who received both lenalidomide and epoetin alfa met International Working Group 2000 criteria for major erythroid response, compared with only 14% of patients receiving lenalidomide monotherapy (P = .03), Alan F. List, MD, reported at the annual meeting of the American Society of Hematology.
Recombinant human erythropoietin improves anemia in some cases of MDS, but salvage options are limited. “Cytokine therapy is generally ineffective in patients with high transfusion burden or elevated serum erythropoietin level,” Dr. List said.
Lenalidomide (Revlimid) promotes the in vitro expansion of primitive erythroid precursors, and in a recent phase III, placebo-controlled trial, the immunomodulator improved erythropoiesis in about 25% of lower-risk, non-del(5q) MDS patients who were azanucleoside-naïve and transfusion-dependent, with effects lasting about 8 months. In another pilot study, adding epoetin alfa to lenalidomide induced erythroid responses in 28% of MDS patients who were not responding to lenalidomide alone. “This suggests that lenalidomide overcomes resistance and augments response to recombinant human erythropoietin,” Dr. List explained.
For their phase III trial, he and his associates randomly assigned erythropoietin-refractory, lower-risk, non-del(5q) MDS patients with hemoglobin levels under 9.5 g/dL to receive lenalidomide (10 mg per day for 21 days every 28 days) with or without epoetin alfa (weekly dose, 60,000 units subcutaneously). A total of 14% of patients had previously received azanucleoside therapy, about 92% had received erythropoietic stimulating agents, and median serum erythropoietin levels were 167 and 143 mU per mL in the monotherapy and dual therapy arms, respectively.
In accordance with International Working Group 2000 criteria, the researchers defined major erythroid response as transfusion independence for least 8 consecutive weeks, with at least a 1 g/dL increase in hemoglobin levels if patients were transfusion-dependent at baseline, and at least a 2 g/dL rise in hemoglobin if they were transfusion-independent.
In an interim analysis of 163 patients, 26% of the dual therapy group and 11% of lenalidomide-only patients met this primary endpoint (P = .02). These results met predefined criteria for stopping the study, after which 34 lenalidomide nonresponders crossed over to dual therapy. In all, 21% of these patients also had a major erythroid response, Dr. List said.
A multivariable analysis that included disease duration, International Prognostic Scoring System low versus intermediate-1 risk status, baseline erythropoietin level, and prior azanucleoside exposure showed that only dual lenalidomide–epoetin alfa therapy predicted major erythroid response. Specifically, dual therapy increased the odds of this outcome by about 63% when compared with lenalidomide monotherapy (P = .03).
Secondary analyses linked major erythroid response to having more low than high molecular weight CD45 isoform. In fact, the median ratio of high to low molecular weight CD45 was 1.5 among responders and 4.2 among nonresponders (P = .04) This finding fits the hypothesis that larger CD45 isoforms keep lenalidomide from enhancing erythropoietin receptor signaling, Dr. List said. Indeed, rates of major erythroid response to lenalidomide–epoetin alfa therapy were 73% when patients had a low isoform ratio, but were only 18% when they had a high isoform ratio (P = .03). The CD45 isoform ratio distinguished responders from nonresponders with a sensitivity and specificity of 80% and 75%, respectively, Dr. List said.
Grade 3 or higher nonhematologic events affected about a quarter of patients in each arm, and rates of individual events were similar. The most common serious adverse event was fatigue (5% of patients), followed by elevated serum creatinine (3.7%). About 10% of patients in each arm died while on study.
The National Institutes of Health supported the study. Dr. List had no relevant financial disclosures.
Key clinical point: Dual therapy with lenalidomide and epoetin alfa was more effective than lenalidomide monotherapy in patients with erythropoietin-refractory, lower-risk, non-del(5q) myelodysplastic syndrome.
Major finding: After 16 weeks of treatment, 33% of patients who received both agents met International Working Group 2000 criteria for major erythroid response, compared with 14% of patients receiving lenalidomide monotherapy (P = .03).
Data source: An interim analysis of 163 patients in the phase III ECOG-ACRIN E2905 Intergroup Study.
Disclosures: The National Institutes of Health supported the study. Dr. List had no relevant financial disclosures.
Study reveals potential therapeutic targets for MDS
Preclinical research has revealed potential therapeutic targets for
myelodysplastic syndromes (MDS).
Investigators
found evidence to suggest that TRAF6, a toll-like receptor effector
with ubiquitin ligase activity, plays a key role in MDS.
So TRAF6 and
proteins regulated by TRAF6 may be therapeutic targets for MDS.
Daniel Starczynowski, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio, and his colleagues reported these findings in Nature Immunology.
The investigators first found that TRAF6 is overexpressed in hematopoietic stem/progenitor cells from MDS patients.
To more closely examine the role of TRAF6 in MDS, the team created mouse models in which the protein was overexpressed.
“We found that TRAF6 overexpression in mouse hematopoietic stem cells results in impaired blood cell formation and bone marrow failure,” Dr Starczynowski said.
Further investigation revealed that hnRNPA1, an RNA-binding protein and auxiliary splicing factor, is a substrate of TRAF6. And TRAF6 ubiquitination of hnRNPA1 regulates alternative splicing of Arhgap1.
This activates the GTP-binding Rho family protein Cdc42 and accounts for the defects observed in hematopoietic stem/progenitor cells that express TRAF6.
All of these proteins could be potential treatment targets for cases of MDS triggered by overexpression of TRAF6, according to Dr Starczynowski, who said future studies will test their therapeutic potential in mouse models of MDS.
“Based on our paper, a number of therapeutic approaches can be tested and directed against TRAF6 and other related proteins responsible for MDS,” he said.
Beyond the potential for new therapeutic approaches in MDS, this research revealed a new and critical immune-related function for TRAF6, according to the investigators.
TRAF6 regulates RNA isoform expression in response to various pathogens. In the context of the current study, TRAF6’s regulation of RNA isoform expression is important to the function of hematopoietic cells and reveals another dimension to how cells respond to infection, Dr Starczynowski said.
Preclinical research has revealed potential therapeutic targets for
myelodysplastic syndromes (MDS).
Investigators
found evidence to suggest that TRAF6, a toll-like receptor effector
with ubiquitin ligase activity, plays a key role in MDS.
So TRAF6 and
proteins regulated by TRAF6 may be therapeutic targets for MDS.
Daniel Starczynowski, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio, and his colleagues reported these findings in Nature Immunology.
The investigators first found that TRAF6 is overexpressed in hematopoietic stem/progenitor cells from MDS patients.
To more closely examine the role of TRAF6 in MDS, the team created mouse models in which the protein was overexpressed.
“We found that TRAF6 overexpression in mouse hematopoietic stem cells results in impaired blood cell formation and bone marrow failure,” Dr Starczynowski said.
Further investigation revealed that hnRNPA1, an RNA-binding protein and auxiliary splicing factor, is a substrate of TRAF6. And TRAF6 ubiquitination of hnRNPA1 regulates alternative splicing of Arhgap1.
This activates the GTP-binding Rho family protein Cdc42 and accounts for the defects observed in hematopoietic stem/progenitor cells that express TRAF6.
All of these proteins could be potential treatment targets for cases of MDS triggered by overexpression of TRAF6, according to Dr Starczynowski, who said future studies will test their therapeutic potential in mouse models of MDS.
“Based on our paper, a number of therapeutic approaches can be tested and directed against TRAF6 and other related proteins responsible for MDS,” he said.
Beyond the potential for new therapeutic approaches in MDS, this research revealed a new and critical immune-related function for TRAF6, according to the investigators.
TRAF6 regulates RNA isoform expression in response to various pathogens. In the context of the current study, TRAF6’s regulation of RNA isoform expression is important to the function of hematopoietic cells and reveals another dimension to how cells respond to infection, Dr Starczynowski said.
Preclinical research has revealed potential therapeutic targets for
myelodysplastic syndromes (MDS).
Investigators
found evidence to suggest that TRAF6, a toll-like receptor effector
with ubiquitin ligase activity, plays a key role in MDS.
So TRAF6 and
proteins regulated by TRAF6 may be therapeutic targets for MDS.
Daniel Starczynowski, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio, and his colleagues reported these findings in Nature Immunology.
The investigators first found that TRAF6 is overexpressed in hematopoietic stem/progenitor cells from MDS patients.
To more closely examine the role of TRAF6 in MDS, the team created mouse models in which the protein was overexpressed.
“We found that TRAF6 overexpression in mouse hematopoietic stem cells results in impaired blood cell formation and bone marrow failure,” Dr Starczynowski said.
Further investigation revealed that hnRNPA1, an RNA-binding protein and auxiliary splicing factor, is a substrate of TRAF6. And TRAF6 ubiquitination of hnRNPA1 regulates alternative splicing of Arhgap1.
This activates the GTP-binding Rho family protein Cdc42 and accounts for the defects observed in hematopoietic stem/progenitor cells that express TRAF6.
All of these proteins could be potential treatment targets for cases of MDS triggered by overexpression of TRAF6, according to Dr Starczynowski, who said future studies will test their therapeutic potential in mouse models of MDS.
“Based on our paper, a number of therapeutic approaches can be tested and directed against TRAF6 and other related proteins responsible for MDS,” he said.
Beyond the potential for new therapeutic approaches in MDS, this research revealed a new and critical immune-related function for TRAF6, according to the investigators.
TRAF6 regulates RNA isoform expression in response to various pathogens. In the context of the current study, TRAF6’s regulation of RNA isoform expression is important to the function of hematopoietic cells and reveals another dimension to how cells respond to infection, Dr Starczynowski said.
MDS patients with mutated IDH2 benefit from enasidenib
Photo courtesy of ASH
SAN DIEGO—Daily treatment with enasidenib monotherapy in patients with mutated IDH2-positive myelodysplastic syndromes (MDS) induced responses in the majority of patients treated, according to a presentation at the 2016 ASH Annual Meeting.
The study was a portion of a larger phase 1/2 trial of the agent in patients with acute myeloid leukemia (AML) and other hematologic malignancies, so the subset was relatively small, numbering 17 patients.
Nevertheless, enasidenib was well tolerated and induced responses in these predominantly higher-risk patients.
Enasidenib (AG-221/CC-9007) is a selective, oral, potent inhibitor of mutant IDH2 (mIDH2), which produces 2-HG and thus alters DNA methylation and blocks cellular differentiation of hematopoietic progenitor cells.
Approximately 15% of AML patients and 5% of MDS patients have mIDH2. So investigators undertook the study to evaluate the safety and efficacy of enasidenib monotherapy in these diseases.
Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the analysis of enasidenib in mIDH2-positive MDS patients as abstract 343.*
Study design
MDS patients were allowed to enroll during the dose-escalation and expansion phase of the study, Dr Stein explained.
Patients had to be 18 or older and have an advanced hematologic malignancy with mutated IDH2—relapsed or refractory AML, relapsed or refractory MDS, untreated AML, or other hematologic malignancy with mIDH2.
MDS patients could not be candidates for other therapies, had to be IPSS-R high risk, and had to have relapsed or refractory RAEB-1/RAEB-2 disease.
Investigators also performed co-molecular profiling using next-generation sequencing with a FoundationOne® Heme Panel.
All patients received daily oral enasidenib at 100 mg daily in 28-day cycles.
Patient characteristics
The study accrued a total of 239 patients—176 with relapsed or refractory AML, 37 with untreated AML, 9 with another hematologic malignancy, and 17 with MDS.
The median age of the MDS patients was 67 (range, 45-78), and 71% were male. All had the IDH2 mutation, 88% had R140 mutations, and 12% had R172.
Thirteen patients (76%) had an ECOG performance status of 0-1, and 4 (24%) had a performance status of 2.
A little more than a third (35%) of patients had 2 or more prior anti-cancer regimens.
Two patients (12%) received prior lenalidomide therapy, 8 (47%) received other treatments, including sorafenib (n=2) and vosaroxin, epoetin alfa, pracinostat, cytarabine plus clofarabine, ruxolitinib, and rigosertib (n=1 each). Four patients (24%) were untreated.
“I want to make the point,” Dr Stein said, “that, of those patients, three quarters of them, 76% [n=13], had received a prior hypomethylating agent, really understanding that this is a very poor-risk group of patients that we are studying here.”
About half of patients (47%) had intermediate-2/high IPSS risk status, good MDS cytogenetic risk, and high/very high IPSS-R risk status.
Adverse events
Grade 3-4 treatment-emergent adverse events (AEs) occurring in 2 or more patients were hyperbilirubinemia (n=5), pneumonia (n=4), thrombocytopenia (n=4), anemia (n=3), hypokalemia (n=3), dyspnea (n=2), and tumor lysis syndrome (n=2).
“As I’ve said in a number of meetings where I’ve talked about IDH2 inhibitors, and specifically enasidenib, the hyperbilirubinemia that is seen with this drug is an indirect hyperbilirubinemia,” Dr Stein said.
“A known off-target effect of this drug is inhibition of the UGT1a1 enzyme, which conjugates bilirubin, and this indirect hyperbilirubinemia, which is typically relatively mild [and] does not appear to have any clinical sequelae.”
Investigators considered 9 of the AEs reported for 6 patients to be drug-related.
Four serious enasidenib-related AEs included tumor lysis syndrome (n=2), increased blood bilirubin (n=1), and transaminitis (n=1).
There were no treatment-related deaths.
Response and survival
Ten of 17 patients (59%) achieved an overall response, defined as complete response (CR) plus partial response, plus marrow CR, plus hematologic improvement (HI).
One patient achieved CR, 1 had a partial response, 3 had marrow CR, and 5 had HI.
Dr Stein noted that, of the 13 patients who had received prior hypomethylating agent therapy, 7 (54%) had a response with enasidenib.
Of the patients who attained HI, 2 had trilineage and 2 had bilineage improvement.
The median time to response was 21 days (range, 10-87), and the median number of treatment cycles was 3.0.
Patients remained on study for up to 24 months. Four patients in hematologic remission are still on study, and 3 patients proceeded to stem cell or bone marrow transplant, Dr Stein said.
Two patients discontinued because of investigator decision, and 8 discontinued therapy due to death or disease progression.
The limitation of the study regarding overall survival, Dr Stein said, is that the number is very small.
At a median follow-up of 7.5 months, the median overall survival was not reached.
“So I’m not arguing that this is the end word of this,” he said. “This is going to be dynamic as more patients come on these studies. But I think it’s a nice indication that this treatment appears to be well-tolerated and doing good for a large subset of patients.”
Co-occurring mutations
The investigators also analyzed co-occurring mutations in 13 MDS patients.
The small patient population prevented the investigators from making definitive conclusions regarding potential correlations between response and co-mutations.
Nevertheless, Dr Stein said the analysis revealed something “very, very intriguing.”
He noted that 7 patients had ASXL1 mutations, and “those are typically patients who are bad actors.”
“Five of those 7 patients had a response,” Dr Stein said. “And of those 5, 3 of them had received a prior hypomethylating agent. I think it’s at least food for thought that you can salvage a patient who has failed a hypomethylating agent, with poor risk disease. I think this is very, very exciting.”
Celgene Corporation and its collaborator, Agios Pharmaceuticals, sponsored the trial.
*Information in the abstract differs from the presentation.
Photo courtesy of ASH
SAN DIEGO—Daily treatment with enasidenib monotherapy in patients with mutated IDH2-positive myelodysplastic syndromes (MDS) induced responses in the majority of patients treated, according to a presentation at the 2016 ASH Annual Meeting.
The study was a portion of a larger phase 1/2 trial of the agent in patients with acute myeloid leukemia (AML) and other hematologic malignancies, so the subset was relatively small, numbering 17 patients.
Nevertheless, enasidenib was well tolerated and induced responses in these predominantly higher-risk patients.
Enasidenib (AG-221/CC-9007) is a selective, oral, potent inhibitor of mutant IDH2 (mIDH2), which produces 2-HG and thus alters DNA methylation and blocks cellular differentiation of hematopoietic progenitor cells.
Approximately 15% of AML patients and 5% of MDS patients have mIDH2. So investigators undertook the study to evaluate the safety and efficacy of enasidenib monotherapy in these diseases.
Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the analysis of enasidenib in mIDH2-positive MDS patients as abstract 343.*
Study design
MDS patients were allowed to enroll during the dose-escalation and expansion phase of the study, Dr Stein explained.
Patients had to be 18 or older and have an advanced hematologic malignancy with mutated IDH2—relapsed or refractory AML, relapsed or refractory MDS, untreated AML, or other hematologic malignancy with mIDH2.
MDS patients could not be candidates for other therapies, had to be IPSS-R high risk, and had to have relapsed or refractory RAEB-1/RAEB-2 disease.
Investigators also performed co-molecular profiling using next-generation sequencing with a FoundationOne® Heme Panel.
All patients received daily oral enasidenib at 100 mg daily in 28-day cycles.
Patient characteristics
The study accrued a total of 239 patients—176 with relapsed or refractory AML, 37 with untreated AML, 9 with another hematologic malignancy, and 17 with MDS.
The median age of the MDS patients was 67 (range, 45-78), and 71% were male. All had the IDH2 mutation, 88% had R140 mutations, and 12% had R172.
Thirteen patients (76%) had an ECOG performance status of 0-1, and 4 (24%) had a performance status of 2.
A little more than a third (35%) of patients had 2 or more prior anti-cancer regimens.
Two patients (12%) received prior lenalidomide therapy, 8 (47%) received other treatments, including sorafenib (n=2) and vosaroxin, epoetin alfa, pracinostat, cytarabine plus clofarabine, ruxolitinib, and rigosertib (n=1 each). Four patients (24%) were untreated.
“I want to make the point,” Dr Stein said, “that, of those patients, three quarters of them, 76% [n=13], had received a prior hypomethylating agent, really understanding that this is a very poor-risk group of patients that we are studying here.”
About half of patients (47%) had intermediate-2/high IPSS risk status, good MDS cytogenetic risk, and high/very high IPSS-R risk status.
Adverse events
Grade 3-4 treatment-emergent adverse events (AEs) occurring in 2 or more patients were hyperbilirubinemia (n=5), pneumonia (n=4), thrombocytopenia (n=4), anemia (n=3), hypokalemia (n=3), dyspnea (n=2), and tumor lysis syndrome (n=2).
“As I’ve said in a number of meetings where I’ve talked about IDH2 inhibitors, and specifically enasidenib, the hyperbilirubinemia that is seen with this drug is an indirect hyperbilirubinemia,” Dr Stein said.
“A known off-target effect of this drug is inhibition of the UGT1a1 enzyme, which conjugates bilirubin, and this indirect hyperbilirubinemia, which is typically relatively mild [and] does not appear to have any clinical sequelae.”
Investigators considered 9 of the AEs reported for 6 patients to be drug-related.
Four serious enasidenib-related AEs included tumor lysis syndrome (n=2), increased blood bilirubin (n=1), and transaminitis (n=1).
There were no treatment-related deaths.
Response and survival
Ten of 17 patients (59%) achieved an overall response, defined as complete response (CR) plus partial response, plus marrow CR, plus hematologic improvement (HI).
One patient achieved CR, 1 had a partial response, 3 had marrow CR, and 5 had HI.
Dr Stein noted that, of the 13 patients who had received prior hypomethylating agent therapy, 7 (54%) had a response with enasidenib.
Of the patients who attained HI, 2 had trilineage and 2 had bilineage improvement.
The median time to response was 21 days (range, 10-87), and the median number of treatment cycles was 3.0.
Patients remained on study for up to 24 months. Four patients in hematologic remission are still on study, and 3 patients proceeded to stem cell or bone marrow transplant, Dr Stein said.
Two patients discontinued because of investigator decision, and 8 discontinued therapy due to death or disease progression.
The limitation of the study regarding overall survival, Dr Stein said, is that the number is very small.
At a median follow-up of 7.5 months, the median overall survival was not reached.
“So I’m not arguing that this is the end word of this,” he said. “This is going to be dynamic as more patients come on these studies. But I think it’s a nice indication that this treatment appears to be well-tolerated and doing good for a large subset of patients.”
Co-occurring mutations
The investigators also analyzed co-occurring mutations in 13 MDS patients.
The small patient population prevented the investigators from making definitive conclusions regarding potential correlations between response and co-mutations.
Nevertheless, Dr Stein said the analysis revealed something “very, very intriguing.”
He noted that 7 patients had ASXL1 mutations, and “those are typically patients who are bad actors.”
“Five of those 7 patients had a response,” Dr Stein said. “And of those 5, 3 of them had received a prior hypomethylating agent. I think it’s at least food for thought that you can salvage a patient who has failed a hypomethylating agent, with poor risk disease. I think this is very, very exciting.”
Celgene Corporation and its collaborator, Agios Pharmaceuticals, sponsored the trial.
*Information in the abstract differs from the presentation.
Photo courtesy of ASH
SAN DIEGO—Daily treatment with enasidenib monotherapy in patients with mutated IDH2-positive myelodysplastic syndromes (MDS) induced responses in the majority of patients treated, according to a presentation at the 2016 ASH Annual Meeting.
The study was a portion of a larger phase 1/2 trial of the agent in patients with acute myeloid leukemia (AML) and other hematologic malignancies, so the subset was relatively small, numbering 17 patients.
Nevertheless, enasidenib was well tolerated and induced responses in these predominantly higher-risk patients.
Enasidenib (AG-221/CC-9007) is a selective, oral, potent inhibitor of mutant IDH2 (mIDH2), which produces 2-HG and thus alters DNA methylation and blocks cellular differentiation of hematopoietic progenitor cells.
Approximately 15% of AML patients and 5% of MDS patients have mIDH2. So investigators undertook the study to evaluate the safety and efficacy of enasidenib monotherapy in these diseases.
Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the analysis of enasidenib in mIDH2-positive MDS patients as abstract 343.*
Study design
MDS patients were allowed to enroll during the dose-escalation and expansion phase of the study, Dr Stein explained.
Patients had to be 18 or older and have an advanced hematologic malignancy with mutated IDH2—relapsed or refractory AML, relapsed or refractory MDS, untreated AML, or other hematologic malignancy with mIDH2.
MDS patients could not be candidates for other therapies, had to be IPSS-R high risk, and had to have relapsed or refractory RAEB-1/RAEB-2 disease.
Investigators also performed co-molecular profiling using next-generation sequencing with a FoundationOne® Heme Panel.
All patients received daily oral enasidenib at 100 mg daily in 28-day cycles.
Patient characteristics
The study accrued a total of 239 patients—176 with relapsed or refractory AML, 37 with untreated AML, 9 with another hematologic malignancy, and 17 with MDS.
The median age of the MDS patients was 67 (range, 45-78), and 71% were male. All had the IDH2 mutation, 88% had R140 mutations, and 12% had R172.
Thirteen patients (76%) had an ECOG performance status of 0-1, and 4 (24%) had a performance status of 2.
A little more than a third (35%) of patients had 2 or more prior anti-cancer regimens.
Two patients (12%) received prior lenalidomide therapy, 8 (47%) received other treatments, including sorafenib (n=2) and vosaroxin, epoetin alfa, pracinostat, cytarabine plus clofarabine, ruxolitinib, and rigosertib (n=1 each). Four patients (24%) were untreated.
“I want to make the point,” Dr Stein said, “that, of those patients, three quarters of them, 76% [n=13], had received a prior hypomethylating agent, really understanding that this is a very poor-risk group of patients that we are studying here.”
About half of patients (47%) had intermediate-2/high IPSS risk status, good MDS cytogenetic risk, and high/very high IPSS-R risk status.
Adverse events
Grade 3-4 treatment-emergent adverse events (AEs) occurring in 2 or more patients were hyperbilirubinemia (n=5), pneumonia (n=4), thrombocytopenia (n=4), anemia (n=3), hypokalemia (n=3), dyspnea (n=2), and tumor lysis syndrome (n=2).
“As I’ve said in a number of meetings where I’ve talked about IDH2 inhibitors, and specifically enasidenib, the hyperbilirubinemia that is seen with this drug is an indirect hyperbilirubinemia,” Dr Stein said.
“A known off-target effect of this drug is inhibition of the UGT1a1 enzyme, which conjugates bilirubin, and this indirect hyperbilirubinemia, which is typically relatively mild [and] does not appear to have any clinical sequelae.”
Investigators considered 9 of the AEs reported for 6 patients to be drug-related.
Four serious enasidenib-related AEs included tumor lysis syndrome (n=2), increased blood bilirubin (n=1), and transaminitis (n=1).
There were no treatment-related deaths.
Response and survival
Ten of 17 patients (59%) achieved an overall response, defined as complete response (CR) plus partial response, plus marrow CR, plus hematologic improvement (HI).
One patient achieved CR, 1 had a partial response, 3 had marrow CR, and 5 had HI.
Dr Stein noted that, of the 13 patients who had received prior hypomethylating agent therapy, 7 (54%) had a response with enasidenib.
Of the patients who attained HI, 2 had trilineage and 2 had bilineage improvement.
The median time to response was 21 days (range, 10-87), and the median number of treatment cycles was 3.0.
Patients remained on study for up to 24 months. Four patients in hematologic remission are still on study, and 3 patients proceeded to stem cell or bone marrow transplant, Dr Stein said.
Two patients discontinued because of investigator decision, and 8 discontinued therapy due to death or disease progression.
The limitation of the study regarding overall survival, Dr Stein said, is that the number is very small.
At a median follow-up of 7.5 months, the median overall survival was not reached.
“So I’m not arguing that this is the end word of this,” he said. “This is going to be dynamic as more patients come on these studies. But I think it’s a nice indication that this treatment appears to be well-tolerated and doing good for a large subset of patients.”
Co-occurring mutations
The investigators also analyzed co-occurring mutations in 13 MDS patients.
The small patient population prevented the investigators from making definitive conclusions regarding potential correlations between response and co-mutations.
Nevertheless, Dr Stein said the analysis revealed something “very, very intriguing.”
He noted that 7 patients had ASXL1 mutations, and “those are typically patients who are bad actors.”
“Five of those 7 patients had a response,” Dr Stein said. “And of those 5, 3 of them had received a prior hypomethylating agent. I think it’s at least food for thought that you can salvage a patient who has failed a hypomethylating agent, with poor risk disease. I think this is very, very exciting.”
Celgene Corporation and its collaborator, Agios Pharmaceuticals, sponsored the trial.
*Information in the abstract differs from the presentation.
Predicting therapy-related myeloid neoplasms
Photo courtesy of
MD Anderson Cancer Center
SAN DIEGO―Clonal hematopoiesis could be used as a predictive marker to identify cancer patients at risk of developing therapy-related myeloid neoplasms (t-MNs), according to researchers.
The team conducted a case-control study, which showed that patients who developed t-MNs—acute myeloid leukemia and myelodysplastic syndromes—were significantly more likely than patients without t-MNs to have clonal hematopoiesis at the time of primary cancer diagnosis.
“Based on these findings, we believe pre-leukemic mutations may function as a new biomarker that would predict t-MN development,” said Andy Futreal, PhD, of The University of Texas MD Anderson Cancer Center in Houston.
Dr Futreal and his colleagues reported these findings in The Lancet Oncology.
Co-author Koichi Takashi, MD, also of MD Anderson, presented the findings at the 2016 ASH Annual Meeting (abstract 38).
Initial cohort
The researchers analyzed data on patients treated at MD Anderson from 1997 to 2015.
The 14 cases the team identified had been treated for a primary cancer and later developed t-MNs. The 54 age-matched control subjects had been treated for lymphoma, received combination chemotherapy, and did not develop t-MNs after at least 5 years of follow-up.
For both cases and controls, the researchers performed gene sequencing on pre-treatment peripheral blood samples. For cases, the researchers also performed targeted gene sequencing on bone marrow samples taken at t-MN diagnosis.
“We found that prevalence of pre-leukemic mutations was significantly higher in patients who developed t-MNs versus those who did not,” Dr Futreal said.
Clonal hematopoiesis was present in 71% of cases (n=10) and 31% of controls (n=17).
“We found genetic mutations that are present in t-MNs leukemia samples actually could be found in blood samples obtained at the time of their original cancer diagnosis,” Dr Takashi noted.
Overall, the cumulative incidence of t-MNs at 5 years was significantly higher in patients with clonal hematopoiesis than in those without it—30% and 7%, respectively (P=0.016).
Validation cohort
The researchers also assessed clonal hematopoiesis in an external cohort of 74 patients with lymphoma who were treated in a trial of front-line chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without melatonin.
In this cohort, 7% (n=5) of patients developed t-MNs. Eighty percent of these patients (n=4) had clonal hematopoiesis.
Of the 69 patients who did not develop t-MNs, 16% (n=11) had clonal hematopoiesis.
The cumulative incidence of t-MNs at 10 years was significantly higher in patients with clonal hematopoiesis than in those without it—29% and 0%, respectively (P=0.0009).
Multivariate analysis suggested clonal hematopoiesis significantly increased the risk of t-MNs, with a hazard ratio of 13.7 (P=0.013).
“[W]e believe the data suggest potential approaches of screening for clonal hematopoiesis in cancer patients that may identify patients at risk of developing t-MNs, although further studies are needed,” Dr Takashi concluded.
Photo courtesy of
MD Anderson Cancer Center
SAN DIEGO―Clonal hematopoiesis could be used as a predictive marker to identify cancer patients at risk of developing therapy-related myeloid neoplasms (t-MNs), according to researchers.
The team conducted a case-control study, which showed that patients who developed t-MNs—acute myeloid leukemia and myelodysplastic syndromes—were significantly more likely than patients without t-MNs to have clonal hematopoiesis at the time of primary cancer diagnosis.
“Based on these findings, we believe pre-leukemic mutations may function as a new biomarker that would predict t-MN development,” said Andy Futreal, PhD, of The University of Texas MD Anderson Cancer Center in Houston.
Dr Futreal and his colleagues reported these findings in The Lancet Oncology.
Co-author Koichi Takashi, MD, also of MD Anderson, presented the findings at the 2016 ASH Annual Meeting (abstract 38).
Initial cohort
The researchers analyzed data on patients treated at MD Anderson from 1997 to 2015.
The 14 cases the team identified had been treated for a primary cancer and later developed t-MNs. The 54 age-matched control subjects had been treated for lymphoma, received combination chemotherapy, and did not develop t-MNs after at least 5 years of follow-up.
For both cases and controls, the researchers performed gene sequencing on pre-treatment peripheral blood samples. For cases, the researchers also performed targeted gene sequencing on bone marrow samples taken at t-MN diagnosis.
“We found that prevalence of pre-leukemic mutations was significantly higher in patients who developed t-MNs versus those who did not,” Dr Futreal said.
Clonal hematopoiesis was present in 71% of cases (n=10) and 31% of controls (n=17).
“We found genetic mutations that are present in t-MNs leukemia samples actually could be found in blood samples obtained at the time of their original cancer diagnosis,” Dr Takashi noted.
Overall, the cumulative incidence of t-MNs at 5 years was significantly higher in patients with clonal hematopoiesis than in those without it—30% and 7%, respectively (P=0.016).
Validation cohort
The researchers also assessed clonal hematopoiesis in an external cohort of 74 patients with lymphoma who were treated in a trial of front-line chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without melatonin.
In this cohort, 7% (n=5) of patients developed t-MNs. Eighty percent of these patients (n=4) had clonal hematopoiesis.
Of the 69 patients who did not develop t-MNs, 16% (n=11) had clonal hematopoiesis.
The cumulative incidence of t-MNs at 10 years was significantly higher in patients with clonal hematopoiesis than in those without it—29% and 0%, respectively (P=0.0009).
Multivariate analysis suggested clonal hematopoiesis significantly increased the risk of t-MNs, with a hazard ratio of 13.7 (P=0.013).
“[W]e believe the data suggest potential approaches of screening for clonal hematopoiesis in cancer patients that may identify patients at risk of developing t-MNs, although further studies are needed,” Dr Takashi concluded.
Photo courtesy of
MD Anderson Cancer Center
SAN DIEGO―Clonal hematopoiesis could be used as a predictive marker to identify cancer patients at risk of developing therapy-related myeloid neoplasms (t-MNs), according to researchers.
The team conducted a case-control study, which showed that patients who developed t-MNs—acute myeloid leukemia and myelodysplastic syndromes—were significantly more likely than patients without t-MNs to have clonal hematopoiesis at the time of primary cancer diagnosis.
“Based on these findings, we believe pre-leukemic mutations may function as a new biomarker that would predict t-MN development,” said Andy Futreal, PhD, of The University of Texas MD Anderson Cancer Center in Houston.
Dr Futreal and his colleagues reported these findings in The Lancet Oncology.
Co-author Koichi Takashi, MD, also of MD Anderson, presented the findings at the 2016 ASH Annual Meeting (abstract 38).
Initial cohort
The researchers analyzed data on patients treated at MD Anderson from 1997 to 2015.
The 14 cases the team identified had been treated for a primary cancer and later developed t-MNs. The 54 age-matched control subjects had been treated for lymphoma, received combination chemotherapy, and did not develop t-MNs after at least 5 years of follow-up.
For both cases and controls, the researchers performed gene sequencing on pre-treatment peripheral blood samples. For cases, the researchers also performed targeted gene sequencing on bone marrow samples taken at t-MN diagnosis.
“We found that prevalence of pre-leukemic mutations was significantly higher in patients who developed t-MNs versus those who did not,” Dr Futreal said.
Clonal hematopoiesis was present in 71% of cases (n=10) and 31% of controls (n=17).
“We found genetic mutations that are present in t-MNs leukemia samples actually could be found in blood samples obtained at the time of their original cancer diagnosis,” Dr Takashi noted.
Overall, the cumulative incidence of t-MNs at 5 years was significantly higher in patients with clonal hematopoiesis than in those without it—30% and 7%, respectively (P=0.016).
Validation cohort
The researchers also assessed clonal hematopoiesis in an external cohort of 74 patients with lymphoma who were treated in a trial of front-line chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without melatonin.
In this cohort, 7% (n=5) of patients developed t-MNs. Eighty percent of these patients (n=4) had clonal hematopoiesis.
Of the 69 patients who did not develop t-MNs, 16% (n=11) had clonal hematopoiesis.
The cumulative incidence of t-MNs at 10 years was significantly higher in patients with clonal hematopoiesis than in those without it—29% and 0%, respectively (P=0.0009).
Multivariate analysis suggested clonal hematopoiesis significantly increased the risk of t-MNs, with a hazard ratio of 13.7 (P=0.013).
“[W]e believe the data suggest potential approaches of screening for clonal hematopoiesis in cancer patients that may identify patients at risk of developing t-MNs, although further studies are needed,” Dr Takashi concluded.
Decitabine produces responses in high-risk MDS, AML
receiving chemotherapy
Photo by Rhoda Baer
Patients with TP53-mutated myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) may benefit from treatment with decitabine, according to a study published in NEJM.
All patients in this study who had TP53 mutations responded to decitabine.
Although these responses were not durable, the patients’ median overall survival was similar to that of patients with lower-risk disease who received decitabine.
“The findings need to be validated in a larger trial, but they do suggest that TP53 mutations can reliably predict responses to decitabine, potentially prolonging survival in this ultra-high-risk group of patients and providing a bridge to transplantation in some patients who might not otherwise be candidates,” said study author Timothy J. Ley, MD, of Washington University School of Medicine in St. Louis, Missouri.
For this study, Dr Ley and his colleagues analyzed 116 patients—54 with AML, 36 with relapsed AML, and 26 with MDS.
Eighty-four of the patients were enrolled in a prospective trial and received decitabine at a dose of 20 mg/m2/day for 10 consecutive days in monthly cycles. Thirty-two additional patients received decitabine on different protocols.
To determine whether genetic mutations could be used to predict responses to decitabine, the researchers performed enhanced exome or gene-panel sequencing in 67 of the patients. The team also performed sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients.
Response
Thirteen percent of patients (n=15) achieved a complete response (CR), 21% (n=24) had a CR with incomplete count recovery, 5% (n=6) had a morphologic CR with hematologic improvement, and 7% (n=8) had a morphologic CR without hematologic improvement.
Eight percent of patients (n=9) had a partial response, 20% (n=23) had stable disease, and 16% (n=19) had progressive disease.
There were 21 patients with TP53 mutations, and all of them achieved bone marrow blast clearance with less than 5% blasts.
Nineteen percent (n=4) had a CR, 43% (n=9) had a CR with incomplete count recovery, 24% (n=5) had morphologic CR with hematologic improvement, and 14% (n=3) had morphologic CR without hematologic improvement.
“What’s really unique here is that all the patients in the study with TP53 mutations had a response to decitabine and achieved an initial remission,” Dr Ley said.
“With standard aggressive chemotherapy, we only see about 20% to 30% of these patients achieving remission, which is the critical first step to have a chance to cure patients with additional therapies.”
Dr Ley and his colleagues also found that patients in this study were likely to respond to decitabine if they were considered “unfavorable risk” based on extensive chromosomal rearrangements. (Many of these patients also had TP53 mutations.)
Indeed, 67% (29/43) of patients with an unfavorable risk had less than 5% blasts after treatment with decitabine, compared with 34% (24/71) of patients with intermediate or favorable risk.
“The challenge with using decitabine has been knowing which patients are most likely to respond,” said study author Amanda Cashen, MD, of Washington University School of Medicine.
“The value of this study is the comprehensive mutational analysis that helps us figure out which patients are likely to benefit. This information opens the door to using decitabine in a more targeted fashion to treat not just older patients, but also younger patients who carry TP53 mutations.”
Survival and next steps
The researchers found that responses to decitabine were usually short-lived. The drug did not provide complete mutation clearance, which led to relapse.
“Remissions with decitabine typically don’t last long, and no one was cured with this drug,” Dr Ley noted. “But patients who responded to decitabine live longer than what you would expect with aggressive chemotherapy, and that can mean something. Some people live a year or 2 and with a good quality of life because the chemotherapy is not too toxic.”
The median overall survival was 11.6 months among patients with unfavorable risk and 10 months among patients with favorable or intermediate risk (P=0.29).
The median overall survival was 12.7 months among patients with TP53 mutations and 15.4 months among patients with wild-type TP53 (P=0.79).
“It’s important to note that patients with an extremely poor prognosis in this relatively small study had the same survival outcomes as patients facing a better prognosis, which is encouraging,” said study author John Welch, MD, PhD, of Washington University School of Medicine.
“We don’t yet understand why patients with TP53 mutations consistently respond to decitabine, and more work is needed to understand that phenomenon. We’re now planning a larger trial to evaluate decitabine in AML patients of all ages who carry TP53 mutations. It’s exciting to think we may have a therapy that has the potential to improve response rates in this group of high-risk patients.”
receiving chemotherapy
Photo by Rhoda Baer
Patients with TP53-mutated myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) may benefit from treatment with decitabine, according to a study published in NEJM.
All patients in this study who had TP53 mutations responded to decitabine.
Although these responses were not durable, the patients’ median overall survival was similar to that of patients with lower-risk disease who received decitabine.
“The findings need to be validated in a larger trial, but they do suggest that TP53 mutations can reliably predict responses to decitabine, potentially prolonging survival in this ultra-high-risk group of patients and providing a bridge to transplantation in some patients who might not otherwise be candidates,” said study author Timothy J. Ley, MD, of Washington University School of Medicine in St. Louis, Missouri.
For this study, Dr Ley and his colleagues analyzed 116 patients—54 with AML, 36 with relapsed AML, and 26 with MDS.
Eighty-four of the patients were enrolled in a prospective trial and received decitabine at a dose of 20 mg/m2/day for 10 consecutive days in monthly cycles. Thirty-two additional patients received decitabine on different protocols.
To determine whether genetic mutations could be used to predict responses to decitabine, the researchers performed enhanced exome or gene-panel sequencing in 67 of the patients. The team also performed sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients.
Response
Thirteen percent of patients (n=15) achieved a complete response (CR), 21% (n=24) had a CR with incomplete count recovery, 5% (n=6) had a morphologic CR with hematologic improvement, and 7% (n=8) had a morphologic CR without hematologic improvement.
Eight percent of patients (n=9) had a partial response, 20% (n=23) had stable disease, and 16% (n=19) had progressive disease.
There were 21 patients with TP53 mutations, and all of them achieved bone marrow blast clearance with less than 5% blasts.
Nineteen percent (n=4) had a CR, 43% (n=9) had a CR with incomplete count recovery, 24% (n=5) had morphologic CR with hematologic improvement, and 14% (n=3) had morphologic CR without hematologic improvement.
“What’s really unique here is that all the patients in the study with TP53 mutations had a response to decitabine and achieved an initial remission,” Dr Ley said.
“With standard aggressive chemotherapy, we only see about 20% to 30% of these patients achieving remission, which is the critical first step to have a chance to cure patients with additional therapies.”
Dr Ley and his colleagues also found that patients in this study were likely to respond to decitabine if they were considered “unfavorable risk” based on extensive chromosomal rearrangements. (Many of these patients also had TP53 mutations.)
Indeed, 67% (29/43) of patients with an unfavorable risk had less than 5% blasts after treatment with decitabine, compared with 34% (24/71) of patients with intermediate or favorable risk.
“The challenge with using decitabine has been knowing which patients are most likely to respond,” said study author Amanda Cashen, MD, of Washington University School of Medicine.
“The value of this study is the comprehensive mutational analysis that helps us figure out which patients are likely to benefit. This information opens the door to using decitabine in a more targeted fashion to treat not just older patients, but also younger patients who carry TP53 mutations.”
Survival and next steps
The researchers found that responses to decitabine were usually short-lived. The drug did not provide complete mutation clearance, which led to relapse.
“Remissions with decitabine typically don’t last long, and no one was cured with this drug,” Dr Ley noted. “But patients who responded to decitabine live longer than what you would expect with aggressive chemotherapy, and that can mean something. Some people live a year or 2 and with a good quality of life because the chemotherapy is not too toxic.”
The median overall survival was 11.6 months among patients with unfavorable risk and 10 months among patients with favorable or intermediate risk (P=0.29).
The median overall survival was 12.7 months among patients with TP53 mutations and 15.4 months among patients with wild-type TP53 (P=0.79).
“It’s important to note that patients with an extremely poor prognosis in this relatively small study had the same survival outcomes as patients facing a better prognosis, which is encouraging,” said study author John Welch, MD, PhD, of Washington University School of Medicine.
“We don’t yet understand why patients with TP53 mutations consistently respond to decitabine, and more work is needed to understand that phenomenon. We’re now planning a larger trial to evaluate decitabine in AML patients of all ages who carry TP53 mutations. It’s exciting to think we may have a therapy that has the potential to improve response rates in this group of high-risk patients.”
receiving chemotherapy
Photo by Rhoda Baer
Patients with TP53-mutated myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) may benefit from treatment with decitabine, according to a study published in NEJM.
All patients in this study who had TP53 mutations responded to decitabine.
Although these responses were not durable, the patients’ median overall survival was similar to that of patients with lower-risk disease who received decitabine.
“The findings need to be validated in a larger trial, but they do suggest that TP53 mutations can reliably predict responses to decitabine, potentially prolonging survival in this ultra-high-risk group of patients and providing a bridge to transplantation in some patients who might not otherwise be candidates,” said study author Timothy J. Ley, MD, of Washington University School of Medicine in St. Louis, Missouri.
For this study, Dr Ley and his colleagues analyzed 116 patients—54 with AML, 36 with relapsed AML, and 26 with MDS.
Eighty-four of the patients were enrolled in a prospective trial and received decitabine at a dose of 20 mg/m2/day for 10 consecutive days in monthly cycles. Thirty-two additional patients received decitabine on different protocols.
To determine whether genetic mutations could be used to predict responses to decitabine, the researchers performed enhanced exome or gene-panel sequencing in 67 of the patients. The team also performed sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients.
Response
Thirteen percent of patients (n=15) achieved a complete response (CR), 21% (n=24) had a CR with incomplete count recovery, 5% (n=6) had a morphologic CR with hematologic improvement, and 7% (n=8) had a morphologic CR without hematologic improvement.
Eight percent of patients (n=9) had a partial response, 20% (n=23) had stable disease, and 16% (n=19) had progressive disease.
There were 21 patients with TP53 mutations, and all of them achieved bone marrow blast clearance with less than 5% blasts.
Nineteen percent (n=4) had a CR, 43% (n=9) had a CR with incomplete count recovery, 24% (n=5) had morphologic CR with hematologic improvement, and 14% (n=3) had morphologic CR without hematologic improvement.
“What’s really unique here is that all the patients in the study with TP53 mutations had a response to decitabine and achieved an initial remission,” Dr Ley said.
“With standard aggressive chemotherapy, we only see about 20% to 30% of these patients achieving remission, which is the critical first step to have a chance to cure patients with additional therapies.”
Dr Ley and his colleagues also found that patients in this study were likely to respond to decitabine if they were considered “unfavorable risk” based on extensive chromosomal rearrangements. (Many of these patients also had TP53 mutations.)
Indeed, 67% (29/43) of patients with an unfavorable risk had less than 5% blasts after treatment with decitabine, compared with 34% (24/71) of patients with intermediate or favorable risk.
“The challenge with using decitabine has been knowing which patients are most likely to respond,” said study author Amanda Cashen, MD, of Washington University School of Medicine.
“The value of this study is the comprehensive mutational analysis that helps us figure out which patients are likely to benefit. This information opens the door to using decitabine in a more targeted fashion to treat not just older patients, but also younger patients who carry TP53 mutations.”
Survival and next steps
The researchers found that responses to decitabine were usually short-lived. The drug did not provide complete mutation clearance, which led to relapse.
“Remissions with decitabine typically don’t last long, and no one was cured with this drug,” Dr Ley noted. “But patients who responded to decitabine live longer than what you would expect with aggressive chemotherapy, and that can mean something. Some people live a year or 2 and with a good quality of life because the chemotherapy is not too toxic.”
The median overall survival was 11.6 months among patients with unfavorable risk and 10 months among patients with favorable or intermediate risk (P=0.29).
The median overall survival was 12.7 months among patients with TP53 mutations and 15.4 months among patients with wild-type TP53 (P=0.79).
“It’s important to note that patients with an extremely poor prognosis in this relatively small study had the same survival outcomes as patients facing a better prognosis, which is encouraging,” said study author John Welch, MD, PhD, of Washington University School of Medicine.
“We don’t yet understand why patients with TP53 mutations consistently respond to decitabine, and more work is needed to understand that phenomenon. We’re now planning a larger trial to evaluate decitabine in AML patients of all ages who carry TP53 mutations. It’s exciting to think we may have a therapy that has the potential to improve response rates in this group of high-risk patients.”
Inflammation may predict transformation to AML
Inflammatory signaling in mesenchymal niche cells can be used to predict the transformation from pre-leukemic syndrome to acute myeloid leukemia (AML), according to preclinical research published in Cell Stem Cell.
“This discovery sheds new light on the long-standing association between inflammation and cancer,” said study author Marc Raaijmakers, MD, PhD, of the Erasmus MC Cancer Institute in Rotterdam, Netherlands.
“The elucidation of the molecular mechanism underlying this concept opens the prospect of improved diagnosis of patients at increased risk for the development of leukemia and the potential of future, niche-targeted therapy to delay or prevent the development of leukemia.”
In a previous study, Dr Raaijmakers and his colleagues discovered that mutations in mesenchymal progenitor cells can induce myelodysplasia in mice and promote the development of AML.
With the current study, the researchers wanted to build upon those findings by identifying the underlying mechanisms and determining their relevance to human disease.
So the team performed massive parallel RNA sequencing of mesenchymal cells in mice with Shwachman-Diamond syndrome and bone marrow samples from patients with Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and myelodysplastic syndromes (MDS).
The researchers found that mesenchymal cells in these pre-leukemic disorders are under stress. The stress leads to the release of inflammatory molecules called S100A8 and S100A9, which cause mitochondrial and DNA damage in hematopoietic stem and progenitor cells.
The team also found that activation of this inflammatory pathway in mesenchymal cells predicted the development of AML and clinical outcomes in patients with MDS.
Leukemic evolution occurred in 29.4% (5/17) of MDS patients whose mesenchymal cells overexpressed S100A8/9 and 14.2% (4/28) of MDS patients without S100A8/9 overexpression.
The time to leukemic evolution and the length of progression-free survival were both significantly shorter in niche S100A8/9+ patients than niche S100A8/9- patients.
The average time to leukemic evolution was 3.4 months and 18.5 months, respectively (P=0.03). And the median progression-free survival was 11.5 months and 53 months, respectively (P=0.03)
The researchers believe these findings, if confirmed in subsequent studies, could lead to the development of tests to identify patients with pre-leukemic syndromes who have a high risk of developing AML.
“These high-risk patients could be treated more aggressively at an earlier stage, thereby preventing or slowing down disease progression,” Dr Raaijmakers said. “Moreover, the findings suggest that new drugs targeting the inflammatory pathway should be tested in future preclinical studies.”
Inflammatory signaling in mesenchymal niche cells can be used to predict the transformation from pre-leukemic syndrome to acute myeloid leukemia (AML), according to preclinical research published in Cell Stem Cell.
“This discovery sheds new light on the long-standing association between inflammation and cancer,” said study author Marc Raaijmakers, MD, PhD, of the Erasmus MC Cancer Institute in Rotterdam, Netherlands.
“The elucidation of the molecular mechanism underlying this concept opens the prospect of improved diagnosis of patients at increased risk for the development of leukemia and the potential of future, niche-targeted therapy to delay or prevent the development of leukemia.”
In a previous study, Dr Raaijmakers and his colleagues discovered that mutations in mesenchymal progenitor cells can induce myelodysplasia in mice and promote the development of AML.
With the current study, the researchers wanted to build upon those findings by identifying the underlying mechanisms and determining their relevance to human disease.
So the team performed massive parallel RNA sequencing of mesenchymal cells in mice with Shwachman-Diamond syndrome and bone marrow samples from patients with Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and myelodysplastic syndromes (MDS).
The researchers found that mesenchymal cells in these pre-leukemic disorders are under stress. The stress leads to the release of inflammatory molecules called S100A8 and S100A9, which cause mitochondrial and DNA damage in hematopoietic stem and progenitor cells.
The team also found that activation of this inflammatory pathway in mesenchymal cells predicted the development of AML and clinical outcomes in patients with MDS.
Leukemic evolution occurred in 29.4% (5/17) of MDS patients whose mesenchymal cells overexpressed S100A8/9 and 14.2% (4/28) of MDS patients without S100A8/9 overexpression.
The time to leukemic evolution and the length of progression-free survival were both significantly shorter in niche S100A8/9+ patients than niche S100A8/9- patients.
The average time to leukemic evolution was 3.4 months and 18.5 months, respectively (P=0.03). And the median progression-free survival was 11.5 months and 53 months, respectively (P=0.03)
The researchers believe these findings, if confirmed in subsequent studies, could lead to the development of tests to identify patients with pre-leukemic syndromes who have a high risk of developing AML.
“These high-risk patients could be treated more aggressively at an earlier stage, thereby preventing or slowing down disease progression,” Dr Raaijmakers said. “Moreover, the findings suggest that new drugs targeting the inflammatory pathway should be tested in future preclinical studies.”
Inflammatory signaling in mesenchymal niche cells can be used to predict the transformation from pre-leukemic syndrome to acute myeloid leukemia (AML), according to preclinical research published in Cell Stem Cell.
“This discovery sheds new light on the long-standing association between inflammation and cancer,” said study author Marc Raaijmakers, MD, PhD, of the Erasmus MC Cancer Institute in Rotterdam, Netherlands.
“The elucidation of the molecular mechanism underlying this concept opens the prospect of improved diagnosis of patients at increased risk for the development of leukemia and the potential of future, niche-targeted therapy to delay or prevent the development of leukemia.”
In a previous study, Dr Raaijmakers and his colleagues discovered that mutations in mesenchymal progenitor cells can induce myelodysplasia in mice and promote the development of AML.
With the current study, the researchers wanted to build upon those findings by identifying the underlying mechanisms and determining their relevance to human disease.
So the team performed massive parallel RNA sequencing of mesenchymal cells in mice with Shwachman-Diamond syndrome and bone marrow samples from patients with Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and myelodysplastic syndromes (MDS).
The researchers found that mesenchymal cells in these pre-leukemic disorders are under stress. The stress leads to the release of inflammatory molecules called S100A8 and S100A9, which cause mitochondrial and DNA damage in hematopoietic stem and progenitor cells.
The team also found that activation of this inflammatory pathway in mesenchymal cells predicted the development of AML and clinical outcomes in patients with MDS.
Leukemic evolution occurred in 29.4% (5/17) of MDS patients whose mesenchymal cells overexpressed S100A8/9 and 14.2% (4/28) of MDS patients without S100A8/9 overexpression.
The time to leukemic evolution and the length of progression-free survival were both significantly shorter in niche S100A8/9+ patients than niche S100A8/9- patients.
The average time to leukemic evolution was 3.4 months and 18.5 months, respectively (P=0.03). And the median progression-free survival was 11.5 months and 53 months, respectively (P=0.03)
The researchers believe these findings, if confirmed in subsequent studies, could lead to the development of tests to identify patients with pre-leukemic syndromes who have a high risk of developing AML.
“These high-risk patients could be treated more aggressively at an earlier stage, thereby preventing or slowing down disease progression,” Dr Raaijmakers said. “Moreover, the findings suggest that new drugs targeting the inflammatory pathway should be tested in future preclinical studies.”