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Ibrutinib tops chlorambucil against CLL
AMSTERDAM – After 5 years, a large majority of patients with chronic lymphocytic leukemia treated with front-line ibrutinib (Imbruvica) have not experienced disease progression, and the median progression-free survival has still not been reached, long-term follow-up from the RESONATE-2 shows.
The 5-year estimated progression-free survival (PFS) rates were 70% for patients who had been randomized to receive ibrutinib monotherapy, compared with 12% for patients randomized to chlorambucil, reported Alessandra Tedeschi, MD, from Azienda Ospedaliera Niguarda Ca’ Granda in Milan.
Ibrutinib was also associated with a halving of risk for death, compared with chlorambucil, she said at the annual congress of the European Hematology Association.
“Importantly, the rate of progression during ibrutinib treatment was very low; only 8 – that is, 6% of patients” – experienced disease progression while receiving ibrutinib, she noted.
In the RESONATE-2 (PCYC-1115) trial, investigators enrolled 269 adults aged 65 years and older with previously untreated CLL/small lymphocytic lymphoma (SLL). Patients at the younger end of the age range (65-69 years) had to have comorbidities that would have made them ineligible for the FCR chemotherapy regimen (fludarabine, cyclophosphamide, and rituximab). Additionally, patients with the deleterious 17p deletion were excluded.
Patients were stratified by performance status and Rai stage and then randomized to receive either ibrutinib 420 mg once daily until disease progression or unacceptable toxicity (136 patients) or chlorambucil 0.5 mg/kg to a maximum of 0.8 mg/kg for up to 12 cycles (133 patients). The trial also had an extension study for patients who had disease progression as confirmed by an independent review committee or who had completed the RESONATE-2 trial. Of the 133 patients in the chlorambucil arm, 76 (57% of the intention-to-treat population) were crossed over to ibrutinib following disease progression.
The median duration of ibrutinib treatment was 57.1 months, with 73% of patients being on it for more than 3 years, 65% for more than 4 years, and 27% for more than 5 years. As of the data cutoff, 79 patients (58%) were continuing with ibrutinib on study.
At 5 years, 70% of ibrutinib-treated patients and 12% of chlorambucil-treated patients were estimated to be progression-free and alive (hazard ratio for PFS with ibrutinib 0.146 (95% confidence interval, 0.10-0.22). The benefit of ibrutinib was consistent for patients with high-risk genomic features, including the 11q deletion and unmutated immunoglobulin heavy-chain variable genes.
Estimated 5-year overall survival was also better with ibrutinib, at 83% vs. 68% (hazard ratio, 0.45; 95% CI, 0.266-0.761).
The most common grade 3 or greater adverse events occurring with ibrutinib were neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), hyponatremia (6%), atrial fibrillation (5%), and cataract (5%). The rates of most adverse events decreased over time, and dose reductions because of adverse events also diminished over time, from 5% of patients in the first year down to zero in years 4 through 5.
Patients responded to subsequent CLL therapies following ibrutinib discontinuation, including chemoimmunotherapy and other kinase inhibitors, Dr. Tedeschi said.
The trial was sponsored by Pharmacyclics with collaboration from Janssen Research & Development. Dr. Tedeschi reported advisory board activities with Janssen, AbbVie, and BeiGene.
SOURCE: Tedeschi A et al. EHA Congress, Abstract S107.
AMSTERDAM – After 5 years, a large majority of patients with chronic lymphocytic leukemia treated with front-line ibrutinib (Imbruvica) have not experienced disease progression, and the median progression-free survival has still not been reached, long-term follow-up from the RESONATE-2 shows.
The 5-year estimated progression-free survival (PFS) rates were 70% for patients who had been randomized to receive ibrutinib monotherapy, compared with 12% for patients randomized to chlorambucil, reported Alessandra Tedeschi, MD, from Azienda Ospedaliera Niguarda Ca’ Granda in Milan.
Ibrutinib was also associated with a halving of risk for death, compared with chlorambucil, she said at the annual congress of the European Hematology Association.
“Importantly, the rate of progression during ibrutinib treatment was very low; only 8 – that is, 6% of patients” – experienced disease progression while receiving ibrutinib, she noted.
In the RESONATE-2 (PCYC-1115) trial, investigators enrolled 269 adults aged 65 years and older with previously untreated CLL/small lymphocytic lymphoma (SLL). Patients at the younger end of the age range (65-69 years) had to have comorbidities that would have made them ineligible for the FCR chemotherapy regimen (fludarabine, cyclophosphamide, and rituximab). Additionally, patients with the deleterious 17p deletion were excluded.
Patients were stratified by performance status and Rai stage and then randomized to receive either ibrutinib 420 mg once daily until disease progression or unacceptable toxicity (136 patients) or chlorambucil 0.5 mg/kg to a maximum of 0.8 mg/kg for up to 12 cycles (133 patients). The trial also had an extension study for patients who had disease progression as confirmed by an independent review committee or who had completed the RESONATE-2 trial. Of the 133 patients in the chlorambucil arm, 76 (57% of the intention-to-treat population) were crossed over to ibrutinib following disease progression.
The median duration of ibrutinib treatment was 57.1 months, with 73% of patients being on it for more than 3 years, 65% for more than 4 years, and 27% for more than 5 years. As of the data cutoff, 79 patients (58%) were continuing with ibrutinib on study.
At 5 years, 70% of ibrutinib-treated patients and 12% of chlorambucil-treated patients were estimated to be progression-free and alive (hazard ratio for PFS with ibrutinib 0.146 (95% confidence interval, 0.10-0.22). The benefit of ibrutinib was consistent for patients with high-risk genomic features, including the 11q deletion and unmutated immunoglobulin heavy-chain variable genes.
Estimated 5-year overall survival was also better with ibrutinib, at 83% vs. 68% (hazard ratio, 0.45; 95% CI, 0.266-0.761).
The most common grade 3 or greater adverse events occurring with ibrutinib were neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), hyponatremia (6%), atrial fibrillation (5%), and cataract (5%). The rates of most adverse events decreased over time, and dose reductions because of adverse events also diminished over time, from 5% of patients in the first year down to zero in years 4 through 5.
Patients responded to subsequent CLL therapies following ibrutinib discontinuation, including chemoimmunotherapy and other kinase inhibitors, Dr. Tedeschi said.
The trial was sponsored by Pharmacyclics with collaboration from Janssen Research & Development. Dr. Tedeschi reported advisory board activities with Janssen, AbbVie, and BeiGene.
SOURCE: Tedeschi A et al. EHA Congress, Abstract S107.
AMSTERDAM – After 5 years, a large majority of patients with chronic lymphocytic leukemia treated with front-line ibrutinib (Imbruvica) have not experienced disease progression, and the median progression-free survival has still not been reached, long-term follow-up from the RESONATE-2 shows.
The 5-year estimated progression-free survival (PFS) rates were 70% for patients who had been randomized to receive ibrutinib monotherapy, compared with 12% for patients randomized to chlorambucil, reported Alessandra Tedeschi, MD, from Azienda Ospedaliera Niguarda Ca’ Granda in Milan.
Ibrutinib was also associated with a halving of risk for death, compared with chlorambucil, she said at the annual congress of the European Hematology Association.
“Importantly, the rate of progression during ibrutinib treatment was very low; only 8 – that is, 6% of patients” – experienced disease progression while receiving ibrutinib, she noted.
In the RESONATE-2 (PCYC-1115) trial, investigators enrolled 269 adults aged 65 years and older with previously untreated CLL/small lymphocytic lymphoma (SLL). Patients at the younger end of the age range (65-69 years) had to have comorbidities that would have made them ineligible for the FCR chemotherapy regimen (fludarabine, cyclophosphamide, and rituximab). Additionally, patients with the deleterious 17p deletion were excluded.
Patients were stratified by performance status and Rai stage and then randomized to receive either ibrutinib 420 mg once daily until disease progression or unacceptable toxicity (136 patients) or chlorambucil 0.5 mg/kg to a maximum of 0.8 mg/kg for up to 12 cycles (133 patients). The trial also had an extension study for patients who had disease progression as confirmed by an independent review committee or who had completed the RESONATE-2 trial. Of the 133 patients in the chlorambucil arm, 76 (57% of the intention-to-treat population) were crossed over to ibrutinib following disease progression.
The median duration of ibrutinib treatment was 57.1 months, with 73% of patients being on it for more than 3 years, 65% for more than 4 years, and 27% for more than 5 years. As of the data cutoff, 79 patients (58%) were continuing with ibrutinib on study.
At 5 years, 70% of ibrutinib-treated patients and 12% of chlorambucil-treated patients were estimated to be progression-free and alive (hazard ratio for PFS with ibrutinib 0.146 (95% confidence interval, 0.10-0.22). The benefit of ibrutinib was consistent for patients with high-risk genomic features, including the 11q deletion and unmutated immunoglobulin heavy-chain variable genes.
Estimated 5-year overall survival was also better with ibrutinib, at 83% vs. 68% (hazard ratio, 0.45; 95% CI, 0.266-0.761).
The most common grade 3 or greater adverse events occurring with ibrutinib were neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), hyponatremia (6%), atrial fibrillation (5%), and cataract (5%). The rates of most adverse events decreased over time, and dose reductions because of adverse events also diminished over time, from 5% of patients in the first year down to zero in years 4 through 5.
Patients responded to subsequent CLL therapies following ibrutinib discontinuation, including chemoimmunotherapy and other kinase inhibitors, Dr. Tedeschi said.
The trial was sponsored by Pharmacyclics with collaboration from Janssen Research & Development. Dr. Tedeschi reported advisory board activities with Janssen, AbbVie, and BeiGene.
SOURCE: Tedeschi A et al. EHA Congress, Abstract S107.
REPORTING FROM EHA CONGRESS
Recombinant vaccine cut herpes zoster rate in immunocompromised patients
Two doses of recombinant zoster vaccine significantly reduced incidence of herpes zoster in adults who had undergone autologous hematopoietic stem cell transplantation (HSCT), results of a randomized, placebo-controlled trial indicate.
The incidence of herpes zoster was 30 per 1,000 person-years for patients who received the adjuvanted recombinant zoster vaccine (Shingrix) versus 94 per 1,000 person-years for those who received placebo, according to study results.
Recombinant zoster vaccine induced humoral and cellular responses that were strong and occurring at a rate higher than what was seen in the placebo group, said senior author Keith M. Sullivan, MD, of Duke University Medical Center, Durham, N.C., and coauthors, who reported findings on behalf of the Zoster Efficacy Study in Patients Undergoing HSCT (ZOE-HSCT) Study Group.
“The vaccinations were generally well tolerated, and most symptoms were mild and transient and did not substantially deter participants from receiving their second dose,” Dr. Sullivan and colleagues wrote in JAMA.
The risk of herpes zoster is increased for 2-3 years after autologous HSCT because of diminished T-cell immunity, according to the authors.
“Antiviral prophylaxis is commonly administered to patients after HSCT to prevent such complications, but the efficacy depends on adherence to treatment,” they said.
While vaccines could provide long-term protection, immunocompromised individuals receiving live attenuated vaccine would be at increased risk of varicella caused by spread of the vaccine strain, they added.
There have been a few encouraging recent studies of non-live vaccines in this setting, including one large phase 3 trial of a heat-inactivated varicella-zoster virus vaccine that showed patients undergoing autologous HSCT had a 63.8% estimated efficacy in preventing herpes zoster, investigators from that study said in The Lancet (2018 May 26;391[10135]:2116-27).
A phase 1/2a study of the adjuvanted recombinant zoster vaccine in patients undergoing HSCT demonstrated strong humoral and cell-mediated immunity responses, which provided the rationale for studying the vaccine further in the randomized ZOE-HSCT study, according to Dr. Sullivan and coauthors.
Their study included a total of 1,846 adults who had undergone autologous HSCT. They were randomized to receive two doses of the recombinant zoster vaccine, the first at 50-70 days after the procedure and the second 1-2 months later.
Herpes zoster cases were seen in 49 and 136 individuals in the vaccine and placebo groups, respectively, which resulted in overall incidences of 30 and 94 per 1,000 person-years.
The incidence rate ratio of a first episode of herpes zoster was 0.36 for individuals receiving at least one dose, which authors said was equivalent to a vaccine efficacy of 63.7%.
That efficacy rate is “very similar” to the estimated efficacy reported for the heat-inactivated varicella-zoster virus vaccine reported in The Lancet, said Dr. Sullivan and coauthors.
However, the heat-inactivated vaccine achieved that level of protection with a four-dose schedule, including one dose given prior to autologous HSCT.
“An advantage of the short 2-dose posttransplantation schedule is that more patients might complete the vaccination program,” they said in a discussion of the results, noting that 94.7% of the recombinant zoster vaccine recipients completed two doses, compared with 81.9% of recipients who received the heat-inactivated herpes zoster vaccine in the previous report.
The study was funded and sponsored by GlaxoSmithKline Biologicals SA. Dr. Sullivan reported disclosures related to GlaxoSmithKline (GSK), Kiadis Pharmaceutical, Roche Genentech, and the National Institute of Allergy and Infectious Diseases. Coauthors provided disclosures related to GSK, AbbVie, Roche, Gilead, Janssen, Pharmacyclics, Morphosys, Helsinn, Celgene, and others.
SOURCE: Bastidas A et al. JAMA. 2019 July 9. doi: 10.1001/jama.2019.9053.
Two doses of recombinant zoster vaccine significantly reduced incidence of herpes zoster in adults who had undergone autologous hematopoietic stem cell transplantation (HSCT), results of a randomized, placebo-controlled trial indicate.
The incidence of herpes zoster was 30 per 1,000 person-years for patients who received the adjuvanted recombinant zoster vaccine (Shingrix) versus 94 per 1,000 person-years for those who received placebo, according to study results.
Recombinant zoster vaccine induced humoral and cellular responses that were strong and occurring at a rate higher than what was seen in the placebo group, said senior author Keith M. Sullivan, MD, of Duke University Medical Center, Durham, N.C., and coauthors, who reported findings on behalf of the Zoster Efficacy Study in Patients Undergoing HSCT (ZOE-HSCT) Study Group.
“The vaccinations were generally well tolerated, and most symptoms were mild and transient and did not substantially deter participants from receiving their second dose,” Dr. Sullivan and colleagues wrote in JAMA.
The risk of herpes zoster is increased for 2-3 years after autologous HSCT because of diminished T-cell immunity, according to the authors.
“Antiviral prophylaxis is commonly administered to patients after HSCT to prevent such complications, but the efficacy depends on adherence to treatment,” they said.
While vaccines could provide long-term protection, immunocompromised individuals receiving live attenuated vaccine would be at increased risk of varicella caused by spread of the vaccine strain, they added.
There have been a few encouraging recent studies of non-live vaccines in this setting, including one large phase 3 trial of a heat-inactivated varicella-zoster virus vaccine that showed patients undergoing autologous HSCT had a 63.8% estimated efficacy in preventing herpes zoster, investigators from that study said in The Lancet (2018 May 26;391[10135]:2116-27).
A phase 1/2a study of the adjuvanted recombinant zoster vaccine in patients undergoing HSCT demonstrated strong humoral and cell-mediated immunity responses, which provided the rationale for studying the vaccine further in the randomized ZOE-HSCT study, according to Dr. Sullivan and coauthors.
Their study included a total of 1,846 adults who had undergone autologous HSCT. They were randomized to receive two doses of the recombinant zoster vaccine, the first at 50-70 days after the procedure and the second 1-2 months later.
Herpes zoster cases were seen in 49 and 136 individuals in the vaccine and placebo groups, respectively, which resulted in overall incidences of 30 and 94 per 1,000 person-years.
The incidence rate ratio of a first episode of herpes zoster was 0.36 for individuals receiving at least one dose, which authors said was equivalent to a vaccine efficacy of 63.7%.
That efficacy rate is “very similar” to the estimated efficacy reported for the heat-inactivated varicella-zoster virus vaccine reported in The Lancet, said Dr. Sullivan and coauthors.
However, the heat-inactivated vaccine achieved that level of protection with a four-dose schedule, including one dose given prior to autologous HSCT.
“An advantage of the short 2-dose posttransplantation schedule is that more patients might complete the vaccination program,” they said in a discussion of the results, noting that 94.7% of the recombinant zoster vaccine recipients completed two doses, compared with 81.9% of recipients who received the heat-inactivated herpes zoster vaccine in the previous report.
The study was funded and sponsored by GlaxoSmithKline Biologicals SA. Dr. Sullivan reported disclosures related to GlaxoSmithKline (GSK), Kiadis Pharmaceutical, Roche Genentech, and the National Institute of Allergy and Infectious Diseases. Coauthors provided disclosures related to GSK, AbbVie, Roche, Gilead, Janssen, Pharmacyclics, Morphosys, Helsinn, Celgene, and others.
SOURCE: Bastidas A et al. JAMA. 2019 July 9. doi: 10.1001/jama.2019.9053.
Two doses of recombinant zoster vaccine significantly reduced incidence of herpes zoster in adults who had undergone autologous hematopoietic stem cell transplantation (HSCT), results of a randomized, placebo-controlled trial indicate.
The incidence of herpes zoster was 30 per 1,000 person-years for patients who received the adjuvanted recombinant zoster vaccine (Shingrix) versus 94 per 1,000 person-years for those who received placebo, according to study results.
Recombinant zoster vaccine induced humoral and cellular responses that were strong and occurring at a rate higher than what was seen in the placebo group, said senior author Keith M. Sullivan, MD, of Duke University Medical Center, Durham, N.C., and coauthors, who reported findings on behalf of the Zoster Efficacy Study in Patients Undergoing HSCT (ZOE-HSCT) Study Group.
“The vaccinations were generally well tolerated, and most symptoms were mild and transient and did not substantially deter participants from receiving their second dose,” Dr. Sullivan and colleagues wrote in JAMA.
The risk of herpes zoster is increased for 2-3 years after autologous HSCT because of diminished T-cell immunity, according to the authors.
“Antiviral prophylaxis is commonly administered to patients after HSCT to prevent such complications, but the efficacy depends on adherence to treatment,” they said.
While vaccines could provide long-term protection, immunocompromised individuals receiving live attenuated vaccine would be at increased risk of varicella caused by spread of the vaccine strain, they added.
There have been a few encouraging recent studies of non-live vaccines in this setting, including one large phase 3 trial of a heat-inactivated varicella-zoster virus vaccine that showed patients undergoing autologous HSCT had a 63.8% estimated efficacy in preventing herpes zoster, investigators from that study said in The Lancet (2018 May 26;391[10135]:2116-27).
A phase 1/2a study of the adjuvanted recombinant zoster vaccine in patients undergoing HSCT demonstrated strong humoral and cell-mediated immunity responses, which provided the rationale for studying the vaccine further in the randomized ZOE-HSCT study, according to Dr. Sullivan and coauthors.
Their study included a total of 1,846 adults who had undergone autologous HSCT. They were randomized to receive two doses of the recombinant zoster vaccine, the first at 50-70 days after the procedure and the second 1-2 months later.
Herpes zoster cases were seen in 49 and 136 individuals in the vaccine and placebo groups, respectively, which resulted in overall incidences of 30 and 94 per 1,000 person-years.
The incidence rate ratio of a first episode of herpes zoster was 0.36 for individuals receiving at least one dose, which authors said was equivalent to a vaccine efficacy of 63.7%.
That efficacy rate is “very similar” to the estimated efficacy reported for the heat-inactivated varicella-zoster virus vaccine reported in The Lancet, said Dr. Sullivan and coauthors.
However, the heat-inactivated vaccine achieved that level of protection with a four-dose schedule, including one dose given prior to autologous HSCT.
“An advantage of the short 2-dose posttransplantation schedule is that more patients might complete the vaccination program,” they said in a discussion of the results, noting that 94.7% of the recombinant zoster vaccine recipients completed two doses, compared with 81.9% of recipients who received the heat-inactivated herpes zoster vaccine in the previous report.
The study was funded and sponsored by GlaxoSmithKline Biologicals SA. Dr. Sullivan reported disclosures related to GlaxoSmithKline (GSK), Kiadis Pharmaceutical, Roche Genentech, and the National Institute of Allergy and Infectious Diseases. Coauthors provided disclosures related to GSK, AbbVie, Roche, Gilead, Janssen, Pharmacyclics, Morphosys, Helsinn, Celgene, and others.
SOURCE: Bastidas A et al. JAMA. 2019 July 9. doi: 10.1001/jama.2019.9053.
FROM JAMA
Key clinical point: Two doses of recombinant zoster vaccine significantly reduced incidence of herpes zoster versus placebo in adults who had undergone autologous hematopoietic stem cell transplantation (HSCT).
Major finding: Herpes zoster cases were seen in 49 and 136 individuals in the vaccine and placebo groups, respectively, resulting in overall incidences of 30 and 94 per 1,000 person-years.
Study details: A randomized clinical trial (ZOE-HSCT) including 1,846 adults who had undergone autologous HSCT.
Disclosures: The study was funded and sponsored by GlaxoSmithKline Biologicals SA. Study authors reported disclosures related to GlaxoSmithKline, Kiadis Pharmaceutical, Roche Genentech, AbbVie, Roche, Gilead, Janssen, Pharmacyclics, Morphosys, Helsinn, Celgene, and others.
Source: Bastidas A et al. JAMA. 2019 July 9. doi: 10.1001/jama.2019.9053.
FDA approves Xpovio for relapsed/refractory multiple myeloma
The oral therapy was approved for patients who have received at least four prior therapies and whose disease is resistant to several other forms of treatment, including at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody, according to the FDA.
The approval provides a “treatment option for patients with multiple myeloma with no (other) available therapy,” said Richard Pazdur, MD, director of the FDA Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA Center for Drug Evaluation and Research.
The approval was based on a study that included 83 patients with RRMM who had an overall response rate of 25.3% to Xpovio in combination with dexamethasone.
“The median time to first response was 4 weeks, with a range of 1-10 weeks. The median duration of response was 3.8 months. The efficacy evaluation was supported by additional information from an ongoing, randomized trial in patients with multiple myeloma,” according to the statement.
Common side effects seen in patients taking Xpovio in combination with dexamethasone include leukopenia, neutropenia, thrombocytopenia, and anemia. Patients also reported vomiting, nausea, fatigue, diarrhea, fever, decreased appetite and weight, constipation, upper respiratory tract infections, and hyponatremia.
Patients taking Xpovio should be monitored for low blood counts, platelets, and sodium levels, and should avoid other medications that may cause dizziness or confusion. Patients’ hydration status, blood counts, and other medications should be optimized to avoid dizziness or confusion. Females of reproductive age and males with a female partner of reproductive potential must use effective contraception during treatment with Xpovio. Women who are pregnant or breastfeeding should not take Xpovio.
Xpovio must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.
Xpovio in combination with dexamethasone was granted accelerated approval, and further clinical trials are required to verify and describe the drug’s clinical benefit.
The FDA granted the approval of Xpovio to Karyopharm Therapeutics.
The oral therapy was approved for patients who have received at least four prior therapies and whose disease is resistant to several other forms of treatment, including at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody, according to the FDA.
The approval provides a “treatment option for patients with multiple myeloma with no (other) available therapy,” said Richard Pazdur, MD, director of the FDA Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA Center for Drug Evaluation and Research.
The approval was based on a study that included 83 patients with RRMM who had an overall response rate of 25.3% to Xpovio in combination with dexamethasone.
“The median time to first response was 4 weeks, with a range of 1-10 weeks. The median duration of response was 3.8 months. The efficacy evaluation was supported by additional information from an ongoing, randomized trial in patients with multiple myeloma,” according to the statement.
Common side effects seen in patients taking Xpovio in combination with dexamethasone include leukopenia, neutropenia, thrombocytopenia, and anemia. Patients also reported vomiting, nausea, fatigue, diarrhea, fever, decreased appetite and weight, constipation, upper respiratory tract infections, and hyponatremia.
Patients taking Xpovio should be monitored for low blood counts, platelets, and sodium levels, and should avoid other medications that may cause dizziness or confusion. Patients’ hydration status, blood counts, and other medications should be optimized to avoid dizziness or confusion. Females of reproductive age and males with a female partner of reproductive potential must use effective contraception during treatment with Xpovio. Women who are pregnant or breastfeeding should not take Xpovio.
Xpovio must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.
Xpovio in combination with dexamethasone was granted accelerated approval, and further clinical trials are required to verify and describe the drug’s clinical benefit.
The FDA granted the approval of Xpovio to Karyopharm Therapeutics.
The oral therapy was approved for patients who have received at least four prior therapies and whose disease is resistant to several other forms of treatment, including at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody, according to the FDA.
The approval provides a “treatment option for patients with multiple myeloma with no (other) available therapy,” said Richard Pazdur, MD, director of the FDA Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA Center for Drug Evaluation and Research.
The approval was based on a study that included 83 patients with RRMM who had an overall response rate of 25.3% to Xpovio in combination with dexamethasone.
“The median time to first response was 4 weeks, with a range of 1-10 weeks. The median duration of response was 3.8 months. The efficacy evaluation was supported by additional information from an ongoing, randomized trial in patients with multiple myeloma,” according to the statement.
Common side effects seen in patients taking Xpovio in combination with dexamethasone include leukopenia, neutropenia, thrombocytopenia, and anemia. Patients also reported vomiting, nausea, fatigue, diarrhea, fever, decreased appetite and weight, constipation, upper respiratory tract infections, and hyponatremia.
Patients taking Xpovio should be monitored for low blood counts, platelets, and sodium levels, and should avoid other medications that may cause dizziness or confusion. Patients’ hydration status, blood counts, and other medications should be optimized to avoid dizziness or confusion. Females of reproductive age and males with a female partner of reproductive potential must use effective contraception during treatment with Xpovio. Women who are pregnant or breastfeeding should not take Xpovio.
Xpovio must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.
Xpovio in combination with dexamethasone was granted accelerated approval, and further clinical trials are required to verify and describe the drug’s clinical benefit.
The FDA granted the approval of Xpovio to Karyopharm Therapeutics.
Researchers propose new risk groups for NK-AML
NEWPORT BEACH, CALIF. – New research suggests patients with normal karyotype acute myeloid leukemia (NK-AML) can be divided into four risk groups associated with overall survival.
Investigators used machine learning algorithms to study the association between mutations and overall survival in 1,352 patients with NK-AML. The analysis revealed combinations of mutations that could be used to classify NK-AML patients into favorable, intermediate-1, intermediate-2, and unfavorable risk groups.
For example, patients who had NPM1 mutations but wild-type FLT3-ITD and DNMT3A, had a median overall survival of 99.1 months and could be classified as favorable risk. Conversely, patients who had NPM1, FLT3-ITD, and DNMT3A mutations, had a median overall survival of 13.4 months and could be classified as unfavorable risk.
Aziz Nazha, MD, of the Cleveland Clinic, and his colleagues conducted this research and presented the findings at the Acute Leukemia Forum of Hemedicus.
The investigators looked at genomic and clinical data from 1,352 patients with NK-AML. The patients were a median age of 55 years and had a median white blood cell count of 21.3 x 109/L, a median hemoglobin of 9.1 g/dL, and a median platelet count of 61 x 109/L. More than half of patients (57.3%) were male.
The patients were screened for 35 genes that are commonly mutated in AML and other myeloid malignancies. The investigators used machine learning algorithms, including random survival forest and recommender system algorithms, to study the association between mutations and overall survival in an “unbiased” way.
Dr. Nazha said there were a median of three mutations per patient sample, and “there are some competing interests between those mutations to impact the prognosis of the patient.”
The investigators used the mutations and their associations with overall survival to classify patients into the risk groups outlined in the table below.
These findings can improve the risk stratification of NK-AML and may aid physicians in making treatment decisions, according to Dr. Nazha and his colleagues. To move this work forward, the investigators are attempting to develop a personalized model that can make predictions specific to an individual patient based on that patient’s mutation information.
Dr. Nazha reported having no financial disclosures relevant to this research. Other investigators reported relationships with the Munich Leukemia Laboratory.
The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
NEWPORT BEACH, CALIF. – New research suggests patients with normal karyotype acute myeloid leukemia (NK-AML) can be divided into four risk groups associated with overall survival.
Investigators used machine learning algorithms to study the association between mutations and overall survival in 1,352 patients with NK-AML. The analysis revealed combinations of mutations that could be used to classify NK-AML patients into favorable, intermediate-1, intermediate-2, and unfavorable risk groups.
For example, patients who had NPM1 mutations but wild-type FLT3-ITD and DNMT3A, had a median overall survival of 99.1 months and could be classified as favorable risk. Conversely, patients who had NPM1, FLT3-ITD, and DNMT3A mutations, had a median overall survival of 13.4 months and could be classified as unfavorable risk.
Aziz Nazha, MD, of the Cleveland Clinic, and his colleagues conducted this research and presented the findings at the Acute Leukemia Forum of Hemedicus.
The investigators looked at genomic and clinical data from 1,352 patients with NK-AML. The patients were a median age of 55 years and had a median white blood cell count of 21.3 x 109/L, a median hemoglobin of 9.1 g/dL, and a median platelet count of 61 x 109/L. More than half of patients (57.3%) were male.
The patients were screened for 35 genes that are commonly mutated in AML and other myeloid malignancies. The investigators used machine learning algorithms, including random survival forest and recommender system algorithms, to study the association between mutations and overall survival in an “unbiased” way.
Dr. Nazha said there were a median of three mutations per patient sample, and “there are some competing interests between those mutations to impact the prognosis of the patient.”
The investigators used the mutations and their associations with overall survival to classify patients into the risk groups outlined in the table below.
These findings can improve the risk stratification of NK-AML and may aid physicians in making treatment decisions, according to Dr. Nazha and his colleagues. To move this work forward, the investigators are attempting to develop a personalized model that can make predictions specific to an individual patient based on that patient’s mutation information.
Dr. Nazha reported having no financial disclosures relevant to this research. Other investigators reported relationships with the Munich Leukemia Laboratory.
The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
NEWPORT BEACH, CALIF. – New research suggests patients with normal karyotype acute myeloid leukemia (NK-AML) can be divided into four risk groups associated with overall survival.
Investigators used machine learning algorithms to study the association between mutations and overall survival in 1,352 patients with NK-AML. The analysis revealed combinations of mutations that could be used to classify NK-AML patients into favorable, intermediate-1, intermediate-2, and unfavorable risk groups.
For example, patients who had NPM1 mutations but wild-type FLT3-ITD and DNMT3A, had a median overall survival of 99.1 months and could be classified as favorable risk. Conversely, patients who had NPM1, FLT3-ITD, and DNMT3A mutations, had a median overall survival of 13.4 months and could be classified as unfavorable risk.
Aziz Nazha, MD, of the Cleveland Clinic, and his colleagues conducted this research and presented the findings at the Acute Leukemia Forum of Hemedicus.
The investigators looked at genomic and clinical data from 1,352 patients with NK-AML. The patients were a median age of 55 years and had a median white blood cell count of 21.3 x 109/L, a median hemoglobin of 9.1 g/dL, and a median platelet count of 61 x 109/L. More than half of patients (57.3%) were male.
The patients were screened for 35 genes that are commonly mutated in AML and other myeloid malignancies. The investigators used machine learning algorithms, including random survival forest and recommender system algorithms, to study the association between mutations and overall survival in an “unbiased” way.
Dr. Nazha said there were a median of three mutations per patient sample, and “there are some competing interests between those mutations to impact the prognosis of the patient.”
The investigators used the mutations and their associations with overall survival to classify patients into the risk groups outlined in the table below.
These findings can improve the risk stratification of NK-AML and may aid physicians in making treatment decisions, according to Dr. Nazha and his colleagues. To move this work forward, the investigators are attempting to develop a personalized model that can make predictions specific to an individual patient based on that patient’s mutation information.
Dr. Nazha reported having no financial disclosures relevant to this research. Other investigators reported relationships with the Munich Leukemia Laboratory.
The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
REPORTING FROM ALF 2019
CAR T-cell therapy bb2121 performs well in phase 1 trial of refractory multiple myeloma
Chimeric antigen receptor (CAR) T-cell therapy bb2121, which targets B-cell maturation agent (BCMA), appears safe and effective for treating patients with refractory multiple myeloma, according to results of a phase 1 trial.
The objective response rate of 85% among 33 heavily pretreated patients suggests “promising efficacy,” reported lead author Noopur Raje, MD, of Massachusetts General Hospital Cancer Center in Boston and colleagues.
“Although comparisons among studies are complicated by differences in patient populations, CAR constructs, administered doses, and grading scales of toxic effects, the results observed with bb2121 indicate a favorable safety profile,” the investigators wrote in a study published in the New England Journal of Medicine.
The study initially involved 36 patients with refractory multiple myeloma who had received at least three lines of prior therapy, including an immunomodulatory agent and a proteasome inhibitor. Although leukapheresis and therapy manufacturing were successful in all patients, three patients were excluded from receiving the infusion because of disease progression.
The 33 remaining patients were lymphodepleted with fludarabine and cyclophosphamide. Bridging therapy was allowed during the manufacturing process but was stopped at least 2 weeks prior to infusion. In the dose-escalation phase of the study, b2121 was delivered as a single infusion at one of four dose levels: 50 × 106, 150 × 106, 450 × 106, or 800 × 106 CAR T cells. In the expansion phase, the treatment was given at either 150 x 106 or 450 x 106 CAR T cells. The primary endpoint was safety; the secondary endpoints were response rate and duration of response.
After a median follow-up of 11.3 months, most patients (85%) had responded to therapy, and almost half (45%) had achieved a complete response. Of the 15 complete responders, 6 relapsed. The median progression-free survival was 11.8 months; stated differently, two out of five patients (40%) had not experienced disease progression after 1 year. CAR T cells were detectable 1 month after infusion in 96% of patients; however, this value dropped to 86% at 3 months, 57% at 6 months, and 20% at 12 months. The investigators noted that CAR T-cell persistence was associated with treatment response.
All patients had adverse events. Most (85%) had grade 3 or higher hematologic toxicity, which the investigators considered to be the “expected toxic effects of lymphodepleting chemotherapy.” Although other adverse events occurred in the majority of patients, these were generally mild to moderate. Cytokine release syndrome occurred in 25 patients (76%), including two instances of grade 3 toxicity but none of grade 4 or higher. Fourteen patients (42%) developed neurologic toxicities: Most were grade 1 or 2, but one patient had a grade 4 toxicity that resolved after a month. Infections occurred at the same rate (42%), although, again, most were grade 1 or 2.
The study was funded by Bluebird Bio and Celgene. The investigators disclosed financial relationships with Bluebird and other drug companies.
SOURCE: Raje N et al. NEJM. 1 May 2019. doi: 10.1056/NEJMoa1817226.
Chimeric antigen receptor (CAR) T-cell therapy bb2121, which targets B-cell maturation agent (BCMA), appears safe and effective for treating patients with refractory multiple myeloma, according to results of a phase 1 trial.
The objective response rate of 85% among 33 heavily pretreated patients suggests “promising efficacy,” reported lead author Noopur Raje, MD, of Massachusetts General Hospital Cancer Center in Boston and colleagues.
“Although comparisons among studies are complicated by differences in patient populations, CAR constructs, administered doses, and grading scales of toxic effects, the results observed with bb2121 indicate a favorable safety profile,” the investigators wrote in a study published in the New England Journal of Medicine.
The study initially involved 36 patients with refractory multiple myeloma who had received at least three lines of prior therapy, including an immunomodulatory agent and a proteasome inhibitor. Although leukapheresis and therapy manufacturing were successful in all patients, three patients were excluded from receiving the infusion because of disease progression.
The 33 remaining patients were lymphodepleted with fludarabine and cyclophosphamide. Bridging therapy was allowed during the manufacturing process but was stopped at least 2 weeks prior to infusion. In the dose-escalation phase of the study, b2121 was delivered as a single infusion at one of four dose levels: 50 × 106, 150 × 106, 450 × 106, or 800 × 106 CAR T cells. In the expansion phase, the treatment was given at either 150 x 106 or 450 x 106 CAR T cells. The primary endpoint was safety; the secondary endpoints were response rate and duration of response.
After a median follow-up of 11.3 months, most patients (85%) had responded to therapy, and almost half (45%) had achieved a complete response. Of the 15 complete responders, 6 relapsed. The median progression-free survival was 11.8 months; stated differently, two out of five patients (40%) had not experienced disease progression after 1 year. CAR T cells were detectable 1 month after infusion in 96% of patients; however, this value dropped to 86% at 3 months, 57% at 6 months, and 20% at 12 months. The investigators noted that CAR T-cell persistence was associated with treatment response.
All patients had adverse events. Most (85%) had grade 3 or higher hematologic toxicity, which the investigators considered to be the “expected toxic effects of lymphodepleting chemotherapy.” Although other adverse events occurred in the majority of patients, these were generally mild to moderate. Cytokine release syndrome occurred in 25 patients (76%), including two instances of grade 3 toxicity but none of grade 4 or higher. Fourteen patients (42%) developed neurologic toxicities: Most were grade 1 or 2, but one patient had a grade 4 toxicity that resolved after a month. Infections occurred at the same rate (42%), although, again, most were grade 1 or 2.
The study was funded by Bluebird Bio and Celgene. The investigators disclosed financial relationships with Bluebird and other drug companies.
SOURCE: Raje N et al. NEJM. 1 May 2019. doi: 10.1056/NEJMoa1817226.
Chimeric antigen receptor (CAR) T-cell therapy bb2121, which targets B-cell maturation agent (BCMA), appears safe and effective for treating patients with refractory multiple myeloma, according to results of a phase 1 trial.
The objective response rate of 85% among 33 heavily pretreated patients suggests “promising efficacy,” reported lead author Noopur Raje, MD, of Massachusetts General Hospital Cancer Center in Boston and colleagues.
“Although comparisons among studies are complicated by differences in patient populations, CAR constructs, administered doses, and grading scales of toxic effects, the results observed with bb2121 indicate a favorable safety profile,” the investigators wrote in a study published in the New England Journal of Medicine.
The study initially involved 36 patients with refractory multiple myeloma who had received at least three lines of prior therapy, including an immunomodulatory agent and a proteasome inhibitor. Although leukapheresis and therapy manufacturing were successful in all patients, three patients were excluded from receiving the infusion because of disease progression.
The 33 remaining patients were lymphodepleted with fludarabine and cyclophosphamide. Bridging therapy was allowed during the manufacturing process but was stopped at least 2 weeks prior to infusion. In the dose-escalation phase of the study, b2121 was delivered as a single infusion at one of four dose levels: 50 × 106, 150 × 106, 450 × 106, or 800 × 106 CAR T cells. In the expansion phase, the treatment was given at either 150 x 106 or 450 x 106 CAR T cells. The primary endpoint was safety; the secondary endpoints were response rate and duration of response.
After a median follow-up of 11.3 months, most patients (85%) had responded to therapy, and almost half (45%) had achieved a complete response. Of the 15 complete responders, 6 relapsed. The median progression-free survival was 11.8 months; stated differently, two out of five patients (40%) had not experienced disease progression after 1 year. CAR T cells were detectable 1 month after infusion in 96% of patients; however, this value dropped to 86% at 3 months, 57% at 6 months, and 20% at 12 months. The investigators noted that CAR T-cell persistence was associated with treatment response.
All patients had adverse events. Most (85%) had grade 3 or higher hematologic toxicity, which the investigators considered to be the “expected toxic effects of lymphodepleting chemotherapy.” Although other adverse events occurred in the majority of patients, these were generally mild to moderate. Cytokine release syndrome occurred in 25 patients (76%), including two instances of grade 3 toxicity but none of grade 4 or higher. Fourteen patients (42%) developed neurologic toxicities: Most were grade 1 or 2, but one patient had a grade 4 toxicity that resolved after a month. Infections occurred at the same rate (42%), although, again, most were grade 1 or 2.
The study was funded by Bluebird Bio and Celgene. The investigators disclosed financial relationships with Bluebird and other drug companies.
SOURCE: Raje N et al. NEJM. 1 May 2019. doi: 10.1056/NEJMoa1817226.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Advances in CAR T-Cell Therapies (FULL)
Gene therapies, especially chimeric antigen receptor (CAR) T-cell therapies, experienced significant growth in 2017. The CAR T-cell therapies are among the most clinically important of the adoptive cell transfer therapies. In August, the FDA approved tisagenlecleucel for patients aged < 26 years with acute or relapsed lymphoblastic leukemia (ALL). In October, the FDA approved axicabtagene ciloleucel for treatment of adult patients nonresponsive to, or relapsed from treatment of, certain types of large B-cell lymphoma. And in November, the FDA granted breakthrough therapy designation to Celgene and Bluebird Bio for the bb2121 anti-B-cell maturation antigen (BCMA) CAR T-cell therapy for relapsed and refractory multiple myeloma (MM).
Chimeric antigen receptor T-cells circumvent the human major histocompatibility complex that T-cell receptors must navigate, shifting cell-based therapy away from identification of existing cells and toward creating T-cell products through genetic engineering. This broadens the potential for CAR T-cell applications and allows for rapid manufacture of tumor and patient-specific agents.1 Both Novartis’ Kymriah and Kite Pharma’s Yescarta are derived from investigations into anti-CD19 CAR therapy, which has been the most heavily researched of the CARs due to its links with B-cell malignancies, expression in most tumor cells, and absence from vital tissues.2 Studied in relation to a number of cancers, CD19 has not shown much success in either MM or solid tumor cancers.
Targeting the right antigen for myeloma is complicated: first because common MM antigens—CD38, CD56, CD138—also are expressed on essential normal cells, and second, because myeloma cells are synonymous with heterogeneity. The FDA based its designation of bb2121, or BCMA CAR T-cell therapy, on preliminary data from an ongoing phase 1 CRB-401 trial that, as of December 2017, concluded that 94% of 21 patients with MM treated with the highest doses showed complete or partial remissions and high rates of progression-free survival.3 The trial also showed that cytokine-release toxicity (CRS), although severe in some patients, was generally reversible and short lived.
Multiple myeloma BCMA is only one of several CAR targets under consideration for MM treatment; others include CD138, CD38, signaling lymphocyte-activating molecule 7, and κ light chain. However, B-cell maturation antigen is attractive to researchers because BCMA–specific CAR-expressing T lymphocytes recognize and kill B-cell maturation antigen–expressing tumor cells. Also, BCMA acts as a receptor for both a proliferation-inducing ligand and as a B-cell–activating factor and is a member of the tumor necrosis factor receptor superfamily, playing a key role in plasma cell survival. B-cell maturation antigen is expressed in most, if not all, myeloma cells but not in epithelial tissues. Finally, integration of CAR-Ts with other myeloma therapies is an important area of future research.4
Most of the 23 trials looking at CAR T-cell therapy for MM are in the U.S. or China, and several deal jointly with MM, leukemia, and lymphoma. The THINK (THerapeutic Immunotherapy with NKR-2) multinational open-label phase 1 study stands alone in assessing the safety and clinical activity of multiple administrations of autologous NKR-2 cells in 7 refractory cancers, including 5 solid tumors (colorectal, ovarian, bladder, triple-negative breast and pancreatic cancers) and 2 hematologic tumors (acute myeloid leukemia and MM). Unlike traditional CAR T-cell therapy, which targets only 1 tumor antigen, NK cell receptors enable a single receptor to recognize multiple tumor antigens.
Despite challenges of toxicity, costs, and restricted availability for immunotherapies, CAR T-cell therapies seem to offer great possibilities of groundbreaking treatments and possible cures for formerly hard to treat cancers, including MM.5
Click here to read the digital edition.
1. Almåsbak H, Aarvak T, Vemuri MC. CAR T cell therapy: a game changer in cancer treatment. J Immunol Res. 2016;2016:5474602.
2. Sadelain M. CAR therapy: the CD19 paradigm. J Clin Invest. 2015;125(9):3392-3400.
3. C
4. Mikkilineni L, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for multiple myeloma. Blood. 2017;130(24):2594-2602.
5. Vallet S, Pecherstorfer M, Podar K. Adoptive cell therapy in multiple myeloma. Expert Opin Biol Ther. 2017;17(12):1511-1522.
Gene therapies, especially chimeric antigen receptor (CAR) T-cell therapies, experienced significant growth in 2017. The CAR T-cell therapies are among the most clinically important of the adoptive cell transfer therapies. In August, the FDA approved tisagenlecleucel for patients aged < 26 years with acute or relapsed lymphoblastic leukemia (ALL). In October, the FDA approved axicabtagene ciloleucel for treatment of adult patients nonresponsive to, or relapsed from treatment of, certain types of large B-cell lymphoma. And in November, the FDA granted breakthrough therapy designation to Celgene and Bluebird Bio for the bb2121 anti-B-cell maturation antigen (BCMA) CAR T-cell therapy for relapsed and refractory multiple myeloma (MM).
Chimeric antigen receptor T-cells circumvent the human major histocompatibility complex that T-cell receptors must navigate, shifting cell-based therapy away from identification of existing cells and toward creating T-cell products through genetic engineering. This broadens the potential for CAR T-cell applications and allows for rapid manufacture of tumor and patient-specific agents.1 Both Novartis’ Kymriah and Kite Pharma’s Yescarta are derived from investigations into anti-CD19 CAR therapy, which has been the most heavily researched of the CARs due to its links with B-cell malignancies, expression in most tumor cells, and absence from vital tissues.2 Studied in relation to a number of cancers, CD19 has not shown much success in either MM or solid tumor cancers.
Targeting the right antigen for myeloma is complicated: first because common MM antigens—CD38, CD56, CD138—also are expressed on essential normal cells, and second, because myeloma cells are synonymous with heterogeneity. The FDA based its designation of bb2121, or BCMA CAR T-cell therapy, on preliminary data from an ongoing phase 1 CRB-401 trial that, as of December 2017, concluded that 94% of 21 patients with MM treated with the highest doses showed complete or partial remissions and high rates of progression-free survival.3 The trial also showed that cytokine-release toxicity (CRS), although severe in some patients, was generally reversible and short lived.
Multiple myeloma BCMA is only one of several CAR targets under consideration for MM treatment; others include CD138, CD38, signaling lymphocyte-activating molecule 7, and κ light chain. However, B-cell maturation antigen is attractive to researchers because BCMA–specific CAR-expressing T lymphocytes recognize and kill B-cell maturation antigen–expressing tumor cells. Also, BCMA acts as a receptor for both a proliferation-inducing ligand and as a B-cell–activating factor and is a member of the tumor necrosis factor receptor superfamily, playing a key role in plasma cell survival. B-cell maturation antigen is expressed in most, if not all, myeloma cells but not in epithelial tissues. Finally, integration of CAR-Ts with other myeloma therapies is an important area of future research.4
Most of the 23 trials looking at CAR T-cell therapy for MM are in the U.S. or China, and several deal jointly with MM, leukemia, and lymphoma. The THINK (THerapeutic Immunotherapy with NKR-2) multinational open-label phase 1 study stands alone in assessing the safety and clinical activity of multiple administrations of autologous NKR-2 cells in 7 refractory cancers, including 5 solid tumors (colorectal, ovarian, bladder, triple-negative breast and pancreatic cancers) and 2 hematologic tumors (acute myeloid leukemia and MM). Unlike traditional CAR T-cell therapy, which targets only 1 tumor antigen, NK cell receptors enable a single receptor to recognize multiple tumor antigens.
Despite challenges of toxicity, costs, and restricted availability for immunotherapies, CAR T-cell therapies seem to offer great possibilities of groundbreaking treatments and possible cures for formerly hard to treat cancers, including MM.5
Click here to read the digital edition.
Gene therapies, especially chimeric antigen receptor (CAR) T-cell therapies, experienced significant growth in 2017. The CAR T-cell therapies are among the most clinically important of the adoptive cell transfer therapies. In August, the FDA approved tisagenlecleucel for patients aged < 26 years with acute or relapsed lymphoblastic leukemia (ALL). In October, the FDA approved axicabtagene ciloleucel for treatment of adult patients nonresponsive to, or relapsed from treatment of, certain types of large B-cell lymphoma. And in November, the FDA granted breakthrough therapy designation to Celgene and Bluebird Bio for the bb2121 anti-B-cell maturation antigen (BCMA) CAR T-cell therapy for relapsed and refractory multiple myeloma (MM).
Chimeric antigen receptor T-cells circumvent the human major histocompatibility complex that T-cell receptors must navigate, shifting cell-based therapy away from identification of existing cells and toward creating T-cell products through genetic engineering. This broadens the potential for CAR T-cell applications and allows for rapid manufacture of tumor and patient-specific agents.1 Both Novartis’ Kymriah and Kite Pharma’s Yescarta are derived from investigations into anti-CD19 CAR therapy, which has been the most heavily researched of the CARs due to its links with B-cell malignancies, expression in most tumor cells, and absence from vital tissues.2 Studied in relation to a number of cancers, CD19 has not shown much success in either MM or solid tumor cancers.
Targeting the right antigen for myeloma is complicated: first because common MM antigens—CD38, CD56, CD138—also are expressed on essential normal cells, and second, because myeloma cells are synonymous with heterogeneity. The FDA based its designation of bb2121, or BCMA CAR T-cell therapy, on preliminary data from an ongoing phase 1 CRB-401 trial that, as of December 2017, concluded that 94% of 21 patients with MM treated with the highest doses showed complete or partial remissions and high rates of progression-free survival.3 The trial also showed that cytokine-release toxicity (CRS), although severe in some patients, was generally reversible and short lived.
Multiple myeloma BCMA is only one of several CAR targets under consideration for MM treatment; others include CD138, CD38, signaling lymphocyte-activating molecule 7, and κ light chain. However, B-cell maturation antigen is attractive to researchers because BCMA–specific CAR-expressing T lymphocytes recognize and kill B-cell maturation antigen–expressing tumor cells. Also, BCMA acts as a receptor for both a proliferation-inducing ligand and as a B-cell–activating factor and is a member of the tumor necrosis factor receptor superfamily, playing a key role in plasma cell survival. B-cell maturation antigen is expressed in most, if not all, myeloma cells but not in epithelial tissues. Finally, integration of CAR-Ts with other myeloma therapies is an important area of future research.4
Most of the 23 trials looking at CAR T-cell therapy for MM are in the U.S. or China, and several deal jointly with MM, leukemia, and lymphoma. The THINK (THerapeutic Immunotherapy with NKR-2) multinational open-label phase 1 study stands alone in assessing the safety and clinical activity of multiple administrations of autologous NKR-2 cells in 7 refractory cancers, including 5 solid tumors (colorectal, ovarian, bladder, triple-negative breast and pancreatic cancers) and 2 hematologic tumors (acute myeloid leukemia and MM). Unlike traditional CAR T-cell therapy, which targets only 1 tumor antigen, NK cell receptors enable a single receptor to recognize multiple tumor antigens.
Despite challenges of toxicity, costs, and restricted availability for immunotherapies, CAR T-cell therapies seem to offer great possibilities of groundbreaking treatments and possible cures for formerly hard to treat cancers, including MM.5
Click here to read the digital edition.
1. Almåsbak H, Aarvak T, Vemuri MC. CAR T cell therapy: a game changer in cancer treatment. J Immunol Res. 2016;2016:5474602.
2. Sadelain M. CAR therapy: the CD19 paradigm. J Clin Invest. 2015;125(9):3392-3400.
3. C
4. Mikkilineni L, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for multiple myeloma. Blood. 2017;130(24):2594-2602.
5. Vallet S, Pecherstorfer M, Podar K. Adoptive cell therapy in multiple myeloma. Expert Opin Biol Ther. 2017;17(12):1511-1522.
1. Almåsbak H, Aarvak T, Vemuri MC. CAR T cell therapy: a game changer in cancer treatment. J Immunol Res. 2016;2016:5474602.
2. Sadelain M. CAR therapy: the CD19 paradigm. J Clin Invest. 2015;125(9):3392-3400.
3. C
4. Mikkilineni L, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for multiple myeloma. Blood. 2017;130(24):2594-2602.
5. Vallet S, Pecherstorfer M, Podar K. Adoptive cell therapy in multiple myeloma. Expert Opin Biol Ther. 2017;17(12):1511-1522.
Obinutuzumab-based regimens yield durable remissions in CLL
Two different obinutuzumab-based chemoimmunotherapy regimens resulted in excellent long-term disease control as front-line therapy for chronic lymphocytic leukemia (CLL), investigators said in a follow-up report on a phase 1b study.
Both obinutuzumab plus fludarabine/cyclophosphamide (G-FC) and obinutuzumab plus bendamustine (G-B) were well tolerated, with adverse events similar to what has been reported in rituximab-containing immunotherapy regimens, they said in the report of final results from the GALTON trial.
Most evaluable patients had B-cell recovery by 36 months in the study, which included a population of CLL patients largely without 17p deletions, said Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute, Boston, and her coinvestigators.
“These data support moving forward with these regimens in subsequent trials, which are currently ongoing,” they said in their report on the study, which appears in Blood.
The open-label, parallel-arm, multicenter phase 1b GALTON study included 41 patients with CLL, of whom 21 received G-FC and 20 received G-B for up to six cycles of 28 days each. The median age was 60 years, and about one-third of patients had Rai stage III or IV disease. Only one patient had del(17p), and nearly half of patients tested (17 of 38 patients) had unmutated immunoglobulin heavy-chain variable region gene (IGHV). Six patients had del(11q), including four in the G-FC arm and two in the G-B arm.
Both G-FC and G-B had manageable toxicities, with infusion-related reactions being the most common adverse event, occurring in 88% (20% grade 3 or 4), Dr. Brown and her colleagues reported, adding that grade 3 or 4 neutropenia was seen in 48% of the G-FC arm and 55% of the G-B arm.
The objective response rate (ORR) was 62% for G-FC and 90% for GB.
“The ORR in the G-FC arm likely does not reflect the true activity of the regimen, as it is based on an intent-to-treat analysis,” the investigators said.
With a median observation time of 40.4 months, 95% of patients were alive, and 90% had not experienced a progression-free survival event.
Nine patients in the G-FC arm underwent minimal residual disease (MRD) testing in peripheral blood; 100% had undetectable MRD, according to the report.
“With the caveat of small patient numbers and inevitable differences in patient populations across studies, these results suggest that G-FC may clear residual disease more effectively than rituximab plus FC,” the investigators wrote.
Previous studies of R-FC showed an undetectable MRD rate of 45% or less, they said.
The study was sponsored by Genentech. The investigators reported disclosures related to Genentech/Roche and other companies.
SOURCE: Brown JR et al. Blood. 2018 Dec 28. doi: 10.1182/blood-2018-06-857714.
Two different obinutuzumab-based chemoimmunotherapy regimens resulted in excellent long-term disease control as front-line therapy for chronic lymphocytic leukemia (CLL), investigators said in a follow-up report on a phase 1b study.
Both obinutuzumab plus fludarabine/cyclophosphamide (G-FC) and obinutuzumab plus bendamustine (G-B) were well tolerated, with adverse events similar to what has been reported in rituximab-containing immunotherapy regimens, they said in the report of final results from the GALTON trial.
Most evaluable patients had B-cell recovery by 36 months in the study, which included a population of CLL patients largely without 17p deletions, said Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute, Boston, and her coinvestigators.
“These data support moving forward with these regimens in subsequent trials, which are currently ongoing,” they said in their report on the study, which appears in Blood.
The open-label, parallel-arm, multicenter phase 1b GALTON study included 41 patients with CLL, of whom 21 received G-FC and 20 received G-B for up to six cycles of 28 days each. The median age was 60 years, and about one-third of patients had Rai stage III or IV disease. Only one patient had del(17p), and nearly half of patients tested (17 of 38 patients) had unmutated immunoglobulin heavy-chain variable region gene (IGHV). Six patients had del(11q), including four in the G-FC arm and two in the G-B arm.
Both G-FC and G-B had manageable toxicities, with infusion-related reactions being the most common adverse event, occurring in 88% (20% grade 3 or 4), Dr. Brown and her colleagues reported, adding that grade 3 or 4 neutropenia was seen in 48% of the G-FC arm and 55% of the G-B arm.
The objective response rate (ORR) was 62% for G-FC and 90% for GB.
“The ORR in the G-FC arm likely does not reflect the true activity of the regimen, as it is based on an intent-to-treat analysis,” the investigators said.
With a median observation time of 40.4 months, 95% of patients were alive, and 90% had not experienced a progression-free survival event.
Nine patients in the G-FC arm underwent minimal residual disease (MRD) testing in peripheral blood; 100% had undetectable MRD, according to the report.
“With the caveat of small patient numbers and inevitable differences in patient populations across studies, these results suggest that G-FC may clear residual disease more effectively than rituximab plus FC,” the investigators wrote.
Previous studies of R-FC showed an undetectable MRD rate of 45% or less, they said.
The study was sponsored by Genentech. The investigators reported disclosures related to Genentech/Roche and other companies.
SOURCE: Brown JR et al. Blood. 2018 Dec 28. doi: 10.1182/blood-2018-06-857714.
Two different obinutuzumab-based chemoimmunotherapy regimens resulted in excellent long-term disease control as front-line therapy for chronic lymphocytic leukemia (CLL), investigators said in a follow-up report on a phase 1b study.
Both obinutuzumab plus fludarabine/cyclophosphamide (G-FC) and obinutuzumab plus bendamustine (G-B) were well tolerated, with adverse events similar to what has been reported in rituximab-containing immunotherapy regimens, they said in the report of final results from the GALTON trial.
Most evaluable patients had B-cell recovery by 36 months in the study, which included a population of CLL patients largely without 17p deletions, said Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute, Boston, and her coinvestigators.
“These data support moving forward with these regimens in subsequent trials, which are currently ongoing,” they said in their report on the study, which appears in Blood.
The open-label, parallel-arm, multicenter phase 1b GALTON study included 41 patients with CLL, of whom 21 received G-FC and 20 received G-B for up to six cycles of 28 days each. The median age was 60 years, and about one-third of patients had Rai stage III or IV disease. Only one patient had del(17p), and nearly half of patients tested (17 of 38 patients) had unmutated immunoglobulin heavy-chain variable region gene (IGHV). Six patients had del(11q), including four in the G-FC arm and two in the G-B arm.
Both G-FC and G-B had manageable toxicities, with infusion-related reactions being the most common adverse event, occurring in 88% (20% grade 3 or 4), Dr. Brown and her colleagues reported, adding that grade 3 or 4 neutropenia was seen in 48% of the G-FC arm and 55% of the G-B arm.
The objective response rate (ORR) was 62% for G-FC and 90% for GB.
“The ORR in the G-FC arm likely does not reflect the true activity of the regimen, as it is based on an intent-to-treat analysis,” the investigators said.
With a median observation time of 40.4 months, 95% of patients were alive, and 90% had not experienced a progression-free survival event.
Nine patients in the G-FC arm underwent minimal residual disease (MRD) testing in peripheral blood; 100% had undetectable MRD, according to the report.
“With the caveat of small patient numbers and inevitable differences in patient populations across studies, these results suggest that G-FC may clear residual disease more effectively than rituximab plus FC,” the investigators wrote.
Previous studies of R-FC showed an undetectable MRD rate of 45% or less, they said.
The study was sponsored by Genentech. The investigators reported disclosures related to Genentech/Roche and other companies.
SOURCE: Brown JR et al. Blood. 2018 Dec 28. doi: 10.1182/blood-2018-06-857714.
FROM BLOOD
Key clinical point:
Major finding: With a median observation time of 40.4 months, 95% of patients were alive, and 90% had not experienced a progression-free survival event.
Study details: Long-term follow-up of the phase 1b GALTON trial, including 41 patients with CLL.
Disclosures: The study was sponsored by Genentech. The study authors reported disclosures related to Genentech/Roche and other companies.
Source: Brown JR et al. Blood. 2018 Dec 28. doi: 10.1182/blood-2018-06-857714.
10 Important VA Studies You Might Have Missed at ASH
With hundreds of sessions and thousands of abstracts, it can be difficult to wade through all the new findings to find the most significant and relevant findings. Federal Practitioner consulted with Association of VA Hematology/Oncology members who attended the meeting, VA researchers, and other sources to provide these nuggets you might have missed on lymphomas, white blood cells, leukemias, and multiple myeloma:
Lymphomas
This retrospective analysis of diffuse large B cell lymphoma (DCBL) patients who received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at the VA Audie Murphy Hospital in San Antonio, Texas was compared with patients with DLBCL who received R-CHOP in a community setting. According to the researchers, the response to initial treatment was inferior in the veteran population when compared with a patient population with similar demographics and having similar time from diagnosis to treatment. Veteran patients also had worse outcomes when compared with uninsured patients.
This retrospective analysis study identified 2,290 patients with follicular lymphoma treated in the Veterans Health Administration between 2006–2014 and detailed their staging, demographics, and comorbidities. The researchers found that maintenance therapy with rituximab was associated with an improvement in overall survival.
Another retrospective analysis of DBCL using VHA data examined the effectiveness of second-line chemotherapy and chemoimmunotherapy in patients aged ≥ 65 years. The researchers found 230 patients from 2001 to 2015 that met the inclusion criteria. According to the researchers, the overall survival was < 1 year and about half of the patients "did not receive or were not candidates for regimens typically used with intent for high-dose therapy and autologous transplant."
White Blood Cells
Cost-Effective Use of White Blood Cell Growth Factors in the Veterans Administration
This study analyzed the use of granulocyte colony-stimulating (G-CSF) vs pegfilgrastim in the UD Department of Veterans Affairs (VA) health care system. The researchers looked at the relative frequency of use of filgrastim, Tbo-filgrastim, Filgrastim-sndz and pegfilgrastim at 23 VA sites and found that uptake of biosimilar G-CSF has been extremely rapid. All sites are using biosimilar GCSF for all new patients; 6 of 23 sites were comfortable shifting current patients on branded G-CSF to the biosimilar.However, switching to a Tbo-filgrastim brought a cost savings of 2.2% that was "small compared to other clinical changes."
This analysis described the association between white blood cell (EBC) levels and occurrence of thrombotic events among patients with polycythemia vera (PV) using Veterans Health Administration claims data collected between 2005 and 2012. The researchers found A significant, positive association between increased WBC counts and occurrence of thrombotic events in patients with PV was observed in this study. Patients with WBC counts ≥ 8.5 × 109/L had a significantly increased risk of thrombotic events, and those with counts ≥ 11.0 × 109/L were at greatest risk. Effective control of WBC counts is an important component of disease management and may reduce risk of thrombotic events in patients with PV.
Leukemias
Black patients with chronic lymphocytic leukemia tend to have worse overall survival and an earlier age at diagnosis with higher rates of adverse cytogenetics. This retrospective analysis of VHA patients compared black and nonblack patients. It found that black patients had worse survival compared to nonblack patients in a single health care delivery system, which limits differences in access to care. Black patients were younger and had shorter periods of observation and were more frequently given first-line fludarabine.
Induction chemotherapy (7+3) or high-dose ara-C-based (HIDAC) for acute myeloid leukemia (AML) results in prolonged neutropenia with a high risk of serious infection and attendant morbidity, and prolonged hospitalization. Researchers, including former AVAHO president Suman Kambhampati developed a randomized, open-label, controlled Phase 2 trial to study the effect of romyelocel-L in de novo patients receiving HIDAC or 7+3 induction therapy for reduction of fever and infection. The results from pooled and 7+3 cohorts, were previously presented, showing decrease in infections and days in hospital. The results from cohorts receiving HIDAC chemotherapy are presented here. The incidence of infections was decreased during the day 15-28 period and a decrease of three days in hospital stay was observed in de novo HIDAC AML subjects receiving romyelocel-L. Romyelocel-L may provide a new option to reduce infections in AML patients undergoing HIDAC induction therapy.
Multiple Myeloma
Two studies focused on racial disparities in multiple myeloma (MM), while another reported phase 2 data on a relapsed/refractory option.
This group of researchers found an absence of disparity in use of novel agents, no racial disparity was observed in overall survival between black and white patients with MM. Among patients aged < 65 years at diagnosis, the researchers observed a significantly lower age-adjusted risk of death for black patients compared with white patients. The difference in the younger population was not explained by access or utilization of resources. This analysis suggests that when healthcare access is neutralized, younger black patients may even have improved overall survival, which may indicate the possibility of genetic differences that may drive the disease biology and therapeutic outcome in AA patients.
Outcomes of Black Patients with Multiple Myeloma in the Veterans Health Administration
The second study found survival of black patients with MM was improved compared to non-blacks in the VHA, a national comprehensive care delivery system. Black patients also received similar therapies compared to non-blacks, while presenting at a younger age with more comorbidities. These results are strengthened after adjusting for treatments and patient characteristics not available in other large data studies. Despite increased incidence of MM in the black population, outcomes are improved, similar to other large studies of patients in the United States.
Multiple myeloma clinical trial CC-4047-MM-014 (NCT01946477) is a phase 2 study designed to test the safety and efficacy of pomalidomide and low-dose dexamethasone alone (arm A) or in combination with daratumumab, an anti-CD38 antibody, (arm B) subjects with relapsed or refractory MM who have received a first- or second-line treatment of lenalidomide-based therapy. In this trial, researchers (including those from VA facilities, Celgene, and multiple other locations) sought to characterize on-treatment pharmacodynamic changes of immune biomarkers associated with POM + LoDEX + DARA administration (arm B) using multicolor flow cytometry panels designed to characterize T-cell subsets and CD38+ expressing cells. The researchers reported that the triplet regimen POM + LoDEX + DARA has shown notable clinical activity with deep and durable responses in relapsed MM patients progressed and are or refractory to lenalidomide. According to the researchers the results demonstrate that patients treated with the POM + LoDEX + DARA combination do not demonstrate impairment in the innate and adaptive immune compartments and, in contrast, show significant proliferative activity in the subsets of CD4, CD8 and NK cells following treatment.
With hundreds of sessions and thousands of abstracts, it can be difficult to wade through all the new findings to find the most significant and relevant findings. Federal Practitioner consulted with Association of VA Hematology/Oncology members who attended the meeting, VA researchers, and other sources to provide these nuggets you might have missed on lymphomas, white blood cells, leukemias, and multiple myeloma:
Lymphomas
This retrospective analysis of diffuse large B cell lymphoma (DCBL) patients who received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at the VA Audie Murphy Hospital in San Antonio, Texas was compared with patients with DLBCL who received R-CHOP in a community setting. According to the researchers, the response to initial treatment was inferior in the veteran population when compared with a patient population with similar demographics and having similar time from diagnosis to treatment. Veteran patients also had worse outcomes when compared with uninsured patients.
This retrospective analysis study identified 2,290 patients with follicular lymphoma treated in the Veterans Health Administration between 2006–2014 and detailed their staging, demographics, and comorbidities. The researchers found that maintenance therapy with rituximab was associated with an improvement in overall survival.
Another retrospective analysis of DBCL using VHA data examined the effectiveness of second-line chemotherapy and chemoimmunotherapy in patients aged ≥ 65 years. The researchers found 230 patients from 2001 to 2015 that met the inclusion criteria. According to the researchers, the overall survival was < 1 year and about half of the patients "did not receive or were not candidates for regimens typically used with intent for high-dose therapy and autologous transplant."
White Blood Cells
Cost-Effective Use of White Blood Cell Growth Factors in the Veterans Administration
This study analyzed the use of granulocyte colony-stimulating (G-CSF) vs pegfilgrastim in the UD Department of Veterans Affairs (VA) health care system. The researchers looked at the relative frequency of use of filgrastim, Tbo-filgrastim, Filgrastim-sndz and pegfilgrastim at 23 VA sites and found that uptake of biosimilar G-CSF has been extremely rapid. All sites are using biosimilar GCSF for all new patients; 6 of 23 sites were comfortable shifting current patients on branded G-CSF to the biosimilar.However, switching to a Tbo-filgrastim brought a cost savings of 2.2% that was "small compared to other clinical changes."
This analysis described the association between white blood cell (EBC) levels and occurrence of thrombotic events among patients with polycythemia vera (PV) using Veterans Health Administration claims data collected between 2005 and 2012. The researchers found A significant, positive association between increased WBC counts and occurrence of thrombotic events in patients with PV was observed in this study. Patients with WBC counts ≥ 8.5 × 109/L had a significantly increased risk of thrombotic events, and those with counts ≥ 11.0 × 109/L were at greatest risk. Effective control of WBC counts is an important component of disease management and may reduce risk of thrombotic events in patients with PV.
Leukemias
Black patients with chronic lymphocytic leukemia tend to have worse overall survival and an earlier age at diagnosis with higher rates of adverse cytogenetics. This retrospective analysis of VHA patients compared black and nonblack patients. It found that black patients had worse survival compared to nonblack patients in a single health care delivery system, which limits differences in access to care. Black patients were younger and had shorter periods of observation and were more frequently given first-line fludarabine.
Induction chemotherapy (7+3) or high-dose ara-C-based (HIDAC) for acute myeloid leukemia (AML) results in prolonged neutropenia with a high risk of serious infection and attendant morbidity, and prolonged hospitalization. Researchers, including former AVAHO president Suman Kambhampati developed a randomized, open-label, controlled Phase 2 trial to study the effect of romyelocel-L in de novo patients receiving HIDAC or 7+3 induction therapy for reduction of fever and infection. The results from pooled and 7+3 cohorts, were previously presented, showing decrease in infections and days in hospital. The results from cohorts receiving HIDAC chemotherapy are presented here. The incidence of infections was decreased during the day 15-28 period and a decrease of three days in hospital stay was observed in de novo HIDAC AML subjects receiving romyelocel-L. Romyelocel-L may provide a new option to reduce infections in AML patients undergoing HIDAC induction therapy.
Multiple Myeloma
Two studies focused on racial disparities in multiple myeloma (MM), while another reported phase 2 data on a relapsed/refractory option.
This group of researchers found an absence of disparity in use of novel agents, no racial disparity was observed in overall survival between black and white patients with MM. Among patients aged < 65 years at diagnosis, the researchers observed a significantly lower age-adjusted risk of death for black patients compared with white patients. The difference in the younger population was not explained by access or utilization of resources. This analysis suggests that when healthcare access is neutralized, younger black patients may even have improved overall survival, which may indicate the possibility of genetic differences that may drive the disease biology and therapeutic outcome in AA patients.
Outcomes of Black Patients with Multiple Myeloma in the Veterans Health Administration
The second study found survival of black patients with MM was improved compared to non-blacks in the VHA, a national comprehensive care delivery system. Black patients also received similar therapies compared to non-blacks, while presenting at a younger age with more comorbidities. These results are strengthened after adjusting for treatments and patient characteristics not available in other large data studies. Despite increased incidence of MM in the black population, outcomes are improved, similar to other large studies of patients in the United States.
Multiple myeloma clinical trial CC-4047-MM-014 (NCT01946477) is a phase 2 study designed to test the safety and efficacy of pomalidomide and low-dose dexamethasone alone (arm A) or in combination with daratumumab, an anti-CD38 antibody, (arm B) subjects with relapsed or refractory MM who have received a first- or second-line treatment of lenalidomide-based therapy. In this trial, researchers (including those from VA facilities, Celgene, and multiple other locations) sought to characterize on-treatment pharmacodynamic changes of immune biomarkers associated with POM + LoDEX + DARA administration (arm B) using multicolor flow cytometry panels designed to characterize T-cell subsets and CD38+ expressing cells. The researchers reported that the triplet regimen POM + LoDEX + DARA has shown notable clinical activity with deep and durable responses in relapsed MM patients progressed and are or refractory to lenalidomide. According to the researchers the results demonstrate that patients treated with the POM + LoDEX + DARA combination do not demonstrate impairment in the innate and adaptive immune compartments and, in contrast, show significant proliferative activity in the subsets of CD4, CD8 and NK cells following treatment.
With hundreds of sessions and thousands of abstracts, it can be difficult to wade through all the new findings to find the most significant and relevant findings. Federal Practitioner consulted with Association of VA Hematology/Oncology members who attended the meeting, VA researchers, and other sources to provide these nuggets you might have missed on lymphomas, white blood cells, leukemias, and multiple myeloma:
Lymphomas
This retrospective analysis of diffuse large B cell lymphoma (DCBL) patients who received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at the VA Audie Murphy Hospital in San Antonio, Texas was compared with patients with DLBCL who received R-CHOP in a community setting. According to the researchers, the response to initial treatment was inferior in the veteran population when compared with a patient population with similar demographics and having similar time from diagnosis to treatment. Veteran patients also had worse outcomes when compared with uninsured patients.
This retrospective analysis study identified 2,290 patients with follicular lymphoma treated in the Veterans Health Administration between 2006–2014 and detailed their staging, demographics, and comorbidities. The researchers found that maintenance therapy with rituximab was associated with an improvement in overall survival.
Another retrospective analysis of DBCL using VHA data examined the effectiveness of second-line chemotherapy and chemoimmunotherapy in patients aged ≥ 65 years. The researchers found 230 patients from 2001 to 2015 that met the inclusion criteria. According to the researchers, the overall survival was < 1 year and about half of the patients "did not receive or were not candidates for regimens typically used with intent for high-dose therapy and autologous transplant."
White Blood Cells
Cost-Effective Use of White Blood Cell Growth Factors in the Veterans Administration
This study analyzed the use of granulocyte colony-stimulating (G-CSF) vs pegfilgrastim in the UD Department of Veterans Affairs (VA) health care system. The researchers looked at the relative frequency of use of filgrastim, Tbo-filgrastim, Filgrastim-sndz and pegfilgrastim at 23 VA sites and found that uptake of biosimilar G-CSF has been extremely rapid. All sites are using biosimilar GCSF for all new patients; 6 of 23 sites were comfortable shifting current patients on branded G-CSF to the biosimilar.However, switching to a Tbo-filgrastim brought a cost savings of 2.2% that was "small compared to other clinical changes."
This analysis described the association between white blood cell (EBC) levels and occurrence of thrombotic events among patients with polycythemia vera (PV) using Veterans Health Administration claims data collected between 2005 and 2012. The researchers found A significant, positive association between increased WBC counts and occurrence of thrombotic events in patients with PV was observed in this study. Patients with WBC counts ≥ 8.5 × 109/L had a significantly increased risk of thrombotic events, and those with counts ≥ 11.0 × 109/L were at greatest risk. Effective control of WBC counts is an important component of disease management and may reduce risk of thrombotic events in patients with PV.
Leukemias
Black patients with chronic lymphocytic leukemia tend to have worse overall survival and an earlier age at diagnosis with higher rates of adverse cytogenetics. This retrospective analysis of VHA patients compared black and nonblack patients. It found that black patients had worse survival compared to nonblack patients in a single health care delivery system, which limits differences in access to care. Black patients were younger and had shorter periods of observation and were more frequently given first-line fludarabine.
Induction chemotherapy (7+3) or high-dose ara-C-based (HIDAC) for acute myeloid leukemia (AML) results in prolonged neutropenia with a high risk of serious infection and attendant morbidity, and prolonged hospitalization. Researchers, including former AVAHO president Suman Kambhampati developed a randomized, open-label, controlled Phase 2 trial to study the effect of romyelocel-L in de novo patients receiving HIDAC or 7+3 induction therapy for reduction of fever and infection. The results from pooled and 7+3 cohorts, were previously presented, showing decrease in infections and days in hospital. The results from cohorts receiving HIDAC chemotherapy are presented here. The incidence of infections was decreased during the day 15-28 period and a decrease of three days in hospital stay was observed in de novo HIDAC AML subjects receiving romyelocel-L. Romyelocel-L may provide a new option to reduce infections in AML patients undergoing HIDAC induction therapy.
Multiple Myeloma
Two studies focused on racial disparities in multiple myeloma (MM), while another reported phase 2 data on a relapsed/refractory option.
This group of researchers found an absence of disparity in use of novel agents, no racial disparity was observed in overall survival between black and white patients with MM. Among patients aged < 65 years at diagnosis, the researchers observed a significantly lower age-adjusted risk of death for black patients compared with white patients. The difference in the younger population was not explained by access or utilization of resources. This analysis suggests that when healthcare access is neutralized, younger black patients may even have improved overall survival, which may indicate the possibility of genetic differences that may drive the disease biology and therapeutic outcome in AA patients.
Outcomes of Black Patients with Multiple Myeloma in the Veterans Health Administration
The second study found survival of black patients with MM was improved compared to non-blacks in the VHA, a national comprehensive care delivery system. Black patients also received similar therapies compared to non-blacks, while presenting at a younger age with more comorbidities. These results are strengthened after adjusting for treatments and patient characteristics not available in other large data studies. Despite increased incidence of MM in the black population, outcomes are improved, similar to other large studies of patients in the United States.
Multiple myeloma clinical trial CC-4047-MM-014 (NCT01946477) is a phase 2 study designed to test the safety and efficacy of pomalidomide and low-dose dexamethasone alone (arm A) or in combination with daratumumab, an anti-CD38 antibody, (arm B) subjects with relapsed or refractory MM who have received a first- or second-line treatment of lenalidomide-based therapy. In this trial, researchers (including those from VA facilities, Celgene, and multiple other locations) sought to characterize on-treatment pharmacodynamic changes of immune biomarkers associated with POM + LoDEX + DARA administration (arm B) using multicolor flow cytometry panels designed to characterize T-cell subsets and CD38+ expressing cells. The researchers reported that the triplet regimen POM + LoDEX + DARA has shown notable clinical activity with deep and durable responses in relapsed MM patients progressed and are or refractory to lenalidomide. According to the researchers the results demonstrate that patients treated with the POM + LoDEX + DARA combination do not demonstrate impairment in the innate and adaptive immune compartments and, in contrast, show significant proliferative activity in the subsets of CD4, CD8 and NK cells following treatment.
2018: A banner year for hematology drug approvals
SAN DIEGO – It was banner year for new hematology drug approvals, according to R. Angelo de Claro, MD, of the Food and Drug Administration.
, including 12 first-time approvals, 5 new biosimilars, and 15 new indications for previously approved drugs, Dr. de Claro, clinical team leader in the FDA’s division of hematology products in Silver Spring, Md., said during an overview of the approvals at the annual meeting of the American Society of Hematology.
These include six new approvals for first-line treatment, and eight for pediatric indications, he said.
Highlights were discussed at two ASH-FDA joint symposia at the meeting, including one focused on the malignant hematology approvals, and another on the nonmalignant hematology approvals. In a video interview, Dr. de Claro provides some additional insight into their importance and about what might lie ahead.
“I think what’s exciting is that you have drug development occurring in more common conditions such as chronic lymphocytic leukemia, as well as in rare conditions, including hairy cell leukemia – and the first-ever approval in hemophagocytic lymphohistiocytosis,” he said. “It’s been very busy at the FDA; stay tuned ... the year’s not done yet. There could be more coming and we certainly anticipate more applications in the future.”
Dr. de Claro is an FDA employee. He reported having no other relevant disclosures.
SAN DIEGO – It was banner year for new hematology drug approvals, according to R. Angelo de Claro, MD, of the Food and Drug Administration.
, including 12 first-time approvals, 5 new biosimilars, and 15 new indications for previously approved drugs, Dr. de Claro, clinical team leader in the FDA’s division of hematology products in Silver Spring, Md., said during an overview of the approvals at the annual meeting of the American Society of Hematology.
These include six new approvals for first-line treatment, and eight for pediatric indications, he said.
Highlights were discussed at two ASH-FDA joint symposia at the meeting, including one focused on the malignant hematology approvals, and another on the nonmalignant hematology approvals. In a video interview, Dr. de Claro provides some additional insight into their importance and about what might lie ahead.
“I think what’s exciting is that you have drug development occurring in more common conditions such as chronic lymphocytic leukemia, as well as in rare conditions, including hairy cell leukemia – and the first-ever approval in hemophagocytic lymphohistiocytosis,” he said. “It’s been very busy at the FDA; stay tuned ... the year’s not done yet. There could be more coming and we certainly anticipate more applications in the future.”
Dr. de Claro is an FDA employee. He reported having no other relevant disclosures.
SAN DIEGO – It was banner year for new hematology drug approvals, according to R. Angelo de Claro, MD, of the Food and Drug Administration.
, including 12 first-time approvals, 5 new biosimilars, and 15 new indications for previously approved drugs, Dr. de Claro, clinical team leader in the FDA’s division of hematology products in Silver Spring, Md., said during an overview of the approvals at the annual meeting of the American Society of Hematology.
These include six new approvals for first-line treatment, and eight for pediatric indications, he said.
Highlights were discussed at two ASH-FDA joint symposia at the meeting, including one focused on the malignant hematology approvals, and another on the nonmalignant hematology approvals. In a video interview, Dr. de Claro provides some additional insight into their importance and about what might lie ahead.
“I think what’s exciting is that you have drug development occurring in more common conditions such as chronic lymphocytic leukemia, as well as in rare conditions, including hairy cell leukemia – and the first-ever approval in hemophagocytic lymphohistiocytosis,” he said. “It’s been very busy at the FDA; stay tuned ... the year’s not done yet. There could be more coming and we certainly anticipate more applications in the future.”
Dr. de Claro is an FDA employee. He reported having no other relevant disclosures.
REPORTING FROM ASH 2018
CLL resistance mechanism to venetoclax identified
SAN DIEGO – A recurrent mutation in BCL2, the therapeutic target of venetoclax (Venclexta), appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.
The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, said lead author Piers Blombery, MBBS, from the Peter MacCallum Cancer Center in Melbourne.
“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said in a late-breaking oral abstract session at the annual meeting of the American Society of Hematology.
The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” he added.
The paper was published online in Cancer Discovery (2018 Dec 4. doi: 10.1158/2159-8290.CD-18-1119) to coincide with the presentation at ASH.
Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.
To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.
In seven of the patients, they identified a novel mutation that showed up at the time of progression, but was absent from the pre-venetoclax samples. The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.
They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found that the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies. Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.
In other experiments, they determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and that in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage, compared with wild type cells.
Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.
“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.
In an interview, Dr. Blombery said that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.
The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation. Dr. Blombery reported having no relevant disclosures.
SOURCE: Blombery P et al. ASH 2018, Abstract LBA-7.
SAN DIEGO – A recurrent mutation in BCL2, the therapeutic target of venetoclax (Venclexta), appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.
The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, said lead author Piers Blombery, MBBS, from the Peter MacCallum Cancer Center in Melbourne.
“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said in a late-breaking oral abstract session at the annual meeting of the American Society of Hematology.
The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” he added.
The paper was published online in Cancer Discovery (2018 Dec 4. doi: 10.1158/2159-8290.CD-18-1119) to coincide with the presentation at ASH.
Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.
To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.
In seven of the patients, they identified a novel mutation that showed up at the time of progression, but was absent from the pre-venetoclax samples. The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.
They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found that the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies. Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.
In other experiments, they determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and that in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage, compared with wild type cells.
Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.
“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.
In an interview, Dr. Blombery said that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.
The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation. Dr. Blombery reported having no relevant disclosures.
SOURCE: Blombery P et al. ASH 2018, Abstract LBA-7.
SAN DIEGO – A recurrent mutation in BCL2, the therapeutic target of venetoclax (Venclexta), appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.
The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, said lead author Piers Blombery, MBBS, from the Peter MacCallum Cancer Center in Melbourne.
“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said in a late-breaking oral abstract session at the annual meeting of the American Society of Hematology.
The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” he added.
The paper was published online in Cancer Discovery (2018 Dec 4. doi: 10.1158/2159-8290.CD-18-1119) to coincide with the presentation at ASH.
Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.
To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.
In seven of the patients, they identified a novel mutation that showed up at the time of progression, but was absent from the pre-venetoclax samples. The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.
They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found that the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies. Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.
In other experiments, they determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and that in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage, compared with wild type cells.
Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.
“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.
In an interview, Dr. Blombery said that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.
The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation. Dr. Blombery reported having no relevant disclosures.
SOURCE: Blombery P et al. ASH 2018, Abstract LBA-7.
REPORTING FROM ASH 2018
Key clinical point:
Major finding: The mutation was identified in samples from seven patients after venetoclax therapy, but not in any of the pretherapy samples.
Study details: Genetic analysis of CLL mutations in 15 patients enrolled in clinical trials of venetoclax.
Disclosures: The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation. Dr. Blombery reported having no relevant disclosures.
Source: Blombery P et al. ASH 2018, Abstract LBA-7.
