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HMAs plus novel agents may improve outcomes in higher-risk MDS
Several recently approved and late-phase investigational agents may improve care for patients with higher risk myelodysplastic syndrome (MDS) by augmenting hypomethylating agents (HMAs), which are the current standard of care.
“HMA failure remains a challenge, and new approaches, such as ex vivo drug screening, are needed to improve outcomes,” said Brian A. Jonas, MD, PhD, from the University of California, Davis, in an online presentation during the virtual American Society of Hematology (ASH) Meeting on Hematologic Malignancies.
The goal of treatment for patients with higher-risk MDS – defined as a Revised International Prognostic Scoring System (R-IPSS) intermediate, high-risk, or very high–risk category – is to alter as much as possible the natural history of the disease.
Treatment options include monotherapy with HMAs, HMAs in combination with other agents, high-intensity chemotherapy, allogeneic hematopoietic stem cell transplant (allo-HSCT), or a clinical trial, Dr. Jonas said.
Improving bioavailability
Although HMAs, either azacitidine or decitabine, remain the standard of care for patients with higher-risk MDS, the oral bioavailability of these agents is limited by the rapid clearance of cytidine deaminase in the gut and liver.
But as Savona and colleagues reported in The Lancet Haematology, the combination of oral decitabine with cedazuridine, a novel cytidine deaminase inhibitor, significantly improved the bioavailability of the HMA, with an efficacy comparable to that of intravenous decitabine. The findings were confirmed by results from the phase 2 ASCERTAIN trial.
The combination (Inqovi) was approved by the US Food and Drug Administration in July 2020 for the treatment of MDS and chronic myelomonocytic leukemia in IPSS intermediate-1 or higher risk categories. The approved dose is 35 mg decitabine and 100 mg cedazuridine in a single oral tablet once daily on days 1 through 5 of each 28-day cycle.
New drugs, potential new targets
Another promising approach to improving HMA therapy is the combination of azacitidine and the BCL-2 inhibitor venetoclax (Venclexta).
Results of a phase 1b study of the combination as first-line therapy for patients with higher-risk MDS showed a combined complete response and marrow complete response rate of 77.2%, with estimated 6-month and 12-month survival rates of 100% and 93.8%, respectively, for patients who had a complete response and 85.9% at both 6 and 12 months for patients with a marrow complete response.
“The question is does this challenge the standard of care for higher-risk MDS? I would argue that many are using the regimen since the abstract came out, and I myself consider this regimen for use in select patients with high–blast count MDS who are maybe going to transplant or need to have their disease controlled rapidly,” Dr. Jonas said.
A randomized trial of the combination (NCT04401748) is currently recruiting.
Novel checkpoint inhibitor
Another promising combination pairs azacitidine with magrolimab, an experimental immune checkpoint inhibitor that targets CD47, the “don’t eat me” signal that inhibits macrophages from carrying out their crucial phagocytosis role.
As previously reported, magrolimab in combination with rituximab showed good efficacy in patients with relapsed or refractory indolent or aggressive non-Hodgkin lymphomas, and more recently showed promise in combination with azacitidine in a phase 1b study for the treatment of MDS and acute myeloid leukemia (AML).
Among patients with MDS in the trial, the overall response rate was 91% (30 of 33 patients). In all, 14 patients had complete responses, one had a partial response, eight had marrow complete responses, and seven had hematologic improvement.
The tolerability profile was similar to that seen with azacitidine monotherapy, with no significant worsening of cytopenias or infections or autoimmune adverse events. There were no deaths in the first 60 days on therapy, and no treatment discontinuation for drug-related adverse events.
Azacitidine was paired with a different novel agent, APR-246 in a clinical trial testing the combination in patients with TP53 mutant MDS and AML. APR-246 is a novel, first-in-class small molecule that binds covalently to p53, and selectively induces apoptosis in metastatic TP53 cells via thermodynamically stabilizing the p53 protein and shifting equilibrium toward the wild-type conformation.
Among 33 evaluable patients with higher-risk MDS, the combination was associated with an overall response in 29 (81%) including 20 patients (61%) with a complete response. After a median follow-up of 10.8 months, the median duration of response was 7.3 months, and 17 patients went on to allo-HSCT.
The combination of magrolimab and azacitidine has also shown preliminary activity in TP53-mutated MDS, Dr. Jonas noted.
HMA-refractory disease
Patients who experience disease progression to AML or to higher-risk MDS; have stable disease but no complete, partial, or marrow responses; or have hematologic improvement after four to six cycles of HMA may have primary resistance to this class of agents. Patients can also have disease that develops resistance to HMAs after an initial response.
“Unfortunately, the prognosis is very dismal for these patients,” with a median overall survival of 5.6 months and 2-year overall survival of just 15%, Dr. Jonas said.
As reported at the 2019 ASH annual meeting, in patients with relapsed/refractory MDS, venetoclax plus azacitidine was associated with a median progression-free survival of 9.1 months versus 3.3 months for venetoclax alone, and a median overall survival for the combination that was not reached, with a 12-month overall survival estimate of 65%. The median overall survival with venetoclax monotherapy was 5.5 months.
Adverse events included cytopenias, gastrointestinal events, and infections in both arms (ASH 2019 Abstract 565).
There are also data to suggest benefits of the isocitrate dehydrogenase inhibitors ivosidenib in patients with HMA-refractory MDS with IDH1 mutations and enasidenib in patients with HMA-refractory MDS with IDH2 mutations, Dr. Jonas said.
Finally, he described a pilot and feasibility study of ex vivo screening of myeloid neoplasms for drug sensitivity conducted at Stanford (Calif.) University. In 21 patients with HMA-refractory MDS, the ex vivo screening system provided results in a clinically actionable time frame comparable to that of a 596-gene panel. The positive predictive value of the screen was 92%, the negative predictive value was 82%, and the accuracy was 85%.
“This looks like a potentially promising approach to offer personalized therapy in patients with MDS,” he said.
No funding source for the presentation was reported. Dr. Jonas disclosed consulting activities for AbbVie, Celgen, GlycoMimetics, Jazz, Takeda, Tolero, and Treadwell; institutional research funding from multiple companies; and discussion of off-label use of various drugs not specifically approved for MDS.
Several recently approved and late-phase investigational agents may improve care for patients with higher risk myelodysplastic syndrome (MDS) by augmenting hypomethylating agents (HMAs), which are the current standard of care.
“HMA failure remains a challenge, and new approaches, such as ex vivo drug screening, are needed to improve outcomes,” said Brian A. Jonas, MD, PhD, from the University of California, Davis, in an online presentation during the virtual American Society of Hematology (ASH) Meeting on Hematologic Malignancies.
The goal of treatment for patients with higher-risk MDS – defined as a Revised International Prognostic Scoring System (R-IPSS) intermediate, high-risk, or very high–risk category – is to alter as much as possible the natural history of the disease.
Treatment options include monotherapy with HMAs, HMAs in combination with other agents, high-intensity chemotherapy, allogeneic hematopoietic stem cell transplant (allo-HSCT), or a clinical trial, Dr. Jonas said.
Improving bioavailability
Although HMAs, either azacitidine or decitabine, remain the standard of care for patients with higher-risk MDS, the oral bioavailability of these agents is limited by the rapid clearance of cytidine deaminase in the gut and liver.
But as Savona and colleagues reported in The Lancet Haematology, the combination of oral decitabine with cedazuridine, a novel cytidine deaminase inhibitor, significantly improved the bioavailability of the HMA, with an efficacy comparable to that of intravenous decitabine. The findings were confirmed by results from the phase 2 ASCERTAIN trial.
The combination (Inqovi) was approved by the US Food and Drug Administration in July 2020 for the treatment of MDS and chronic myelomonocytic leukemia in IPSS intermediate-1 or higher risk categories. The approved dose is 35 mg decitabine and 100 mg cedazuridine in a single oral tablet once daily on days 1 through 5 of each 28-day cycle.
New drugs, potential new targets
Another promising approach to improving HMA therapy is the combination of azacitidine and the BCL-2 inhibitor venetoclax (Venclexta).
Results of a phase 1b study of the combination as first-line therapy for patients with higher-risk MDS showed a combined complete response and marrow complete response rate of 77.2%, with estimated 6-month and 12-month survival rates of 100% and 93.8%, respectively, for patients who had a complete response and 85.9% at both 6 and 12 months for patients with a marrow complete response.
“The question is does this challenge the standard of care for higher-risk MDS? I would argue that many are using the regimen since the abstract came out, and I myself consider this regimen for use in select patients with high–blast count MDS who are maybe going to transplant or need to have their disease controlled rapidly,” Dr. Jonas said.
A randomized trial of the combination (NCT04401748) is currently recruiting.
Novel checkpoint inhibitor
Another promising combination pairs azacitidine with magrolimab, an experimental immune checkpoint inhibitor that targets CD47, the “don’t eat me” signal that inhibits macrophages from carrying out their crucial phagocytosis role.
As previously reported, magrolimab in combination with rituximab showed good efficacy in patients with relapsed or refractory indolent or aggressive non-Hodgkin lymphomas, and more recently showed promise in combination with azacitidine in a phase 1b study for the treatment of MDS and acute myeloid leukemia (AML).
Among patients with MDS in the trial, the overall response rate was 91% (30 of 33 patients). In all, 14 patients had complete responses, one had a partial response, eight had marrow complete responses, and seven had hematologic improvement.
The tolerability profile was similar to that seen with azacitidine monotherapy, with no significant worsening of cytopenias or infections or autoimmune adverse events. There were no deaths in the first 60 days on therapy, and no treatment discontinuation for drug-related adverse events.
Azacitidine was paired with a different novel agent, APR-246 in a clinical trial testing the combination in patients with TP53 mutant MDS and AML. APR-246 is a novel, first-in-class small molecule that binds covalently to p53, and selectively induces apoptosis in metastatic TP53 cells via thermodynamically stabilizing the p53 protein and shifting equilibrium toward the wild-type conformation.
Among 33 evaluable patients with higher-risk MDS, the combination was associated with an overall response in 29 (81%) including 20 patients (61%) with a complete response. After a median follow-up of 10.8 months, the median duration of response was 7.3 months, and 17 patients went on to allo-HSCT.
The combination of magrolimab and azacitidine has also shown preliminary activity in TP53-mutated MDS, Dr. Jonas noted.
HMA-refractory disease
Patients who experience disease progression to AML or to higher-risk MDS; have stable disease but no complete, partial, or marrow responses; or have hematologic improvement after four to six cycles of HMA may have primary resistance to this class of agents. Patients can also have disease that develops resistance to HMAs after an initial response.
“Unfortunately, the prognosis is very dismal for these patients,” with a median overall survival of 5.6 months and 2-year overall survival of just 15%, Dr. Jonas said.
As reported at the 2019 ASH annual meeting, in patients with relapsed/refractory MDS, venetoclax plus azacitidine was associated with a median progression-free survival of 9.1 months versus 3.3 months for venetoclax alone, and a median overall survival for the combination that was not reached, with a 12-month overall survival estimate of 65%. The median overall survival with venetoclax monotherapy was 5.5 months.
Adverse events included cytopenias, gastrointestinal events, and infections in both arms (ASH 2019 Abstract 565).
There are also data to suggest benefits of the isocitrate dehydrogenase inhibitors ivosidenib in patients with HMA-refractory MDS with IDH1 mutations and enasidenib in patients with HMA-refractory MDS with IDH2 mutations, Dr. Jonas said.
Finally, he described a pilot and feasibility study of ex vivo screening of myeloid neoplasms for drug sensitivity conducted at Stanford (Calif.) University. In 21 patients with HMA-refractory MDS, the ex vivo screening system provided results in a clinically actionable time frame comparable to that of a 596-gene panel. The positive predictive value of the screen was 92%, the negative predictive value was 82%, and the accuracy was 85%.
“This looks like a potentially promising approach to offer personalized therapy in patients with MDS,” he said.
No funding source for the presentation was reported. Dr. Jonas disclosed consulting activities for AbbVie, Celgen, GlycoMimetics, Jazz, Takeda, Tolero, and Treadwell; institutional research funding from multiple companies; and discussion of off-label use of various drugs not specifically approved for MDS.
Several recently approved and late-phase investigational agents may improve care for patients with higher risk myelodysplastic syndrome (MDS) by augmenting hypomethylating agents (HMAs), which are the current standard of care.
“HMA failure remains a challenge, and new approaches, such as ex vivo drug screening, are needed to improve outcomes,” said Brian A. Jonas, MD, PhD, from the University of California, Davis, in an online presentation during the virtual American Society of Hematology (ASH) Meeting on Hematologic Malignancies.
The goal of treatment for patients with higher-risk MDS – defined as a Revised International Prognostic Scoring System (R-IPSS) intermediate, high-risk, or very high–risk category – is to alter as much as possible the natural history of the disease.
Treatment options include monotherapy with HMAs, HMAs in combination with other agents, high-intensity chemotherapy, allogeneic hematopoietic stem cell transplant (allo-HSCT), or a clinical trial, Dr. Jonas said.
Improving bioavailability
Although HMAs, either azacitidine or decitabine, remain the standard of care for patients with higher-risk MDS, the oral bioavailability of these agents is limited by the rapid clearance of cytidine deaminase in the gut and liver.
But as Savona and colleagues reported in The Lancet Haematology, the combination of oral decitabine with cedazuridine, a novel cytidine deaminase inhibitor, significantly improved the bioavailability of the HMA, with an efficacy comparable to that of intravenous decitabine. The findings were confirmed by results from the phase 2 ASCERTAIN trial.
The combination (Inqovi) was approved by the US Food and Drug Administration in July 2020 for the treatment of MDS and chronic myelomonocytic leukemia in IPSS intermediate-1 or higher risk categories. The approved dose is 35 mg decitabine and 100 mg cedazuridine in a single oral tablet once daily on days 1 through 5 of each 28-day cycle.
New drugs, potential new targets
Another promising approach to improving HMA therapy is the combination of azacitidine and the BCL-2 inhibitor venetoclax (Venclexta).
Results of a phase 1b study of the combination as first-line therapy for patients with higher-risk MDS showed a combined complete response and marrow complete response rate of 77.2%, with estimated 6-month and 12-month survival rates of 100% and 93.8%, respectively, for patients who had a complete response and 85.9% at both 6 and 12 months for patients with a marrow complete response.
“The question is does this challenge the standard of care for higher-risk MDS? I would argue that many are using the regimen since the abstract came out, and I myself consider this regimen for use in select patients with high–blast count MDS who are maybe going to transplant or need to have their disease controlled rapidly,” Dr. Jonas said.
A randomized trial of the combination (NCT04401748) is currently recruiting.
Novel checkpoint inhibitor
Another promising combination pairs azacitidine with magrolimab, an experimental immune checkpoint inhibitor that targets CD47, the “don’t eat me” signal that inhibits macrophages from carrying out their crucial phagocytosis role.
As previously reported, magrolimab in combination with rituximab showed good efficacy in patients with relapsed or refractory indolent or aggressive non-Hodgkin lymphomas, and more recently showed promise in combination with azacitidine in a phase 1b study for the treatment of MDS and acute myeloid leukemia (AML).
Among patients with MDS in the trial, the overall response rate was 91% (30 of 33 patients). In all, 14 patients had complete responses, one had a partial response, eight had marrow complete responses, and seven had hematologic improvement.
The tolerability profile was similar to that seen with azacitidine monotherapy, with no significant worsening of cytopenias or infections or autoimmune adverse events. There were no deaths in the first 60 days on therapy, and no treatment discontinuation for drug-related adverse events.
Azacitidine was paired with a different novel agent, APR-246 in a clinical trial testing the combination in patients with TP53 mutant MDS and AML. APR-246 is a novel, first-in-class small molecule that binds covalently to p53, and selectively induces apoptosis in metastatic TP53 cells via thermodynamically stabilizing the p53 protein and shifting equilibrium toward the wild-type conformation.
Among 33 evaluable patients with higher-risk MDS, the combination was associated with an overall response in 29 (81%) including 20 patients (61%) with a complete response. After a median follow-up of 10.8 months, the median duration of response was 7.3 months, and 17 patients went on to allo-HSCT.
The combination of magrolimab and azacitidine has also shown preliminary activity in TP53-mutated MDS, Dr. Jonas noted.
HMA-refractory disease
Patients who experience disease progression to AML or to higher-risk MDS; have stable disease but no complete, partial, or marrow responses; or have hematologic improvement after four to six cycles of HMA may have primary resistance to this class of agents. Patients can also have disease that develops resistance to HMAs after an initial response.
“Unfortunately, the prognosis is very dismal for these patients,” with a median overall survival of 5.6 months and 2-year overall survival of just 15%, Dr. Jonas said.
As reported at the 2019 ASH annual meeting, in patients with relapsed/refractory MDS, venetoclax plus azacitidine was associated with a median progression-free survival of 9.1 months versus 3.3 months for venetoclax alone, and a median overall survival for the combination that was not reached, with a 12-month overall survival estimate of 65%. The median overall survival with venetoclax monotherapy was 5.5 months.
Adverse events included cytopenias, gastrointestinal events, and infections in both arms (ASH 2019 Abstract 565).
There are also data to suggest benefits of the isocitrate dehydrogenase inhibitors ivosidenib in patients with HMA-refractory MDS with IDH1 mutations and enasidenib in patients with HMA-refractory MDS with IDH2 mutations, Dr. Jonas said.
Finally, he described a pilot and feasibility study of ex vivo screening of myeloid neoplasms for drug sensitivity conducted at Stanford (Calif.) University. In 21 patients with HMA-refractory MDS, the ex vivo screening system provided results in a clinically actionable time frame comparable to that of a 596-gene panel. The positive predictive value of the screen was 92%, the negative predictive value was 82%, and the accuracy was 85%.
“This looks like a potentially promising approach to offer personalized therapy in patients with MDS,” he said.
No funding source for the presentation was reported. Dr. Jonas disclosed consulting activities for AbbVie, Celgen, GlycoMimetics, Jazz, Takeda, Tolero, and Treadwell; institutional research funding from multiple companies; and discussion of off-label use of various drugs not specifically approved for MDS.
FROM ASH HEMATOLOGIC MALIGNANCIES
TKI choice key for fit/unfit patients with Ph+ALL
Adding tyrosine kinase inhibitors to the treatment of patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) has significantly improved outcomes in recent years, but it’s still unclear which patients will also benefit from bone marrow transplants, and whether chemotherapy will gradually fade into the therapeutic background, a leukemia researcher contended.
said Anjali S. Advani, MD, of the Cleveland Clinic Taussig Cancer Institute.
Dr. Advani discussed her approach to treating both fit and frail patients with Ph+ALL during the virtual American Society of Hematology (ASH) Meeting on Hematologic Malignancies.
Increasing understanding of the importance of eliminating minimal residual disease (MRD) colors decisions about the best TKI to use in the first line.
“In terms of which TKI to use in the upfront setting, no randomized study has been done, but since MRD is associated with improved response, we often use this data to make a decision,” she said. “This, however, is complicated, because TKIs are combined with chemotherapy, there are many new TKIs, and finally, although we can start with one TKI, we can change to another TKI if we see that a patient is not responding appropriately.”
With the use of second-generation TKIs in combination with chemotherapy, rates of complete molecular remission (CMR) and major molecular remission (MMR) improved significantly over those seen with the first-in-class agent imatinib.
Notably, she said, the combination of ponatinib (Iclusig) with steroids as frontline therapy for elderly or frail patients with Ph+ALL was associated with a 60.5% CMR at week 24 in a phase 2 Italian trial (Blood 2017;130[Suppl. 1]:99).
Combining ponatinib with the hyper-CVAD regimen (cyclophosphamide, vincristine, doxorubicin, dexamethasone) improved the 3-month CMR rate to 74% and, the MMR rate to 15% (Lancet Haematol Dec. 2018 Dec 1;5[12]:e618-e627).
A 2016 propensity-score analysis comparing hyper-CVAD plus ponatinib with the hyper-CVAD plus dasatinib showed significantly better event-free survival (P = .035) and overall survival (P = .025) with the ponatinib-containing combination (Cancer 2016;122[23]:3650-6).
As with all potent regimens, however, the combination of hyper-CVAD and ponatinib is associated with relatively high percentages of grade 3 or greater nonhematologic toxicities, including transaminase and bilirubin elevation, pancreatitis, hypertension, venous thromboembolic events and arterial cardiovascular events.
Transplants in the TKI era
Prior to the advent of TKIs, there was strong evidence of the benefit of allogeneic stem cell transplant in patients with Ph+ALL in first remission (BMT 2003;31:623-32).
“The question is, now that we use TKIs, should we be transplanting patients still?” Dr. Advani said.
In the U.S. intergroup S0805 study looking at the combination of dasatinib and chemotherapy, there were distinct relapse-free and overall survival benefits for patients who underwent transplant. This trial did not evaluate MRD, however, ”so what we don’t know is for those patients achieving a complete molecular remission, would those patients do okay without transplant?” she said.
The current standard of care at Cleveland Clinic is to transplant eligible patients in first remission, ”but I think that’s likely to change as we get more data from these trials.”
In the COG AALL0031 trial of imatinib and chemotherapy in children with Ph+ALL, there was no significant benefit to stem cell transplant (Leukemia 2014 Jan 20;28:1467-71), Dr. Advani noted.
Other prognostic features associated with poor risk, such as 1KZF1 mutations with CDKN2A and/or PAX5 deletions, have been suggested as indicators for transplant, but “what’s less clear is what the impact of these abnormalities is now with the second- and third-generation TKIs, and also whether these various abnormalities correlate with molecular responses or achievement of complete molecular remission,” she said.
Frail/unfit patients
Therapeutic options for frail or unfit patients include the combination of dasatinib and prednisone, which was associated in one study with a 93% complete hematologic remission rate by day 22, and at 20 months with a 69.2% overall survival rate, and 51.1% disease-free survival rate.(Blood. 2011;118[25]:6521-8).
In this study MRD correlated with disease-free survival, but 23 of 53 patients experienced relapse, and 12 patients with relapsed disease had the T3151 mutation. Ponatinib would be a second-line option for this latter group of patients, Dr. Advani said.
A study reported at the 2017 ASH annual meeting looked at the combination of ponatinib with steroids in patients either 60 and older or younger unfit patients with Ph+ALL.
The primary endpoint of complete hematological response at 24 weeks in at least 75% of patients was reached early, with 40 of 42 patients (95.2%) having a complete hematologic response after 1 course of therapy (6 weeks). The CMR rate at 24 weeks was 61%, and 1-year overall survival was 87.5%.
There were 13 serious adverse events related to ponatinib, however, including one death, and one patient who experienced a relapse was found to have the T315L ponatinib-resistance mutation. (Blood 2017 Dec. 7;130[Suppl. 1]:99).
“I think a few things with ponatinib and steroids that we still don’t know are the long-term follow-up results of this as a single agent in combination with steroids, and second, in this elderly population, if you look, patients are dropping out due to adverse events and toxicities,” she said.
TKIs plus antibodies
The S1318 trial conducted by the SWOG cancer research network contains both a Ph+ALL and a Ph-negative ALL cohort. In this trial, patients with Ph+ALL receive dasatinib and steroids as induction, then go on to receive blinatumomab (Blincyto) with dasatinib for three cycles, followed by maintenance therapy with dasitinib and prednisone.
A trial currently in the planning stages, EA9181, will compare in a randomized fashion induction regimens with either dasatinib or ponatinib at the investigator’s discretion with steroids and either blinatumomab or chemotherapy.
No funding source was reported for the presentation. Dr. Advani disclosed steering committee activities, honoraria/consulting, and research funding from multiple companies.
Adding tyrosine kinase inhibitors to the treatment of patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) has significantly improved outcomes in recent years, but it’s still unclear which patients will also benefit from bone marrow transplants, and whether chemotherapy will gradually fade into the therapeutic background, a leukemia researcher contended.
said Anjali S. Advani, MD, of the Cleveland Clinic Taussig Cancer Institute.
Dr. Advani discussed her approach to treating both fit and frail patients with Ph+ALL during the virtual American Society of Hematology (ASH) Meeting on Hematologic Malignancies.
Increasing understanding of the importance of eliminating minimal residual disease (MRD) colors decisions about the best TKI to use in the first line.
“In terms of which TKI to use in the upfront setting, no randomized study has been done, but since MRD is associated with improved response, we often use this data to make a decision,” she said. “This, however, is complicated, because TKIs are combined with chemotherapy, there are many new TKIs, and finally, although we can start with one TKI, we can change to another TKI if we see that a patient is not responding appropriately.”
With the use of second-generation TKIs in combination with chemotherapy, rates of complete molecular remission (CMR) and major molecular remission (MMR) improved significantly over those seen with the first-in-class agent imatinib.
Notably, she said, the combination of ponatinib (Iclusig) with steroids as frontline therapy for elderly or frail patients with Ph+ALL was associated with a 60.5% CMR at week 24 in a phase 2 Italian trial (Blood 2017;130[Suppl. 1]:99).
Combining ponatinib with the hyper-CVAD regimen (cyclophosphamide, vincristine, doxorubicin, dexamethasone) improved the 3-month CMR rate to 74% and, the MMR rate to 15% (Lancet Haematol Dec. 2018 Dec 1;5[12]:e618-e627).
A 2016 propensity-score analysis comparing hyper-CVAD plus ponatinib with the hyper-CVAD plus dasatinib showed significantly better event-free survival (P = .035) and overall survival (P = .025) with the ponatinib-containing combination (Cancer 2016;122[23]:3650-6).
As with all potent regimens, however, the combination of hyper-CVAD and ponatinib is associated with relatively high percentages of grade 3 or greater nonhematologic toxicities, including transaminase and bilirubin elevation, pancreatitis, hypertension, venous thromboembolic events and arterial cardiovascular events.
Transplants in the TKI era
Prior to the advent of TKIs, there was strong evidence of the benefit of allogeneic stem cell transplant in patients with Ph+ALL in first remission (BMT 2003;31:623-32).
“The question is, now that we use TKIs, should we be transplanting patients still?” Dr. Advani said.
In the U.S. intergroup S0805 study looking at the combination of dasatinib and chemotherapy, there were distinct relapse-free and overall survival benefits for patients who underwent transplant. This trial did not evaluate MRD, however, ”so what we don’t know is for those patients achieving a complete molecular remission, would those patients do okay without transplant?” she said.
The current standard of care at Cleveland Clinic is to transplant eligible patients in first remission, ”but I think that’s likely to change as we get more data from these trials.”
In the COG AALL0031 trial of imatinib and chemotherapy in children with Ph+ALL, there was no significant benefit to stem cell transplant (Leukemia 2014 Jan 20;28:1467-71), Dr. Advani noted.
Other prognostic features associated with poor risk, such as 1KZF1 mutations with CDKN2A and/or PAX5 deletions, have been suggested as indicators for transplant, but “what’s less clear is what the impact of these abnormalities is now with the second- and third-generation TKIs, and also whether these various abnormalities correlate with molecular responses or achievement of complete molecular remission,” she said.
Frail/unfit patients
Therapeutic options for frail or unfit patients include the combination of dasatinib and prednisone, which was associated in one study with a 93% complete hematologic remission rate by day 22, and at 20 months with a 69.2% overall survival rate, and 51.1% disease-free survival rate.(Blood. 2011;118[25]:6521-8).
In this study MRD correlated with disease-free survival, but 23 of 53 patients experienced relapse, and 12 patients with relapsed disease had the T3151 mutation. Ponatinib would be a second-line option for this latter group of patients, Dr. Advani said.
A study reported at the 2017 ASH annual meeting looked at the combination of ponatinib with steroids in patients either 60 and older or younger unfit patients with Ph+ALL.
The primary endpoint of complete hematological response at 24 weeks in at least 75% of patients was reached early, with 40 of 42 patients (95.2%) having a complete hematologic response after 1 course of therapy (6 weeks). The CMR rate at 24 weeks was 61%, and 1-year overall survival was 87.5%.
There were 13 serious adverse events related to ponatinib, however, including one death, and one patient who experienced a relapse was found to have the T315L ponatinib-resistance mutation. (Blood 2017 Dec. 7;130[Suppl. 1]:99).
“I think a few things with ponatinib and steroids that we still don’t know are the long-term follow-up results of this as a single agent in combination with steroids, and second, in this elderly population, if you look, patients are dropping out due to adverse events and toxicities,” she said.
TKIs plus antibodies
The S1318 trial conducted by the SWOG cancer research network contains both a Ph+ALL and a Ph-negative ALL cohort. In this trial, patients with Ph+ALL receive dasatinib and steroids as induction, then go on to receive blinatumomab (Blincyto) with dasatinib for three cycles, followed by maintenance therapy with dasitinib and prednisone.
A trial currently in the planning stages, EA9181, will compare in a randomized fashion induction regimens with either dasatinib or ponatinib at the investigator’s discretion with steroids and either blinatumomab or chemotherapy.
No funding source was reported for the presentation. Dr. Advani disclosed steering committee activities, honoraria/consulting, and research funding from multiple companies.
Adding tyrosine kinase inhibitors to the treatment of patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) has significantly improved outcomes in recent years, but it’s still unclear which patients will also benefit from bone marrow transplants, and whether chemotherapy will gradually fade into the therapeutic background, a leukemia researcher contended.
said Anjali S. Advani, MD, of the Cleveland Clinic Taussig Cancer Institute.
Dr. Advani discussed her approach to treating both fit and frail patients with Ph+ALL during the virtual American Society of Hematology (ASH) Meeting on Hematologic Malignancies.
Increasing understanding of the importance of eliminating minimal residual disease (MRD) colors decisions about the best TKI to use in the first line.
“In terms of which TKI to use in the upfront setting, no randomized study has been done, but since MRD is associated with improved response, we often use this data to make a decision,” she said. “This, however, is complicated, because TKIs are combined with chemotherapy, there are many new TKIs, and finally, although we can start with one TKI, we can change to another TKI if we see that a patient is not responding appropriately.”
With the use of second-generation TKIs in combination with chemotherapy, rates of complete molecular remission (CMR) and major molecular remission (MMR) improved significantly over those seen with the first-in-class agent imatinib.
Notably, she said, the combination of ponatinib (Iclusig) with steroids as frontline therapy for elderly or frail patients with Ph+ALL was associated with a 60.5% CMR at week 24 in a phase 2 Italian trial (Blood 2017;130[Suppl. 1]:99).
Combining ponatinib with the hyper-CVAD regimen (cyclophosphamide, vincristine, doxorubicin, dexamethasone) improved the 3-month CMR rate to 74% and, the MMR rate to 15% (Lancet Haematol Dec. 2018 Dec 1;5[12]:e618-e627).
A 2016 propensity-score analysis comparing hyper-CVAD plus ponatinib with the hyper-CVAD plus dasatinib showed significantly better event-free survival (P = .035) and overall survival (P = .025) with the ponatinib-containing combination (Cancer 2016;122[23]:3650-6).
As with all potent regimens, however, the combination of hyper-CVAD and ponatinib is associated with relatively high percentages of grade 3 or greater nonhematologic toxicities, including transaminase and bilirubin elevation, pancreatitis, hypertension, venous thromboembolic events and arterial cardiovascular events.
Transplants in the TKI era
Prior to the advent of TKIs, there was strong evidence of the benefit of allogeneic stem cell transplant in patients with Ph+ALL in first remission (BMT 2003;31:623-32).
“The question is, now that we use TKIs, should we be transplanting patients still?” Dr. Advani said.
In the U.S. intergroup S0805 study looking at the combination of dasatinib and chemotherapy, there were distinct relapse-free and overall survival benefits for patients who underwent transplant. This trial did not evaluate MRD, however, ”so what we don’t know is for those patients achieving a complete molecular remission, would those patients do okay without transplant?” she said.
The current standard of care at Cleveland Clinic is to transplant eligible patients in first remission, ”but I think that’s likely to change as we get more data from these trials.”
In the COG AALL0031 trial of imatinib and chemotherapy in children with Ph+ALL, there was no significant benefit to stem cell transplant (Leukemia 2014 Jan 20;28:1467-71), Dr. Advani noted.
Other prognostic features associated with poor risk, such as 1KZF1 mutations with CDKN2A and/or PAX5 deletions, have been suggested as indicators for transplant, but “what’s less clear is what the impact of these abnormalities is now with the second- and third-generation TKIs, and also whether these various abnormalities correlate with molecular responses or achievement of complete molecular remission,” she said.
Frail/unfit patients
Therapeutic options for frail or unfit patients include the combination of dasatinib and prednisone, which was associated in one study with a 93% complete hematologic remission rate by day 22, and at 20 months with a 69.2% overall survival rate, and 51.1% disease-free survival rate.(Blood. 2011;118[25]:6521-8).
In this study MRD correlated with disease-free survival, but 23 of 53 patients experienced relapse, and 12 patients with relapsed disease had the T3151 mutation. Ponatinib would be a second-line option for this latter group of patients, Dr. Advani said.
A study reported at the 2017 ASH annual meeting looked at the combination of ponatinib with steroids in patients either 60 and older or younger unfit patients with Ph+ALL.
The primary endpoint of complete hematological response at 24 weeks in at least 75% of patients was reached early, with 40 of 42 patients (95.2%) having a complete hematologic response after 1 course of therapy (6 weeks). The CMR rate at 24 weeks was 61%, and 1-year overall survival was 87.5%.
There were 13 serious adverse events related to ponatinib, however, including one death, and one patient who experienced a relapse was found to have the T315L ponatinib-resistance mutation. (Blood 2017 Dec. 7;130[Suppl. 1]:99).
“I think a few things with ponatinib and steroids that we still don’t know are the long-term follow-up results of this as a single agent in combination with steroids, and second, in this elderly population, if you look, patients are dropping out due to adverse events and toxicities,” she said.
TKIs plus antibodies
The S1318 trial conducted by the SWOG cancer research network contains both a Ph+ALL and a Ph-negative ALL cohort. In this trial, patients with Ph+ALL receive dasatinib and steroids as induction, then go on to receive blinatumomab (Blincyto) with dasatinib for three cycles, followed by maintenance therapy with dasitinib and prednisone.
A trial currently in the planning stages, EA9181, will compare in a randomized fashion induction regimens with either dasatinib or ponatinib at the investigator’s discretion with steroids and either blinatumomab or chemotherapy.
No funding source was reported for the presentation. Dr. Advani disclosed steering committee activities, honoraria/consulting, and research funding from multiple companies.
FROM ASH HEMATOLOGIC MALIGNANCIES 2020
For lower-risk MDS, treat ‘what bugs patients most’
Clinicians who treat patients with lower-risk myelodysplastic syndrome should focus on “what bugs patients most,” with therapeutic goals reflecting and respecting the patients’ goals, a specialist in MDS recommended.
“There’s an uncomfortable truth in treating lower-risk MDS: No treatment that we have has ever been demonstrated in a prospective trial to prolong survival in lower-risk MDS, so in the end, what we’re doing is trying to improve transfusion needs and to improve quality of life,” said Michael A. Sekeres, MD, MS, from the Cleveland Clinic.
Dr. Sekeres described optimal therapy for patients with lower-risk MDS in an online presentation during the virtual American Society of Hematology Meeting on Hematologic Malignancies.
He acknowledged that the definition of MDS as “a heterogeneous clonal hematopoietic disorder derived from an abnormal multipotent progenitor cell, characterized by a hyperproliferative bone marrow, dysplasia of the cellular elements, and ineffective hematopoiesis” can be confusing even for hematologists well versed in the disorder.
An easier-to-grasp explanation, he said, is that “MDS is considered a cancer, and like other cancers it has a clonal origin, involves the abnormal growth of cells that exceeds the growth of other cells around them and don’t know when to stop growing, and it takes over normal tissue, so that the normal tissues – in this case the hematopoietic precursors in the bone marrow – don’t function normally, resulting in cytopenias.”
‘Mild displeasure syndrome’
Approximately 95% of patients with MDS have a discrete genetic abnormality, but only one driver mutation, in the gene SF3B1, is considered to be a lower-risk abnormality, with a more favorable prognosis.
Treatment options for patients with lower-risk MDS, defined as an International Prognostic Scoring System score of 1 or less, or a Revised IPSS score of 3.5 or less, will depend on the patients’ transfusion needs and quality of life.
Patients with no transfusion requirements and a generally good quality of life may be followed by observation alone, with blood counts every 1 to 6 months depending on clinical presentation.
“We have some folks coming in who really don’t have very bad blood counts and have a good quality of life,” Dr. Sekeres said. “Those folks we would consider to have a very good risk type of MDS, which one of my patients referred to once as ‘mild displeasure syndrome.’ It was a displeasure to him to have to fight the traffic to come into Cleveland to see me every month, or 2 months, or 6 months, but beyond that we didn’t have to treat his MDS.”
Isolated cytopenias
Patients with isolated anemia, with hemoglobin less than 10 g/dL and/or transfusion dependence, and who are symptomatic should be started on an erythopoiesis-stimulating agent (ESA), either recombinant humanized erythropoietin or darbepoetin, or the erythroid-maturing agent luspatercept (Reblozyl).
The probability of a response to ESAs in this populations ranges from about 15% to 35%, with patients who have low baseline serum erythropoietin and no or few transfusions most likely to respond.
“On the other hand, patients who come into our clinic who are already dependent on red blood cell transfusions and have a sky-high [erythropoietin] level in the hundreds or even thousands have a very low likelihood of responding to exogenously administered ESAs,” he said.
Patients with no response to ESAs or luspatercept or a loss of response suggestive of disease progression should undergo repeat bone marrow biopsy. Patients who develop deletion 5q should be started on lenalidomide (Revlimid). In these patients, next-generation sequencing may also reveal targetable abnormalities.
For patients with isolated thrombocytopenia, thrombopoietin agonists such as romiplostim or eltrombopag may help to reduce platelet transfusion requirements and clinically significant bleeding events, but these agents come with a very important caveat: in addition to promoting platelet production, thrombopoietin receptor agonists can promote the growth of blasts, which could in turn promote the transformation of MDS to acute myeloid leukemia.
“This is an off-label use of romiplostim for the treatment of MDS with thrombocytopenia, and this drug should never, never, never be given to a patient who has excess blasts at baseline MDS; the same is true of its cousin eltrombopag.” Dr. Sekeres said.
Multlineage dysplasia
Patients with multilineage dysplasia can have good responses to hypomethylating agents, either azacitidine 75 mg/m2 IV or subcutaneously for 3 days every 4 weeks, or decitabine 20 mg/m2 IV for 3 days every 4 weeks.
“Another approach to treating patients with multilineage dysplasia is to consider the use of antithymocyte globulin; in other words, treat these patients as if they have aplastic anemia, because there are some types of MDS in which immune-mediated destruction of bone marrow plays a role,” Dr. Sekeres said.
“This is particularly appealing in patients who have a hyperplastic marrow, or those who have other autoimmune conditions that are going on that may indicate a broader autoimmune process that’s involved in the bone marrow,” he added.
Patients treated with antithymocyte globulin require hospitalization with discharge on steroids for 1 month to prevent serum sickness in response to the treatment, and maintenance on low-dose cyclosporine.
“In MDS, unfortunately, our understanding of the biology of the disease far exceeds what we can do about it, but we’re starting to catch up,” Dr. Sekeres said.
No funding source for the presentation was disclosed. Dr. Sekeres disclosed serving on advisory boards for Celegene/Bristol-Myers Squibb, Takeda/Millenium, and Pfizer.
Clinicians who treat patients with lower-risk myelodysplastic syndrome should focus on “what bugs patients most,” with therapeutic goals reflecting and respecting the patients’ goals, a specialist in MDS recommended.
“There’s an uncomfortable truth in treating lower-risk MDS: No treatment that we have has ever been demonstrated in a prospective trial to prolong survival in lower-risk MDS, so in the end, what we’re doing is trying to improve transfusion needs and to improve quality of life,” said Michael A. Sekeres, MD, MS, from the Cleveland Clinic.
Dr. Sekeres described optimal therapy for patients with lower-risk MDS in an online presentation during the virtual American Society of Hematology Meeting on Hematologic Malignancies.
He acknowledged that the definition of MDS as “a heterogeneous clonal hematopoietic disorder derived from an abnormal multipotent progenitor cell, characterized by a hyperproliferative bone marrow, dysplasia of the cellular elements, and ineffective hematopoiesis” can be confusing even for hematologists well versed in the disorder.
An easier-to-grasp explanation, he said, is that “MDS is considered a cancer, and like other cancers it has a clonal origin, involves the abnormal growth of cells that exceeds the growth of other cells around them and don’t know when to stop growing, and it takes over normal tissue, so that the normal tissues – in this case the hematopoietic precursors in the bone marrow – don’t function normally, resulting in cytopenias.”
‘Mild displeasure syndrome’
Approximately 95% of patients with MDS have a discrete genetic abnormality, but only one driver mutation, in the gene SF3B1, is considered to be a lower-risk abnormality, with a more favorable prognosis.
Treatment options for patients with lower-risk MDS, defined as an International Prognostic Scoring System score of 1 or less, or a Revised IPSS score of 3.5 or less, will depend on the patients’ transfusion needs and quality of life.
Patients with no transfusion requirements and a generally good quality of life may be followed by observation alone, with blood counts every 1 to 6 months depending on clinical presentation.
“We have some folks coming in who really don’t have very bad blood counts and have a good quality of life,” Dr. Sekeres said. “Those folks we would consider to have a very good risk type of MDS, which one of my patients referred to once as ‘mild displeasure syndrome.’ It was a displeasure to him to have to fight the traffic to come into Cleveland to see me every month, or 2 months, or 6 months, but beyond that we didn’t have to treat his MDS.”
Isolated cytopenias
Patients with isolated anemia, with hemoglobin less than 10 g/dL and/or transfusion dependence, and who are symptomatic should be started on an erythopoiesis-stimulating agent (ESA), either recombinant humanized erythropoietin or darbepoetin, or the erythroid-maturing agent luspatercept (Reblozyl).
The probability of a response to ESAs in this populations ranges from about 15% to 35%, with patients who have low baseline serum erythropoietin and no or few transfusions most likely to respond.
“On the other hand, patients who come into our clinic who are already dependent on red blood cell transfusions and have a sky-high [erythropoietin] level in the hundreds or even thousands have a very low likelihood of responding to exogenously administered ESAs,” he said.
Patients with no response to ESAs or luspatercept or a loss of response suggestive of disease progression should undergo repeat bone marrow biopsy. Patients who develop deletion 5q should be started on lenalidomide (Revlimid). In these patients, next-generation sequencing may also reveal targetable abnormalities.
For patients with isolated thrombocytopenia, thrombopoietin agonists such as romiplostim or eltrombopag may help to reduce platelet transfusion requirements and clinically significant bleeding events, but these agents come with a very important caveat: in addition to promoting platelet production, thrombopoietin receptor agonists can promote the growth of blasts, which could in turn promote the transformation of MDS to acute myeloid leukemia.
“This is an off-label use of romiplostim for the treatment of MDS with thrombocytopenia, and this drug should never, never, never be given to a patient who has excess blasts at baseline MDS; the same is true of its cousin eltrombopag.” Dr. Sekeres said.
Multlineage dysplasia
Patients with multilineage dysplasia can have good responses to hypomethylating agents, either azacitidine 75 mg/m2 IV or subcutaneously for 3 days every 4 weeks, or decitabine 20 mg/m2 IV for 3 days every 4 weeks.
“Another approach to treating patients with multilineage dysplasia is to consider the use of antithymocyte globulin; in other words, treat these patients as if they have aplastic anemia, because there are some types of MDS in which immune-mediated destruction of bone marrow plays a role,” Dr. Sekeres said.
“This is particularly appealing in patients who have a hyperplastic marrow, or those who have other autoimmune conditions that are going on that may indicate a broader autoimmune process that’s involved in the bone marrow,” he added.
Patients treated with antithymocyte globulin require hospitalization with discharge on steroids for 1 month to prevent serum sickness in response to the treatment, and maintenance on low-dose cyclosporine.
“In MDS, unfortunately, our understanding of the biology of the disease far exceeds what we can do about it, but we’re starting to catch up,” Dr. Sekeres said.
No funding source for the presentation was disclosed. Dr. Sekeres disclosed serving on advisory boards for Celegene/Bristol-Myers Squibb, Takeda/Millenium, and Pfizer.
Clinicians who treat patients with lower-risk myelodysplastic syndrome should focus on “what bugs patients most,” with therapeutic goals reflecting and respecting the patients’ goals, a specialist in MDS recommended.
“There’s an uncomfortable truth in treating lower-risk MDS: No treatment that we have has ever been demonstrated in a prospective trial to prolong survival in lower-risk MDS, so in the end, what we’re doing is trying to improve transfusion needs and to improve quality of life,” said Michael A. Sekeres, MD, MS, from the Cleveland Clinic.
Dr. Sekeres described optimal therapy for patients with lower-risk MDS in an online presentation during the virtual American Society of Hematology Meeting on Hematologic Malignancies.
He acknowledged that the definition of MDS as “a heterogeneous clonal hematopoietic disorder derived from an abnormal multipotent progenitor cell, characterized by a hyperproliferative bone marrow, dysplasia of the cellular elements, and ineffective hematopoiesis” can be confusing even for hematologists well versed in the disorder.
An easier-to-grasp explanation, he said, is that “MDS is considered a cancer, and like other cancers it has a clonal origin, involves the abnormal growth of cells that exceeds the growth of other cells around them and don’t know when to stop growing, and it takes over normal tissue, so that the normal tissues – in this case the hematopoietic precursors in the bone marrow – don’t function normally, resulting in cytopenias.”
‘Mild displeasure syndrome’
Approximately 95% of patients with MDS have a discrete genetic abnormality, but only one driver mutation, in the gene SF3B1, is considered to be a lower-risk abnormality, with a more favorable prognosis.
Treatment options for patients with lower-risk MDS, defined as an International Prognostic Scoring System score of 1 or less, or a Revised IPSS score of 3.5 or less, will depend on the patients’ transfusion needs and quality of life.
Patients with no transfusion requirements and a generally good quality of life may be followed by observation alone, with blood counts every 1 to 6 months depending on clinical presentation.
“We have some folks coming in who really don’t have very bad blood counts and have a good quality of life,” Dr. Sekeres said. “Those folks we would consider to have a very good risk type of MDS, which one of my patients referred to once as ‘mild displeasure syndrome.’ It was a displeasure to him to have to fight the traffic to come into Cleveland to see me every month, or 2 months, or 6 months, but beyond that we didn’t have to treat his MDS.”
Isolated cytopenias
Patients with isolated anemia, with hemoglobin less than 10 g/dL and/or transfusion dependence, and who are symptomatic should be started on an erythopoiesis-stimulating agent (ESA), either recombinant humanized erythropoietin or darbepoetin, or the erythroid-maturing agent luspatercept (Reblozyl).
The probability of a response to ESAs in this populations ranges from about 15% to 35%, with patients who have low baseline serum erythropoietin and no or few transfusions most likely to respond.
“On the other hand, patients who come into our clinic who are already dependent on red blood cell transfusions and have a sky-high [erythropoietin] level in the hundreds or even thousands have a very low likelihood of responding to exogenously administered ESAs,” he said.
Patients with no response to ESAs or luspatercept or a loss of response suggestive of disease progression should undergo repeat bone marrow biopsy. Patients who develop deletion 5q should be started on lenalidomide (Revlimid). In these patients, next-generation sequencing may also reveal targetable abnormalities.
For patients with isolated thrombocytopenia, thrombopoietin agonists such as romiplostim or eltrombopag may help to reduce platelet transfusion requirements and clinically significant bleeding events, but these agents come with a very important caveat: in addition to promoting platelet production, thrombopoietin receptor agonists can promote the growth of blasts, which could in turn promote the transformation of MDS to acute myeloid leukemia.
“This is an off-label use of romiplostim for the treatment of MDS with thrombocytopenia, and this drug should never, never, never be given to a patient who has excess blasts at baseline MDS; the same is true of its cousin eltrombopag.” Dr. Sekeres said.
Multlineage dysplasia
Patients with multilineage dysplasia can have good responses to hypomethylating agents, either azacitidine 75 mg/m2 IV or subcutaneously for 3 days every 4 weeks, or decitabine 20 mg/m2 IV for 3 days every 4 weeks.
“Another approach to treating patients with multilineage dysplasia is to consider the use of antithymocyte globulin; in other words, treat these patients as if they have aplastic anemia, because there are some types of MDS in which immune-mediated destruction of bone marrow plays a role,” Dr. Sekeres said.
“This is particularly appealing in patients who have a hyperplastic marrow, or those who have other autoimmune conditions that are going on that may indicate a broader autoimmune process that’s involved in the bone marrow,” he added.
Patients treated with antithymocyte globulin require hospitalization with discharge on steroids for 1 month to prevent serum sickness in response to the treatment, and maintenance on low-dose cyclosporine.
“In MDS, unfortunately, our understanding of the biology of the disease far exceeds what we can do about it, but we’re starting to catch up,” Dr. Sekeres said.
No funding source for the presentation was disclosed. Dr. Sekeres disclosed serving on advisory boards for Celegene/Bristol-Myers Squibb, Takeda/Millenium, and Pfizer.
FROM ASH HEMATOLOGIC MALIGNANCIES 2020
Oxidative stress linked to cytogenetic abnormalities in CLL
Oxidative stress may play a role in pathogenesis of B-cell chronic lymphocytic leukemia (B-CLL), according to the results of a biochemical and cytogenetic study of patients published online in Experimental and Molecular Pathology.
The study evaluated the serum levels of oxidative stress biomarkers [conjugated dienes (CD), malondialdehyde (MDA), and nitrite levels] and the levels of antioxidant biomarkers [ceruloplasmin (CP) and glutathione peroxidase (GPx)] in 64 B-CLL patients. The relationship between these biomarkers and the presence of cytogenetic abnormalities was examined, according to Tatiana Zhevak, MD, of Sechenov First Moscow (Russia) State Medical University, and colleagues.
Cytogenetic abnormalities have previously been determined to be linked to a poorer prognosis in CLL patients, and factors that increase the frequency of CA have been shown to increase the risk of rapid tumor progression, Dr. Zhevak and her colleagues stated.
Oxidative stress connection
Enhanced oxidative stress was detected in B-CLL patients as shown by their increased levels of serum CD, MDA, and nitrite, as well as a demonstrated imbalance in the antioxidant defense system as shown by an increased serum CP level and decreased serum GPx activity, according to the researchers.
In addition, these metabolic changes were found to be greater in those patients whose lymphocytes harbored specific cytogenetic abnormalities, and could be predicted by the serum levels of CD. Specifically, the odds of harboring a cytogenetic abnormality increased by a factor of 1.88 (P = .004) for every one-unit increase in serum CD level (mcmol/L), according to the authors.
“Collectively, the results support our hypothesis that oxidative stress and resulting lipid peroxidation play a role in pathogenesis of B-CLL and provide a rational basis for the use of agents regulating the pro-oxidant and antioxidant activity in the treatment of B-CLL patients,” the researchers concluded.
The research was unsponsored and the authors reported having no conflicts.
SOURCE: Zhevak T et al. Exp Mol Patholo. 2020 Oct;16:104524 doi: 10.1016/j.yexmp.2020.104524.
Oxidative stress may play a role in pathogenesis of B-cell chronic lymphocytic leukemia (B-CLL), according to the results of a biochemical and cytogenetic study of patients published online in Experimental and Molecular Pathology.
The study evaluated the serum levels of oxidative stress biomarkers [conjugated dienes (CD), malondialdehyde (MDA), and nitrite levels] and the levels of antioxidant biomarkers [ceruloplasmin (CP) and glutathione peroxidase (GPx)] in 64 B-CLL patients. The relationship between these biomarkers and the presence of cytogenetic abnormalities was examined, according to Tatiana Zhevak, MD, of Sechenov First Moscow (Russia) State Medical University, and colleagues.
Cytogenetic abnormalities have previously been determined to be linked to a poorer prognosis in CLL patients, and factors that increase the frequency of CA have been shown to increase the risk of rapid tumor progression, Dr. Zhevak and her colleagues stated.
Oxidative stress connection
Enhanced oxidative stress was detected in B-CLL patients as shown by their increased levels of serum CD, MDA, and nitrite, as well as a demonstrated imbalance in the antioxidant defense system as shown by an increased serum CP level and decreased serum GPx activity, according to the researchers.
In addition, these metabolic changes were found to be greater in those patients whose lymphocytes harbored specific cytogenetic abnormalities, and could be predicted by the serum levels of CD. Specifically, the odds of harboring a cytogenetic abnormality increased by a factor of 1.88 (P = .004) for every one-unit increase in serum CD level (mcmol/L), according to the authors.
“Collectively, the results support our hypothesis that oxidative stress and resulting lipid peroxidation play a role in pathogenesis of B-CLL and provide a rational basis for the use of agents regulating the pro-oxidant and antioxidant activity in the treatment of B-CLL patients,” the researchers concluded.
The research was unsponsored and the authors reported having no conflicts.
SOURCE: Zhevak T et al. Exp Mol Patholo. 2020 Oct;16:104524 doi: 10.1016/j.yexmp.2020.104524.
Oxidative stress may play a role in pathogenesis of B-cell chronic lymphocytic leukemia (B-CLL), according to the results of a biochemical and cytogenetic study of patients published online in Experimental and Molecular Pathology.
The study evaluated the serum levels of oxidative stress biomarkers [conjugated dienes (CD), malondialdehyde (MDA), and nitrite levels] and the levels of antioxidant biomarkers [ceruloplasmin (CP) and glutathione peroxidase (GPx)] in 64 B-CLL patients. The relationship between these biomarkers and the presence of cytogenetic abnormalities was examined, according to Tatiana Zhevak, MD, of Sechenov First Moscow (Russia) State Medical University, and colleagues.
Cytogenetic abnormalities have previously been determined to be linked to a poorer prognosis in CLL patients, and factors that increase the frequency of CA have been shown to increase the risk of rapid tumor progression, Dr. Zhevak and her colleagues stated.
Oxidative stress connection
Enhanced oxidative stress was detected in B-CLL patients as shown by their increased levels of serum CD, MDA, and nitrite, as well as a demonstrated imbalance in the antioxidant defense system as shown by an increased serum CP level and decreased serum GPx activity, according to the researchers.
In addition, these metabolic changes were found to be greater in those patients whose lymphocytes harbored specific cytogenetic abnormalities, and could be predicted by the serum levels of CD. Specifically, the odds of harboring a cytogenetic abnormality increased by a factor of 1.88 (P = .004) for every one-unit increase in serum CD level (mcmol/L), according to the authors.
“Collectively, the results support our hypothesis that oxidative stress and resulting lipid peroxidation play a role in pathogenesis of B-CLL and provide a rational basis for the use of agents regulating the pro-oxidant and antioxidant activity in the treatment of B-CLL patients,” the researchers concluded.
The research was unsponsored and the authors reported having no conflicts.
SOURCE: Zhevak T et al. Exp Mol Patholo. 2020 Oct;16:104524 doi: 10.1016/j.yexmp.2020.104524.
FROM Experimental and Molecular Pathology
CSF metabolomic profile linked to cancer-related fatigue in children with ALL
Children and adolescents with cancer report significantly more fatigue than their counterparts without cancer, and cancer-related fatigue (CRF) is “one of the most prevalent and distressing symptoms reported during childhood cancer therapy,” according to Austin L. Brown, PhD, and his colleagues.
Cerebrospinal fluid (CSF) profiles suggest three metabolites are significantly associated with CRF in children with acute lymphoblastic leukemia (ALL), according to a report published in the Journal of Pain and Symptom Management.
The researchers assessed the clinical and demographic characteristics of 171 pediatric ALL patients, who were divided into discovery (n = 86) and replication (n = 85) cohorts.
The entire population had a mean age at diagnosis of 8.48 years; was 56.1% male; and 85.4% had B-lineage ALL. A total of 63.7% received high- or very-high-risk treatment.
CSF samples were obtained and subjected to metabolomic analysis, according to Dr. Brown, an assistant professor at the Baylor College of Medicine, Houston, and colleagues.
The researchers analyzed postinduction CSF from the aforementioned 171 patients as well as diagnostic CSF from 48 patients in an additional replication cohort.
Significant metabolites
Analysis of postinduction CSF showed that three metabolites were significantly associated with fatigue in both the discovery and replication cohorts, comprising gamma-glutamylglutamine, dimethylglycine, and asparagine (P < .05).
In diagnostic CSF samples, the abundance of gamma-glutamylglutamine was significantly associated with fatigue (P =.0062).
The metabolites have been implicated in neurotransmitter transportation and glutathione recycling, suggesting glutamatergic pathways or oxidative stress may contribute to ALL-associated CRF, according to the researchers.
“Ultimately, this line of investigation may aid in the development of new prevention and treatment approaches informed by an improved understanding of the etiology and risk factors for cancer-related fatigue,” the researchers concluded.
The study was sponsored by the National Cancer Institute and several nonprofit organizations. The authors reported that they had no conflicts of interest.
SOURCE: Brown AL et al. J Pain Symptom Manage. 2020 Sep 1. doi: 10.1016/j.jpainsymman.2020.08.030.
Children and adolescents with cancer report significantly more fatigue than their counterparts without cancer, and cancer-related fatigue (CRF) is “one of the most prevalent and distressing symptoms reported during childhood cancer therapy,” according to Austin L. Brown, PhD, and his colleagues.
Cerebrospinal fluid (CSF) profiles suggest three metabolites are significantly associated with CRF in children with acute lymphoblastic leukemia (ALL), according to a report published in the Journal of Pain and Symptom Management.
The researchers assessed the clinical and demographic characteristics of 171 pediatric ALL patients, who were divided into discovery (n = 86) and replication (n = 85) cohorts.
The entire population had a mean age at diagnosis of 8.48 years; was 56.1% male; and 85.4% had B-lineage ALL. A total of 63.7% received high- or very-high-risk treatment.
CSF samples were obtained and subjected to metabolomic analysis, according to Dr. Brown, an assistant professor at the Baylor College of Medicine, Houston, and colleagues.
The researchers analyzed postinduction CSF from the aforementioned 171 patients as well as diagnostic CSF from 48 patients in an additional replication cohort.
Significant metabolites
Analysis of postinduction CSF showed that three metabolites were significantly associated with fatigue in both the discovery and replication cohorts, comprising gamma-glutamylglutamine, dimethylglycine, and asparagine (P < .05).
In diagnostic CSF samples, the abundance of gamma-glutamylglutamine was significantly associated with fatigue (P =.0062).
The metabolites have been implicated in neurotransmitter transportation and glutathione recycling, suggesting glutamatergic pathways or oxidative stress may contribute to ALL-associated CRF, according to the researchers.
“Ultimately, this line of investigation may aid in the development of new prevention and treatment approaches informed by an improved understanding of the etiology and risk factors for cancer-related fatigue,” the researchers concluded.
The study was sponsored by the National Cancer Institute and several nonprofit organizations. The authors reported that they had no conflicts of interest.
SOURCE: Brown AL et al. J Pain Symptom Manage. 2020 Sep 1. doi: 10.1016/j.jpainsymman.2020.08.030.
Children and adolescents with cancer report significantly more fatigue than their counterparts without cancer, and cancer-related fatigue (CRF) is “one of the most prevalent and distressing symptoms reported during childhood cancer therapy,” according to Austin L. Brown, PhD, and his colleagues.
Cerebrospinal fluid (CSF) profiles suggest three metabolites are significantly associated with CRF in children with acute lymphoblastic leukemia (ALL), according to a report published in the Journal of Pain and Symptom Management.
The researchers assessed the clinical and demographic characteristics of 171 pediatric ALL patients, who were divided into discovery (n = 86) and replication (n = 85) cohorts.
The entire population had a mean age at diagnosis of 8.48 years; was 56.1% male; and 85.4% had B-lineage ALL. A total of 63.7% received high- or very-high-risk treatment.
CSF samples were obtained and subjected to metabolomic analysis, according to Dr. Brown, an assistant professor at the Baylor College of Medicine, Houston, and colleagues.
The researchers analyzed postinduction CSF from the aforementioned 171 patients as well as diagnostic CSF from 48 patients in an additional replication cohort.
Significant metabolites
Analysis of postinduction CSF showed that three metabolites were significantly associated with fatigue in both the discovery and replication cohorts, comprising gamma-glutamylglutamine, dimethylglycine, and asparagine (P < .05).
In diagnostic CSF samples, the abundance of gamma-glutamylglutamine was significantly associated with fatigue (P =.0062).
The metabolites have been implicated in neurotransmitter transportation and glutathione recycling, suggesting glutamatergic pathways or oxidative stress may contribute to ALL-associated CRF, according to the researchers.
“Ultimately, this line of investigation may aid in the development of new prevention and treatment approaches informed by an improved understanding of the etiology and risk factors for cancer-related fatigue,” the researchers concluded.
The study was sponsored by the National Cancer Institute and several nonprofit organizations. The authors reported that they had no conflicts of interest.
SOURCE: Brown AL et al. J Pain Symptom Manage. 2020 Sep 1. doi: 10.1016/j.jpainsymman.2020.08.030.
FROM THE JOURNAL OF PAIN AND SYMPTOM MANAGEMENT
Hair dye and cancer study ‘offers some reassurance’
Findings limited to White women in United States
The largest study of its kind has found no positive association between personal use of permanent hair dye and the risk for most cancers and cancer mortality.
The findings come from the Nurses’ Health Study, an ongoing prospective cohort study of more than 117,000 women who have been followed for 36 years and who did not have cancer at baseline.
The findings were published online on September 2 in the BMJ.
The results “offer some reassurance against concerns that personal use of permanent hair dyes might be associated with increased cancer risk or mortality,” write the investigators, with first author Yin Zhang, PhD, of Harvard Medical School, Boston.
The findings, which are limited to White women in the United States, indicate correlation, not causation, the authors emphasize.
Nevertheless, the researchers found an increased risk for some cancers among hair dye users, especially with greater cumulative dose (200 or more uses during the study period). The risk was increased for basal cell carcinoma, breast cancer (specifically, estrogen receptor negative [ER–], progesterone receptor negative [PR–], and hormone receptor negative [ER–, PR–]), and ovarian cancer.
A British expert not involved in the study dismissed these findings. “The reported associations are very weak, and, given the number of associations reported in this manuscript, they are very likely to be chance findings,” commented Paul Pharoah, PhD, professor of cancer epidemiology at the University of Cambridge (England).
“For the cancers where an increase in risk is reported, the results are not compelling. Even if they were real findings, the associations may not be cause-and-effect, and, even if they were causal associations, the magnitude of the effects are so small that any risk would be trivial.
“In short, none of the findings reported in this manuscript suggest that women who use hair dye are putting themselves at increased risk of cancer,” he stated.
A U.S. researcher who has previously coauthored a study suggesting an association between hair dye and breast cancer agreed that the increases in risk reported in this current study are “small.” But they are “of interest,” especially for breast and ovarian cancer, said Alexandra White, PhD, of the National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, N.C.
Hair dyes include compounds that “are not just potential carcinogens but also act as endocrine disruptors,” she said in an interview.
“In both breast and ovarian cancer, we know that hormones play an important part in the etiology ... so it’s biologically plausible that you would see [these associations in the current study],” added Dr. White, who was approached for comment.
However, she added that, even with the “modest” 20%-28% increase in the relative risk for certain breast cancers linked to a heavy cumulative dose of dyes in the current study, “there doesn’t seem to be any strong association with any cancer type.”
But she also pointed out that the most outstanding risk association was among ER–/PR– breast cancers, which are the “most aggressive and difficult to treat,” and thus the new findings are “important.”
Dr. White is the lead author of a 2019 study that received a lot of media attention because it rang an alarm bell about hair dyes and breast cancer risk.
That study concluded that ever using permanent hair dye or hair straighteners was associated with a higher risk for breast cancer than never using them and that this higher risk was especially associated with Black women. However, the study participants were from the prospective Sister Study. The participants in that study had no history of breast cancer, but they each had at least one sister who did. This family history of breast cancer may represent selection bias.
With changes in the 1980s, even safer now?
The study of hair dyes and cancer has “major public health implications” because the use of hair dye is widespread, Dr. Zhang and colleagues write in their article. They estimate that 50% to 80% of women and 10% of men aged 40 years and older in the United States and Europe use hair dye.
Permanent hair dyes “pose the greatest potential concern,” they stated, adding that these account for approximately 80% of hair dyes used in the United States and Europe and an even higher percentage in Asia.
The International Agency for Research on Cancer classifies occupational exposure to hair dyes as probably carcinogenic, but the carcinogenicity resulting from personal use of hair dyes is not classifiable – thus, there is no warning about at-home usage.
Notably, there was “a huge and very important” change in hair dye ingredients in the 1980s after the Food and Drug Administration warned about some chemicals in permanent hair dyes and the cosmetic industry altered their formulas, lead author Dr. Zhang said.
However, the researchers could not analyze use before and after the changes because not enough women reported first use of permanent hair dye after 1980 (only 1890 of 117,200 participants).
“We could expect that the current ingredients should make it safer,” Dr. Zhang said.
Study details
The researchers report that ever-users of permanent hair dyes had no significant increases in risk for solid cancers (n = 20,805; hazard ratio, 0.98, 95% confidence interval, 0.96-1.01) or hematopoietic cancers overall (n = 1,807; HR, 1.00; 95% CI, 0.91-1.10) compared with nonusers.
Additionally, ever-users did not have an increased risk for most specific cancers or cancer-related death (n = 4,860; HR, 0.96; 95% CI, 0.91-1.02).
As noted above, there were some exceptions.
Basal cell carcinoma risk was slightly increased for ever-users (n = 22,560; HR, 1.05; 95% CI, 1.02-1.08). Cumulative dose (a calculation of duration and frequency) was positively associated with risk for ER– breast cancer, PR– breast cancer, ER–/PR– breast cancer, and ovarian cancer, with risk rising in accordance with the total amount of dye.
Notably, at a cumulative dose of ≥200 uses, there was a 20% increase in the relative risk for ER- breast cancer (n = 1521; HR, 1.20; 95% CI, 1.02-1.41; P value for trend, .03). At the same cumulative dose, there was a 28% increase in the relative risk for ER-/PR- breast cancer (n = 1287; HR, 1.28, 95% CI, 1.08-1.52; P value for trend, .006).
In addition, an increased risk for Hodgkin lymphoma was observed, but only for women with naturally dark hair (the calculation was based on 70 women, 24 of whom had dark hair).
In a press statement, senior author Eva Schernhammer, PhD, of Harvard and the Medical University of Vienna, said the results “justify further prospective validation.”
She also explained that there are many variables to consider in this research, including different populations and countries, different susceptibility genotypes, different exposure settings (personal use vs. occupational exposure), and different colors of the permanent hair dyes used (dark dyes vs. light dyes).
Geographic location is a particularly important variable, suggested the study authors.
They pointed out that Europe, but not the United States, banned some individual hair dye ingredients that were considered carcinogenic during both the 1980s and 2000s. One country has even tighter oversight: “The most restrictive regulation of hair dyes exists in Japan, where cosmetic products are considered equivalent to drugs.”
The study was funded by the Centers for Disease Control and Prevention and the National Institute for Occupational Safety and Health. The study authors and Dr. White have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Findings limited to White women in United States
Findings limited to White women in United States
The largest study of its kind has found no positive association between personal use of permanent hair dye and the risk for most cancers and cancer mortality.
The findings come from the Nurses’ Health Study, an ongoing prospective cohort study of more than 117,000 women who have been followed for 36 years and who did not have cancer at baseline.
The findings were published online on September 2 in the BMJ.
The results “offer some reassurance against concerns that personal use of permanent hair dyes might be associated with increased cancer risk or mortality,” write the investigators, with first author Yin Zhang, PhD, of Harvard Medical School, Boston.
The findings, which are limited to White women in the United States, indicate correlation, not causation, the authors emphasize.
Nevertheless, the researchers found an increased risk for some cancers among hair dye users, especially with greater cumulative dose (200 or more uses during the study period). The risk was increased for basal cell carcinoma, breast cancer (specifically, estrogen receptor negative [ER–], progesterone receptor negative [PR–], and hormone receptor negative [ER–, PR–]), and ovarian cancer.
A British expert not involved in the study dismissed these findings. “The reported associations are very weak, and, given the number of associations reported in this manuscript, they are very likely to be chance findings,” commented Paul Pharoah, PhD, professor of cancer epidemiology at the University of Cambridge (England).
“For the cancers where an increase in risk is reported, the results are not compelling. Even if they were real findings, the associations may not be cause-and-effect, and, even if they were causal associations, the magnitude of the effects are so small that any risk would be trivial.
“In short, none of the findings reported in this manuscript suggest that women who use hair dye are putting themselves at increased risk of cancer,” he stated.
A U.S. researcher who has previously coauthored a study suggesting an association between hair dye and breast cancer agreed that the increases in risk reported in this current study are “small.” But they are “of interest,” especially for breast and ovarian cancer, said Alexandra White, PhD, of the National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, N.C.
Hair dyes include compounds that “are not just potential carcinogens but also act as endocrine disruptors,” she said in an interview.
“In both breast and ovarian cancer, we know that hormones play an important part in the etiology ... so it’s biologically plausible that you would see [these associations in the current study],” added Dr. White, who was approached for comment.
However, she added that, even with the “modest” 20%-28% increase in the relative risk for certain breast cancers linked to a heavy cumulative dose of dyes in the current study, “there doesn’t seem to be any strong association with any cancer type.”
But she also pointed out that the most outstanding risk association was among ER–/PR– breast cancers, which are the “most aggressive and difficult to treat,” and thus the new findings are “important.”
Dr. White is the lead author of a 2019 study that received a lot of media attention because it rang an alarm bell about hair dyes and breast cancer risk.
That study concluded that ever using permanent hair dye or hair straighteners was associated with a higher risk for breast cancer than never using them and that this higher risk was especially associated with Black women. However, the study participants were from the prospective Sister Study. The participants in that study had no history of breast cancer, but they each had at least one sister who did. This family history of breast cancer may represent selection bias.
With changes in the 1980s, even safer now?
The study of hair dyes and cancer has “major public health implications” because the use of hair dye is widespread, Dr. Zhang and colleagues write in their article. They estimate that 50% to 80% of women and 10% of men aged 40 years and older in the United States and Europe use hair dye.
Permanent hair dyes “pose the greatest potential concern,” they stated, adding that these account for approximately 80% of hair dyes used in the United States and Europe and an even higher percentage in Asia.
The International Agency for Research on Cancer classifies occupational exposure to hair dyes as probably carcinogenic, but the carcinogenicity resulting from personal use of hair dyes is not classifiable – thus, there is no warning about at-home usage.
Notably, there was “a huge and very important” change in hair dye ingredients in the 1980s after the Food and Drug Administration warned about some chemicals in permanent hair dyes and the cosmetic industry altered their formulas, lead author Dr. Zhang said.
However, the researchers could not analyze use before and after the changes because not enough women reported first use of permanent hair dye after 1980 (only 1890 of 117,200 participants).
“We could expect that the current ingredients should make it safer,” Dr. Zhang said.
Study details
The researchers report that ever-users of permanent hair dyes had no significant increases in risk for solid cancers (n = 20,805; hazard ratio, 0.98, 95% confidence interval, 0.96-1.01) or hematopoietic cancers overall (n = 1,807; HR, 1.00; 95% CI, 0.91-1.10) compared with nonusers.
Additionally, ever-users did not have an increased risk for most specific cancers or cancer-related death (n = 4,860; HR, 0.96; 95% CI, 0.91-1.02).
As noted above, there were some exceptions.
Basal cell carcinoma risk was slightly increased for ever-users (n = 22,560; HR, 1.05; 95% CI, 1.02-1.08). Cumulative dose (a calculation of duration and frequency) was positively associated with risk for ER– breast cancer, PR– breast cancer, ER–/PR– breast cancer, and ovarian cancer, with risk rising in accordance with the total amount of dye.
Notably, at a cumulative dose of ≥200 uses, there was a 20% increase in the relative risk for ER- breast cancer (n = 1521; HR, 1.20; 95% CI, 1.02-1.41; P value for trend, .03). At the same cumulative dose, there was a 28% increase in the relative risk for ER-/PR- breast cancer (n = 1287; HR, 1.28, 95% CI, 1.08-1.52; P value for trend, .006).
In addition, an increased risk for Hodgkin lymphoma was observed, but only for women with naturally dark hair (the calculation was based on 70 women, 24 of whom had dark hair).
In a press statement, senior author Eva Schernhammer, PhD, of Harvard and the Medical University of Vienna, said the results “justify further prospective validation.”
She also explained that there are many variables to consider in this research, including different populations and countries, different susceptibility genotypes, different exposure settings (personal use vs. occupational exposure), and different colors of the permanent hair dyes used (dark dyes vs. light dyes).
Geographic location is a particularly important variable, suggested the study authors.
They pointed out that Europe, but not the United States, banned some individual hair dye ingredients that were considered carcinogenic during both the 1980s and 2000s. One country has even tighter oversight: “The most restrictive regulation of hair dyes exists in Japan, where cosmetic products are considered equivalent to drugs.”
The study was funded by the Centers for Disease Control and Prevention and the National Institute for Occupational Safety and Health. The study authors and Dr. White have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
The largest study of its kind has found no positive association between personal use of permanent hair dye and the risk for most cancers and cancer mortality.
The findings come from the Nurses’ Health Study, an ongoing prospective cohort study of more than 117,000 women who have been followed for 36 years and who did not have cancer at baseline.
The findings were published online on September 2 in the BMJ.
The results “offer some reassurance against concerns that personal use of permanent hair dyes might be associated with increased cancer risk or mortality,” write the investigators, with first author Yin Zhang, PhD, of Harvard Medical School, Boston.
The findings, which are limited to White women in the United States, indicate correlation, not causation, the authors emphasize.
Nevertheless, the researchers found an increased risk for some cancers among hair dye users, especially with greater cumulative dose (200 or more uses during the study period). The risk was increased for basal cell carcinoma, breast cancer (specifically, estrogen receptor negative [ER–], progesterone receptor negative [PR–], and hormone receptor negative [ER–, PR–]), and ovarian cancer.
A British expert not involved in the study dismissed these findings. “The reported associations are very weak, and, given the number of associations reported in this manuscript, they are very likely to be chance findings,” commented Paul Pharoah, PhD, professor of cancer epidemiology at the University of Cambridge (England).
“For the cancers where an increase in risk is reported, the results are not compelling. Even if they were real findings, the associations may not be cause-and-effect, and, even if they were causal associations, the magnitude of the effects are so small that any risk would be trivial.
“In short, none of the findings reported in this manuscript suggest that women who use hair dye are putting themselves at increased risk of cancer,” he stated.
A U.S. researcher who has previously coauthored a study suggesting an association between hair dye and breast cancer agreed that the increases in risk reported in this current study are “small.” But they are “of interest,” especially for breast and ovarian cancer, said Alexandra White, PhD, of the National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, N.C.
Hair dyes include compounds that “are not just potential carcinogens but also act as endocrine disruptors,” she said in an interview.
“In both breast and ovarian cancer, we know that hormones play an important part in the etiology ... so it’s biologically plausible that you would see [these associations in the current study],” added Dr. White, who was approached for comment.
However, she added that, even with the “modest” 20%-28% increase in the relative risk for certain breast cancers linked to a heavy cumulative dose of dyes in the current study, “there doesn’t seem to be any strong association with any cancer type.”
But she also pointed out that the most outstanding risk association was among ER–/PR– breast cancers, which are the “most aggressive and difficult to treat,” and thus the new findings are “important.”
Dr. White is the lead author of a 2019 study that received a lot of media attention because it rang an alarm bell about hair dyes and breast cancer risk.
That study concluded that ever using permanent hair dye or hair straighteners was associated with a higher risk for breast cancer than never using them and that this higher risk was especially associated with Black women. However, the study participants were from the prospective Sister Study. The participants in that study had no history of breast cancer, but they each had at least one sister who did. This family history of breast cancer may represent selection bias.
With changes in the 1980s, even safer now?
The study of hair dyes and cancer has “major public health implications” because the use of hair dye is widespread, Dr. Zhang and colleagues write in their article. They estimate that 50% to 80% of women and 10% of men aged 40 years and older in the United States and Europe use hair dye.
Permanent hair dyes “pose the greatest potential concern,” they stated, adding that these account for approximately 80% of hair dyes used in the United States and Europe and an even higher percentage in Asia.
The International Agency for Research on Cancer classifies occupational exposure to hair dyes as probably carcinogenic, but the carcinogenicity resulting from personal use of hair dyes is not classifiable – thus, there is no warning about at-home usage.
Notably, there was “a huge and very important” change in hair dye ingredients in the 1980s after the Food and Drug Administration warned about some chemicals in permanent hair dyes and the cosmetic industry altered their formulas, lead author Dr. Zhang said.
However, the researchers could not analyze use before and after the changes because not enough women reported first use of permanent hair dye after 1980 (only 1890 of 117,200 participants).
“We could expect that the current ingredients should make it safer,” Dr. Zhang said.
Study details
The researchers report that ever-users of permanent hair dyes had no significant increases in risk for solid cancers (n = 20,805; hazard ratio, 0.98, 95% confidence interval, 0.96-1.01) or hematopoietic cancers overall (n = 1,807; HR, 1.00; 95% CI, 0.91-1.10) compared with nonusers.
Additionally, ever-users did not have an increased risk for most specific cancers or cancer-related death (n = 4,860; HR, 0.96; 95% CI, 0.91-1.02).
As noted above, there were some exceptions.
Basal cell carcinoma risk was slightly increased for ever-users (n = 22,560; HR, 1.05; 95% CI, 1.02-1.08). Cumulative dose (a calculation of duration and frequency) was positively associated with risk for ER– breast cancer, PR– breast cancer, ER–/PR– breast cancer, and ovarian cancer, with risk rising in accordance with the total amount of dye.
Notably, at a cumulative dose of ≥200 uses, there was a 20% increase in the relative risk for ER- breast cancer (n = 1521; HR, 1.20; 95% CI, 1.02-1.41; P value for trend, .03). At the same cumulative dose, there was a 28% increase in the relative risk for ER-/PR- breast cancer (n = 1287; HR, 1.28, 95% CI, 1.08-1.52; P value for trend, .006).
In addition, an increased risk for Hodgkin lymphoma was observed, but only for women with naturally dark hair (the calculation was based on 70 women, 24 of whom had dark hair).
In a press statement, senior author Eva Schernhammer, PhD, of Harvard and the Medical University of Vienna, said the results “justify further prospective validation.”
She also explained that there are many variables to consider in this research, including different populations and countries, different susceptibility genotypes, different exposure settings (personal use vs. occupational exposure), and different colors of the permanent hair dyes used (dark dyes vs. light dyes).
Geographic location is a particularly important variable, suggested the study authors.
They pointed out that Europe, but not the United States, banned some individual hair dye ingredients that were considered carcinogenic during both the 1980s and 2000s. One country has even tighter oversight: “The most restrictive regulation of hair dyes exists in Japan, where cosmetic products are considered equivalent to drugs.”
The study was funded by the Centers for Disease Control and Prevention and the National Institute for Occupational Safety and Health. The study authors and Dr. White have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
FDA approves first maintenance therapy for AML
The Food and Drug Administration has approved an oral form of azacitidine (Onureg) for use as maintenance therapy for patients with acute myeloid leukemia (AML) who have achieved a first complete remission.
The approval extends to patients who have achieved complete remission with incomplete blood count recovery following intensive induction chemotherapy and who are unable to complete intensive curative therapy.
The approval was based on data from the QUAZAR AML-001 trial, which showed that oral azacitidine significantly improved overall survival when compared with placebo.
“It’s not too hard to get these patients into remission,” Harry P. Erba, MD, PhD, director of the Leukemia Program at the Duke Cancer Institute, Durham, N.C., said in an interview last year when these results were first presented at the 2019 annual meeting of the American Society of Hematology. “The problem comes in keeping them in remission.”
Despite various attempts, there has been no success over the past 30 years in defining maintenance treatment for these patients, Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne, Australia, said.
“Oral azacitidine represents a new therapeutic standard for patients with AML in remission,” he said.
Azacitidine is a hypomethylating agent that incorporates into DNA and RNA. It has long been used as an injectable therapy for the treatment of myelodysplastic syndromes.
The approval of the new oral formulation for the new indication of AML “is the culmination of over a decade of research and 13 preclinical and clinical trials,” said Giovanni Caforio, M.D., chairman and chief executive officer of Bristol-Myers Squibb, in a statement.
QUAZAR results
The QUAZAR AML-001 trial was a phase 3, international study involving 472 patients with AML who were within achieving a first complete remission or remission with incomplete blood recovery. All patients had received intensive induction chemotherapy with or without consolidation treatment per investigator preference prior to study entry and were not candidates for hematopoietic stem cell transplant at the time of screening.
Patients were randomly assigned to receive either oral azacitidine 200 mg daily on days 1-14 of a repeat 28-day cycle (n = 278) or matching placebo (n = 274). Treatment was continued indefinitely until blast count was more than 15% or patients experienced unacceptable toxicity or underwent transplant.
At a median follow-up of more than 41.2 months, the median overall survival was significantly longer for patients who received oral azacitidine at 24.7 months versus 14.8 months for those who received placebo (hazard ratio, 0.69; P < .0009).
Relapse-free survival was also significantly prolonged to 10.2 months for patients who received oral azacitidine vs. 4.8 months for those who received placebo (HR, 0.65; P < .0001).
Serious adverse reactions occurred in 15% of patients who received azacitidine. Events that occurred in 2% of patients or more include pneumonia (8%) and febrile neutropenia (7%). There was one fatal event.
The most common adverse reactions were nausea (65% vs. 24%), vomiting (60% vs. 10%), diarrhea (50% vs. 21%), fatigue/asthenia (44% vs. 25%), constipation (39% vs. 24%), pneumonia (27% vs. 17%), abdominal pain (22% vs. 13%) arthralgia (14% vs. 10%), decreased appetite (13% vs. 6%), febrile neutropenia (12% vs. 8%), dizziness (11% vs. 9%), and pain in extremity (11% vs. 5%). Permanent discontinuation because of an adverse reaction occurred in 8% of patients.
A version of this article originally appeared on Medscape.com.
The Food and Drug Administration has approved an oral form of azacitidine (Onureg) for use as maintenance therapy for patients with acute myeloid leukemia (AML) who have achieved a first complete remission.
The approval extends to patients who have achieved complete remission with incomplete blood count recovery following intensive induction chemotherapy and who are unable to complete intensive curative therapy.
The approval was based on data from the QUAZAR AML-001 trial, which showed that oral azacitidine significantly improved overall survival when compared with placebo.
“It’s not too hard to get these patients into remission,” Harry P. Erba, MD, PhD, director of the Leukemia Program at the Duke Cancer Institute, Durham, N.C., said in an interview last year when these results were first presented at the 2019 annual meeting of the American Society of Hematology. “The problem comes in keeping them in remission.”
Despite various attempts, there has been no success over the past 30 years in defining maintenance treatment for these patients, Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne, Australia, said.
“Oral azacitidine represents a new therapeutic standard for patients with AML in remission,” he said.
Azacitidine is a hypomethylating agent that incorporates into DNA and RNA. It has long been used as an injectable therapy for the treatment of myelodysplastic syndromes.
The approval of the new oral formulation for the new indication of AML “is the culmination of over a decade of research and 13 preclinical and clinical trials,” said Giovanni Caforio, M.D., chairman and chief executive officer of Bristol-Myers Squibb, in a statement.
QUAZAR results
The QUAZAR AML-001 trial was a phase 3, international study involving 472 patients with AML who were within achieving a first complete remission or remission with incomplete blood recovery. All patients had received intensive induction chemotherapy with or without consolidation treatment per investigator preference prior to study entry and were not candidates for hematopoietic stem cell transplant at the time of screening.
Patients were randomly assigned to receive either oral azacitidine 200 mg daily on days 1-14 of a repeat 28-day cycle (n = 278) or matching placebo (n = 274). Treatment was continued indefinitely until blast count was more than 15% or patients experienced unacceptable toxicity or underwent transplant.
At a median follow-up of more than 41.2 months, the median overall survival was significantly longer for patients who received oral azacitidine at 24.7 months versus 14.8 months for those who received placebo (hazard ratio, 0.69; P < .0009).
Relapse-free survival was also significantly prolonged to 10.2 months for patients who received oral azacitidine vs. 4.8 months for those who received placebo (HR, 0.65; P < .0001).
Serious adverse reactions occurred in 15% of patients who received azacitidine. Events that occurred in 2% of patients or more include pneumonia (8%) and febrile neutropenia (7%). There was one fatal event.
The most common adverse reactions were nausea (65% vs. 24%), vomiting (60% vs. 10%), diarrhea (50% vs. 21%), fatigue/asthenia (44% vs. 25%), constipation (39% vs. 24%), pneumonia (27% vs. 17%), abdominal pain (22% vs. 13%) arthralgia (14% vs. 10%), decreased appetite (13% vs. 6%), febrile neutropenia (12% vs. 8%), dizziness (11% vs. 9%), and pain in extremity (11% vs. 5%). Permanent discontinuation because of an adverse reaction occurred in 8% of patients.
A version of this article originally appeared on Medscape.com.
The Food and Drug Administration has approved an oral form of azacitidine (Onureg) for use as maintenance therapy for patients with acute myeloid leukemia (AML) who have achieved a first complete remission.
The approval extends to patients who have achieved complete remission with incomplete blood count recovery following intensive induction chemotherapy and who are unable to complete intensive curative therapy.
The approval was based on data from the QUAZAR AML-001 trial, which showed that oral azacitidine significantly improved overall survival when compared with placebo.
“It’s not too hard to get these patients into remission,” Harry P. Erba, MD, PhD, director of the Leukemia Program at the Duke Cancer Institute, Durham, N.C., said in an interview last year when these results were first presented at the 2019 annual meeting of the American Society of Hematology. “The problem comes in keeping them in remission.”
Despite various attempts, there has been no success over the past 30 years in defining maintenance treatment for these patients, Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne, Australia, said.
“Oral azacitidine represents a new therapeutic standard for patients with AML in remission,” he said.
Azacitidine is a hypomethylating agent that incorporates into DNA and RNA. It has long been used as an injectable therapy for the treatment of myelodysplastic syndromes.
The approval of the new oral formulation for the new indication of AML “is the culmination of over a decade of research and 13 preclinical and clinical trials,” said Giovanni Caforio, M.D., chairman and chief executive officer of Bristol-Myers Squibb, in a statement.
QUAZAR results
The QUAZAR AML-001 trial was a phase 3, international study involving 472 patients with AML who were within achieving a first complete remission or remission with incomplete blood recovery. All patients had received intensive induction chemotherapy with or without consolidation treatment per investigator preference prior to study entry and were not candidates for hematopoietic stem cell transplant at the time of screening.
Patients were randomly assigned to receive either oral azacitidine 200 mg daily on days 1-14 of a repeat 28-day cycle (n = 278) or matching placebo (n = 274). Treatment was continued indefinitely until blast count was more than 15% or patients experienced unacceptable toxicity or underwent transplant.
At a median follow-up of more than 41.2 months, the median overall survival was significantly longer for patients who received oral azacitidine at 24.7 months versus 14.8 months for those who received placebo (hazard ratio, 0.69; P < .0009).
Relapse-free survival was also significantly prolonged to 10.2 months for patients who received oral azacitidine vs. 4.8 months for those who received placebo (HR, 0.65; P < .0001).
Serious adverse reactions occurred in 15% of patients who received azacitidine. Events that occurred in 2% of patients or more include pneumonia (8%) and febrile neutropenia (7%). There was one fatal event.
The most common adverse reactions were nausea (65% vs. 24%), vomiting (60% vs. 10%), diarrhea (50% vs. 21%), fatigue/asthenia (44% vs. 25%), constipation (39% vs. 24%), pneumonia (27% vs. 17%), abdominal pain (22% vs. 13%) arthralgia (14% vs. 10%), decreased appetite (13% vs. 6%), febrile neutropenia (12% vs. 8%), dizziness (11% vs. 9%), and pain in extremity (11% vs. 5%). Permanent discontinuation because of an adverse reaction occurred in 8% of patients.
A version of this article originally appeared on Medscape.com.
Sequential Targeted Treatment of an Elderly Patient With Acute Myeloid Leukemia Harboring Concurrent FLT3-TKD and IDH1 Mutations: A Case Report
INTRODUCTION: With the increasing availability of novel targeted therapies and next-generation sequencing (NGS) hematology panels, the treatment paradigm for patients with acute myeloid leukemia (AML) has recently been altered. Specifically, patients who bear mutations within the FMS-like tyrosine kinase (FLT3) gene or the isocitrate dehydrogenase (IDH) 1 or IDH2 genes may now be candidates for targeted treatments either in the frontline or relapsed or refractory (R/R) settings. The sequential targeted approach to AML patients who harbor mutations within both FLT3 and IDH genes has yet to be elucidated.
CASE PRESENTATION: Herein, we report a case of an elderly patient with FLT3 and IDH1 mutations who underwent induction chemotherapy in combination with midostaurin, and subsequently, ivosidenib in the R/R setting. Clonal evaluation was demonstrated with repeated cytogenetic analysis and NGS of blood and bone marrow specimens. At diagnosis, the patient’s AML harbored several pathogenic gene variants, including FLT3 and IDH1 mutations. Following induction chemotherapy with midostaurin, the patient’s FLT3 mutation was no longer detected. Upon relapse, the FLT3 mutation was still undetectable, however the IDH1 mutation remained. Unfortunately, the patient’s AML did not respond to ivosidenib, and expansion of a leukemic clone with a BCOR mutation was observed.
CONCLUSION: This case conveys the use of multiple targeted therapies in a sequential fashion for an AML patient with frequent completion of NGS panels to monitor clonal evolution. Given that a considerable minority of patients harbor both FLT3 and IDH mutations, further investigations evaluating optimal sequencing or combinations of targeted therapies are required.
INTRODUCTION: With the increasing availability of novel targeted therapies and next-generation sequencing (NGS) hematology panels, the treatment paradigm for patients with acute myeloid leukemia (AML) has recently been altered. Specifically, patients who bear mutations within the FMS-like tyrosine kinase (FLT3) gene or the isocitrate dehydrogenase (IDH) 1 or IDH2 genes may now be candidates for targeted treatments either in the frontline or relapsed or refractory (R/R) settings. The sequential targeted approach to AML patients who harbor mutations within both FLT3 and IDH genes has yet to be elucidated.
CASE PRESENTATION: Herein, we report a case of an elderly patient with FLT3 and IDH1 mutations who underwent induction chemotherapy in combination with midostaurin, and subsequently, ivosidenib in the R/R setting. Clonal evaluation was demonstrated with repeated cytogenetic analysis and NGS of blood and bone marrow specimens. At diagnosis, the patient’s AML harbored several pathogenic gene variants, including FLT3 and IDH1 mutations. Following induction chemotherapy with midostaurin, the patient’s FLT3 mutation was no longer detected. Upon relapse, the FLT3 mutation was still undetectable, however the IDH1 mutation remained. Unfortunately, the patient’s AML did not respond to ivosidenib, and expansion of a leukemic clone with a BCOR mutation was observed.
CONCLUSION: This case conveys the use of multiple targeted therapies in a sequential fashion for an AML patient with frequent completion of NGS panels to monitor clonal evolution. Given that a considerable minority of patients harbor both FLT3 and IDH mutations, further investigations evaluating optimal sequencing or combinations of targeted therapies are required.
INTRODUCTION: With the increasing availability of novel targeted therapies and next-generation sequencing (NGS) hematology panels, the treatment paradigm for patients with acute myeloid leukemia (AML) has recently been altered. Specifically, patients who bear mutations within the FMS-like tyrosine kinase (FLT3) gene or the isocitrate dehydrogenase (IDH) 1 or IDH2 genes may now be candidates for targeted treatments either in the frontline or relapsed or refractory (R/R) settings. The sequential targeted approach to AML patients who harbor mutations within both FLT3 and IDH genes has yet to be elucidated.
CASE PRESENTATION: Herein, we report a case of an elderly patient with FLT3 and IDH1 mutations who underwent induction chemotherapy in combination with midostaurin, and subsequently, ivosidenib in the R/R setting. Clonal evaluation was demonstrated with repeated cytogenetic analysis and NGS of blood and bone marrow specimens. At diagnosis, the patient’s AML harbored several pathogenic gene variants, including FLT3 and IDH1 mutations. Following induction chemotherapy with midostaurin, the patient’s FLT3 mutation was no longer detected. Upon relapse, the FLT3 mutation was still undetectable, however the IDH1 mutation remained. Unfortunately, the patient’s AML did not respond to ivosidenib, and expansion of a leukemic clone with a BCOR mutation was observed.
CONCLUSION: This case conveys the use of multiple targeted therapies in a sequential fashion for an AML patient with frequent completion of NGS panels to monitor clonal evolution. Given that a considerable minority of patients harbor both FLT3 and IDH mutations, further investigations evaluating optimal sequencing or combinations of targeted therapies are required.
Review of Efficacy and Safety Outcomes of Ibrutinib in a Veteran Population with Chronic Lymphocytic Leukemia
BACKGROUND/RATIONALE: Chronic lymphocytic leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) are indolent hematologic malignancies that account for one-quarter of all lymphomas primarily affecting older patients. Survival has improved due to the development of novel oral drugs with 85.1% 5-year survival in 2019. Ibrutinib is an oral Bruton’s tyrosine kinase inhibitor that interferes with malignant B-cell proliferation and survival. The National Comprehensive Cancer Network recommends ibrutinib as a category one treatment recommendation in all settings of CLL including relapsed/refractory disease and adverse cytogenetics. This study aims to improve clinical knowledge of ibrutinib’s efficacy and safety in a Veteran population.
OBJECTIVES: The primary objective was to determine the efficacy of ibrutinib in the Veteran population as defined by progression-free survival. Secondary objectives included overall survival, overall response, duration of therapy, and prevalence of adverse drug reactions.
METHODS: This was a single center, retrospective study conducted at the Southern Arizona VA Health Care System. A retrospective chart review of patients age 18-89 with CLL or SLL treated with ibrutinib between November 1st, 2013 to August 1st, 2019 was conducted. The Kaplan-Meier method was used to estimate overall survival and progression-free survival. Descriptive statistics was used for all other endpoints. RESULTS: Twenty-three patients were included in this study. Progression free survival and overall survival at 63 months (5.25 years) was 68.2% and 72.7%, respectively. The average duration of therapy was 20.3 months with 65.2% achieving partial response, 17.3% with stable disease, and 17.3% with progression of disease. The most common adverse events were gastrointestinal (21.7%) and cardiac (17.4%) including 3 patients who developed atrial fibrillation; 34.7% of patients required a dose reduction due to toxicity.
CONCLUSION: Use of ibrutinib in the Veteran population had similar progression-free survival as the clinical trials that led to its approval; however, slightly lower overall survival was noted compared to the clinical trials. The rate of atrial fibrillation was higher in the Veteran population compared to clinical trials, whereas the prevalence of gastrointestinal, dermatologic, neurologic, and musculoskeletal adverse events was consistent with published data.
BACKGROUND/RATIONALE: Chronic lymphocytic leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) are indolent hematologic malignancies that account for one-quarter of all lymphomas primarily affecting older patients. Survival has improved due to the development of novel oral drugs with 85.1% 5-year survival in 2019. Ibrutinib is an oral Bruton’s tyrosine kinase inhibitor that interferes with malignant B-cell proliferation and survival. The National Comprehensive Cancer Network recommends ibrutinib as a category one treatment recommendation in all settings of CLL including relapsed/refractory disease and adverse cytogenetics. This study aims to improve clinical knowledge of ibrutinib’s efficacy and safety in a Veteran population.
OBJECTIVES: The primary objective was to determine the efficacy of ibrutinib in the Veteran population as defined by progression-free survival. Secondary objectives included overall survival, overall response, duration of therapy, and prevalence of adverse drug reactions.
METHODS: This was a single center, retrospective study conducted at the Southern Arizona VA Health Care System. A retrospective chart review of patients age 18-89 with CLL or SLL treated with ibrutinib between November 1st, 2013 to August 1st, 2019 was conducted. The Kaplan-Meier method was used to estimate overall survival and progression-free survival. Descriptive statistics was used for all other endpoints. RESULTS: Twenty-three patients were included in this study. Progression free survival and overall survival at 63 months (5.25 years) was 68.2% and 72.7%, respectively. The average duration of therapy was 20.3 months with 65.2% achieving partial response, 17.3% with stable disease, and 17.3% with progression of disease. The most common adverse events were gastrointestinal (21.7%) and cardiac (17.4%) including 3 patients who developed atrial fibrillation; 34.7% of patients required a dose reduction due to toxicity.
CONCLUSION: Use of ibrutinib in the Veteran population had similar progression-free survival as the clinical trials that led to its approval; however, slightly lower overall survival was noted compared to the clinical trials. The rate of atrial fibrillation was higher in the Veteran population compared to clinical trials, whereas the prevalence of gastrointestinal, dermatologic, neurologic, and musculoskeletal adverse events was consistent with published data.
BACKGROUND/RATIONALE: Chronic lymphocytic leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) are indolent hematologic malignancies that account for one-quarter of all lymphomas primarily affecting older patients. Survival has improved due to the development of novel oral drugs with 85.1% 5-year survival in 2019. Ibrutinib is an oral Bruton’s tyrosine kinase inhibitor that interferes with malignant B-cell proliferation and survival. The National Comprehensive Cancer Network recommends ibrutinib as a category one treatment recommendation in all settings of CLL including relapsed/refractory disease and adverse cytogenetics. This study aims to improve clinical knowledge of ibrutinib’s efficacy and safety in a Veteran population.
OBJECTIVES: The primary objective was to determine the efficacy of ibrutinib in the Veteran population as defined by progression-free survival. Secondary objectives included overall survival, overall response, duration of therapy, and prevalence of adverse drug reactions.
METHODS: This was a single center, retrospective study conducted at the Southern Arizona VA Health Care System. A retrospective chart review of patients age 18-89 with CLL or SLL treated with ibrutinib between November 1st, 2013 to August 1st, 2019 was conducted. The Kaplan-Meier method was used to estimate overall survival and progression-free survival. Descriptive statistics was used for all other endpoints. RESULTS: Twenty-three patients were included in this study. Progression free survival and overall survival at 63 months (5.25 years) was 68.2% and 72.7%, respectively. The average duration of therapy was 20.3 months with 65.2% achieving partial response, 17.3% with stable disease, and 17.3% with progression of disease. The most common adverse events were gastrointestinal (21.7%) and cardiac (17.4%) including 3 patients who developed atrial fibrillation; 34.7% of patients required a dose reduction due to toxicity.
CONCLUSION: Use of ibrutinib in the Veteran population had similar progression-free survival as the clinical trials that led to its approval; however, slightly lower overall survival was noted compared to the clinical trials. The rate of atrial fibrillation was higher in the Veteran population compared to clinical trials, whereas the prevalence of gastrointestinal, dermatologic, neurologic, and musculoskeletal adverse events was consistent with published data.
VTE, sepsis risk increased among COVID-19 patients with cancer
, according to data from a registry study.
Researchers analyzed data on 5,556 patients with COVID-19 who had an inpatient or emergency encounter at Mount Sinai Health System (MSHS) in New York between March 1 and May 27, 2020. Patients were included in an anonymous MSHS COVID-19 registry.
There were 421 patients who had cancer: 96 with a hematologic malignancy and 325 with solid tumors.
After adjustment for age, gender, and number of comorbidities, the odds ratios for acute VTE and sepsis for patients with cancer (versus those without cancer) were 1.77 and 1.34, respectively. The adjusted odds ratio for mortality in cancer patients was 1.02.
The results remained “relatively consistent” after stratification by solid and nonsolid cancer types, with no significant difference in outcomes between those two groups, and results remained consistent in a propensity-matched model, according to Naomi Alpert, a biostatistician at Icahn School of Medicine at Mount Sinai, New York.
Ms. Alpert reported these findings at the AACR virtual meeting: COVID-19 and Cancer.
She noted that the cancer patients were older than the noncancer patients (mean age, 69.2 years vs. 63.8 years), and cancer patients were more likely to have two or more comorbid conditions (48.2% vs. 30.4%). Cancer patients also had significantly lower hemoglobin levels and red blood cell, platelet, and white blood cell counts (P < .01 for all).
“Low white blood cell count may be one of the reasons for higher risk of sepsis in cancer patients, as it may lead to a higher risk of infection,” Ms. Alpert said. “However, it’s not clear what role cancer therapies play in the risks of COVID-19 morbidity and mortality, so there is still quite a bit to learn.”
In fact, the findings are limited by a lack of information about cancer treatment, as the registry was not designed for that purpose, she noted.
Another study limitation is the short follow-up of a month or less in most patients, due, in part, to the novelty of COVID-19, but also to the lack of information on patients after they left the hospital.
“However, we had a very large sample size, with more than 400 cancer patients included, and, to our knowledge, this is the largest analysis of its kind to be done so far,” Ms. Alpert said. “In the future, it’s going to be very important to assess the effect of cancer therapies on COVID-19 complications and to see if prior therapies had any effect on outcomes.”
Longer follow-up would also be helpful for assessing the chronic effects of COVID-19 on cancer patients over time, she said. “It would be important to see whether some of these elevated risks of venous thromboembolism and sepsis are associated with longer-term mortality risks than what we were able to measure here,” she added.
Asked about the discrepancy between mortality in this study and those of larger registries, such as the COVID-19 and Cancer Consortium (CCC19) and TERAVOLT, Ms. Alpert noted that the current study included only patients who required hospitalization or emergency care.
“Our mortality rate was actually a bit higher than what was reported in some of the other studies,” she said. “We had about a 30% mortality rate in the cancer patients and about 25% for the noncancer patients, so ... we’re sort of looking at a subset of patients who we know are the sickest of the sick, which may explain some of the higher mortality that we’re seeing.”
Ms. Alpert reported having no disclosures.
SOURCE: Alpert N et al. AACR COVID-19 and Cancer, Abstract S12-02.
, according to data from a registry study.
Researchers analyzed data on 5,556 patients with COVID-19 who had an inpatient or emergency encounter at Mount Sinai Health System (MSHS) in New York between March 1 and May 27, 2020. Patients were included in an anonymous MSHS COVID-19 registry.
There were 421 patients who had cancer: 96 with a hematologic malignancy and 325 with solid tumors.
After adjustment for age, gender, and number of comorbidities, the odds ratios for acute VTE and sepsis for patients with cancer (versus those without cancer) were 1.77 and 1.34, respectively. The adjusted odds ratio for mortality in cancer patients was 1.02.
The results remained “relatively consistent” after stratification by solid and nonsolid cancer types, with no significant difference in outcomes between those two groups, and results remained consistent in a propensity-matched model, according to Naomi Alpert, a biostatistician at Icahn School of Medicine at Mount Sinai, New York.
Ms. Alpert reported these findings at the AACR virtual meeting: COVID-19 and Cancer.
She noted that the cancer patients were older than the noncancer patients (mean age, 69.2 years vs. 63.8 years), and cancer patients were more likely to have two or more comorbid conditions (48.2% vs. 30.4%). Cancer patients also had significantly lower hemoglobin levels and red blood cell, platelet, and white blood cell counts (P < .01 for all).
“Low white blood cell count may be one of the reasons for higher risk of sepsis in cancer patients, as it may lead to a higher risk of infection,” Ms. Alpert said. “However, it’s not clear what role cancer therapies play in the risks of COVID-19 morbidity and mortality, so there is still quite a bit to learn.”
In fact, the findings are limited by a lack of information about cancer treatment, as the registry was not designed for that purpose, she noted.
Another study limitation is the short follow-up of a month or less in most patients, due, in part, to the novelty of COVID-19, but also to the lack of information on patients after they left the hospital.
“However, we had a very large sample size, with more than 400 cancer patients included, and, to our knowledge, this is the largest analysis of its kind to be done so far,” Ms. Alpert said. “In the future, it’s going to be very important to assess the effect of cancer therapies on COVID-19 complications and to see if prior therapies had any effect on outcomes.”
Longer follow-up would also be helpful for assessing the chronic effects of COVID-19 on cancer patients over time, she said. “It would be important to see whether some of these elevated risks of venous thromboembolism and sepsis are associated with longer-term mortality risks than what we were able to measure here,” she added.
Asked about the discrepancy between mortality in this study and those of larger registries, such as the COVID-19 and Cancer Consortium (CCC19) and TERAVOLT, Ms. Alpert noted that the current study included only patients who required hospitalization or emergency care.
“Our mortality rate was actually a bit higher than what was reported in some of the other studies,” she said. “We had about a 30% mortality rate in the cancer patients and about 25% for the noncancer patients, so ... we’re sort of looking at a subset of patients who we know are the sickest of the sick, which may explain some of the higher mortality that we’re seeing.”
Ms. Alpert reported having no disclosures.
SOURCE: Alpert N et al. AACR COVID-19 and Cancer, Abstract S12-02.
, according to data from a registry study.
Researchers analyzed data on 5,556 patients with COVID-19 who had an inpatient or emergency encounter at Mount Sinai Health System (MSHS) in New York between March 1 and May 27, 2020. Patients were included in an anonymous MSHS COVID-19 registry.
There were 421 patients who had cancer: 96 with a hematologic malignancy and 325 with solid tumors.
After adjustment for age, gender, and number of comorbidities, the odds ratios for acute VTE and sepsis for patients with cancer (versus those without cancer) were 1.77 and 1.34, respectively. The adjusted odds ratio for mortality in cancer patients was 1.02.
The results remained “relatively consistent” after stratification by solid and nonsolid cancer types, with no significant difference in outcomes between those two groups, and results remained consistent in a propensity-matched model, according to Naomi Alpert, a biostatistician at Icahn School of Medicine at Mount Sinai, New York.
Ms. Alpert reported these findings at the AACR virtual meeting: COVID-19 and Cancer.
She noted that the cancer patients were older than the noncancer patients (mean age, 69.2 years vs. 63.8 years), and cancer patients were more likely to have two or more comorbid conditions (48.2% vs. 30.4%). Cancer patients also had significantly lower hemoglobin levels and red blood cell, platelet, and white blood cell counts (P < .01 for all).
“Low white blood cell count may be one of the reasons for higher risk of sepsis in cancer patients, as it may lead to a higher risk of infection,” Ms. Alpert said. “However, it’s not clear what role cancer therapies play in the risks of COVID-19 morbidity and mortality, so there is still quite a bit to learn.”
In fact, the findings are limited by a lack of information about cancer treatment, as the registry was not designed for that purpose, she noted.
Another study limitation is the short follow-up of a month or less in most patients, due, in part, to the novelty of COVID-19, but also to the lack of information on patients after they left the hospital.
“However, we had a very large sample size, with more than 400 cancer patients included, and, to our knowledge, this is the largest analysis of its kind to be done so far,” Ms. Alpert said. “In the future, it’s going to be very important to assess the effect of cancer therapies on COVID-19 complications and to see if prior therapies had any effect on outcomes.”
Longer follow-up would also be helpful for assessing the chronic effects of COVID-19 on cancer patients over time, she said. “It would be important to see whether some of these elevated risks of venous thromboembolism and sepsis are associated with longer-term mortality risks than what we were able to measure here,” she added.
Asked about the discrepancy between mortality in this study and those of larger registries, such as the COVID-19 and Cancer Consortium (CCC19) and TERAVOLT, Ms. Alpert noted that the current study included only patients who required hospitalization or emergency care.
“Our mortality rate was actually a bit higher than what was reported in some of the other studies,” she said. “We had about a 30% mortality rate in the cancer patients and about 25% for the noncancer patients, so ... we’re sort of looking at a subset of patients who we know are the sickest of the sick, which may explain some of the higher mortality that we’re seeing.”
Ms. Alpert reported having no disclosures.
SOURCE: Alpert N et al. AACR COVID-19 and Cancer, Abstract S12-02.
FROM AACR: COVID-19 AND CANCER