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RIT consolidation may be an option for unfit MCL patients
For older, less fit patients with mantle cell lymphoma (MCL) who may not be able to withstand the rigors of autologous stem cell transplants (ASCT), induction chemotherapy followed by radioimmunotherapy (RIT) consolidation with ibritumomab tiuxetan (Zevalin) was associated with good response rates and promising progression-free and overall survival rates, according to results of a phase 2 prospective study.
RIT consolidation improved the complete response rate following first-line therapy from 41% to 91%, reported Wojciech Jurczak, MD, PhD, from the department of hematology at the Uniwersytet Jagiellonski in Krakow, Poland, and colleagues.
In the patients who received RIT following first-line induction, median progression-free survival was 3.3 years, and median overall survival was 6.5 years.
“The achieved responses are durable. Although, several novel agents and targeted therapies alone or in combination are currently being studied and developed in both the upfront and relapsed settings, RIT constitutes a valid and underused option especially in the first-line setting,” they wrote in a study published in Leukemia & Lymphoma.
The investigators enrolled 46 patients with clinical stage III to IV MCL who were either ineligible for, or unwilling to undergo, ASCT. The cohort included 34 patients with newly diagnosed advanced MCL and 12 with chemo-sensitive MCL in first relapse.
Patients were assigned to induction with six cycles of chemotherapy, with or without rituximab. Patients then underwent consolidation with RIT if they had confirmed reductions of the maximal lymph node diameter below 3 cm, their longest spleen measurement was below 15 cm, and bone marrow infiltration was less than 20%.
The chemotherapy regimens included either CVP (cyclophosphamide, vincristine and prednisone), CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), FC (fludarabine and cyclophosphamide), or FCM (FC plus mitoxantrone). Additionally, 27 of the 46 patients received rituximab, which was not considered the standard of care in Poland when the study began in 2005 and was delivered based on availability.
Of the 34 patients who received first-line chemotherapy, 20 received FC or FCM (with or without rituximab), and 14 received CHOP or CVP (with or without rituximab). In this group, 14 patients (41%) had a complete response, and 20 (95%) had a partial response. Of the 12 patients treated after first relapse, two (17%) had a complete response and 10 (83%) had partial response after induction.
RIT consolidation was performed 3-5 weeks after the last chemotherapy cycle. Patients with cytopenias after chemotherapy could wait an additional 3 weeks, during which they would receive a bridging dose of rituximab at the standard 375 mg/m2 dose. The patients received two doses of rituximab 250 mg/m2 administered 7 days then 24 hours prior to intravenous injection of 90Y-labeled ibritumomab tiuxetan. The radiation doses delivered were 0.4 mCi/kg for patients with normal platelet counts and 0.3 mCi/kg for those with platelet counts from 100,000 to 150,000 cells/mm3. The maximum dose was 32.0 mCi.
The longest follow-up was out to slightly more than 8 years.
For the patients who received RIT after first-line induction, the complete response rate was 91%, and the partial response rate was 9%, compared with 41% complete response and 59% partial response after induction. In this group, the median progression-free survival was 3.3 years, and the median overall survival was 6.5 years.
For the patients who received RIT consolidation after first relapse and second chemotherapy regimen, the complete response rate was 75% and the partial response rate was 25%, compared with 17% and 83% at the end of second induction therapy. In this group, the median progression-free survival was 1.8 years (P less than .05, compared with patients treated after first-line responses), and the median overall survival was 2.2 years (P less than .05).
At 8 years of follow-up, 30% of patients who received RIT consolidation following first-line therapy were alive.
Adverse events included cytopenias in the majority of patients (77%), which were grade 1 or 2 in severity in 43% and grade 3 or 4 in 34%. Grade 3 or 4 thrombocytopenia and leukopenia occurred more frequently in patients treated with fludarabine-based regimens, and the thrombocytopenias in these patients lasted longer and required more platelet transfusions than those in CHOP- or CVP-treated patients. Two patients who underwent RIT following FCM induction died from prolonged thrombocytopenia, resulting in hemorrhagic strokes.
Among all patients, 22 patients developed infections following RIT consolidation. Five patients, all of whom had received fludarabine, required hospitalization for the treatment of the infections. There were no infection-related deaths, however.
Five patients developed the myelodysplastic syndrome, with a median onset time of 26 months. Of these patients, four had received fludarabine, and one had undergone a prior ASCT.
The trial was sponsored by Schering AG. Dr. Jurczak reported speakers bureau participation and research funding from multiple companies, not including Schering AG.
SOURCE: Jurczak W et al. Leuk Lymphoma. 2019 Apr 9. doi: 10.1080/10428194.2019.1602261.
For older, less fit patients with mantle cell lymphoma (MCL) who may not be able to withstand the rigors of autologous stem cell transplants (ASCT), induction chemotherapy followed by radioimmunotherapy (RIT) consolidation with ibritumomab tiuxetan (Zevalin) was associated with good response rates and promising progression-free and overall survival rates, according to results of a phase 2 prospective study.
RIT consolidation improved the complete response rate following first-line therapy from 41% to 91%, reported Wojciech Jurczak, MD, PhD, from the department of hematology at the Uniwersytet Jagiellonski in Krakow, Poland, and colleagues.
In the patients who received RIT following first-line induction, median progression-free survival was 3.3 years, and median overall survival was 6.5 years.
“The achieved responses are durable. Although, several novel agents and targeted therapies alone or in combination are currently being studied and developed in both the upfront and relapsed settings, RIT constitutes a valid and underused option especially in the first-line setting,” they wrote in a study published in Leukemia & Lymphoma.
The investigators enrolled 46 patients with clinical stage III to IV MCL who were either ineligible for, or unwilling to undergo, ASCT. The cohort included 34 patients with newly diagnosed advanced MCL and 12 with chemo-sensitive MCL in first relapse.
Patients were assigned to induction with six cycles of chemotherapy, with or without rituximab. Patients then underwent consolidation with RIT if they had confirmed reductions of the maximal lymph node diameter below 3 cm, their longest spleen measurement was below 15 cm, and bone marrow infiltration was less than 20%.
The chemotherapy regimens included either CVP (cyclophosphamide, vincristine and prednisone), CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), FC (fludarabine and cyclophosphamide), or FCM (FC plus mitoxantrone). Additionally, 27 of the 46 patients received rituximab, which was not considered the standard of care in Poland when the study began in 2005 and was delivered based on availability.
Of the 34 patients who received first-line chemotherapy, 20 received FC or FCM (with or without rituximab), and 14 received CHOP or CVP (with or without rituximab). In this group, 14 patients (41%) had a complete response, and 20 (95%) had a partial response. Of the 12 patients treated after first relapse, two (17%) had a complete response and 10 (83%) had partial response after induction.
RIT consolidation was performed 3-5 weeks after the last chemotherapy cycle. Patients with cytopenias after chemotherapy could wait an additional 3 weeks, during which they would receive a bridging dose of rituximab at the standard 375 mg/m2 dose. The patients received two doses of rituximab 250 mg/m2 administered 7 days then 24 hours prior to intravenous injection of 90Y-labeled ibritumomab tiuxetan. The radiation doses delivered were 0.4 mCi/kg for patients with normal platelet counts and 0.3 mCi/kg for those with platelet counts from 100,000 to 150,000 cells/mm3. The maximum dose was 32.0 mCi.
The longest follow-up was out to slightly more than 8 years.
For the patients who received RIT after first-line induction, the complete response rate was 91%, and the partial response rate was 9%, compared with 41% complete response and 59% partial response after induction. In this group, the median progression-free survival was 3.3 years, and the median overall survival was 6.5 years.
For the patients who received RIT consolidation after first relapse and second chemotherapy regimen, the complete response rate was 75% and the partial response rate was 25%, compared with 17% and 83% at the end of second induction therapy. In this group, the median progression-free survival was 1.8 years (P less than .05, compared with patients treated after first-line responses), and the median overall survival was 2.2 years (P less than .05).
At 8 years of follow-up, 30% of patients who received RIT consolidation following first-line therapy were alive.
Adverse events included cytopenias in the majority of patients (77%), which were grade 1 or 2 in severity in 43% and grade 3 or 4 in 34%. Grade 3 or 4 thrombocytopenia and leukopenia occurred more frequently in patients treated with fludarabine-based regimens, and the thrombocytopenias in these patients lasted longer and required more platelet transfusions than those in CHOP- or CVP-treated patients. Two patients who underwent RIT following FCM induction died from prolonged thrombocytopenia, resulting in hemorrhagic strokes.
Among all patients, 22 patients developed infections following RIT consolidation. Five patients, all of whom had received fludarabine, required hospitalization for the treatment of the infections. There were no infection-related deaths, however.
Five patients developed the myelodysplastic syndrome, with a median onset time of 26 months. Of these patients, four had received fludarabine, and one had undergone a prior ASCT.
The trial was sponsored by Schering AG. Dr. Jurczak reported speakers bureau participation and research funding from multiple companies, not including Schering AG.
SOURCE: Jurczak W et al. Leuk Lymphoma. 2019 Apr 9. doi: 10.1080/10428194.2019.1602261.
For older, less fit patients with mantle cell lymphoma (MCL) who may not be able to withstand the rigors of autologous stem cell transplants (ASCT), induction chemotherapy followed by radioimmunotherapy (RIT) consolidation with ibritumomab tiuxetan (Zevalin) was associated with good response rates and promising progression-free and overall survival rates, according to results of a phase 2 prospective study.
RIT consolidation improved the complete response rate following first-line therapy from 41% to 91%, reported Wojciech Jurczak, MD, PhD, from the department of hematology at the Uniwersytet Jagiellonski in Krakow, Poland, and colleagues.
In the patients who received RIT following first-line induction, median progression-free survival was 3.3 years, and median overall survival was 6.5 years.
“The achieved responses are durable. Although, several novel agents and targeted therapies alone or in combination are currently being studied and developed in both the upfront and relapsed settings, RIT constitutes a valid and underused option especially in the first-line setting,” they wrote in a study published in Leukemia & Lymphoma.
The investigators enrolled 46 patients with clinical stage III to IV MCL who were either ineligible for, or unwilling to undergo, ASCT. The cohort included 34 patients with newly diagnosed advanced MCL and 12 with chemo-sensitive MCL in first relapse.
Patients were assigned to induction with six cycles of chemotherapy, with or without rituximab. Patients then underwent consolidation with RIT if they had confirmed reductions of the maximal lymph node diameter below 3 cm, their longest spleen measurement was below 15 cm, and bone marrow infiltration was less than 20%.
The chemotherapy regimens included either CVP (cyclophosphamide, vincristine and prednisone), CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), FC (fludarabine and cyclophosphamide), or FCM (FC plus mitoxantrone). Additionally, 27 of the 46 patients received rituximab, which was not considered the standard of care in Poland when the study began in 2005 and was delivered based on availability.
Of the 34 patients who received first-line chemotherapy, 20 received FC or FCM (with or without rituximab), and 14 received CHOP or CVP (with or without rituximab). In this group, 14 patients (41%) had a complete response, and 20 (95%) had a partial response. Of the 12 patients treated after first relapse, two (17%) had a complete response and 10 (83%) had partial response after induction.
RIT consolidation was performed 3-5 weeks after the last chemotherapy cycle. Patients with cytopenias after chemotherapy could wait an additional 3 weeks, during which they would receive a bridging dose of rituximab at the standard 375 mg/m2 dose. The patients received two doses of rituximab 250 mg/m2 administered 7 days then 24 hours prior to intravenous injection of 90Y-labeled ibritumomab tiuxetan. The radiation doses delivered were 0.4 mCi/kg for patients with normal platelet counts and 0.3 mCi/kg for those with platelet counts from 100,000 to 150,000 cells/mm3. The maximum dose was 32.0 mCi.
The longest follow-up was out to slightly more than 8 years.
For the patients who received RIT after first-line induction, the complete response rate was 91%, and the partial response rate was 9%, compared with 41% complete response and 59% partial response after induction. In this group, the median progression-free survival was 3.3 years, and the median overall survival was 6.5 years.
For the patients who received RIT consolidation after first relapse and second chemotherapy regimen, the complete response rate was 75% and the partial response rate was 25%, compared with 17% and 83% at the end of second induction therapy. In this group, the median progression-free survival was 1.8 years (P less than .05, compared with patients treated after first-line responses), and the median overall survival was 2.2 years (P less than .05).
At 8 years of follow-up, 30% of patients who received RIT consolidation following first-line therapy were alive.
Adverse events included cytopenias in the majority of patients (77%), which were grade 1 or 2 in severity in 43% and grade 3 or 4 in 34%. Grade 3 or 4 thrombocytopenia and leukopenia occurred more frequently in patients treated with fludarabine-based regimens, and the thrombocytopenias in these patients lasted longer and required more platelet transfusions than those in CHOP- or CVP-treated patients. Two patients who underwent RIT following FCM induction died from prolonged thrombocytopenia, resulting in hemorrhagic strokes.
Among all patients, 22 patients developed infections following RIT consolidation. Five patients, all of whom had received fludarabine, required hospitalization for the treatment of the infections. There were no infection-related deaths, however.
Five patients developed the myelodysplastic syndrome, with a median onset time of 26 months. Of these patients, four had received fludarabine, and one had undergone a prior ASCT.
The trial was sponsored by Schering AG. Dr. Jurczak reported speakers bureau participation and research funding from multiple companies, not including Schering AG.
SOURCE: Jurczak W et al. Leuk Lymphoma. 2019 Apr 9. doi: 10.1080/10428194.2019.1602261.
FROM LEUKEMIA & LYMPHOMA
Creating CAR T-cell therapies for T-cell malignancies
NEWPORT BEACH, CALIF. – Preclinical research has revealed workarounds that may make chimeric antigen receptor (CAR) T-cell therapy feasible for patients with T-cell malignancies.
Researchers have found that using allogeneic cells for CAR T-cell therapy can eliminate contamination by malignant T cells, and editing those allogeneic T cells to delete the target antigen and the T-cell receptor alpha chain (TRAC) can prevent fratricide and graft-versus-host disease (GVHD).
Additionally, an interleukin-7 molecule called NT-I7 has been shown to enhance CAR T-cell proliferation, differentiation, and tumor killing in a mouse model of a T-cell malignancy.
John F. DiPersio, MD, PhD, of Washington University in St. Louis, described this work in a presentation at the Acute Leukemia Forum of Hemedicus.
Obstacles to development
“The primary obstacle for targeting T-cell malignancies with a T cell is that all of the targets that are on the [malignant] T cells are also expressed on the normal T cells,” Dr. DiPersio said. “So when you put a CAR into a normal T cell, it just kills itself. It’s called fratricide.”
A second issue that has limited development is that the phenotype of the malignant T cell in the blood is similar to a normal T cell, so they can’t be separated, he explained.
“So if you were to do anything to a normal T cell, you would also be doing it, in theory, to the malignant T cell – in theory, making it resistant to therapy,” he said.
A third obstacle, which has been seen in patients with B-cell malignancies as well, is the inability to harvest enough T cells to generate effective CAR T-cell therapy.
And a fourth obstacle is that T cells from patients with malignancies may not function normally because they have been exposed to prior therapies.
Dr. DiPersio and his colleagues believe these obstacles can be overcome by creating CAR T-cell therapies using T cells derived from healthy donors or cord blood, using gene editing to remove the target antigen and TRAC, and using NT-I7 to enhance the efficacy of these universal, “off-the-shelf” CAR T cells.
The researchers have tested these theories, and achieved successes, in preclinical models. The team is now planning a clinical trial in patients at Washington University. Dr. DiPersio and his colleagues also created a company called WUGEN that will develop the universal CAR T-cell therapies if the initial proof-of-principle trial proves successful.
UCART7
One of the universal CAR T-cell therapies Dr. DiPersio and his colleagues have tested is UCART7, which targets CD7. Dr. DiPersio noted that CD7 is expressed on 98% of T-cell acute lymphoblastic leukemias (T-ALLs), 24% of acute myeloid leukemias, natural killer (NK) cells, and T cells.
The researchers created UCART7 by using CRISPR/Cas9 to delete CD7 and TRAC from allogeneic T cells and following this with lentiviral transduction with a third-generation CD7-CAR. The team found a way to delete both TRAC and CD7 in a single day with 95% efficiency, Dr. DiPersio noted.
“Knocking out CD7 doesn’t seem to have any impact on the expansion or trafficking of these T cells in vivo,” Dr. DiPersio said. “So we think that deleting that target in a normal T cell will not affect its overall ability to kill a target when we put a CAR into those T cells.”
In fact, the researchers’ experiments showed that UCART7 can kill T-ALL cells in vitro and target primary T-ALL in vivo without inducing GVHD (Leukemia. 2018 Sep;32[9]:1970-83.)
UCART2 and NT-I7
Dr. DiPersio and his colleagues have also tested UCART2, an allogeneic CAR T-cell therapy in which CD2 and TRAC are deleted. The therapy targets CD2 because this antigen is expressed on T-ALL and other T-cell and NK-cell malignancies. Experiments showed that UCART2 targets T-cell malignancies, including T-ALL and cutaneous T-cell lymphoma, in vitro.
The researchers also tested UCART2 in a mouse model of Sézary syndrome. In these experiments, UCART2 was combined with NT-I7.
NT-I7 enhanced the proliferation, persistence, and tumor killing ability of UCART2. Sézary mice that received UCART2 and NT-I7 had “virtually no tumor burden,” according to researchers, and survived longer than mice treated with UCART2 alone (Blood. 2018;132:340).
Dr. DiPersio noted that there was no cytokine release syndrome because these were immunodeficient mice. However, cytokine release syndrome may be a side effect of NT-I7 in patients as NT-I7 induces rapid expansion of CAR T cells.
Dr. DiPersio reported ownership and investment in WUGEN and Magenta Therapeutics. He also has relationships with Cellworks Group, Tioma Therapeutics, RiverVest Venture Partners, Bioline, Asterias Biotherapeutics, Amphivena Therapeutics, Bluebird Bio, Celgene, Incyte, NeoImuneTech, and MacroGenics.
The Acute Leukemia Forum is organized by Hemedicus, which is owned by the same company as this news organization.
NEWPORT BEACH, CALIF. – Preclinical research has revealed workarounds that may make chimeric antigen receptor (CAR) T-cell therapy feasible for patients with T-cell malignancies.
Researchers have found that using allogeneic cells for CAR T-cell therapy can eliminate contamination by malignant T cells, and editing those allogeneic T cells to delete the target antigen and the T-cell receptor alpha chain (TRAC) can prevent fratricide and graft-versus-host disease (GVHD).
Additionally, an interleukin-7 molecule called NT-I7 has been shown to enhance CAR T-cell proliferation, differentiation, and tumor killing in a mouse model of a T-cell malignancy.
John F. DiPersio, MD, PhD, of Washington University in St. Louis, described this work in a presentation at the Acute Leukemia Forum of Hemedicus.
Obstacles to development
“The primary obstacle for targeting T-cell malignancies with a T cell is that all of the targets that are on the [malignant] T cells are also expressed on the normal T cells,” Dr. DiPersio said. “So when you put a CAR into a normal T cell, it just kills itself. It’s called fratricide.”
A second issue that has limited development is that the phenotype of the malignant T cell in the blood is similar to a normal T cell, so they can’t be separated, he explained.
“So if you were to do anything to a normal T cell, you would also be doing it, in theory, to the malignant T cell – in theory, making it resistant to therapy,” he said.
A third obstacle, which has been seen in patients with B-cell malignancies as well, is the inability to harvest enough T cells to generate effective CAR T-cell therapy.
And a fourth obstacle is that T cells from patients with malignancies may not function normally because they have been exposed to prior therapies.
Dr. DiPersio and his colleagues believe these obstacles can be overcome by creating CAR T-cell therapies using T cells derived from healthy donors or cord blood, using gene editing to remove the target antigen and TRAC, and using NT-I7 to enhance the efficacy of these universal, “off-the-shelf” CAR T cells.
The researchers have tested these theories, and achieved successes, in preclinical models. The team is now planning a clinical trial in patients at Washington University. Dr. DiPersio and his colleagues also created a company called WUGEN that will develop the universal CAR T-cell therapies if the initial proof-of-principle trial proves successful.
UCART7
One of the universal CAR T-cell therapies Dr. DiPersio and his colleagues have tested is UCART7, which targets CD7. Dr. DiPersio noted that CD7 is expressed on 98% of T-cell acute lymphoblastic leukemias (T-ALLs), 24% of acute myeloid leukemias, natural killer (NK) cells, and T cells.
The researchers created UCART7 by using CRISPR/Cas9 to delete CD7 and TRAC from allogeneic T cells and following this with lentiviral transduction with a third-generation CD7-CAR. The team found a way to delete both TRAC and CD7 in a single day with 95% efficiency, Dr. DiPersio noted.
“Knocking out CD7 doesn’t seem to have any impact on the expansion or trafficking of these T cells in vivo,” Dr. DiPersio said. “So we think that deleting that target in a normal T cell will not affect its overall ability to kill a target when we put a CAR into those T cells.”
In fact, the researchers’ experiments showed that UCART7 can kill T-ALL cells in vitro and target primary T-ALL in vivo without inducing GVHD (Leukemia. 2018 Sep;32[9]:1970-83.)
UCART2 and NT-I7
Dr. DiPersio and his colleagues have also tested UCART2, an allogeneic CAR T-cell therapy in which CD2 and TRAC are deleted. The therapy targets CD2 because this antigen is expressed on T-ALL and other T-cell and NK-cell malignancies. Experiments showed that UCART2 targets T-cell malignancies, including T-ALL and cutaneous T-cell lymphoma, in vitro.
The researchers also tested UCART2 in a mouse model of Sézary syndrome. In these experiments, UCART2 was combined with NT-I7.
NT-I7 enhanced the proliferation, persistence, and tumor killing ability of UCART2. Sézary mice that received UCART2 and NT-I7 had “virtually no tumor burden,” according to researchers, and survived longer than mice treated with UCART2 alone (Blood. 2018;132:340).
Dr. DiPersio noted that there was no cytokine release syndrome because these were immunodeficient mice. However, cytokine release syndrome may be a side effect of NT-I7 in patients as NT-I7 induces rapid expansion of CAR T cells.
Dr. DiPersio reported ownership and investment in WUGEN and Magenta Therapeutics. He also has relationships with Cellworks Group, Tioma Therapeutics, RiverVest Venture Partners, Bioline, Asterias Biotherapeutics, Amphivena Therapeutics, Bluebird Bio, Celgene, Incyte, NeoImuneTech, and MacroGenics.
The Acute Leukemia Forum is organized by Hemedicus, which is owned by the same company as this news organization.
NEWPORT BEACH, CALIF. – Preclinical research has revealed workarounds that may make chimeric antigen receptor (CAR) T-cell therapy feasible for patients with T-cell malignancies.
Researchers have found that using allogeneic cells for CAR T-cell therapy can eliminate contamination by malignant T cells, and editing those allogeneic T cells to delete the target antigen and the T-cell receptor alpha chain (TRAC) can prevent fratricide and graft-versus-host disease (GVHD).
Additionally, an interleukin-7 molecule called NT-I7 has been shown to enhance CAR T-cell proliferation, differentiation, and tumor killing in a mouse model of a T-cell malignancy.
John F. DiPersio, MD, PhD, of Washington University in St. Louis, described this work in a presentation at the Acute Leukemia Forum of Hemedicus.
Obstacles to development
“The primary obstacle for targeting T-cell malignancies with a T cell is that all of the targets that are on the [malignant] T cells are also expressed on the normal T cells,” Dr. DiPersio said. “So when you put a CAR into a normal T cell, it just kills itself. It’s called fratricide.”
A second issue that has limited development is that the phenotype of the malignant T cell in the blood is similar to a normal T cell, so they can’t be separated, he explained.
“So if you were to do anything to a normal T cell, you would also be doing it, in theory, to the malignant T cell – in theory, making it resistant to therapy,” he said.
A third obstacle, which has been seen in patients with B-cell malignancies as well, is the inability to harvest enough T cells to generate effective CAR T-cell therapy.
And a fourth obstacle is that T cells from patients with malignancies may not function normally because they have been exposed to prior therapies.
Dr. DiPersio and his colleagues believe these obstacles can be overcome by creating CAR T-cell therapies using T cells derived from healthy donors or cord blood, using gene editing to remove the target antigen and TRAC, and using NT-I7 to enhance the efficacy of these universal, “off-the-shelf” CAR T cells.
The researchers have tested these theories, and achieved successes, in preclinical models. The team is now planning a clinical trial in patients at Washington University. Dr. DiPersio and his colleagues also created a company called WUGEN that will develop the universal CAR T-cell therapies if the initial proof-of-principle trial proves successful.
UCART7
One of the universal CAR T-cell therapies Dr. DiPersio and his colleagues have tested is UCART7, which targets CD7. Dr. DiPersio noted that CD7 is expressed on 98% of T-cell acute lymphoblastic leukemias (T-ALLs), 24% of acute myeloid leukemias, natural killer (NK) cells, and T cells.
The researchers created UCART7 by using CRISPR/Cas9 to delete CD7 and TRAC from allogeneic T cells and following this with lentiviral transduction with a third-generation CD7-CAR. The team found a way to delete both TRAC and CD7 in a single day with 95% efficiency, Dr. DiPersio noted.
“Knocking out CD7 doesn’t seem to have any impact on the expansion or trafficking of these T cells in vivo,” Dr. DiPersio said. “So we think that deleting that target in a normal T cell will not affect its overall ability to kill a target when we put a CAR into those T cells.”
In fact, the researchers’ experiments showed that UCART7 can kill T-ALL cells in vitro and target primary T-ALL in vivo without inducing GVHD (Leukemia. 2018 Sep;32[9]:1970-83.)
UCART2 and NT-I7
Dr. DiPersio and his colleagues have also tested UCART2, an allogeneic CAR T-cell therapy in which CD2 and TRAC are deleted. The therapy targets CD2 because this antigen is expressed on T-ALL and other T-cell and NK-cell malignancies. Experiments showed that UCART2 targets T-cell malignancies, including T-ALL and cutaneous T-cell lymphoma, in vitro.
The researchers also tested UCART2 in a mouse model of Sézary syndrome. In these experiments, UCART2 was combined with NT-I7.
NT-I7 enhanced the proliferation, persistence, and tumor killing ability of UCART2. Sézary mice that received UCART2 and NT-I7 had “virtually no tumor burden,” according to researchers, and survived longer than mice treated with UCART2 alone (Blood. 2018;132:340).
Dr. DiPersio noted that there was no cytokine release syndrome because these were immunodeficient mice. However, cytokine release syndrome may be a side effect of NT-I7 in patients as NT-I7 induces rapid expansion of CAR T cells.
Dr. DiPersio reported ownership and investment in WUGEN and Magenta Therapeutics. He also has relationships with Cellworks Group, Tioma Therapeutics, RiverVest Venture Partners, Bioline, Asterias Biotherapeutics, Amphivena Therapeutics, Bluebird Bio, Celgene, Incyte, NeoImuneTech, and MacroGenics.
The Acute Leukemia Forum is organized by Hemedicus, which is owned by the same company as this news organization.
EXPERT ANALYSIS FROM ALF 2019
Bendamustine/rituximab combo proves viable for comorbid CLL
A combination of bendamustine and rituximab generated an 88% overall response rate and 96% overall survival rate at 2 years among patients with chronic lymphocytic leukemia (CLL) in a study of 83 patients aged 53-83 years.
Although combined fludarabine, cyclophosphamide, and rituximab has demonstrated success in younger patients with CLL, this therapy is often considered too aggressive for the majority of CLL patients, who tend to be older and have multiple comorbidities, wrote Martin Špacek, MD, of Charles University and General University Hospital in Prague and his colleagues.
The alternative treatment combination of bendamustine and rituximab (BR) has not been well studied in patients with comorbidities, they said.
In a study published in Leukemia Research, the researchers enrolled 83 previously untreated adults with progressive CLL. The average age of the participants was 71 years, and 61% were men. The median creatinine clearance for the study population was 65 mL/min, and all patients had comorbidities, defined as scores greater than 6 on the Cumulative Illness Rating Scale (CIRS).
All patients were prescribed 90 mg/m2 bendamustine on days 1 and 2 combined with 375 mg/m2 rituximab on day 0 of the first course, and 500 mg/m2 rituximab on day 1 during subsequent courses every 28 days for a maximum of six cycles.
The overall response rate to BR was 88.0%, with a complete response rate of 20.5%. At 2 years, progression-free survival and overall survival rates were 69.9% and 96.2%, respectively.
A total of 51 patients (61.4%) experienced at least one grade 3 or 4 adverse event. The most common hematologic effects were neutropenia (40 patients), thrombocytopenia (14 patients), and anemia (8 patients). The most common nonhematologic effects were grade 3– or grade 4–level infections in 12 patients. Six patients developed severe skin rash.
Additionally, one patient developed sepsis during treatment and died after the first course of therapy.
“Age and CIRS failed to predict any severe toxicities or BR dose reduction,” the researchers noted.
The findings support data from previous studies and represent the largest study of CLL patients with significant comorbidities to be treated with BR, the researchers said.
More prospective research is needed, but the results demonstrate that “chemoimmunotherapy with BR is an effective therapeutic option with manageable toxicity for the initial treatment of CLL patients with significant comorbidities,” the investigators wrote.
The study was supported by the Ministry of Health, Czech Republic, the Charles University Progres program, and the Czech CLL Study Group. Researchers reported honoraria and travel grants from Mundipharma and Roche.
SOURCE: Spacek M et al. Leuk Res. 2019;79:17-21.
A combination of bendamustine and rituximab generated an 88% overall response rate and 96% overall survival rate at 2 years among patients with chronic lymphocytic leukemia (CLL) in a study of 83 patients aged 53-83 years.
Although combined fludarabine, cyclophosphamide, and rituximab has demonstrated success in younger patients with CLL, this therapy is often considered too aggressive for the majority of CLL patients, who tend to be older and have multiple comorbidities, wrote Martin Špacek, MD, of Charles University and General University Hospital in Prague and his colleagues.
The alternative treatment combination of bendamustine and rituximab (BR) has not been well studied in patients with comorbidities, they said.
In a study published in Leukemia Research, the researchers enrolled 83 previously untreated adults with progressive CLL. The average age of the participants was 71 years, and 61% were men. The median creatinine clearance for the study population was 65 mL/min, and all patients had comorbidities, defined as scores greater than 6 on the Cumulative Illness Rating Scale (CIRS).
All patients were prescribed 90 mg/m2 bendamustine on days 1 and 2 combined with 375 mg/m2 rituximab on day 0 of the first course, and 500 mg/m2 rituximab on day 1 during subsequent courses every 28 days for a maximum of six cycles.
The overall response rate to BR was 88.0%, with a complete response rate of 20.5%. At 2 years, progression-free survival and overall survival rates were 69.9% and 96.2%, respectively.
A total of 51 patients (61.4%) experienced at least one grade 3 or 4 adverse event. The most common hematologic effects were neutropenia (40 patients), thrombocytopenia (14 patients), and anemia (8 patients). The most common nonhematologic effects were grade 3– or grade 4–level infections in 12 patients. Six patients developed severe skin rash.
Additionally, one patient developed sepsis during treatment and died after the first course of therapy.
“Age and CIRS failed to predict any severe toxicities or BR dose reduction,” the researchers noted.
The findings support data from previous studies and represent the largest study of CLL patients with significant comorbidities to be treated with BR, the researchers said.
More prospective research is needed, but the results demonstrate that “chemoimmunotherapy with BR is an effective therapeutic option with manageable toxicity for the initial treatment of CLL patients with significant comorbidities,” the investigators wrote.
The study was supported by the Ministry of Health, Czech Republic, the Charles University Progres program, and the Czech CLL Study Group. Researchers reported honoraria and travel grants from Mundipharma and Roche.
SOURCE: Spacek M et al. Leuk Res. 2019;79:17-21.
A combination of bendamustine and rituximab generated an 88% overall response rate and 96% overall survival rate at 2 years among patients with chronic lymphocytic leukemia (CLL) in a study of 83 patients aged 53-83 years.
Although combined fludarabine, cyclophosphamide, and rituximab has demonstrated success in younger patients with CLL, this therapy is often considered too aggressive for the majority of CLL patients, who tend to be older and have multiple comorbidities, wrote Martin Špacek, MD, of Charles University and General University Hospital in Prague and his colleagues.
The alternative treatment combination of bendamustine and rituximab (BR) has not been well studied in patients with comorbidities, they said.
In a study published in Leukemia Research, the researchers enrolled 83 previously untreated adults with progressive CLL. The average age of the participants was 71 years, and 61% were men. The median creatinine clearance for the study population was 65 mL/min, and all patients had comorbidities, defined as scores greater than 6 on the Cumulative Illness Rating Scale (CIRS).
All patients were prescribed 90 mg/m2 bendamustine on days 1 and 2 combined with 375 mg/m2 rituximab on day 0 of the first course, and 500 mg/m2 rituximab on day 1 during subsequent courses every 28 days for a maximum of six cycles.
The overall response rate to BR was 88.0%, with a complete response rate of 20.5%. At 2 years, progression-free survival and overall survival rates were 69.9% and 96.2%, respectively.
A total of 51 patients (61.4%) experienced at least one grade 3 or 4 adverse event. The most common hematologic effects were neutropenia (40 patients), thrombocytopenia (14 patients), and anemia (8 patients). The most common nonhematologic effects were grade 3– or grade 4–level infections in 12 patients. Six patients developed severe skin rash.
Additionally, one patient developed sepsis during treatment and died after the first course of therapy.
“Age and CIRS failed to predict any severe toxicities or BR dose reduction,” the researchers noted.
The findings support data from previous studies and represent the largest study of CLL patients with significant comorbidities to be treated with BR, the researchers said.
More prospective research is needed, but the results demonstrate that “chemoimmunotherapy with BR is an effective therapeutic option with manageable toxicity for the initial treatment of CLL patients with significant comorbidities,” the investigators wrote.
The study was supported by the Ministry of Health, Czech Republic, the Charles University Progres program, and the Czech CLL Study Group. Researchers reported honoraria and travel grants from Mundipharma and Roche.
SOURCE: Spacek M et al. Leuk Res. 2019;79:17-21.
FROM LEUKEMIA RESEARCH
Key clinical point:
Major finding: The overall response rate for the combination therapy was 88.0%; complete response was 20.5%.
Study details: A prospective, observational study of 83 patients with chronic lymphocytic leukemia.
Disclosures: The study was supported by the Ministry of Health, Czech Republic, the Charles University Progres program, and the Czech CLL Study Group. Researchers reported honoraria and travel grants from Mundipharma and Roche.
Source: Spacek M et al. Leuk Res. 2019;79:17-21.
Study explores intracranial hemorrhage management in type 2 VWD
A lack of consistency exists surrounding the management of intracranial hemorrhage (ICH) in patients with von Willebrand disease (VWD), according to a clinical case report and literature review.
“Intracranial hemorrhage (ICH) in von Willebrand patients is a very rare event,” Ezio Zanon, MD, of the University Hospital of Padua (Italy), and his colleagues wrote in a letter to the editor published in Haemophilia.
The researchers reported findings from a case of a woman with type 2B VWD who experienced two spontaneous ICH events 12 years apart. Shortly after her admission for the second episode, the patient died as a result of severe bleeding.
Additionally, the team reviewed the body of literature for other cases of ICH and summarized the management strategies used in these patients.
“To date, only a few cases of intracranial hemorrhages in VWD are reported in literature,” the researchers wrote.
After analysis, the researchers found that a lack of consistency exists in the management of ICH in patients with VWD.
With respect to management strategies, Dr. Zanon and his colleagues suggested that ongoing prophylactic therapy with replacement concentrate could lower the risk of ICH recurrence. In the case presented, the patient was started on prophylaxis after the first ICH episode but it was interrupted 1 year later.
The team also recommended that hypertension should be closely monitored as it is a key risk factor for developing ICH. In the case presented, the patient had poorly controlled arterial hypertension.
“Studies and registries would be very important to define the burden of ICH in VWD patients clearly and establish its proper management,” they wrote.
No funding sources were reported. The authors reported having no conflicts of interest.
SOURCE: Zanon E et al. Haemophilia. 2019 Mar 29. doi: 10.1111/hae.13742.
A lack of consistency exists surrounding the management of intracranial hemorrhage (ICH) in patients with von Willebrand disease (VWD), according to a clinical case report and literature review.
“Intracranial hemorrhage (ICH) in von Willebrand patients is a very rare event,” Ezio Zanon, MD, of the University Hospital of Padua (Italy), and his colleagues wrote in a letter to the editor published in Haemophilia.
The researchers reported findings from a case of a woman with type 2B VWD who experienced two spontaneous ICH events 12 years apart. Shortly after her admission for the second episode, the patient died as a result of severe bleeding.
Additionally, the team reviewed the body of literature for other cases of ICH and summarized the management strategies used in these patients.
“To date, only a few cases of intracranial hemorrhages in VWD are reported in literature,” the researchers wrote.
After analysis, the researchers found that a lack of consistency exists in the management of ICH in patients with VWD.
With respect to management strategies, Dr. Zanon and his colleagues suggested that ongoing prophylactic therapy with replacement concentrate could lower the risk of ICH recurrence. In the case presented, the patient was started on prophylaxis after the first ICH episode but it was interrupted 1 year later.
The team also recommended that hypertension should be closely monitored as it is a key risk factor for developing ICH. In the case presented, the patient had poorly controlled arterial hypertension.
“Studies and registries would be very important to define the burden of ICH in VWD patients clearly and establish its proper management,” they wrote.
No funding sources were reported. The authors reported having no conflicts of interest.
SOURCE: Zanon E et al. Haemophilia. 2019 Mar 29. doi: 10.1111/hae.13742.
A lack of consistency exists surrounding the management of intracranial hemorrhage (ICH) in patients with von Willebrand disease (VWD), according to a clinical case report and literature review.
“Intracranial hemorrhage (ICH) in von Willebrand patients is a very rare event,” Ezio Zanon, MD, of the University Hospital of Padua (Italy), and his colleagues wrote in a letter to the editor published in Haemophilia.
The researchers reported findings from a case of a woman with type 2B VWD who experienced two spontaneous ICH events 12 years apart. Shortly after her admission for the second episode, the patient died as a result of severe bleeding.
Additionally, the team reviewed the body of literature for other cases of ICH and summarized the management strategies used in these patients.
“To date, only a few cases of intracranial hemorrhages in VWD are reported in literature,” the researchers wrote.
After analysis, the researchers found that a lack of consistency exists in the management of ICH in patients with VWD.
With respect to management strategies, Dr. Zanon and his colleagues suggested that ongoing prophylactic therapy with replacement concentrate could lower the risk of ICH recurrence. In the case presented, the patient was started on prophylaxis after the first ICH episode but it was interrupted 1 year later.
The team also recommended that hypertension should be closely monitored as it is a key risk factor for developing ICH. In the case presented, the patient had poorly controlled arterial hypertension.
“Studies and registries would be very important to define the burden of ICH in VWD patients clearly and establish its proper management,” they wrote.
No funding sources were reported. The authors reported having no conflicts of interest.
SOURCE: Zanon E et al. Haemophilia. 2019 Mar 29. doi: 10.1111/hae.13742.
FROM HAEMOPHILIA
Genetic analysis detects novel gene mutations in hemophilia A
A wide variety of genetic mutations, including two novel variants, were found in a cohort of Vietnamese patients with hemophilia A, according to a recent report.
Dung Vu Luu, MD, of the Hanoi (Vietnam) Medical University and his colleagues conducted a genetic analysis of 103 patients with hemophilia A. The results of the analysis were reported in a letter to the editor published in Haemophilia.
“In this letter, we report the spectrum of F8 mutations in Vietnamese patients with a well‐established clinical diagnosis of hemophilia A,” the researchers wrote.
Clinical assessment and validation of hemophilia was completed by hematologists from Vietnam’s National Institute of Hematology and Blood Transfusion. The team analyzed DNA that was extracted and isolated from blood samples collected from the patients.
After analysis, the researchers found that disease-causing genetic variants were present in 89% of patients. The intron 22 inversion mutation was detected in 34% of patients in the cohort.
Dr. Luu and his colleagues reported that two novel F8 mutations were also detected that resulted in a severe clinical phenotype: c.4550‐4551insA; p.His1518Serfs*13 and c.1268‐1269insG; p.Asp366GluFs*5.
“To our knowledge, and after an extensive search in many databases, these two variants have not been reported in any F8 mutation database or reported in any published articles,” they explained.
The researchers acknowledged that future studies need to be larger in size.
“The results of this study are adding to the global knowledge base for [hemophilia A] and thus will promote better awareness for molecular diagnosis and care for [hemophilia A] patients in Vietnam,” they wrote.
The study was supported by grant funding from the Ministry of Health of Vietnam. The authors reported having no conflicts of interest.
SOURCE: Luu DV et al. Haemophilia. 2019 Mar 26. doi: 10.1111/hae.13738.
A wide variety of genetic mutations, including two novel variants, were found in a cohort of Vietnamese patients with hemophilia A, according to a recent report.
Dung Vu Luu, MD, of the Hanoi (Vietnam) Medical University and his colleagues conducted a genetic analysis of 103 patients with hemophilia A. The results of the analysis were reported in a letter to the editor published in Haemophilia.
“In this letter, we report the spectrum of F8 mutations in Vietnamese patients with a well‐established clinical diagnosis of hemophilia A,” the researchers wrote.
Clinical assessment and validation of hemophilia was completed by hematologists from Vietnam’s National Institute of Hematology and Blood Transfusion. The team analyzed DNA that was extracted and isolated from blood samples collected from the patients.
After analysis, the researchers found that disease-causing genetic variants were present in 89% of patients. The intron 22 inversion mutation was detected in 34% of patients in the cohort.
Dr. Luu and his colleagues reported that two novel F8 mutations were also detected that resulted in a severe clinical phenotype: c.4550‐4551insA; p.His1518Serfs*13 and c.1268‐1269insG; p.Asp366GluFs*5.
“To our knowledge, and after an extensive search in many databases, these two variants have not been reported in any F8 mutation database or reported in any published articles,” they explained.
The researchers acknowledged that future studies need to be larger in size.
“The results of this study are adding to the global knowledge base for [hemophilia A] and thus will promote better awareness for molecular diagnosis and care for [hemophilia A] patients in Vietnam,” they wrote.
The study was supported by grant funding from the Ministry of Health of Vietnam. The authors reported having no conflicts of interest.
SOURCE: Luu DV et al. Haemophilia. 2019 Mar 26. doi: 10.1111/hae.13738.
A wide variety of genetic mutations, including two novel variants, were found in a cohort of Vietnamese patients with hemophilia A, according to a recent report.
Dung Vu Luu, MD, of the Hanoi (Vietnam) Medical University and his colleagues conducted a genetic analysis of 103 patients with hemophilia A. The results of the analysis were reported in a letter to the editor published in Haemophilia.
“In this letter, we report the spectrum of F8 mutations in Vietnamese patients with a well‐established clinical diagnosis of hemophilia A,” the researchers wrote.
Clinical assessment and validation of hemophilia was completed by hematologists from Vietnam’s National Institute of Hematology and Blood Transfusion. The team analyzed DNA that was extracted and isolated from blood samples collected from the patients.
After analysis, the researchers found that disease-causing genetic variants were present in 89% of patients. The intron 22 inversion mutation was detected in 34% of patients in the cohort.
Dr. Luu and his colleagues reported that two novel F8 mutations were also detected that resulted in a severe clinical phenotype: c.4550‐4551insA; p.His1518Serfs*13 and c.1268‐1269insG; p.Asp366GluFs*5.
“To our knowledge, and after an extensive search in many databases, these two variants have not been reported in any F8 mutation database or reported in any published articles,” they explained.
The researchers acknowledged that future studies need to be larger in size.
“The results of this study are adding to the global knowledge base for [hemophilia A] and thus will promote better awareness for molecular diagnosis and care for [hemophilia A] patients in Vietnam,” they wrote.
The study was supported by grant funding from the Ministry of Health of Vietnam. The authors reported having no conflicts of interest.
SOURCE: Luu DV et al. Haemophilia. 2019 Mar 26. doi: 10.1111/hae.13738.
FROM HAEMOPHILIA
Platelet-rich plasma shows promise in hemophilic arthropathy of the knee
A single intra-articular injection of platelet-rich plasma showed better pain and function scores at 6 months than did weekly injections of hyaluronic acid in patients with hemophilic arthropathy of the knee.
“In patients with chronic knee joint pain, our study shows that treatment with intra-articular [platelet-rich plasma] injection could reduce pain, improve hyperaemia and enhance knee joint function,” wrote Tsung-Ying Li, MD, of Tri-Service General Hospital in Taipei, Taiwan, and his colleagues. The results of the comparison study were published in Haemophilia.
Researchers conducted a nonrandomized, single-center, open-label comparison study of 22 patients with hemophilia A who had chronic hemophilic arthropathy of the knee. Patients were stratified into two treatment groups using a matched sampling method.
“Patients who could commit to hyaluronic acid treatment were allocated to the hyaluronic acid group, otherwise patients were allocated to the platelet‐rich plasma group,” the researchers wrote.
Participants in the hyaluronic acid arm were given five sequential weekly injections and those in the platelet-rich plasma arm received only a single injection. Outcomes were measured via the visual analogue scale (VAS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Chinese Version, and ultrasonography to determine synovial change.
Pain and function scores were significantly lower in patients administered intra-articular platelet-rich plasma versus hyaluronic acid at 6 months (P less than .05), the researchers reported. However, comparative analysis found no significant differences at earlier follow-up time points.
“Both treatments were found to be effective in reducing pain and improving functional status of the knee,” the researchers wrote.
They acknowledged a key limitation of the study was the short duration of follow-up, which was due to budget restrictions at the treatment facility.
“Further investigation using rigorous research methodology is warranted to establish the benefit of [platelet-rich plasma] on hemophilic arthropathy and standardized [platelet-rich plasma] preparation and dosing regimens,” they wrote.
The study was supported by grant funding from Tri-Service General Hospital in Taiwan. Three of the authors reported receiving research grants from Shire.
SOURCE: Li TY et al. Haemophilia. 2019 Mar 13. doi: 10.1111/hae.13711.
A single intra-articular injection of platelet-rich plasma showed better pain and function scores at 6 months than did weekly injections of hyaluronic acid in patients with hemophilic arthropathy of the knee.
“In patients with chronic knee joint pain, our study shows that treatment with intra-articular [platelet-rich plasma] injection could reduce pain, improve hyperaemia and enhance knee joint function,” wrote Tsung-Ying Li, MD, of Tri-Service General Hospital in Taipei, Taiwan, and his colleagues. The results of the comparison study were published in Haemophilia.
Researchers conducted a nonrandomized, single-center, open-label comparison study of 22 patients with hemophilia A who had chronic hemophilic arthropathy of the knee. Patients were stratified into two treatment groups using a matched sampling method.
“Patients who could commit to hyaluronic acid treatment were allocated to the hyaluronic acid group, otherwise patients were allocated to the platelet‐rich plasma group,” the researchers wrote.
Participants in the hyaluronic acid arm were given five sequential weekly injections and those in the platelet-rich plasma arm received only a single injection. Outcomes were measured via the visual analogue scale (VAS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Chinese Version, and ultrasonography to determine synovial change.
Pain and function scores were significantly lower in patients administered intra-articular platelet-rich plasma versus hyaluronic acid at 6 months (P less than .05), the researchers reported. However, comparative analysis found no significant differences at earlier follow-up time points.
“Both treatments were found to be effective in reducing pain and improving functional status of the knee,” the researchers wrote.
They acknowledged a key limitation of the study was the short duration of follow-up, which was due to budget restrictions at the treatment facility.
“Further investigation using rigorous research methodology is warranted to establish the benefit of [platelet-rich plasma] on hemophilic arthropathy and standardized [platelet-rich plasma] preparation and dosing regimens,” they wrote.
The study was supported by grant funding from Tri-Service General Hospital in Taiwan. Three of the authors reported receiving research grants from Shire.
SOURCE: Li TY et al. Haemophilia. 2019 Mar 13. doi: 10.1111/hae.13711.
A single intra-articular injection of platelet-rich plasma showed better pain and function scores at 6 months than did weekly injections of hyaluronic acid in patients with hemophilic arthropathy of the knee.
“In patients with chronic knee joint pain, our study shows that treatment with intra-articular [platelet-rich plasma] injection could reduce pain, improve hyperaemia and enhance knee joint function,” wrote Tsung-Ying Li, MD, of Tri-Service General Hospital in Taipei, Taiwan, and his colleagues. The results of the comparison study were published in Haemophilia.
Researchers conducted a nonrandomized, single-center, open-label comparison study of 22 patients with hemophilia A who had chronic hemophilic arthropathy of the knee. Patients were stratified into two treatment groups using a matched sampling method.
“Patients who could commit to hyaluronic acid treatment were allocated to the hyaluronic acid group, otherwise patients were allocated to the platelet‐rich plasma group,” the researchers wrote.
Participants in the hyaluronic acid arm were given five sequential weekly injections and those in the platelet-rich plasma arm received only a single injection. Outcomes were measured via the visual analogue scale (VAS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Chinese Version, and ultrasonography to determine synovial change.
Pain and function scores were significantly lower in patients administered intra-articular platelet-rich plasma versus hyaluronic acid at 6 months (P less than .05), the researchers reported. However, comparative analysis found no significant differences at earlier follow-up time points.
“Both treatments were found to be effective in reducing pain and improving functional status of the knee,” the researchers wrote.
They acknowledged a key limitation of the study was the short duration of follow-up, which was due to budget restrictions at the treatment facility.
“Further investigation using rigorous research methodology is warranted to establish the benefit of [platelet-rich plasma] on hemophilic arthropathy and standardized [platelet-rich plasma] preparation and dosing regimens,” they wrote.
The study was supported by grant funding from Tri-Service General Hospital in Taiwan. Three of the authors reported receiving research grants from Shire.
SOURCE: Li TY et al. Haemophilia. 2019 Mar 13. doi: 10.1111/hae.13711.
FROM HAEMOPHILIA
Women with FXI deficiency face hemorrhage risk with gyn surgery
Women with factor XI (FXI) deficiency, particularly those with a history of bleeding and low plasmatic FXI levels, are at risk of experiencing obstetric and gynecologic hemorrhage, according to a retrospective analysis.
“[W]hile spontaneous bleeding episodes are unusual, FXI-deficient patients tend to bleed excessively after trauma or surgery, especially when highly fibrinolytic tissues are involved, such as rhino/oropharyngeal and genitourinary mucosa,” wrote Carlos Bravo-Perez, MD, of Universidad de Murcia in Spain, along with his colleagues. The report is in Medicina Clínica. “Menstruation, pregnancy and birth labour constitute intrinsic haemostatic challenges for FXI deficient women,” they noted.
The researchers conducted a retrospective analysis of 95 women with FXI deficiency. Cohort data was collected over a period of 20 years (1994 to 2014) from the city of Yecla, Spain.
Clinical information obtained included blood group, age, sex, aPTT ratio, and FXI coagulant levels, among others. The team completed a comprehensive molecular and biochemical analysis on all study patients.
“Surgical interventions and postoperative bleeding were recorded, as well as the use of antihemorrhagic prophylaxis or treatment,” the researchers wrote.
Bleeding occurred in 27.4% of women with FXI deficiency, with the majority of events being a single episode. The team reported that 52.5% of hemorrhagic events were provoked by surgical, obstetric, or dental procedures, while 47.5% were spontaneous bleeding events.
Among women who experienced bleeding events, 73.1% were gynecologic or obstetric hemorrhagic episodes. These included abnormal uterine bleeding, postpartum hemorrhage, excessive bleeding after a miscarriage, and bleeding after gynecologic surgery.
Overall, the proportion of abnormal uterine bleeding was 12.6%, the proportion of postpartum hemorrhage was 6.6%, and the proportion of gynecologic postoperative hemorrhage was 16%.
While the proportion of these bleeding events is higher than what has been observed in the general population, it is lower than what has been reported in other reviews for women with FXI deficiency, the researchers noted.
They also found that a positive history of bleeding and low plasmatic FXI levels were associated with a higher prevalence of gynecologic or obstetric bleeding.
The study was funded by Fundación Española de Trombosis y Hemostasia and Sociedad Española de Hematología y Hemoterapia in Spain. The authors reported having no conflicts of interest.
SOURCE: Bravo-Perez C et al. Med Clin (Barc). 2019 Mar 26. doi: 10.1016/j.medcli.2019.01.029.
Women with factor XI (FXI) deficiency, particularly those with a history of bleeding and low plasmatic FXI levels, are at risk of experiencing obstetric and gynecologic hemorrhage, according to a retrospective analysis.
“[W]hile spontaneous bleeding episodes are unusual, FXI-deficient patients tend to bleed excessively after trauma or surgery, especially when highly fibrinolytic tissues are involved, such as rhino/oropharyngeal and genitourinary mucosa,” wrote Carlos Bravo-Perez, MD, of Universidad de Murcia in Spain, along with his colleagues. The report is in Medicina Clínica. “Menstruation, pregnancy and birth labour constitute intrinsic haemostatic challenges for FXI deficient women,” they noted.
The researchers conducted a retrospective analysis of 95 women with FXI deficiency. Cohort data was collected over a period of 20 years (1994 to 2014) from the city of Yecla, Spain.
Clinical information obtained included blood group, age, sex, aPTT ratio, and FXI coagulant levels, among others. The team completed a comprehensive molecular and biochemical analysis on all study patients.
“Surgical interventions and postoperative bleeding were recorded, as well as the use of antihemorrhagic prophylaxis or treatment,” the researchers wrote.
Bleeding occurred in 27.4% of women with FXI deficiency, with the majority of events being a single episode. The team reported that 52.5% of hemorrhagic events were provoked by surgical, obstetric, or dental procedures, while 47.5% were spontaneous bleeding events.
Among women who experienced bleeding events, 73.1% were gynecologic or obstetric hemorrhagic episodes. These included abnormal uterine bleeding, postpartum hemorrhage, excessive bleeding after a miscarriage, and bleeding after gynecologic surgery.
Overall, the proportion of abnormal uterine bleeding was 12.6%, the proportion of postpartum hemorrhage was 6.6%, and the proportion of gynecologic postoperative hemorrhage was 16%.
While the proportion of these bleeding events is higher than what has been observed in the general population, it is lower than what has been reported in other reviews for women with FXI deficiency, the researchers noted.
They also found that a positive history of bleeding and low plasmatic FXI levels were associated with a higher prevalence of gynecologic or obstetric bleeding.
The study was funded by Fundación Española de Trombosis y Hemostasia and Sociedad Española de Hematología y Hemoterapia in Spain. The authors reported having no conflicts of interest.
SOURCE: Bravo-Perez C et al. Med Clin (Barc). 2019 Mar 26. doi: 10.1016/j.medcli.2019.01.029.
Women with factor XI (FXI) deficiency, particularly those with a history of bleeding and low plasmatic FXI levels, are at risk of experiencing obstetric and gynecologic hemorrhage, according to a retrospective analysis.
“[W]hile spontaneous bleeding episodes are unusual, FXI-deficient patients tend to bleed excessively after trauma or surgery, especially when highly fibrinolytic tissues are involved, such as rhino/oropharyngeal and genitourinary mucosa,” wrote Carlos Bravo-Perez, MD, of Universidad de Murcia in Spain, along with his colleagues. The report is in Medicina Clínica. “Menstruation, pregnancy and birth labour constitute intrinsic haemostatic challenges for FXI deficient women,” they noted.
The researchers conducted a retrospective analysis of 95 women with FXI deficiency. Cohort data was collected over a period of 20 years (1994 to 2014) from the city of Yecla, Spain.
Clinical information obtained included blood group, age, sex, aPTT ratio, and FXI coagulant levels, among others. The team completed a comprehensive molecular and biochemical analysis on all study patients.
“Surgical interventions and postoperative bleeding were recorded, as well as the use of antihemorrhagic prophylaxis or treatment,” the researchers wrote.
Bleeding occurred in 27.4% of women with FXI deficiency, with the majority of events being a single episode. The team reported that 52.5% of hemorrhagic events were provoked by surgical, obstetric, or dental procedures, while 47.5% were spontaneous bleeding events.
Among women who experienced bleeding events, 73.1% were gynecologic or obstetric hemorrhagic episodes. These included abnormal uterine bleeding, postpartum hemorrhage, excessive bleeding after a miscarriage, and bleeding after gynecologic surgery.
Overall, the proportion of abnormal uterine bleeding was 12.6%, the proportion of postpartum hemorrhage was 6.6%, and the proportion of gynecologic postoperative hemorrhage was 16%.
While the proportion of these bleeding events is higher than what has been observed in the general population, it is lower than what has been reported in other reviews for women with FXI deficiency, the researchers noted.
They also found that a positive history of bleeding and low plasmatic FXI levels were associated with a higher prevalence of gynecologic or obstetric bleeding.
The study was funded by Fundación Española de Trombosis y Hemostasia and Sociedad Española de Hematología y Hemoterapia in Spain. The authors reported having no conflicts of interest.
SOURCE: Bravo-Perez C et al. Med Clin (Barc). 2019 Mar 26. doi: 10.1016/j.medcli.2019.01.029.
FROM MEDICINA CLÍNICA
Study finds higher than expected rates of hemophilia in Indiana
The state of Indiana had higher hemophilia incidence and prevalence rates, compared with national estimates, according to results from a statewide epidemiologic analysis.
“[The study] aimed to identify all persons with hemophilia, including those not served by an hemophilia treatment center, who resided in Indiana,” Amanda I. Okolo, MPH, of the Indiana Hemophilia and Thrombosis Center, Indianapolis, and her colleagues wrote in Haemophilia.
The researchers retrospectively reviewed medical chart data from federally identified hemophilia treatment centers in Indiana during 2011-2013. Various data sources were used to find hemophilia cases, including administrative claims, clinic reports, and hospital records. The team estimated incidence and prevalence rates using both confirmed and possible cases of hemophilia. With respect to incidence, the calculation was based on the 10 years leading up to the study surveillance period.
“During the study period, 599, 623, and 634 male cases of hemophilia were identified in 2011, 2012 and 2013, respectively, with a total of 704 unique male cases,” the researchers wrote. Among these cases, 35.2% had factor IX deficiency and 64.8% had factor VIII deficiency.
Health care utilization was high among this group of patients, with more than 80% of cases seen at a hemophilia treatment center at least once during the 3-year study period.
The age-adjusted prevalence rate for hemophilia in 2013 was 19.4 cases per 100,000 males. The mean incidence rate over the 10 years leading up to the study period was 30.1 per 100,000, or 1 per 3,688 live male births, noticeably higher than the generally accepted national frequency of hemophilia at about 1 per 5,000 live male births.
“The estimated hemophilia prevalence in Indiana was 45% higher than previously reported in the United States,” the researchers added.
The higher prevalence could be partly caused by improvements in hemophilia care, namely increased adoption of prophylaxis. But a more important factor may be the reduction in HIV infections and the decreasing mortality from HIV among hemophilia patients.
The researchers acknowledged a key limitation of the study was the lack of data on patients assessed in other clinical settings. As a result, the reported rates could be an underestimation.
“Our results may be relevant to other countries where the hemophilia treatment center model is utilized,” they wrote.
No funding sources were reported. The authors reported having no conflicts of interest.
SOURCE: Okolo AI et al. Haemophilia. 2019 Mar 29. doi: 10.1111/hae.13734.
The state of Indiana had higher hemophilia incidence and prevalence rates, compared with national estimates, according to results from a statewide epidemiologic analysis.
“[The study] aimed to identify all persons with hemophilia, including those not served by an hemophilia treatment center, who resided in Indiana,” Amanda I. Okolo, MPH, of the Indiana Hemophilia and Thrombosis Center, Indianapolis, and her colleagues wrote in Haemophilia.
The researchers retrospectively reviewed medical chart data from federally identified hemophilia treatment centers in Indiana during 2011-2013. Various data sources were used to find hemophilia cases, including administrative claims, clinic reports, and hospital records. The team estimated incidence and prevalence rates using both confirmed and possible cases of hemophilia. With respect to incidence, the calculation was based on the 10 years leading up to the study surveillance period.
“During the study period, 599, 623, and 634 male cases of hemophilia were identified in 2011, 2012 and 2013, respectively, with a total of 704 unique male cases,” the researchers wrote. Among these cases, 35.2% had factor IX deficiency and 64.8% had factor VIII deficiency.
Health care utilization was high among this group of patients, with more than 80% of cases seen at a hemophilia treatment center at least once during the 3-year study period.
The age-adjusted prevalence rate for hemophilia in 2013 was 19.4 cases per 100,000 males. The mean incidence rate over the 10 years leading up to the study period was 30.1 per 100,000, or 1 per 3,688 live male births, noticeably higher than the generally accepted national frequency of hemophilia at about 1 per 5,000 live male births.
“The estimated hemophilia prevalence in Indiana was 45% higher than previously reported in the United States,” the researchers added.
The higher prevalence could be partly caused by improvements in hemophilia care, namely increased adoption of prophylaxis. But a more important factor may be the reduction in HIV infections and the decreasing mortality from HIV among hemophilia patients.
The researchers acknowledged a key limitation of the study was the lack of data on patients assessed in other clinical settings. As a result, the reported rates could be an underestimation.
“Our results may be relevant to other countries where the hemophilia treatment center model is utilized,” they wrote.
No funding sources were reported. The authors reported having no conflicts of interest.
SOURCE: Okolo AI et al. Haemophilia. 2019 Mar 29. doi: 10.1111/hae.13734.
The state of Indiana had higher hemophilia incidence and prevalence rates, compared with national estimates, according to results from a statewide epidemiologic analysis.
“[The study] aimed to identify all persons with hemophilia, including those not served by an hemophilia treatment center, who resided in Indiana,” Amanda I. Okolo, MPH, of the Indiana Hemophilia and Thrombosis Center, Indianapolis, and her colleagues wrote in Haemophilia.
The researchers retrospectively reviewed medical chart data from federally identified hemophilia treatment centers in Indiana during 2011-2013. Various data sources were used to find hemophilia cases, including administrative claims, clinic reports, and hospital records. The team estimated incidence and prevalence rates using both confirmed and possible cases of hemophilia. With respect to incidence, the calculation was based on the 10 years leading up to the study surveillance period.
“During the study period, 599, 623, and 634 male cases of hemophilia were identified in 2011, 2012 and 2013, respectively, with a total of 704 unique male cases,” the researchers wrote. Among these cases, 35.2% had factor IX deficiency and 64.8% had factor VIII deficiency.
Health care utilization was high among this group of patients, with more than 80% of cases seen at a hemophilia treatment center at least once during the 3-year study period.
The age-adjusted prevalence rate for hemophilia in 2013 was 19.4 cases per 100,000 males. The mean incidence rate over the 10 years leading up to the study period was 30.1 per 100,000, or 1 per 3,688 live male births, noticeably higher than the generally accepted national frequency of hemophilia at about 1 per 5,000 live male births.
“The estimated hemophilia prevalence in Indiana was 45% higher than previously reported in the United States,” the researchers added.
The higher prevalence could be partly caused by improvements in hemophilia care, namely increased adoption of prophylaxis. But a more important factor may be the reduction in HIV infections and the decreasing mortality from HIV among hemophilia patients.
The researchers acknowledged a key limitation of the study was the lack of data on patients assessed in other clinical settings. As a result, the reported rates could be an underestimation.
“Our results may be relevant to other countries where the hemophilia treatment center model is utilized,” they wrote.
No funding sources were reported. The authors reported having no conflicts of interest.
SOURCE: Okolo AI et al. Haemophilia. 2019 Mar 29. doi: 10.1111/hae.13734.
FROM HAEMOPHILIA
SB-525 gene therapy looks viable for hemophilia A
Interim data suggest SB-525, an investigational gene therapy, may be safe and effective for patients with severe hemophilia A.
In the phase 1/2 Alta trial, SB-525 produced dose-dependent increases in factor VIII activity, with two of eight patients achieving normal factor VIII levels.
In addition, SB-525 was considered well tolerated. One patient did experience treatment-related serious adverse events – hypotension and fever – but these resolved within 24 hours.
Sangamo Therapeutics and Pfizer recently released these data in a press release and conference call.
The data include eight patients with severe hemophilia A who received SB-525 at 9e11 vg/kg, 2e12 vg/kg, 1e13 vg/kg, and 3e13 vg/kg.
Patient 1 (9e11 vg/kg), Patient 2 (9e11 vg/kg), and Patient 3 (2e12 vg/kg) did not experience clinically relevant increases in factor VIII levels and still require prophylactic recombinant factor VIII therapy.
Patient 4 (2e12 vg/kg) and Patient 5 (1e13 vg/kg) discontinued factor VIII therapy but have experienced spontaneous bleeds. Patient 4 had three bleeds in 48 weeks of follow-up, and Patient 5 had two bleeds in 40 weeks of follow-up.
Patient 6 (1e13 vg/kg), Patient 7 (3e13 vg/kg), and Patient 8 (3e13 vg/kg) have stopped factor VIII therapy and remain free of spontaneous bleeds at 28 weeks, 12 weeks, and 6 weeks of follow-up, respectively.
Patients 7 and 8 have achieved normal factor VIII levels. At 6 weeks, their factor VIII levels reached 140% and 94% of normal, respectively, according to a one-stage clotting assay, and 93% and 65%, respectively, according to a chromogenic assay.
“It appears the patients achieve their peak factor level at week 5 to 7 and maintain that level,” Edward Conner, MD, chief medical officer of Sangamo, said during the conference call.
The adverse events observed in this trial include grade 1 tachycardia (n = 1), grade 1 fatigue (n = 1), grade 1 alanine aminotransferase increase (n = 3), grade 1 myalgia (n = 1), grade 2 pyrexia (n = 2), and grade 3 hypotension (n = 1).
“These interim results indicate that SB-525 has the potential to comprise a well-tolerated, reliable, and predictable treatment, features that we believe will be a hallmark of the future gene therapy treatment of hemophilia A,” Dr. Conner said during the call.
Sangamo and Pfizer are enrolling additional patients in this trial, with the goal of expanding the 3e13 vg/kg cohort by up to five patients. The companies plan to present longer-term follow-up data at an upcoming scientific meeting.
The Alta trial is sponsored by Sangamo Therapeutics in collaboration with Pfizer.
Interim data suggest SB-525, an investigational gene therapy, may be safe and effective for patients with severe hemophilia A.
In the phase 1/2 Alta trial, SB-525 produced dose-dependent increases in factor VIII activity, with two of eight patients achieving normal factor VIII levels.
In addition, SB-525 was considered well tolerated. One patient did experience treatment-related serious adverse events – hypotension and fever – but these resolved within 24 hours.
Sangamo Therapeutics and Pfizer recently released these data in a press release and conference call.
The data include eight patients with severe hemophilia A who received SB-525 at 9e11 vg/kg, 2e12 vg/kg, 1e13 vg/kg, and 3e13 vg/kg.
Patient 1 (9e11 vg/kg), Patient 2 (9e11 vg/kg), and Patient 3 (2e12 vg/kg) did not experience clinically relevant increases in factor VIII levels and still require prophylactic recombinant factor VIII therapy.
Patient 4 (2e12 vg/kg) and Patient 5 (1e13 vg/kg) discontinued factor VIII therapy but have experienced spontaneous bleeds. Patient 4 had three bleeds in 48 weeks of follow-up, and Patient 5 had two bleeds in 40 weeks of follow-up.
Patient 6 (1e13 vg/kg), Patient 7 (3e13 vg/kg), and Patient 8 (3e13 vg/kg) have stopped factor VIII therapy and remain free of spontaneous bleeds at 28 weeks, 12 weeks, and 6 weeks of follow-up, respectively.
Patients 7 and 8 have achieved normal factor VIII levels. At 6 weeks, their factor VIII levels reached 140% and 94% of normal, respectively, according to a one-stage clotting assay, and 93% and 65%, respectively, according to a chromogenic assay.
“It appears the patients achieve their peak factor level at week 5 to 7 and maintain that level,” Edward Conner, MD, chief medical officer of Sangamo, said during the conference call.
The adverse events observed in this trial include grade 1 tachycardia (n = 1), grade 1 fatigue (n = 1), grade 1 alanine aminotransferase increase (n = 3), grade 1 myalgia (n = 1), grade 2 pyrexia (n = 2), and grade 3 hypotension (n = 1).
“These interim results indicate that SB-525 has the potential to comprise a well-tolerated, reliable, and predictable treatment, features that we believe will be a hallmark of the future gene therapy treatment of hemophilia A,” Dr. Conner said during the call.
Sangamo and Pfizer are enrolling additional patients in this trial, with the goal of expanding the 3e13 vg/kg cohort by up to five patients. The companies plan to present longer-term follow-up data at an upcoming scientific meeting.
The Alta trial is sponsored by Sangamo Therapeutics in collaboration with Pfizer.
Interim data suggest SB-525, an investigational gene therapy, may be safe and effective for patients with severe hemophilia A.
In the phase 1/2 Alta trial, SB-525 produced dose-dependent increases in factor VIII activity, with two of eight patients achieving normal factor VIII levels.
In addition, SB-525 was considered well tolerated. One patient did experience treatment-related serious adverse events – hypotension and fever – but these resolved within 24 hours.
Sangamo Therapeutics and Pfizer recently released these data in a press release and conference call.
The data include eight patients with severe hemophilia A who received SB-525 at 9e11 vg/kg, 2e12 vg/kg, 1e13 vg/kg, and 3e13 vg/kg.
Patient 1 (9e11 vg/kg), Patient 2 (9e11 vg/kg), and Patient 3 (2e12 vg/kg) did not experience clinically relevant increases in factor VIII levels and still require prophylactic recombinant factor VIII therapy.
Patient 4 (2e12 vg/kg) and Patient 5 (1e13 vg/kg) discontinued factor VIII therapy but have experienced spontaneous bleeds. Patient 4 had three bleeds in 48 weeks of follow-up, and Patient 5 had two bleeds in 40 weeks of follow-up.
Patient 6 (1e13 vg/kg), Patient 7 (3e13 vg/kg), and Patient 8 (3e13 vg/kg) have stopped factor VIII therapy and remain free of spontaneous bleeds at 28 weeks, 12 weeks, and 6 weeks of follow-up, respectively.
Patients 7 and 8 have achieved normal factor VIII levels. At 6 weeks, their factor VIII levels reached 140% and 94% of normal, respectively, according to a one-stage clotting assay, and 93% and 65%, respectively, according to a chromogenic assay.
“It appears the patients achieve their peak factor level at week 5 to 7 and maintain that level,” Edward Conner, MD, chief medical officer of Sangamo, said during the conference call.
The adverse events observed in this trial include grade 1 tachycardia (n = 1), grade 1 fatigue (n = 1), grade 1 alanine aminotransferase increase (n = 3), grade 1 myalgia (n = 1), grade 2 pyrexia (n = 2), and grade 3 hypotension (n = 1).
“These interim results indicate that SB-525 has the potential to comprise a well-tolerated, reliable, and predictable treatment, features that we believe will be a hallmark of the future gene therapy treatment of hemophilia A,” Dr. Conner said during the call.
Sangamo and Pfizer are enrolling additional patients in this trial, with the goal of expanding the 3e13 vg/kg cohort by up to five patients. The companies plan to present longer-term follow-up data at an upcoming scientific meeting.
The Alta trial is sponsored by Sangamo Therapeutics in collaboration with Pfizer.
In situ vaccination produced responses in indolent NHL
A three-pronged treatment approach can produce responses in indolent non-Hodgkin lymphoma (iNHL), according to research published in Nature Medicine.
The approach – “in situ vaccination (ISV)” – involves intratumoral injections of Fms-like tyrosine kinase 3 ligand (Flt3L), local radiotherapy, and intratumoral injections of a TLR3 agonist (poly-ICLC).
ISV produced responses in patients with iNHL, prompting regression of tumors that were directly targeted with ISV, as well as untreated tumors.
In preclinical experiments, ISV induced tumor regression in mice but also overcame resistance to PD1 inhibition. This result led researchers to initiate a trial testing ISV in combination with pembrolizumab in patients with lymphoma and solid tumors.
“We discovered why some tumors do not respond to PD1 blockade: insufficient dendritic cells (DCs) and cross-presentation,” lead study author Joshua Brody, MD, of the Icahn School of Medicine at Mount Sinai, New York, said in an interview. “We developed a treatment, in situ vaccination (ISV), which brings DCs to the tumor, loads them with tumor antigens, and activates the DCs.”
Specifically, the researchers found that injecting Flt3L into a tumor recruits intratumoral DCs, local radiotherapy loads the DCs with tumor-associated antigens, and poly-ICLC activates DCs. This approach produced responses in mouse models of lymphoma and patients with iNHL.
Preclinical results
Dr. Brody and his colleagues tested ISV in A20 tumor-bearing mice. The mice received intratumoral injections of Flt3L, followed by local radiotherapy and poly-ICLC.
Tumor regression occurred within days of radiotherapy. About 40% of mice experienced tumor-free survival of at least 3 months, although most tumors recurred within 4 weeks of ISV administration.
However, the researchers observed increased PD1 and PD-L1 expression in ISV-treated mice, so the team theorized that an anti-PD1 monoclonal antibody (RMP1-14) could improve the efficacy of ISV.
The researchers found that ISV plus RMP1-14 delayed tumor growth when compared with ISV alone, and the rate of durable remissions increased from about 40% to about 80%.
Clinical results
Dr. Brody and his colleagues also tested ISV in a clinical trial. That trial included 11 iNHL patients – 9 with follicular lymphoma, 1 with marginal zone lymphoma, and 1 with small lymphocytic lymphoma.
The patients received nine daily injections of Flt3L (25 mcg/kg) into a target lesion, then two doses of radiation (2 Gy) to the same lesion, and eight intratumoral injections of poly-ICLC (2 mg).
“We ... have observed dramatic clinical responses; i.e., we administer ISV at one tumor site, and tumors throughout the body regress,” Dr. Brody said.
At the target lesion, there were two complete responses, six partial responses, and three cases of stable disease. At nontarget lesions, there was one complete response, two partial responses, six cases of stable disease, and two cases of progression.
ISV was considered well tolerated. One patient had grade 2 fever, three had grade 1 fever, and nine had grade 1 flu-like symptoms. Two patients did not have any adverse events.
This research was supported by Merck, Celldex Therapeutics, Oncovir, and Genentech. The authors reported relationships with Acerta Pharma, Bristol Myers Squibb, Genentech, Gilead Sciences, Seattle Genetics, Pharmacyclics, Celgene, Celldex Therapeutics, and Oncovir.
SOURCE: Hammerich L et al. Nat Med. 2019 Apr 8. doi: 10.1038/s41591-019-0410-x.
A three-pronged treatment approach can produce responses in indolent non-Hodgkin lymphoma (iNHL), according to research published in Nature Medicine.
The approach – “in situ vaccination (ISV)” – involves intratumoral injections of Fms-like tyrosine kinase 3 ligand (Flt3L), local radiotherapy, and intratumoral injections of a TLR3 agonist (poly-ICLC).
ISV produced responses in patients with iNHL, prompting regression of tumors that were directly targeted with ISV, as well as untreated tumors.
In preclinical experiments, ISV induced tumor regression in mice but also overcame resistance to PD1 inhibition. This result led researchers to initiate a trial testing ISV in combination with pembrolizumab in patients with lymphoma and solid tumors.
“We discovered why some tumors do not respond to PD1 blockade: insufficient dendritic cells (DCs) and cross-presentation,” lead study author Joshua Brody, MD, of the Icahn School of Medicine at Mount Sinai, New York, said in an interview. “We developed a treatment, in situ vaccination (ISV), which brings DCs to the tumor, loads them with tumor antigens, and activates the DCs.”
Specifically, the researchers found that injecting Flt3L into a tumor recruits intratumoral DCs, local radiotherapy loads the DCs with tumor-associated antigens, and poly-ICLC activates DCs. This approach produced responses in mouse models of lymphoma and patients with iNHL.
Preclinical results
Dr. Brody and his colleagues tested ISV in A20 tumor-bearing mice. The mice received intratumoral injections of Flt3L, followed by local radiotherapy and poly-ICLC.
Tumor regression occurred within days of radiotherapy. About 40% of mice experienced tumor-free survival of at least 3 months, although most tumors recurred within 4 weeks of ISV administration.
However, the researchers observed increased PD1 and PD-L1 expression in ISV-treated mice, so the team theorized that an anti-PD1 monoclonal antibody (RMP1-14) could improve the efficacy of ISV.
The researchers found that ISV plus RMP1-14 delayed tumor growth when compared with ISV alone, and the rate of durable remissions increased from about 40% to about 80%.
Clinical results
Dr. Brody and his colleagues also tested ISV in a clinical trial. That trial included 11 iNHL patients – 9 with follicular lymphoma, 1 with marginal zone lymphoma, and 1 with small lymphocytic lymphoma.
The patients received nine daily injections of Flt3L (25 mcg/kg) into a target lesion, then two doses of radiation (2 Gy) to the same lesion, and eight intratumoral injections of poly-ICLC (2 mg).
“We ... have observed dramatic clinical responses; i.e., we administer ISV at one tumor site, and tumors throughout the body regress,” Dr. Brody said.
At the target lesion, there were two complete responses, six partial responses, and three cases of stable disease. At nontarget lesions, there was one complete response, two partial responses, six cases of stable disease, and two cases of progression.
ISV was considered well tolerated. One patient had grade 2 fever, three had grade 1 fever, and nine had grade 1 flu-like symptoms. Two patients did not have any adverse events.
This research was supported by Merck, Celldex Therapeutics, Oncovir, and Genentech. The authors reported relationships with Acerta Pharma, Bristol Myers Squibb, Genentech, Gilead Sciences, Seattle Genetics, Pharmacyclics, Celgene, Celldex Therapeutics, and Oncovir.
SOURCE: Hammerich L et al. Nat Med. 2019 Apr 8. doi: 10.1038/s41591-019-0410-x.
A three-pronged treatment approach can produce responses in indolent non-Hodgkin lymphoma (iNHL), according to research published in Nature Medicine.
The approach – “in situ vaccination (ISV)” – involves intratumoral injections of Fms-like tyrosine kinase 3 ligand (Flt3L), local radiotherapy, and intratumoral injections of a TLR3 agonist (poly-ICLC).
ISV produced responses in patients with iNHL, prompting regression of tumors that were directly targeted with ISV, as well as untreated tumors.
In preclinical experiments, ISV induced tumor regression in mice but also overcame resistance to PD1 inhibition. This result led researchers to initiate a trial testing ISV in combination with pembrolizumab in patients with lymphoma and solid tumors.
“We discovered why some tumors do not respond to PD1 blockade: insufficient dendritic cells (DCs) and cross-presentation,” lead study author Joshua Brody, MD, of the Icahn School of Medicine at Mount Sinai, New York, said in an interview. “We developed a treatment, in situ vaccination (ISV), which brings DCs to the tumor, loads them with tumor antigens, and activates the DCs.”
Specifically, the researchers found that injecting Flt3L into a tumor recruits intratumoral DCs, local radiotherapy loads the DCs with tumor-associated antigens, and poly-ICLC activates DCs. This approach produced responses in mouse models of lymphoma and patients with iNHL.
Preclinical results
Dr. Brody and his colleagues tested ISV in A20 tumor-bearing mice. The mice received intratumoral injections of Flt3L, followed by local radiotherapy and poly-ICLC.
Tumor regression occurred within days of radiotherapy. About 40% of mice experienced tumor-free survival of at least 3 months, although most tumors recurred within 4 weeks of ISV administration.
However, the researchers observed increased PD1 and PD-L1 expression in ISV-treated mice, so the team theorized that an anti-PD1 monoclonal antibody (RMP1-14) could improve the efficacy of ISV.
The researchers found that ISV plus RMP1-14 delayed tumor growth when compared with ISV alone, and the rate of durable remissions increased from about 40% to about 80%.
Clinical results
Dr. Brody and his colleagues also tested ISV in a clinical trial. That trial included 11 iNHL patients – 9 with follicular lymphoma, 1 with marginal zone lymphoma, and 1 with small lymphocytic lymphoma.
The patients received nine daily injections of Flt3L (25 mcg/kg) into a target lesion, then two doses of radiation (2 Gy) to the same lesion, and eight intratumoral injections of poly-ICLC (2 mg).
“We ... have observed dramatic clinical responses; i.e., we administer ISV at one tumor site, and tumors throughout the body regress,” Dr. Brody said.
At the target lesion, there were two complete responses, six partial responses, and three cases of stable disease. At nontarget lesions, there was one complete response, two partial responses, six cases of stable disease, and two cases of progression.
ISV was considered well tolerated. One patient had grade 2 fever, three had grade 1 fever, and nine had grade 1 flu-like symptoms. Two patients did not have any adverse events.
This research was supported by Merck, Celldex Therapeutics, Oncovir, and Genentech. The authors reported relationships with Acerta Pharma, Bristol Myers Squibb, Genentech, Gilead Sciences, Seattle Genetics, Pharmacyclics, Celgene, Celldex Therapeutics, and Oncovir.
SOURCE: Hammerich L et al. Nat Med. 2019 Apr 8. doi: 10.1038/s41591-019-0410-x.
FROM NATURE MEDICINE