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KD025 produces durable responses in patients with cGVHD
HOUSTON – The according to a speaker at the Transplantation & Cellular Therapy Meetings.
In an ongoing phase 2 trial (NCT02841995), KD025 produced an overall response rate of 59%. Responses occurred in all affected organ systems, and 72% of responders experienced an improvement in Lee Symptom Scale (LSS) score.
The median duration of response was 28 weeks, but durability data are still maturing, according to Madan Jagasia, MBBS, of Vanderbilt University in Nashville, Tenn.
Dr. Jagasia and his colleagues evaluated KD025 in 54 adults who had persistent, active cGVHD after at least 2 months of steroid therapy. Sixty-seven percent of patients had received at least two prior lines of therapy, and 48% had involvement in four or more organs.
KD025 was given at three doses: 200 mg once daily (cohort 1), 200 mg twice daily (cohort 2), and 400 mg once daily (cohort 3). Patients also received glucocorticoid therapy, with or without calcineurin inhibitor therapy.
Cohort 1 included 17 patients who had a median age of 50 years (range, 20-63). They received KD025 for a median of 37 weeks, and six patients were still receiving KD025 at last follow-up.
Cohort 2 included 16 patients who had a median age of 55 years (range, 30-75). They received KD025 for a median of 33 weeks, and three patients were still receiving KD025 at last follow-up.
Cohort 3 included 21 patients who had a median age of 46 years (range, 25-75). They received KD025 for a median of 27 weeks, and 11 patients were still receiving KD025 at last follow-up.
The ORR was 59% (32/54) across the study, 65% (11/17) in cohort 1, 63% (10/16) in cohort 2, and 52% (11/21) in cohort 3. Three patients in cohort 3 didn’t reach the first response assessment, so the ORR in response-evaluable patients was 61% (11/18).
The ORR was 58% in patients who had received two or more prior lines of therapy, 55% in patients with severe cGVHD, and 62% in patients who had four or more organs involved.
“Responses were observed across all affected organ systems,” Dr. Jagasia said. “CRs [complete responses] were seen in all organs except the lung, and there were two partial responses observed in the lung.”
The median duration of response was 28 weeks. Eighty-two percent of responders in cohort 1, 50% of responders in cohort 2, and 36% of responders in cohort 3 had responses lasting 20 weeks or more.
“Keep in mind, the median duration of follow-up in cohort 3 is still short, and the durability data will continue to mature,” Dr. Jagasia said.
Most responders (72%) had at least a 7-point reduction in LSS score. Considering responders and nonresponders together, 65% of patients in cohort 1, 56% in cohort 2, and 52% in cohort 3 had an improvement in LSS score.
In all, 69% of patients stopped or reduced their use of steroids or other immunosuppressants. Seven patients completely discontinued steroids.
Forty-four percent of patients (n = 24) had a treatment-related adverse event (AE), but none of these AEs were considered serious. Four percent of patients (n = 2) had a related AE that led to treatment discontinuation, and 15% (n = 8) had grade 3/4 related AEs.
“The AEs were, overall, consistent with those expected in chronic graft-versus-host disease patients receiving corticosteroids,” Dr. Jagasia said. “Most important to note, there was no apparent increased risk of infection. Specifically, there was no CMV [cytomegalovirus] infection.”
The most common AEs were upper respiratory tract infection, fatigue, nausea, AST/ALT increase, and diarrhea. The most common grade 3/4 AEs were gamma-glutamyltransferase increase, hyperglycemia, anemia, and dyspnea.
There were three on-study deaths, all considered unrelated to KD025. One patient died of leukemia relapse, one died of lung infection, and one died of cardiac arrest.
Dr. Jagasia presented these results at the Transplantation & Cellular Therapy Meetings, held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At the meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: the American Society for Transplantation and Cellular Therapy (ASTCT).
Dr. Jagasia reported relationships with Kadmon Holdings, Mallinckrodt, and Janssen. The trial was sponsored by Kadmon Holdings.
SOURCE: Jagasia M et al. TCT 2019, Abstract 36.
HOUSTON – The according to a speaker at the Transplantation & Cellular Therapy Meetings.
In an ongoing phase 2 trial (NCT02841995), KD025 produced an overall response rate of 59%. Responses occurred in all affected organ systems, and 72% of responders experienced an improvement in Lee Symptom Scale (LSS) score.
The median duration of response was 28 weeks, but durability data are still maturing, according to Madan Jagasia, MBBS, of Vanderbilt University in Nashville, Tenn.
Dr. Jagasia and his colleagues evaluated KD025 in 54 adults who had persistent, active cGVHD after at least 2 months of steroid therapy. Sixty-seven percent of patients had received at least two prior lines of therapy, and 48% had involvement in four or more organs.
KD025 was given at three doses: 200 mg once daily (cohort 1), 200 mg twice daily (cohort 2), and 400 mg once daily (cohort 3). Patients also received glucocorticoid therapy, with or without calcineurin inhibitor therapy.
Cohort 1 included 17 patients who had a median age of 50 years (range, 20-63). They received KD025 for a median of 37 weeks, and six patients were still receiving KD025 at last follow-up.
Cohort 2 included 16 patients who had a median age of 55 years (range, 30-75). They received KD025 for a median of 33 weeks, and three patients were still receiving KD025 at last follow-up.
Cohort 3 included 21 patients who had a median age of 46 years (range, 25-75). They received KD025 for a median of 27 weeks, and 11 patients were still receiving KD025 at last follow-up.
The ORR was 59% (32/54) across the study, 65% (11/17) in cohort 1, 63% (10/16) in cohort 2, and 52% (11/21) in cohort 3. Three patients in cohort 3 didn’t reach the first response assessment, so the ORR in response-evaluable patients was 61% (11/18).
The ORR was 58% in patients who had received two or more prior lines of therapy, 55% in patients with severe cGVHD, and 62% in patients who had four or more organs involved.
“Responses were observed across all affected organ systems,” Dr. Jagasia said. “CRs [complete responses] were seen in all organs except the lung, and there were two partial responses observed in the lung.”
The median duration of response was 28 weeks. Eighty-two percent of responders in cohort 1, 50% of responders in cohort 2, and 36% of responders in cohort 3 had responses lasting 20 weeks or more.
“Keep in mind, the median duration of follow-up in cohort 3 is still short, and the durability data will continue to mature,” Dr. Jagasia said.
Most responders (72%) had at least a 7-point reduction in LSS score. Considering responders and nonresponders together, 65% of patients in cohort 1, 56% in cohort 2, and 52% in cohort 3 had an improvement in LSS score.
In all, 69% of patients stopped or reduced their use of steroids or other immunosuppressants. Seven patients completely discontinued steroids.
Forty-four percent of patients (n = 24) had a treatment-related adverse event (AE), but none of these AEs were considered serious. Four percent of patients (n = 2) had a related AE that led to treatment discontinuation, and 15% (n = 8) had grade 3/4 related AEs.
“The AEs were, overall, consistent with those expected in chronic graft-versus-host disease patients receiving corticosteroids,” Dr. Jagasia said. “Most important to note, there was no apparent increased risk of infection. Specifically, there was no CMV [cytomegalovirus] infection.”
The most common AEs were upper respiratory tract infection, fatigue, nausea, AST/ALT increase, and diarrhea. The most common grade 3/4 AEs were gamma-glutamyltransferase increase, hyperglycemia, anemia, and dyspnea.
There were three on-study deaths, all considered unrelated to KD025. One patient died of leukemia relapse, one died of lung infection, and one died of cardiac arrest.
Dr. Jagasia presented these results at the Transplantation & Cellular Therapy Meetings, held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At the meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: the American Society for Transplantation and Cellular Therapy (ASTCT).
Dr. Jagasia reported relationships with Kadmon Holdings, Mallinckrodt, and Janssen. The trial was sponsored by Kadmon Holdings.
SOURCE: Jagasia M et al. TCT 2019, Abstract 36.
HOUSTON – The according to a speaker at the Transplantation & Cellular Therapy Meetings.
In an ongoing phase 2 trial (NCT02841995), KD025 produced an overall response rate of 59%. Responses occurred in all affected organ systems, and 72% of responders experienced an improvement in Lee Symptom Scale (LSS) score.
The median duration of response was 28 weeks, but durability data are still maturing, according to Madan Jagasia, MBBS, of Vanderbilt University in Nashville, Tenn.
Dr. Jagasia and his colleagues evaluated KD025 in 54 adults who had persistent, active cGVHD after at least 2 months of steroid therapy. Sixty-seven percent of patients had received at least two prior lines of therapy, and 48% had involvement in four or more organs.
KD025 was given at three doses: 200 mg once daily (cohort 1), 200 mg twice daily (cohort 2), and 400 mg once daily (cohort 3). Patients also received glucocorticoid therapy, with or without calcineurin inhibitor therapy.
Cohort 1 included 17 patients who had a median age of 50 years (range, 20-63). They received KD025 for a median of 37 weeks, and six patients were still receiving KD025 at last follow-up.
Cohort 2 included 16 patients who had a median age of 55 years (range, 30-75). They received KD025 for a median of 33 weeks, and three patients were still receiving KD025 at last follow-up.
Cohort 3 included 21 patients who had a median age of 46 years (range, 25-75). They received KD025 for a median of 27 weeks, and 11 patients were still receiving KD025 at last follow-up.
The ORR was 59% (32/54) across the study, 65% (11/17) in cohort 1, 63% (10/16) in cohort 2, and 52% (11/21) in cohort 3. Three patients in cohort 3 didn’t reach the first response assessment, so the ORR in response-evaluable patients was 61% (11/18).
The ORR was 58% in patients who had received two or more prior lines of therapy, 55% in patients with severe cGVHD, and 62% in patients who had four or more organs involved.
“Responses were observed across all affected organ systems,” Dr. Jagasia said. “CRs [complete responses] were seen in all organs except the lung, and there were two partial responses observed in the lung.”
The median duration of response was 28 weeks. Eighty-two percent of responders in cohort 1, 50% of responders in cohort 2, and 36% of responders in cohort 3 had responses lasting 20 weeks or more.
“Keep in mind, the median duration of follow-up in cohort 3 is still short, and the durability data will continue to mature,” Dr. Jagasia said.
Most responders (72%) had at least a 7-point reduction in LSS score. Considering responders and nonresponders together, 65% of patients in cohort 1, 56% in cohort 2, and 52% in cohort 3 had an improvement in LSS score.
In all, 69% of patients stopped or reduced their use of steroids or other immunosuppressants. Seven patients completely discontinued steroids.
Forty-four percent of patients (n = 24) had a treatment-related adverse event (AE), but none of these AEs were considered serious. Four percent of patients (n = 2) had a related AE that led to treatment discontinuation, and 15% (n = 8) had grade 3/4 related AEs.
“The AEs were, overall, consistent with those expected in chronic graft-versus-host disease patients receiving corticosteroids,” Dr. Jagasia said. “Most important to note, there was no apparent increased risk of infection. Specifically, there was no CMV [cytomegalovirus] infection.”
The most common AEs were upper respiratory tract infection, fatigue, nausea, AST/ALT increase, and diarrhea. The most common grade 3/4 AEs were gamma-glutamyltransferase increase, hyperglycemia, anemia, and dyspnea.
There were three on-study deaths, all considered unrelated to KD025. One patient died of leukemia relapse, one died of lung infection, and one died of cardiac arrest.
Dr. Jagasia presented these results at the Transplantation & Cellular Therapy Meetings, held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At the meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: the American Society for Transplantation and Cellular Therapy (ASTCT).
Dr. Jagasia reported relationships with Kadmon Holdings, Mallinckrodt, and Janssen. The trial was sponsored by Kadmon Holdings.
SOURCE: Jagasia M et al. TCT 2019, Abstract 36.
REPORTING FROM TCT 2019
Lentiviral gene therapy appears effective in X-CGD
HOUSTON – , said Donald B. Kohn, MD, of the University of California, Los Angeles.
Seven of nine patients treated were “alive and well” at 12 months’ follow-up after receiving lentiviral vector transduced CD34+ cells, Dr. Kohn reported in a late-breaking clinical trial session at the Transplantation & Cellular Therapy Meetings.
Most patients were able to discontinue antibiotic prophylaxis for this disease, which is associated with severe, recurrent, and prolonged life-threatening infections, he said.
Results of the small study provide “proof of concept” for use of the gene therapy in the disease, though additional studies are needed to formally assess the clinical safety and efficacy of the approach, he said.
The estimated incidence of chronic granulomatous disease is 1 in 200,000 births in the United States, and the X-linked form is most common, occurring in about 60% of patients, Dr. Kohn told attendees of the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
Most of these patients are treated with antibacterial or antifungal prophylaxis. While allogeneic hematopoietic stem cell transplantation is also an option, according to Dr. Kohn, the approach is limited by a lack of matched donors and graft-versus-host disease.
Dr. Kohn reported results for nine patients in the United States and the United Kingdom who were treated with the same G1XCGD lentiviral vector. The patients, who ranged in age from 2 to 27 years, underwent CD34+ cell mobilization or bone marrow isolation, transduction with the lentiviral vector, busulfan conditioning, and autologous transplantation.
All patients had confirmed X-linked chronic granulomatous disease, and had had at least one severe infection or inflammatory complication requiring hospitalization.
There were no infusion-related adverse events, and one serious adverse event, which was an inflammatory syndrome that resolved with steroids. Two patients died from complications unrelated to gene therapy, Dr. Kohn reported.
“The other patients are basically doing quite well,” he said.
Of the seven patients alive at the 12-month follow up, six were reported as “clinically well” and off antibiotic prophylaxis, according to Dr. Kohn, while the seventh patient was clinically well and receiving antimicrobial support.
Dr. Kohn is a scientific advisory board member for Orchard Therapeutics, which licensed the lentiviral gene therapy for X-CGD discussed in his presentation. He is also an inventor of intellectual property related to the therapy that UCLA has licensed to Orchard.
At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
SOURCE: Kohn DB et al. TCT 2019, Abstract LBA1.
HOUSTON – , said Donald B. Kohn, MD, of the University of California, Los Angeles.
Seven of nine patients treated were “alive and well” at 12 months’ follow-up after receiving lentiviral vector transduced CD34+ cells, Dr. Kohn reported in a late-breaking clinical trial session at the Transplantation & Cellular Therapy Meetings.
Most patients were able to discontinue antibiotic prophylaxis for this disease, which is associated with severe, recurrent, and prolonged life-threatening infections, he said.
Results of the small study provide “proof of concept” for use of the gene therapy in the disease, though additional studies are needed to formally assess the clinical safety and efficacy of the approach, he said.
The estimated incidence of chronic granulomatous disease is 1 in 200,000 births in the United States, and the X-linked form is most common, occurring in about 60% of patients, Dr. Kohn told attendees of the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
Most of these patients are treated with antibacterial or antifungal prophylaxis. While allogeneic hematopoietic stem cell transplantation is also an option, according to Dr. Kohn, the approach is limited by a lack of matched donors and graft-versus-host disease.
Dr. Kohn reported results for nine patients in the United States and the United Kingdom who were treated with the same G1XCGD lentiviral vector. The patients, who ranged in age from 2 to 27 years, underwent CD34+ cell mobilization or bone marrow isolation, transduction with the lentiviral vector, busulfan conditioning, and autologous transplantation.
All patients had confirmed X-linked chronic granulomatous disease, and had had at least one severe infection or inflammatory complication requiring hospitalization.
There were no infusion-related adverse events, and one serious adverse event, which was an inflammatory syndrome that resolved with steroids. Two patients died from complications unrelated to gene therapy, Dr. Kohn reported.
“The other patients are basically doing quite well,” he said.
Of the seven patients alive at the 12-month follow up, six were reported as “clinically well” and off antibiotic prophylaxis, according to Dr. Kohn, while the seventh patient was clinically well and receiving antimicrobial support.
Dr. Kohn is a scientific advisory board member for Orchard Therapeutics, which licensed the lentiviral gene therapy for X-CGD discussed in his presentation. He is also an inventor of intellectual property related to the therapy that UCLA has licensed to Orchard.
At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
SOURCE: Kohn DB et al. TCT 2019, Abstract LBA1.
HOUSTON – , said Donald B. Kohn, MD, of the University of California, Los Angeles.
Seven of nine patients treated were “alive and well” at 12 months’ follow-up after receiving lentiviral vector transduced CD34+ cells, Dr. Kohn reported in a late-breaking clinical trial session at the Transplantation & Cellular Therapy Meetings.
Most patients were able to discontinue antibiotic prophylaxis for this disease, which is associated with severe, recurrent, and prolonged life-threatening infections, he said.
Results of the small study provide “proof of concept” for use of the gene therapy in the disease, though additional studies are needed to formally assess the clinical safety and efficacy of the approach, he said.
The estimated incidence of chronic granulomatous disease is 1 in 200,000 births in the United States, and the X-linked form is most common, occurring in about 60% of patients, Dr. Kohn told attendees of the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
Most of these patients are treated with antibacterial or antifungal prophylaxis. While allogeneic hematopoietic stem cell transplantation is also an option, according to Dr. Kohn, the approach is limited by a lack of matched donors and graft-versus-host disease.
Dr. Kohn reported results for nine patients in the United States and the United Kingdom who were treated with the same G1XCGD lentiviral vector. The patients, who ranged in age from 2 to 27 years, underwent CD34+ cell mobilization or bone marrow isolation, transduction with the lentiviral vector, busulfan conditioning, and autologous transplantation.
All patients had confirmed X-linked chronic granulomatous disease, and had had at least one severe infection or inflammatory complication requiring hospitalization.
There were no infusion-related adverse events, and one serious adverse event, which was an inflammatory syndrome that resolved with steroids. Two patients died from complications unrelated to gene therapy, Dr. Kohn reported.
“The other patients are basically doing quite well,” he said.
Of the seven patients alive at the 12-month follow up, six were reported as “clinically well” and off antibiotic prophylaxis, according to Dr. Kohn, while the seventh patient was clinically well and receiving antimicrobial support.
Dr. Kohn is a scientific advisory board member for Orchard Therapeutics, which licensed the lentiviral gene therapy for X-CGD discussed in his presentation. He is also an inventor of intellectual property related to the therapy that UCLA has licensed to Orchard.
At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
SOURCE: Kohn DB et al. TCT 2019, Abstract LBA1.
REPORTING FROM TCT 2019
Novel transplant regimen improves survival in primary immunodeficiency
HOUSTON – Allogeneic hematopoietic stem cell transplantation (allo-HCT) following a novel reduced-intensity conditioning regimen was largely successful in a heterogeneous cohort of 29 adults and children with primary immunodeficiency in a prospective clinical trial.
At 1 year after transplant, overall survival was 98% and the estimated graft failure–free and graft-versus-host disease (GVHD)–free survival was 82% among the participants, who had various underlying primary immunodeficiencies (PIDs), Dimana Dimitrova, MD, reported at the Transplantation and Cellular Therapy Meetings.
GVHD-free survival was defined in this National Institutes of Health study as the absence of steroid-refractory grade 3-4 acute GVHD and chronic GVHD, noted Dr. Dimitrova of the NIH.
All patients, including 19 adults and 10 children (median age, 25 years), received a serotherapy-free, radiation-free, reduced-intensity conditioning regimen designed to optimize immune reconstitution, minimize toxicity and GVHD, reduce the risk of infectious complications, and enable successful use of alternative donors.
The conditioning platform included pentostatin on day –11 and day –7 at 4 mg/m2 along with 8 days of low-dose cyclophosphamide and 2 days of pharmacokinetically dosed busulfan at 4,600 mmol/min. GVHD prophylaxis included posttransplantation cyclophosphamide, mycophenolate mofetil (MMF), and sirolimus.
All patients received T cell–replete bone marrow or peripheral blood stem cell allografts; 72% received alternative donor grafts, Dr. Dimitrova said.
Two patients died, including one with bacterial sepsis and invasive aspergillosis who died on day +44 and one with presumed viral encephalitis who died on day +110. The patients were high risk overall (median HCT–comorbidity index score of 3, with a range of 0-11), and the two who died had HCT-CI scores of 6 and 8, respectively.
An additional accidental death occurred at 18 months after transplant “in the setting of continued remission, good graft function, and no transplant-related complications,” she said.
Neutrophil recovery occurred at a median of 17 days after transplant; three patients experienced graft failure, including one primary failure with autologous recovery on day +14 and two secondary graft failures.
“Two patients with known underlying difficult-to-engraft diseases required second transplants using different nonmyeloabalative platforms, and nevertheless required donor lymphocyte infusions to avoid threatened secondary graft failure,” she said. “The third patient actually had sufficiently improved infectious disease control and has not needed a second transplant to date.”
Overall GVHD incidence using the novel platform has been extremely low, she said, noting that 14% of patients had grade 2-4 GVHD and 3% had grade 3-4 acute GVHD. There was no steroid-refractory GVHD or chronic GVHD.
Among the infectious complications, other than those that led to the two deaths, were cytomegalovirus reactivation in 7 of 16 patients at risk, BK virus–associated hemorrhagic cystitis in 19 of 22 patients at risk, and a suspected case of viral cardiomyopathy that ultimately resolved.
“Importantly, although many patients had Epstein-Barr virus [EBV] control issues prior to transplant, no patients received preemptive EBV-directed therapy, and no patients had EBV-PTLD [posttransplant lymphoproliferative disorder],” she said.
Additionally, blood stream infections were detected in five patients, there were two cases of confirmed aspergillosis, and one child developed cutaneous candidiasis. Other complications and toxicities appeared to relate to underlying pretransplant issues in the affected organ or exuberant immune responses to existing infection.
“Phenotype reversal was evident to some degree in all evaluable patients, even in those with mixed chimerism or unknown underlying genetic defect,” Dr. Dimitrova said.
All 10 patients with malignancy or lymphoproliferative disease as an additional indication for allo-HCT remain in remission, and most patients who required immunoglobulin replacement therapy prior to transplant have been able to discontinue it, she noted.
The findings of this study are of note, because while it has been known for decades that allo-HCT is a potentially curative therapy for patients with PIDs that arise from defects in cells of hematopoietic origin, it frequently fails because of complicating factors or is not an option, Dr. Dimitrova said.
“These patients will often enter transplant with multiple comorbidities and disease sequelae, particularly as diagnosis of PIDs increases in older children and adults following years of illness,” she explained, adding that related donor options may be limited if family members are also affected.
For this reason, and with the goal of improving access to allo-HCT to all who require it, the novel conditioning platform used in this study was developed.
The platform was well tolerated overall, Dr. Dimitrova said, emphasizing the “notably low” GVHD rates.
“Currently we are investigating reduced MMF with the goal of promoting earlier immune reconstitution, and a separate protocol has opened that includes several modifications to this platform aimed at patients with increased risk of graft failure who may not tolerate mixed chimerism early on,” she said, noting that both protocols are currently enrolling.
The meeting was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
Dr. Dimitrova reported having no financial disclosures.
SOURCE: Dimitrova D et al. TCT 2019, Abstract 54.
HOUSTON – Allogeneic hematopoietic stem cell transplantation (allo-HCT) following a novel reduced-intensity conditioning regimen was largely successful in a heterogeneous cohort of 29 adults and children with primary immunodeficiency in a prospective clinical trial.
At 1 year after transplant, overall survival was 98% and the estimated graft failure–free and graft-versus-host disease (GVHD)–free survival was 82% among the participants, who had various underlying primary immunodeficiencies (PIDs), Dimana Dimitrova, MD, reported at the Transplantation and Cellular Therapy Meetings.
GVHD-free survival was defined in this National Institutes of Health study as the absence of steroid-refractory grade 3-4 acute GVHD and chronic GVHD, noted Dr. Dimitrova of the NIH.
All patients, including 19 adults and 10 children (median age, 25 years), received a serotherapy-free, radiation-free, reduced-intensity conditioning regimen designed to optimize immune reconstitution, minimize toxicity and GVHD, reduce the risk of infectious complications, and enable successful use of alternative donors.
The conditioning platform included pentostatin on day –11 and day –7 at 4 mg/m2 along with 8 days of low-dose cyclophosphamide and 2 days of pharmacokinetically dosed busulfan at 4,600 mmol/min. GVHD prophylaxis included posttransplantation cyclophosphamide, mycophenolate mofetil (MMF), and sirolimus.
All patients received T cell–replete bone marrow or peripheral blood stem cell allografts; 72% received alternative donor grafts, Dr. Dimitrova said.
Two patients died, including one with bacterial sepsis and invasive aspergillosis who died on day +44 and one with presumed viral encephalitis who died on day +110. The patients were high risk overall (median HCT–comorbidity index score of 3, with a range of 0-11), and the two who died had HCT-CI scores of 6 and 8, respectively.
An additional accidental death occurred at 18 months after transplant “in the setting of continued remission, good graft function, and no transplant-related complications,” she said.
Neutrophil recovery occurred at a median of 17 days after transplant; three patients experienced graft failure, including one primary failure with autologous recovery on day +14 and two secondary graft failures.
“Two patients with known underlying difficult-to-engraft diseases required second transplants using different nonmyeloabalative platforms, and nevertheless required donor lymphocyte infusions to avoid threatened secondary graft failure,” she said. “The third patient actually had sufficiently improved infectious disease control and has not needed a second transplant to date.”
Overall GVHD incidence using the novel platform has been extremely low, she said, noting that 14% of patients had grade 2-4 GVHD and 3% had grade 3-4 acute GVHD. There was no steroid-refractory GVHD or chronic GVHD.
Among the infectious complications, other than those that led to the two deaths, were cytomegalovirus reactivation in 7 of 16 patients at risk, BK virus–associated hemorrhagic cystitis in 19 of 22 patients at risk, and a suspected case of viral cardiomyopathy that ultimately resolved.
“Importantly, although many patients had Epstein-Barr virus [EBV] control issues prior to transplant, no patients received preemptive EBV-directed therapy, and no patients had EBV-PTLD [posttransplant lymphoproliferative disorder],” she said.
Additionally, blood stream infections were detected in five patients, there were two cases of confirmed aspergillosis, and one child developed cutaneous candidiasis. Other complications and toxicities appeared to relate to underlying pretransplant issues in the affected organ or exuberant immune responses to existing infection.
“Phenotype reversal was evident to some degree in all evaluable patients, even in those with mixed chimerism or unknown underlying genetic defect,” Dr. Dimitrova said.
All 10 patients with malignancy or lymphoproliferative disease as an additional indication for allo-HCT remain in remission, and most patients who required immunoglobulin replacement therapy prior to transplant have been able to discontinue it, she noted.
The findings of this study are of note, because while it has been known for decades that allo-HCT is a potentially curative therapy for patients with PIDs that arise from defects in cells of hematopoietic origin, it frequently fails because of complicating factors or is not an option, Dr. Dimitrova said.
“These patients will often enter transplant with multiple comorbidities and disease sequelae, particularly as diagnosis of PIDs increases in older children and adults following years of illness,” she explained, adding that related donor options may be limited if family members are also affected.
For this reason, and with the goal of improving access to allo-HCT to all who require it, the novel conditioning platform used in this study was developed.
The platform was well tolerated overall, Dr. Dimitrova said, emphasizing the “notably low” GVHD rates.
“Currently we are investigating reduced MMF with the goal of promoting earlier immune reconstitution, and a separate protocol has opened that includes several modifications to this platform aimed at patients with increased risk of graft failure who may not tolerate mixed chimerism early on,” she said, noting that both protocols are currently enrolling.
The meeting was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
Dr. Dimitrova reported having no financial disclosures.
SOURCE: Dimitrova D et al. TCT 2019, Abstract 54.
HOUSTON – Allogeneic hematopoietic stem cell transplantation (allo-HCT) following a novel reduced-intensity conditioning regimen was largely successful in a heterogeneous cohort of 29 adults and children with primary immunodeficiency in a prospective clinical trial.
At 1 year after transplant, overall survival was 98% and the estimated graft failure–free and graft-versus-host disease (GVHD)–free survival was 82% among the participants, who had various underlying primary immunodeficiencies (PIDs), Dimana Dimitrova, MD, reported at the Transplantation and Cellular Therapy Meetings.
GVHD-free survival was defined in this National Institutes of Health study as the absence of steroid-refractory grade 3-4 acute GVHD and chronic GVHD, noted Dr. Dimitrova of the NIH.
All patients, including 19 adults and 10 children (median age, 25 years), received a serotherapy-free, radiation-free, reduced-intensity conditioning regimen designed to optimize immune reconstitution, minimize toxicity and GVHD, reduce the risk of infectious complications, and enable successful use of alternative donors.
The conditioning platform included pentostatin on day –11 and day –7 at 4 mg/m2 along with 8 days of low-dose cyclophosphamide and 2 days of pharmacokinetically dosed busulfan at 4,600 mmol/min. GVHD prophylaxis included posttransplantation cyclophosphamide, mycophenolate mofetil (MMF), and sirolimus.
All patients received T cell–replete bone marrow or peripheral blood stem cell allografts; 72% received alternative donor grafts, Dr. Dimitrova said.
Two patients died, including one with bacterial sepsis and invasive aspergillosis who died on day +44 and one with presumed viral encephalitis who died on day +110. The patients were high risk overall (median HCT–comorbidity index score of 3, with a range of 0-11), and the two who died had HCT-CI scores of 6 and 8, respectively.
An additional accidental death occurred at 18 months after transplant “in the setting of continued remission, good graft function, and no transplant-related complications,” she said.
Neutrophil recovery occurred at a median of 17 days after transplant; three patients experienced graft failure, including one primary failure with autologous recovery on day +14 and two secondary graft failures.
“Two patients with known underlying difficult-to-engraft diseases required second transplants using different nonmyeloabalative platforms, and nevertheless required donor lymphocyte infusions to avoid threatened secondary graft failure,” she said. “The third patient actually had sufficiently improved infectious disease control and has not needed a second transplant to date.”
Overall GVHD incidence using the novel platform has been extremely low, she said, noting that 14% of patients had grade 2-4 GVHD and 3% had grade 3-4 acute GVHD. There was no steroid-refractory GVHD or chronic GVHD.
Among the infectious complications, other than those that led to the two deaths, were cytomegalovirus reactivation in 7 of 16 patients at risk, BK virus–associated hemorrhagic cystitis in 19 of 22 patients at risk, and a suspected case of viral cardiomyopathy that ultimately resolved.
“Importantly, although many patients had Epstein-Barr virus [EBV] control issues prior to transplant, no patients received preemptive EBV-directed therapy, and no patients had EBV-PTLD [posttransplant lymphoproliferative disorder],” she said.
Additionally, blood stream infections were detected in five patients, there were two cases of confirmed aspergillosis, and one child developed cutaneous candidiasis. Other complications and toxicities appeared to relate to underlying pretransplant issues in the affected organ or exuberant immune responses to existing infection.
“Phenotype reversal was evident to some degree in all evaluable patients, even in those with mixed chimerism or unknown underlying genetic defect,” Dr. Dimitrova said.
All 10 patients with malignancy or lymphoproliferative disease as an additional indication for allo-HCT remain in remission, and most patients who required immunoglobulin replacement therapy prior to transplant have been able to discontinue it, she noted.
The findings of this study are of note, because while it has been known for decades that allo-HCT is a potentially curative therapy for patients with PIDs that arise from defects in cells of hematopoietic origin, it frequently fails because of complicating factors or is not an option, Dr. Dimitrova said.
“These patients will often enter transplant with multiple comorbidities and disease sequelae, particularly as diagnosis of PIDs increases in older children and adults following years of illness,” she explained, adding that related donor options may be limited if family members are also affected.
For this reason, and with the goal of improving access to allo-HCT to all who require it, the novel conditioning platform used in this study was developed.
The platform was well tolerated overall, Dr. Dimitrova said, emphasizing the “notably low” GVHD rates.
“Currently we are investigating reduced MMF with the goal of promoting earlier immune reconstitution, and a separate protocol has opened that includes several modifications to this platform aimed at patients with increased risk of graft failure who may not tolerate mixed chimerism early on,” she said, noting that both protocols are currently enrolling.
The meeting was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
Dr. Dimitrova reported having no financial disclosures.
SOURCE: Dimitrova D et al. TCT 2019, Abstract 54.
REPORTING FROM TCT 2019
Ixazomib targets treatment failure in chronic GVHD
HOUSTON –
Patients who received ixazomib in this trial had a lower rate of treatment failure – a composite endpoint of death, relapse, and need for additional systemic immunosuppressive therapy – than that of historical controls.
Joseph Pidala, MD, PhD, of Moffitt Cancer Center in Tampa, Fla., presented this finding at the Transplantation & Cellular Therapy Meetings.
The trial (NCT02513498) included 50 patients with a median age of 58 years (range, 44-65). Patients had acute leukemia (52%), lymphoma (18%), chronic leukemia (12%), myelodysplastic syndromes/myeloproliferative neoplasms (8%), and myeloma (4%).
Most patients (90%) received peripheral blood transplants, but 10% received bone marrow. Patients had matched unrelated donors (48%), matched related donors (44%), mismatched unrelated donors (6%), and mismatched related donors (2%).
Most patients (84%) had severe cGVHD, but 16% had moderate cGVHD. About half of patients (52%) had four or more organs involved, and 78% received three or more prior lines of systemic therapy for cGVHD. The median time from cGVHD onset to trial enrollment was 33.5 months.
“[I]t was an advanced population that was highly treatment experienced,” Dr. Pidala said.
Initially, patients received ixazomib at 4 mg on days 1, 8, and 15 of a 28-day cycle for up to six cycles. However, the protocol was amended to allow additional cycles for responders.
Fifty-two percent of patients (n = 26) completed at least six cycles of therapy. The remaining patients stopped treatment because of unresolved toxicity, treatment failure, withdrawal, noncompliance, and death.
“Seven patients, in total, did continue therapy beyond six cycles,” Dr. Pidala said. “Six of these had partial response at 6 months, and one had stable disease.”
The overall response rate at 6 months was 40%. All 20 responders had partial responses.
The 6-month treatment failure rate was significantly lower in this trial than in historical controls (Blood 2013 121:2340-6). The rates of treatment failure were 28% and 44%, respectively (P = .01).
Treatment failure was largely due to the need for additional treatment, Dr. Pidala noted. Relapse and nonrelapse mortality were “uncommon” in this trial.
The investigators did not find any patient, transplant, or cGVHD-related factors significantly associated with 6-month treatment failure.
The failure-free survival rate at 6 months was 72% in this trial and 56% in historical controls. The failure-free survival rate at 12 months was 57% and 45%, respectively.
Serious adverse events occurred in 38% of patients on this trial. Patients required ixazomib dose reductions due to thrombocytopenia, fatigue, diarrhea, and infection.
There were five deaths, and two of them were considered possibly related to ixazomib.
“This was driven by the proximity of the death events to the last dose of ixazomib, specifically, within 1 month,” Dr. Pidala said. “One of these death events was a case of respiratory failure. The other was a case of sudden, unexplained death.”
The meeting was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At the meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
Dr. Pidala reported having nothing to disclose. Other investigators reported relationships with Pfizer, CSL Behring, Agios, Incyte, Genentech, and Takeda. The trial was sponsored by the Fred Hutchinson Cancer Research Center in collaboration with the National Cancer Institute.
SOURCE: Pidala J et al. TCT 2019, Abstract 35.
HOUSTON –
Patients who received ixazomib in this trial had a lower rate of treatment failure – a composite endpoint of death, relapse, and need for additional systemic immunosuppressive therapy – than that of historical controls.
Joseph Pidala, MD, PhD, of Moffitt Cancer Center in Tampa, Fla., presented this finding at the Transplantation & Cellular Therapy Meetings.
The trial (NCT02513498) included 50 patients with a median age of 58 years (range, 44-65). Patients had acute leukemia (52%), lymphoma (18%), chronic leukemia (12%), myelodysplastic syndromes/myeloproliferative neoplasms (8%), and myeloma (4%).
Most patients (90%) received peripheral blood transplants, but 10% received bone marrow. Patients had matched unrelated donors (48%), matched related donors (44%), mismatched unrelated donors (6%), and mismatched related donors (2%).
Most patients (84%) had severe cGVHD, but 16% had moderate cGVHD. About half of patients (52%) had four or more organs involved, and 78% received three or more prior lines of systemic therapy for cGVHD. The median time from cGVHD onset to trial enrollment was 33.5 months.
“[I]t was an advanced population that was highly treatment experienced,” Dr. Pidala said.
Initially, patients received ixazomib at 4 mg on days 1, 8, and 15 of a 28-day cycle for up to six cycles. However, the protocol was amended to allow additional cycles for responders.
Fifty-two percent of patients (n = 26) completed at least six cycles of therapy. The remaining patients stopped treatment because of unresolved toxicity, treatment failure, withdrawal, noncompliance, and death.
“Seven patients, in total, did continue therapy beyond six cycles,” Dr. Pidala said. “Six of these had partial response at 6 months, and one had stable disease.”
The overall response rate at 6 months was 40%. All 20 responders had partial responses.
The 6-month treatment failure rate was significantly lower in this trial than in historical controls (Blood 2013 121:2340-6). The rates of treatment failure were 28% and 44%, respectively (P = .01).
Treatment failure was largely due to the need for additional treatment, Dr. Pidala noted. Relapse and nonrelapse mortality were “uncommon” in this trial.
The investigators did not find any patient, transplant, or cGVHD-related factors significantly associated with 6-month treatment failure.
The failure-free survival rate at 6 months was 72% in this trial and 56% in historical controls. The failure-free survival rate at 12 months was 57% and 45%, respectively.
Serious adverse events occurred in 38% of patients on this trial. Patients required ixazomib dose reductions due to thrombocytopenia, fatigue, diarrhea, and infection.
There were five deaths, and two of them were considered possibly related to ixazomib.
“This was driven by the proximity of the death events to the last dose of ixazomib, specifically, within 1 month,” Dr. Pidala said. “One of these death events was a case of respiratory failure. The other was a case of sudden, unexplained death.”
The meeting was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At the meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
Dr. Pidala reported having nothing to disclose. Other investigators reported relationships with Pfizer, CSL Behring, Agios, Incyte, Genentech, and Takeda. The trial was sponsored by the Fred Hutchinson Cancer Research Center in collaboration with the National Cancer Institute.
SOURCE: Pidala J et al. TCT 2019, Abstract 35.
HOUSTON –
Patients who received ixazomib in this trial had a lower rate of treatment failure – a composite endpoint of death, relapse, and need for additional systemic immunosuppressive therapy – than that of historical controls.
Joseph Pidala, MD, PhD, of Moffitt Cancer Center in Tampa, Fla., presented this finding at the Transplantation & Cellular Therapy Meetings.
The trial (NCT02513498) included 50 patients with a median age of 58 years (range, 44-65). Patients had acute leukemia (52%), lymphoma (18%), chronic leukemia (12%), myelodysplastic syndromes/myeloproliferative neoplasms (8%), and myeloma (4%).
Most patients (90%) received peripheral blood transplants, but 10% received bone marrow. Patients had matched unrelated donors (48%), matched related donors (44%), mismatched unrelated donors (6%), and mismatched related donors (2%).
Most patients (84%) had severe cGVHD, but 16% had moderate cGVHD. About half of patients (52%) had four or more organs involved, and 78% received three or more prior lines of systemic therapy for cGVHD. The median time from cGVHD onset to trial enrollment was 33.5 months.
“[I]t was an advanced population that was highly treatment experienced,” Dr. Pidala said.
Initially, patients received ixazomib at 4 mg on days 1, 8, and 15 of a 28-day cycle for up to six cycles. However, the protocol was amended to allow additional cycles for responders.
Fifty-two percent of patients (n = 26) completed at least six cycles of therapy. The remaining patients stopped treatment because of unresolved toxicity, treatment failure, withdrawal, noncompliance, and death.
“Seven patients, in total, did continue therapy beyond six cycles,” Dr. Pidala said. “Six of these had partial response at 6 months, and one had stable disease.”
The overall response rate at 6 months was 40%. All 20 responders had partial responses.
The 6-month treatment failure rate was significantly lower in this trial than in historical controls (Blood 2013 121:2340-6). The rates of treatment failure were 28% and 44%, respectively (P = .01).
Treatment failure was largely due to the need for additional treatment, Dr. Pidala noted. Relapse and nonrelapse mortality were “uncommon” in this trial.
The investigators did not find any patient, transplant, or cGVHD-related factors significantly associated with 6-month treatment failure.
The failure-free survival rate at 6 months was 72% in this trial and 56% in historical controls. The failure-free survival rate at 12 months was 57% and 45%, respectively.
Serious adverse events occurred in 38% of patients on this trial. Patients required ixazomib dose reductions due to thrombocytopenia, fatigue, diarrhea, and infection.
There were five deaths, and two of them were considered possibly related to ixazomib.
“This was driven by the proximity of the death events to the last dose of ixazomib, specifically, within 1 month,” Dr. Pidala said. “One of these death events was a case of respiratory failure. The other was a case of sudden, unexplained death.”
The meeting was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At the meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
Dr. Pidala reported having nothing to disclose. Other investigators reported relationships with Pfizer, CSL Behring, Agios, Incyte, Genentech, and Takeda. The trial was sponsored by the Fred Hutchinson Cancer Research Center in collaboration with the National Cancer Institute.
SOURCE: Pidala J et al. TCT 2019, Abstract 35.
REPORTING FROM TCT 2019
Key clinical point: Ixazomib may reduce treatment failure in patients with advanced chronic graft-versus-host disease.
Major finding: The 6-month treatment failure rate was significantly lower in this trial than in historical controls – 28% and 44%, respectively (P = .01).
Study details: A phase 2 trial of 50 patients with hematologic malignancies.
Disclosures: The trial was sponsored by the Fred Hutchinson Cancer Research Center in collaboration with the National Cancer Institute. The investigators reported relationships with Pfizer, CSL Behring, Agios, Incyte, Genentech, and Takeda.
Source: Pidala J et al. TCT 2019, Abstract 35.
Post-HCT azithromycin doesn’t increase relapse risk, study suggests
HOUSTON — When given after transplant, azithromycin does not increase the risk of relapse in patients with moderate to severe chronic graft-versus-host disease (cGVHD) and bronchiolitis obliterans syndrome (BOS), according to a retrospective study.
A prior study, ALLOZITHRO (JAMA. 2017 Aug 8;318[6]:557-66), showed an increased risk of relapse and death in patients who received azithromycin as BOS prophylaxis prior to hematopoietic cell transplant (HCT).
That discovery prompted the Food and Drug Administration to release a safety communication warning prescribers about the risks associated with azithromycin as BOS prophylaxis. However, it wasn’t clear if the same risks exist when azithromycin is given for cGVHD management after HCT.
To gain some insight, Mark Shamoun, MD, of the University of Michigan, Ann Arbor, and his colleagues examined data on patients with moderate to severe cGVHD and BOS who received azithromycin after undergoing HCT to treat a hematologic malignancy.
Dr. Shamoun presented the group’s findings at the Transplantation & Cellular Therapy Meetings.
The researchers reviewed data on 239 patients enrolled in the University of Michigan’s HCT database from 2010 to 2017. The median age at baseline was 55 years (range, 4-72 years).
The patients received transplants to treat acute myeloid leukemia or myelodysplastic syndromes (n = 141), acute lymphoblastic leukemia (n = 40), lymphoma (n = 26), chronic leukemia (n = 24), multiple myeloma (n = 6), and myeloproliferative neoplasms (n = 2).
The patients had matched related donors (43%) or matched unrelated donors (57%). Most patients received peripheral blood transplants (84%), though some received bone marrow (14%) or cord blood (2%). All patients had moderate (38%) or severe (62%) cGVHD.
Patients were split into two cohorts. Patients in cohort A (n = 86) had BOS and received azithromycin for more than 14 days.
Patients in cohort B (n = 153) either did not receive azithromycin or received it for 14 days or less. Fewer than 5% of patients in cohort B had BOS.
Most other baseline characteristics were similar between the cohorts. However, severe cGVHD was more prevalent in cohort A than B — 78% and 51%, respectively.
In cohort A, the median time to the start of azithromycin was 15 months after HCT (range, 3-68 months). The median duration of azithromycin treatment was 26 months (range, 1-77 months).
Results
The 2-year relapse rate was significantly lower in patients who received azithromycin than in those who did not — 4% and 17%, respectively (P = .001).
There was a significant difference in relapse rate both from the time of HCT (P = .001) and from the start of azithromycin or cGVHD (P = .011).
There was no significant difference in overall survival between the cohorts, either from the time of HCT (P = .294) or from the start of azithromycin or cGVHD (P = .428).
Dr. Shamoun said these results suggest azithromycin does not increase the risk of relapse when it is used to manage cGVHD. However, this study is limited by its retrospective nature. In addition, most patients in cohort B did not have BOS, severe cGVHD was more common in cohort A, and the incidence of relapse was not calculated from the time of azithromycin initiation in both cohorts. Therefore, additional investigation is needed.
Dr. Shamoun presented these results at Transplantation & Cellular Therapy Meetings, which is held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At the meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society, the American Society for Transplantation and Cellular Therapy (ASTCT).
Dr. Shamoun reported no conflicts of interest.
SOURCE: Shamoun M et al. TCT 2019, Abstract 33.
HOUSTON — When given after transplant, azithromycin does not increase the risk of relapse in patients with moderate to severe chronic graft-versus-host disease (cGVHD) and bronchiolitis obliterans syndrome (BOS), according to a retrospective study.
A prior study, ALLOZITHRO (JAMA. 2017 Aug 8;318[6]:557-66), showed an increased risk of relapse and death in patients who received azithromycin as BOS prophylaxis prior to hematopoietic cell transplant (HCT).
That discovery prompted the Food and Drug Administration to release a safety communication warning prescribers about the risks associated with azithromycin as BOS prophylaxis. However, it wasn’t clear if the same risks exist when azithromycin is given for cGVHD management after HCT.
To gain some insight, Mark Shamoun, MD, of the University of Michigan, Ann Arbor, and his colleagues examined data on patients with moderate to severe cGVHD and BOS who received azithromycin after undergoing HCT to treat a hematologic malignancy.
Dr. Shamoun presented the group’s findings at the Transplantation & Cellular Therapy Meetings.
The researchers reviewed data on 239 patients enrolled in the University of Michigan’s HCT database from 2010 to 2017. The median age at baseline was 55 years (range, 4-72 years).
The patients received transplants to treat acute myeloid leukemia or myelodysplastic syndromes (n = 141), acute lymphoblastic leukemia (n = 40), lymphoma (n = 26), chronic leukemia (n = 24), multiple myeloma (n = 6), and myeloproliferative neoplasms (n = 2).
The patients had matched related donors (43%) or matched unrelated donors (57%). Most patients received peripheral blood transplants (84%), though some received bone marrow (14%) or cord blood (2%). All patients had moderate (38%) or severe (62%) cGVHD.
Patients were split into two cohorts. Patients in cohort A (n = 86) had BOS and received azithromycin for more than 14 days.
Patients in cohort B (n = 153) either did not receive azithromycin or received it for 14 days or less. Fewer than 5% of patients in cohort B had BOS.
Most other baseline characteristics were similar between the cohorts. However, severe cGVHD was more prevalent in cohort A than B — 78% and 51%, respectively.
In cohort A, the median time to the start of azithromycin was 15 months after HCT (range, 3-68 months). The median duration of azithromycin treatment was 26 months (range, 1-77 months).
Results
The 2-year relapse rate was significantly lower in patients who received azithromycin than in those who did not — 4% and 17%, respectively (P = .001).
There was a significant difference in relapse rate both from the time of HCT (P = .001) and from the start of azithromycin or cGVHD (P = .011).
There was no significant difference in overall survival between the cohorts, either from the time of HCT (P = .294) or from the start of azithromycin or cGVHD (P = .428).
Dr. Shamoun said these results suggest azithromycin does not increase the risk of relapse when it is used to manage cGVHD. However, this study is limited by its retrospective nature. In addition, most patients in cohort B did not have BOS, severe cGVHD was more common in cohort A, and the incidence of relapse was not calculated from the time of azithromycin initiation in both cohorts. Therefore, additional investigation is needed.
Dr. Shamoun presented these results at Transplantation & Cellular Therapy Meetings, which is held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At the meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society, the American Society for Transplantation and Cellular Therapy (ASTCT).
Dr. Shamoun reported no conflicts of interest.
SOURCE: Shamoun M et al. TCT 2019, Abstract 33.
HOUSTON — When given after transplant, azithromycin does not increase the risk of relapse in patients with moderate to severe chronic graft-versus-host disease (cGVHD) and bronchiolitis obliterans syndrome (BOS), according to a retrospective study.
A prior study, ALLOZITHRO (JAMA. 2017 Aug 8;318[6]:557-66), showed an increased risk of relapse and death in patients who received azithromycin as BOS prophylaxis prior to hematopoietic cell transplant (HCT).
That discovery prompted the Food and Drug Administration to release a safety communication warning prescribers about the risks associated with azithromycin as BOS prophylaxis. However, it wasn’t clear if the same risks exist when azithromycin is given for cGVHD management after HCT.
To gain some insight, Mark Shamoun, MD, of the University of Michigan, Ann Arbor, and his colleagues examined data on patients with moderate to severe cGVHD and BOS who received azithromycin after undergoing HCT to treat a hematologic malignancy.
Dr. Shamoun presented the group’s findings at the Transplantation & Cellular Therapy Meetings.
The researchers reviewed data on 239 patients enrolled in the University of Michigan’s HCT database from 2010 to 2017. The median age at baseline was 55 years (range, 4-72 years).
The patients received transplants to treat acute myeloid leukemia or myelodysplastic syndromes (n = 141), acute lymphoblastic leukemia (n = 40), lymphoma (n = 26), chronic leukemia (n = 24), multiple myeloma (n = 6), and myeloproliferative neoplasms (n = 2).
The patients had matched related donors (43%) or matched unrelated donors (57%). Most patients received peripheral blood transplants (84%), though some received bone marrow (14%) or cord blood (2%). All patients had moderate (38%) or severe (62%) cGVHD.
Patients were split into two cohorts. Patients in cohort A (n = 86) had BOS and received azithromycin for more than 14 days.
Patients in cohort B (n = 153) either did not receive azithromycin or received it for 14 days or less. Fewer than 5% of patients in cohort B had BOS.
Most other baseline characteristics were similar between the cohorts. However, severe cGVHD was more prevalent in cohort A than B — 78% and 51%, respectively.
In cohort A, the median time to the start of azithromycin was 15 months after HCT (range, 3-68 months). The median duration of azithromycin treatment was 26 months (range, 1-77 months).
Results
The 2-year relapse rate was significantly lower in patients who received azithromycin than in those who did not — 4% and 17%, respectively (P = .001).
There was a significant difference in relapse rate both from the time of HCT (P = .001) and from the start of azithromycin or cGVHD (P = .011).
There was no significant difference in overall survival between the cohorts, either from the time of HCT (P = .294) or from the start of azithromycin or cGVHD (P = .428).
Dr. Shamoun said these results suggest azithromycin does not increase the risk of relapse when it is used to manage cGVHD. However, this study is limited by its retrospective nature. In addition, most patients in cohort B did not have BOS, severe cGVHD was more common in cohort A, and the incidence of relapse was not calculated from the time of azithromycin initiation in both cohorts. Therefore, additional investigation is needed.
Dr. Shamoun presented these results at Transplantation & Cellular Therapy Meetings, which is held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At the meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society, the American Society for Transplantation and Cellular Therapy (ASTCT).
Dr. Shamoun reported no conflicts of interest.
SOURCE: Shamoun M et al. TCT 2019, Abstract 33.
REPORTING FROM TCT 2019
Gene expression signature reveals high-grade GCB DLBCL
New research suggests a gene expression signature can distinguish high-grade diffuse large B-cell lymphomas (DLBCLs) from other germinal center B-cell–like (GCB) DLBCLs.
Researchers identified GCB DLBCL patients with this 104-gene signature who had a “distinct mutational landscape” and inferior treatment outcomes. David W. Scott, MBChB, PhD, of the British Columbia Cancer Research Centre in Vancouver, and his colleagues described these patients in the Journal of Clinical Oncology.
The findings were published alongside a related editorial and a similar study from another group.
Dr. Scott and his colleagues began their study by analyzing data from 157 patients with de novo GCB DLBCL. Twenty-five of these patients had double- or triple-hit high-grade B-cell lymphoma with BCL2 translocations (HGBL-DH/TH-BCL2).
The researchers identified 104 genes that were the “most significantly differentially expressed between HGBL-DH/TH-BCL2 and other GCB DLBCLs” to create their double-hit gene signature (DHITsig).
The signature divided the patients into two groups — 42 patients (27%) whose tumors were positive for the DHITsig and 115 (73%) whose tumors were negative. Notably, 22 of the 25 HGBL-DH/TH-BCL2 tumors were DHITsig-positive and 3 were negative.
The DHITsig was not associated with clinical variables such as tumor volume, but it was associated with prognosis. Treatment outcomes were inferior in patients who were DHITsig-positive.
The 5-year time to progression rate was 81% in patients who were DHITsig-negative and 57% in those who were positive (P less than .001). The 5-year overall survival rate was 81% and 60%, respectively (P = .001).
The researchers observed similar results in a validation cohort of 262 patients with GCB-DLBCL who received rituximab-based therapy. The 5-year overall survival rate was 76% in patients who were DHITsig-negative and 49% in those who were positive (P less than .001).
Dr. Scott and his colleagues also evaluated the DHITsig in a second validation cohort of 162 patients with GCB DLBCL.
In analyzing data from all three cohorts, the researchers found that mutations in MYC, BCL2, CREBBP, EZH2Y646, DDX3X, TP53, and KMT2D were more frequent in DHITsig-positive patients and mutations in TNFAIP3, KLHL6, NFKBIE, TET2, CD58, and STAT3 were more common in DHITsig-negative patients.
Additional analyses suggested the cell of origin for DHITsig-positive tumors comes from the intermediate zone or dark zone of the germinal center.
Finally, the researchers found they could use a “clinically relevant assay” to detect the DHITsig. They added a 30-gene module to the Lymph3Cx assay to create a NanoString-based assay called DLBCL90.
The team tested DLBCL90 in 171 GCB DLBCL patients. In this group, 26% of patients were DHITsig-positive, 64% were negative, and 10% were indeterminate. The prognostic significance of the signature was maintained with the assay results, according to the researchers.
Dr. Scott and his colleagues also wanted to validate the association between the DHITsig and HGBL-DH/TH-BCL2, so they tested the DLBCL90 assay in two additional groups of patients.
First, the assay was used in 88 patients who had transformed follicular lymphoma with DLBCL morphology. Eleven of the 25 DHITsig-positive tumors and 4 of the 13 DHITsig-indeterminate tumors were HGBL-DH/TH-BCL2. However, none of the 50 DHITsig-negative tumors were HGBL-DH/TH-BCL2.
The researchers then used the DLBCL90 assay on 26 HGBL tumors. Twenty-three of these were DHITsig-positive and 3 were indeterminate.
This research was supported by the Canadian Cancer Society Research Institute and other organizations. The researchers reported relationships with Seattle Genetics, Roche, Janssen, Celgene, and various other companies.
SOURCE: Scott DW et al. J Clin Oncol. 2019 Jan 20;37(3):190-201.
New research suggests a gene expression signature can distinguish high-grade diffuse large B-cell lymphomas (DLBCLs) from other germinal center B-cell–like (GCB) DLBCLs.
Researchers identified GCB DLBCL patients with this 104-gene signature who had a “distinct mutational landscape” and inferior treatment outcomes. David W. Scott, MBChB, PhD, of the British Columbia Cancer Research Centre in Vancouver, and his colleagues described these patients in the Journal of Clinical Oncology.
The findings were published alongside a related editorial and a similar study from another group.
Dr. Scott and his colleagues began their study by analyzing data from 157 patients with de novo GCB DLBCL. Twenty-five of these patients had double- or triple-hit high-grade B-cell lymphoma with BCL2 translocations (HGBL-DH/TH-BCL2).
The researchers identified 104 genes that were the “most significantly differentially expressed between HGBL-DH/TH-BCL2 and other GCB DLBCLs” to create their double-hit gene signature (DHITsig).
The signature divided the patients into two groups — 42 patients (27%) whose tumors were positive for the DHITsig and 115 (73%) whose tumors were negative. Notably, 22 of the 25 HGBL-DH/TH-BCL2 tumors were DHITsig-positive and 3 were negative.
The DHITsig was not associated with clinical variables such as tumor volume, but it was associated with prognosis. Treatment outcomes were inferior in patients who were DHITsig-positive.
The 5-year time to progression rate was 81% in patients who were DHITsig-negative and 57% in those who were positive (P less than .001). The 5-year overall survival rate was 81% and 60%, respectively (P = .001).
The researchers observed similar results in a validation cohort of 262 patients with GCB-DLBCL who received rituximab-based therapy. The 5-year overall survival rate was 76% in patients who were DHITsig-negative and 49% in those who were positive (P less than .001).
Dr. Scott and his colleagues also evaluated the DHITsig in a second validation cohort of 162 patients with GCB DLBCL.
In analyzing data from all three cohorts, the researchers found that mutations in MYC, BCL2, CREBBP, EZH2Y646, DDX3X, TP53, and KMT2D were more frequent in DHITsig-positive patients and mutations in TNFAIP3, KLHL6, NFKBIE, TET2, CD58, and STAT3 were more common in DHITsig-negative patients.
Additional analyses suggested the cell of origin for DHITsig-positive tumors comes from the intermediate zone or dark zone of the germinal center.
Finally, the researchers found they could use a “clinically relevant assay” to detect the DHITsig. They added a 30-gene module to the Lymph3Cx assay to create a NanoString-based assay called DLBCL90.
The team tested DLBCL90 in 171 GCB DLBCL patients. In this group, 26% of patients were DHITsig-positive, 64% were negative, and 10% were indeterminate. The prognostic significance of the signature was maintained with the assay results, according to the researchers.
Dr. Scott and his colleagues also wanted to validate the association between the DHITsig and HGBL-DH/TH-BCL2, so they tested the DLBCL90 assay in two additional groups of patients.
First, the assay was used in 88 patients who had transformed follicular lymphoma with DLBCL morphology. Eleven of the 25 DHITsig-positive tumors and 4 of the 13 DHITsig-indeterminate tumors were HGBL-DH/TH-BCL2. However, none of the 50 DHITsig-negative tumors were HGBL-DH/TH-BCL2.
The researchers then used the DLBCL90 assay on 26 HGBL tumors. Twenty-three of these were DHITsig-positive and 3 were indeterminate.
This research was supported by the Canadian Cancer Society Research Institute and other organizations. The researchers reported relationships with Seattle Genetics, Roche, Janssen, Celgene, and various other companies.
SOURCE: Scott DW et al. J Clin Oncol. 2019 Jan 20;37(3):190-201.
New research suggests a gene expression signature can distinguish high-grade diffuse large B-cell lymphomas (DLBCLs) from other germinal center B-cell–like (GCB) DLBCLs.
Researchers identified GCB DLBCL patients with this 104-gene signature who had a “distinct mutational landscape” and inferior treatment outcomes. David W. Scott, MBChB, PhD, of the British Columbia Cancer Research Centre in Vancouver, and his colleagues described these patients in the Journal of Clinical Oncology.
The findings were published alongside a related editorial and a similar study from another group.
Dr. Scott and his colleagues began their study by analyzing data from 157 patients with de novo GCB DLBCL. Twenty-five of these patients had double- or triple-hit high-grade B-cell lymphoma with BCL2 translocations (HGBL-DH/TH-BCL2).
The researchers identified 104 genes that were the “most significantly differentially expressed between HGBL-DH/TH-BCL2 and other GCB DLBCLs” to create their double-hit gene signature (DHITsig).
The signature divided the patients into two groups — 42 patients (27%) whose tumors were positive for the DHITsig and 115 (73%) whose tumors were negative. Notably, 22 of the 25 HGBL-DH/TH-BCL2 tumors were DHITsig-positive and 3 were negative.
The DHITsig was not associated with clinical variables such as tumor volume, but it was associated with prognosis. Treatment outcomes were inferior in patients who were DHITsig-positive.
The 5-year time to progression rate was 81% in patients who were DHITsig-negative and 57% in those who were positive (P less than .001). The 5-year overall survival rate was 81% and 60%, respectively (P = .001).
The researchers observed similar results in a validation cohort of 262 patients with GCB-DLBCL who received rituximab-based therapy. The 5-year overall survival rate was 76% in patients who were DHITsig-negative and 49% in those who were positive (P less than .001).
Dr. Scott and his colleagues also evaluated the DHITsig in a second validation cohort of 162 patients with GCB DLBCL.
In analyzing data from all three cohorts, the researchers found that mutations in MYC, BCL2, CREBBP, EZH2Y646, DDX3X, TP53, and KMT2D were more frequent in DHITsig-positive patients and mutations in TNFAIP3, KLHL6, NFKBIE, TET2, CD58, and STAT3 were more common in DHITsig-negative patients.
Additional analyses suggested the cell of origin for DHITsig-positive tumors comes from the intermediate zone or dark zone of the germinal center.
Finally, the researchers found they could use a “clinically relevant assay” to detect the DHITsig. They added a 30-gene module to the Lymph3Cx assay to create a NanoString-based assay called DLBCL90.
The team tested DLBCL90 in 171 GCB DLBCL patients. In this group, 26% of patients were DHITsig-positive, 64% were negative, and 10% were indeterminate. The prognostic significance of the signature was maintained with the assay results, according to the researchers.
Dr. Scott and his colleagues also wanted to validate the association between the DHITsig and HGBL-DH/TH-BCL2, so they tested the DLBCL90 assay in two additional groups of patients.
First, the assay was used in 88 patients who had transformed follicular lymphoma with DLBCL morphology. Eleven of the 25 DHITsig-positive tumors and 4 of the 13 DHITsig-indeterminate tumors were HGBL-DH/TH-BCL2. However, none of the 50 DHITsig-negative tumors were HGBL-DH/TH-BCL2.
The researchers then used the DLBCL90 assay on 26 HGBL tumors. Twenty-three of these were DHITsig-positive and 3 were indeterminate.
This research was supported by the Canadian Cancer Society Research Institute and other organizations. The researchers reported relationships with Seattle Genetics, Roche, Janssen, Celgene, and various other companies.
SOURCE: Scott DW et al. J Clin Oncol. 2019 Jan 20;37(3):190-201.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Priority review granted to lenalidomide for FL, MZL
The Food and Drug Administration has granted priority review to a supplemental new drug application (sNDA) for lenalidomide (Revlimid).
Celgene is seeking approval for lenalidomide in combination with rituximab to treat patients with previously treated follicular lymphoma (FL) or marginal zone lymphoma (MZL).
The FDA plans to make a decision on the sNDA by June 27, 2019.
The FDA aims to take action on a priority review application within 6 months of receiving it rather than the standard 10 months. The FDA grants priority review to applications for products that are expected to provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The sNDA for lenalidomide is supported by the phase 3 AUGMENT study (NCT01938001) in which researchers compared rituximab plus lenalidomide to rituximab plus placebo in patients with relapsed/refractory FL or MZL.
Results from AUGMENT were presented at the 2018 annual meeting of the American Society of Hematology (Blood 2018 Nov 29;132:445).
According to the ASH abstract, the trial included 358 patients who were randomized to receive rituximab plus lenalidomide (n = 178) or rituximab plus placebo (n = 180).
At a median follow-up of 28.3 months, the overall response rate was 78% in the lenalidomide arm and 53% in the placebo arm (P less than .0001). The complete response rate was 34% and 18%, respectively (P = .001).
The median progression-free survival was 39.4 months in the lenalidomide arm and 14.1 months in the placebo arm. Overall survival data were not mature, but there were 16 deaths reported in the lenalidomide arm and 26 deaths in the placebo arm.
Treatment-emergent adverse events that were more common in the lenalidomide arm than the placebo arm included infections, cutaneous reactions, constipation, thrombocytopenia, and tumor flare reaction.
The Food and Drug Administration has granted priority review to a supplemental new drug application (sNDA) for lenalidomide (Revlimid).
Celgene is seeking approval for lenalidomide in combination with rituximab to treat patients with previously treated follicular lymphoma (FL) or marginal zone lymphoma (MZL).
The FDA plans to make a decision on the sNDA by June 27, 2019.
The FDA aims to take action on a priority review application within 6 months of receiving it rather than the standard 10 months. The FDA grants priority review to applications for products that are expected to provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The sNDA for lenalidomide is supported by the phase 3 AUGMENT study (NCT01938001) in which researchers compared rituximab plus lenalidomide to rituximab plus placebo in patients with relapsed/refractory FL or MZL.
Results from AUGMENT were presented at the 2018 annual meeting of the American Society of Hematology (Blood 2018 Nov 29;132:445).
According to the ASH abstract, the trial included 358 patients who were randomized to receive rituximab plus lenalidomide (n = 178) or rituximab plus placebo (n = 180).
At a median follow-up of 28.3 months, the overall response rate was 78% in the lenalidomide arm and 53% in the placebo arm (P less than .0001). The complete response rate was 34% and 18%, respectively (P = .001).
The median progression-free survival was 39.4 months in the lenalidomide arm and 14.1 months in the placebo arm. Overall survival data were not mature, but there were 16 deaths reported in the lenalidomide arm and 26 deaths in the placebo arm.
Treatment-emergent adverse events that were more common in the lenalidomide arm than the placebo arm included infections, cutaneous reactions, constipation, thrombocytopenia, and tumor flare reaction.
The Food and Drug Administration has granted priority review to a supplemental new drug application (sNDA) for lenalidomide (Revlimid).
Celgene is seeking approval for lenalidomide in combination with rituximab to treat patients with previously treated follicular lymphoma (FL) or marginal zone lymphoma (MZL).
The FDA plans to make a decision on the sNDA by June 27, 2019.
The FDA aims to take action on a priority review application within 6 months of receiving it rather than the standard 10 months. The FDA grants priority review to applications for products that are expected to provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The sNDA for lenalidomide is supported by the phase 3 AUGMENT study (NCT01938001) in which researchers compared rituximab plus lenalidomide to rituximab plus placebo in patients with relapsed/refractory FL or MZL.
Results from AUGMENT were presented at the 2018 annual meeting of the American Society of Hematology (Blood 2018 Nov 29;132:445).
According to the ASH abstract, the trial included 358 patients who were randomized to receive rituximab plus lenalidomide (n = 178) or rituximab plus placebo (n = 180).
At a median follow-up of 28.3 months, the overall response rate was 78% in the lenalidomide arm and 53% in the placebo arm (P less than .0001). The complete response rate was 34% and 18%, respectively (P = .001).
The median progression-free survival was 39.4 months in the lenalidomide arm and 14.1 months in the placebo arm. Overall survival data were not mature, but there were 16 deaths reported in the lenalidomide arm and 26 deaths in the placebo arm.
Treatment-emergent adverse events that were more common in the lenalidomide arm than the placebo arm included infections, cutaneous reactions, constipation, thrombocytopenia, and tumor flare reaction.
Gene therapy in hemophilia is just version 1.0
PRAGUE – Adeno-associated virus (AAV)–based gene therapy is probably not the “endgame” in gene therapy for hemophilia, according to John Pasi, MD, PhD, director of the Haemophilia Centre at the Royal London Hospital.
“Gene therapy today is essentially gene therapy version 1.0,” Dr. Pasi said, kicking off the third day at the annual congress of the European Association for Haemophilia and Allied Disorders.
Interwoven with a summary of recent research and upcoming trends, Dr. Pasi reflected upon the medical community’s expectations for gene therapy, both past and present.
“For years,” Dr. Pasi said, “gene therapy has been regarded, essentially, as the Holy Grail of treatment for hemophilia.” This sentiment has been supported by the fact that hemophilia “is a single-gene disorder with a cause and effect relationship that is extremely clear and straightforward for us to recognize.”
A small increase in clotting factor can significantly reduce bleeding while providing a measurable efficacy outcome, making it a strong research candidate.
Looking back, however, when gene therapy research began in the early 1990s, it “really did go through a peak of inflated expectations,” Dr. Pasi said. “We thought for years it was just around the corner. But there were abject failures; there were learning curves we had to go through to understand many of the issues that gene therapy threw up, which we didn’t understand at the beginning.”
When this early excitement was met with tough realities, a period of disillusionment began and persisted through the early 2000s. Dr. Pasi suggested that this period of disillusionment may be reaching an end because of a “huge amount of steady work” that has ushered in a new period of productivity.
Dr. Pasi cited two 2017 studies published in the New England Journal of Medicine by Savita Rangarajan, MBBS, and colleagues and Lindsey A. George, MD, and colleagues for hemophilia A and B, respectively (N Engl J Med. 2017; 377:2519-30; N Engl J Med. 2017; 377:2215-27).
In contrast with previous studies showing factor levels in the single digits, recent studies have achieved normal-range values. Seeing such improvements in hemophilia A, is a particular source of optimism; historically, gene therapy for hemophilia A has lagged behind hemophilia B because of a larger gene that is more difficult to work with.
“This has stepped up the game hugely,” Dr. Pasi said.
The elements of gene therapy for hemophilia may change over time. For instance, lentiviruses could be used instead of AAV-based methods, and ex vivo techniques could make a comeback, potentially using different tissue sources. These changes are likely on the distant horizon, however.
Gene modification is also not coming anytime soon.
“Gene replacement, gene editing, and gene repair are something that we hear a lot about in the general field of gene therapy,” Dr. Pasi said, “But in practical terms for our patients, we probably are a significant way off from this at the moment, and this is because we know and we all recognize that there are a wide range of mutations causing hemophilia, and many of these are highly specific; we will need specific gene therapies to address specific mutations.”
Dr. Pasi likened the current state of gene therapy to that of the self-driving car, suggesting that “we still have strides to make, and there are still things we can improve on beyond what we have today.
“The biggest question for gene therapy today is durability,” Dr. Pasi said. “How long are these things going to last?”
Patients from earlier studies are now crossing the half-decade mark, albeit with relatively low factor levels, compared with recent techniques. One such study, presented at the 2018 annual meeting of the American Society of Hematology by Amit C. Nathwani, MD, PhD, and colleagues, is “very critical to our understanding,” Dr. Pasi said, referring to patients who are now 6-8 years post treatment. “What we see is … continued, stable expression of factor IX,” he said.
Alongside questions of durability, safety remains paramount in the quest for better methods of gene therapy.
“We are seeing liver function abnormalities,” Dr. Pasi said, noting that these tend to be transient elevations of ALT. “We know that many patients now have to receive steroid treatment, which very effectively reduces the immune response, but it is something that we are increasingly having to bear in mind.”
The latest techniques are using liver-specific promoters in novel synthetic capsids, and more capsids are under development.
Dr. Pasi also emphasized safety and caution. “We must never forget that gene therapy is a completely new approach to treatment, and we’ve got to think about safety. It is the number one priority when we are investigating new treatments.”
Safety remains untested in several key patient subpopulations, including children and those with comorbidities or inhibitors.
“For gene therapy in 2019,” he said, “we’ve made massive strides, but we’re not quite there yet.”
PRAGUE – Adeno-associated virus (AAV)–based gene therapy is probably not the “endgame” in gene therapy for hemophilia, according to John Pasi, MD, PhD, director of the Haemophilia Centre at the Royal London Hospital.
“Gene therapy today is essentially gene therapy version 1.0,” Dr. Pasi said, kicking off the third day at the annual congress of the European Association for Haemophilia and Allied Disorders.
Interwoven with a summary of recent research and upcoming trends, Dr. Pasi reflected upon the medical community’s expectations for gene therapy, both past and present.
“For years,” Dr. Pasi said, “gene therapy has been regarded, essentially, as the Holy Grail of treatment for hemophilia.” This sentiment has been supported by the fact that hemophilia “is a single-gene disorder with a cause and effect relationship that is extremely clear and straightforward for us to recognize.”
A small increase in clotting factor can significantly reduce bleeding while providing a measurable efficacy outcome, making it a strong research candidate.
Looking back, however, when gene therapy research began in the early 1990s, it “really did go through a peak of inflated expectations,” Dr. Pasi said. “We thought for years it was just around the corner. But there were abject failures; there were learning curves we had to go through to understand many of the issues that gene therapy threw up, which we didn’t understand at the beginning.”
When this early excitement was met with tough realities, a period of disillusionment began and persisted through the early 2000s. Dr. Pasi suggested that this period of disillusionment may be reaching an end because of a “huge amount of steady work” that has ushered in a new period of productivity.
Dr. Pasi cited two 2017 studies published in the New England Journal of Medicine by Savita Rangarajan, MBBS, and colleagues and Lindsey A. George, MD, and colleagues for hemophilia A and B, respectively (N Engl J Med. 2017; 377:2519-30; N Engl J Med. 2017; 377:2215-27).
In contrast with previous studies showing factor levels in the single digits, recent studies have achieved normal-range values. Seeing such improvements in hemophilia A, is a particular source of optimism; historically, gene therapy for hemophilia A has lagged behind hemophilia B because of a larger gene that is more difficult to work with.
“This has stepped up the game hugely,” Dr. Pasi said.
The elements of gene therapy for hemophilia may change over time. For instance, lentiviruses could be used instead of AAV-based methods, and ex vivo techniques could make a comeback, potentially using different tissue sources. These changes are likely on the distant horizon, however.
Gene modification is also not coming anytime soon.
“Gene replacement, gene editing, and gene repair are something that we hear a lot about in the general field of gene therapy,” Dr. Pasi said, “But in practical terms for our patients, we probably are a significant way off from this at the moment, and this is because we know and we all recognize that there are a wide range of mutations causing hemophilia, and many of these are highly specific; we will need specific gene therapies to address specific mutations.”
Dr. Pasi likened the current state of gene therapy to that of the self-driving car, suggesting that “we still have strides to make, and there are still things we can improve on beyond what we have today.
“The biggest question for gene therapy today is durability,” Dr. Pasi said. “How long are these things going to last?”
Patients from earlier studies are now crossing the half-decade mark, albeit with relatively low factor levels, compared with recent techniques. One such study, presented at the 2018 annual meeting of the American Society of Hematology by Amit C. Nathwani, MD, PhD, and colleagues, is “very critical to our understanding,” Dr. Pasi said, referring to patients who are now 6-8 years post treatment. “What we see is … continued, stable expression of factor IX,” he said.
Alongside questions of durability, safety remains paramount in the quest for better methods of gene therapy.
“We are seeing liver function abnormalities,” Dr. Pasi said, noting that these tend to be transient elevations of ALT. “We know that many patients now have to receive steroid treatment, which very effectively reduces the immune response, but it is something that we are increasingly having to bear in mind.”
The latest techniques are using liver-specific promoters in novel synthetic capsids, and more capsids are under development.
Dr. Pasi also emphasized safety and caution. “We must never forget that gene therapy is a completely new approach to treatment, and we’ve got to think about safety. It is the number one priority when we are investigating new treatments.”
Safety remains untested in several key patient subpopulations, including children and those with comorbidities or inhibitors.
“For gene therapy in 2019,” he said, “we’ve made massive strides, but we’re not quite there yet.”
PRAGUE – Adeno-associated virus (AAV)–based gene therapy is probably not the “endgame” in gene therapy for hemophilia, according to John Pasi, MD, PhD, director of the Haemophilia Centre at the Royal London Hospital.
“Gene therapy today is essentially gene therapy version 1.0,” Dr. Pasi said, kicking off the third day at the annual congress of the European Association for Haemophilia and Allied Disorders.
Interwoven with a summary of recent research and upcoming trends, Dr. Pasi reflected upon the medical community’s expectations for gene therapy, both past and present.
“For years,” Dr. Pasi said, “gene therapy has been regarded, essentially, as the Holy Grail of treatment for hemophilia.” This sentiment has been supported by the fact that hemophilia “is a single-gene disorder with a cause and effect relationship that is extremely clear and straightforward for us to recognize.”
A small increase in clotting factor can significantly reduce bleeding while providing a measurable efficacy outcome, making it a strong research candidate.
Looking back, however, when gene therapy research began in the early 1990s, it “really did go through a peak of inflated expectations,” Dr. Pasi said. “We thought for years it was just around the corner. But there were abject failures; there were learning curves we had to go through to understand many of the issues that gene therapy threw up, which we didn’t understand at the beginning.”
When this early excitement was met with tough realities, a period of disillusionment began and persisted through the early 2000s. Dr. Pasi suggested that this period of disillusionment may be reaching an end because of a “huge amount of steady work” that has ushered in a new period of productivity.
Dr. Pasi cited two 2017 studies published in the New England Journal of Medicine by Savita Rangarajan, MBBS, and colleagues and Lindsey A. George, MD, and colleagues for hemophilia A and B, respectively (N Engl J Med. 2017; 377:2519-30; N Engl J Med. 2017; 377:2215-27).
In contrast with previous studies showing factor levels in the single digits, recent studies have achieved normal-range values. Seeing such improvements in hemophilia A, is a particular source of optimism; historically, gene therapy for hemophilia A has lagged behind hemophilia B because of a larger gene that is more difficult to work with.
“This has stepped up the game hugely,” Dr. Pasi said.
The elements of gene therapy for hemophilia may change over time. For instance, lentiviruses could be used instead of AAV-based methods, and ex vivo techniques could make a comeback, potentially using different tissue sources. These changes are likely on the distant horizon, however.
Gene modification is also not coming anytime soon.
“Gene replacement, gene editing, and gene repair are something that we hear a lot about in the general field of gene therapy,” Dr. Pasi said, “But in practical terms for our patients, we probably are a significant way off from this at the moment, and this is because we know and we all recognize that there are a wide range of mutations causing hemophilia, and many of these are highly specific; we will need specific gene therapies to address specific mutations.”
Dr. Pasi likened the current state of gene therapy to that of the self-driving car, suggesting that “we still have strides to make, and there are still things we can improve on beyond what we have today.
“The biggest question for gene therapy today is durability,” Dr. Pasi said. “How long are these things going to last?”
Patients from earlier studies are now crossing the half-decade mark, albeit with relatively low factor levels, compared with recent techniques. One such study, presented at the 2018 annual meeting of the American Society of Hematology by Amit C. Nathwani, MD, PhD, and colleagues, is “very critical to our understanding,” Dr. Pasi said, referring to patients who are now 6-8 years post treatment. “What we see is … continued, stable expression of factor IX,” he said.
Alongside questions of durability, safety remains paramount in the quest for better methods of gene therapy.
“We are seeing liver function abnormalities,” Dr. Pasi said, noting that these tend to be transient elevations of ALT. “We know that many patients now have to receive steroid treatment, which very effectively reduces the immune response, but it is something that we are increasingly having to bear in mind.”
The latest techniques are using liver-specific promoters in novel synthetic capsids, and more capsids are under development.
Dr. Pasi also emphasized safety and caution. “We must never forget that gene therapy is a completely new approach to treatment, and we’ve got to think about safety. It is the number one priority when we are investigating new treatments.”
Safety remains untested in several key patient subpopulations, including children and those with comorbidities or inhibitors.
“For gene therapy in 2019,” he said, “we’ve made massive strides, but we’re not quite there yet.”
EXPERT ANALYSIS FROM EAHAD 2019
Myeloma therapies raise cardiovascular risks
WASHINGTON – Proteasome inhibitors are essential components of therapeutic regimens for multiple myeloma, but at least one member of this class of life-extending agents, carfilzomib (Kyprolis), is also associated with a significant increase in risk of heart failure, cautioned a specialist in plasma cell disorders.
In addition, immunomodulating agents such as lenalidomide (Revlimid) and pomalidomide (Pomalyst) are associated with increased risk for thromboembolic events, said R. Frank Cornell, MD, clinical director of plasma cell disorders at Vanderbilt University Medical Center in Nashville, Tenn.
In an ongoing, prospective study comparing rates of cardiac adverse events in patients receiving carfilzomib or another proteasome inhibitor, bortezomib (Velcade), Dr. Cornell and his colleagues found that while there were no significant differences in progression-free survival (PFS) or overall survival (OS) between the treatments, “patients who experienced a cardiovascular event had significantly worse progression-free and overall survival compared to those that did not have a cardiovascular event,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
The Prospective Observation of Cardiac Safety With Proteasome Inhibition (PROTECT) trial, scheduled for completion in August 2019, enrolled 95 patients with relapsed multiple myeloma and randomly assigned them on a 2:1 basis to receive carfilzomib or bortezomib.
The investigators found that cardiovascular adverse events occurred in 33 of the 65 patients (51%) randomized to carfilzomib, compared with 5 of 30 patients (17%) assigned to bortezomib.
The events included grade 1 or 2 heart failure (HF) in 12 patients on carfilzomib vs. 2 on bortezomib, and grade 3 or 4 HF in 11 vs. 1, respectively. Hypertension was significantly more frequent among patients on carfilzomib, and one patient on carfilzomib died from the acute coronary syndrome 24 hours after receiving carfilzomib in the second week of treatment.
The investigators found that both B-type natriuretic peptide (BNP) and N-terminal pro b-type natriuretic peptide (NT-proBNP) were highly predictive of cardiovascular adverse events. Patients on carfilzomib who had levels of the markers above normal at baseline had an odds ratio (OR) for cardiovascular events of 7.39 (P less than .0001), and those with BNP or NT-proBNP increases at week 2 or 3 during cycle 1 had an OR for a cardiovascular adverse event of 63.5 (P less than .001).
In multivariate analysis, the risk for cardiovascular events for patients treated with carfilzomib was significantly lower for patients with one or no traditional cardiovascular risk factors, compared with patients with two or more.
“Prospective monitoring with natriuretic peptides should be considered, particularly early in treatment,” Dr. Cornell said.
IMiDs and thromboembolism
In early clinical trials of immunomodulators (IMiDs) for multiple myeloma, investigators saw that the incidence of thromboembolic events was lower among patients who received thromboprophylaxis than among those who did not, Dr. Cornell noted.
“From this, certain guidelines have been developed such that all patients considered to be at risk should at least receive an aspirin, 81-325 mg, and patients at higher risk for thromboembolism should receive low-molecular-weight heparin or therapeutic-dose warfarin,” he said.
There is little guidance, however, about the use of direct oral anticoagulants in this population, he added, a fact that prompted him and his colleagues in oncology and cardiology to perform a pilot study of apixaban (Eliquis) for primary prevention of venous thromboembolism (VTE) in patients with multiple myeloma who were receiving immunodulatory drugs.
Results of the pilot study, reported in a poster session at the 2018 annual meeting of the American Society of Hematology, showed that among 50 patients who received apixaban 2.5 mg twice daily for 6 months during IMiD therapy, there were no VTEs, stroke, or myocardial infarction, and no episodes of major bleeding. There were just three nonmajor bleeding events, and one early withdrawal from apixaban due to an allergic reaction manifesting as generalized edema.
“Further study is needed to validate this as a potential primary prophylaxis in patients receiving IMiDs for multiple myeloma,” Dr. Cornell said.
He reported having no financial disclosures. Millennium Pharmaceuticals is a sponsor of the PROTECT trial.
WASHINGTON – Proteasome inhibitors are essential components of therapeutic regimens for multiple myeloma, but at least one member of this class of life-extending agents, carfilzomib (Kyprolis), is also associated with a significant increase in risk of heart failure, cautioned a specialist in plasma cell disorders.
In addition, immunomodulating agents such as lenalidomide (Revlimid) and pomalidomide (Pomalyst) are associated with increased risk for thromboembolic events, said R. Frank Cornell, MD, clinical director of plasma cell disorders at Vanderbilt University Medical Center in Nashville, Tenn.
In an ongoing, prospective study comparing rates of cardiac adverse events in patients receiving carfilzomib or another proteasome inhibitor, bortezomib (Velcade), Dr. Cornell and his colleagues found that while there were no significant differences in progression-free survival (PFS) or overall survival (OS) between the treatments, “patients who experienced a cardiovascular event had significantly worse progression-free and overall survival compared to those that did not have a cardiovascular event,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
The Prospective Observation of Cardiac Safety With Proteasome Inhibition (PROTECT) trial, scheduled for completion in August 2019, enrolled 95 patients with relapsed multiple myeloma and randomly assigned them on a 2:1 basis to receive carfilzomib or bortezomib.
The investigators found that cardiovascular adverse events occurred in 33 of the 65 patients (51%) randomized to carfilzomib, compared with 5 of 30 patients (17%) assigned to bortezomib.
The events included grade 1 or 2 heart failure (HF) in 12 patients on carfilzomib vs. 2 on bortezomib, and grade 3 or 4 HF in 11 vs. 1, respectively. Hypertension was significantly more frequent among patients on carfilzomib, and one patient on carfilzomib died from the acute coronary syndrome 24 hours after receiving carfilzomib in the second week of treatment.
The investigators found that both B-type natriuretic peptide (BNP) and N-terminal pro b-type natriuretic peptide (NT-proBNP) were highly predictive of cardiovascular adverse events. Patients on carfilzomib who had levels of the markers above normal at baseline had an odds ratio (OR) for cardiovascular events of 7.39 (P less than .0001), and those with BNP or NT-proBNP increases at week 2 or 3 during cycle 1 had an OR for a cardiovascular adverse event of 63.5 (P less than .001).
In multivariate analysis, the risk for cardiovascular events for patients treated with carfilzomib was significantly lower for patients with one or no traditional cardiovascular risk factors, compared with patients with two or more.
“Prospective monitoring with natriuretic peptides should be considered, particularly early in treatment,” Dr. Cornell said.
IMiDs and thromboembolism
In early clinical trials of immunomodulators (IMiDs) for multiple myeloma, investigators saw that the incidence of thromboembolic events was lower among patients who received thromboprophylaxis than among those who did not, Dr. Cornell noted.
“From this, certain guidelines have been developed such that all patients considered to be at risk should at least receive an aspirin, 81-325 mg, and patients at higher risk for thromboembolism should receive low-molecular-weight heparin or therapeutic-dose warfarin,” he said.
There is little guidance, however, about the use of direct oral anticoagulants in this population, he added, a fact that prompted him and his colleagues in oncology and cardiology to perform a pilot study of apixaban (Eliquis) for primary prevention of venous thromboembolism (VTE) in patients with multiple myeloma who were receiving immunodulatory drugs.
Results of the pilot study, reported in a poster session at the 2018 annual meeting of the American Society of Hematology, showed that among 50 patients who received apixaban 2.5 mg twice daily for 6 months during IMiD therapy, there were no VTEs, stroke, or myocardial infarction, and no episodes of major bleeding. There were just three nonmajor bleeding events, and one early withdrawal from apixaban due to an allergic reaction manifesting as generalized edema.
“Further study is needed to validate this as a potential primary prophylaxis in patients receiving IMiDs for multiple myeloma,” Dr. Cornell said.
He reported having no financial disclosures. Millennium Pharmaceuticals is a sponsor of the PROTECT trial.
WASHINGTON – Proteasome inhibitors are essential components of therapeutic regimens for multiple myeloma, but at least one member of this class of life-extending agents, carfilzomib (Kyprolis), is also associated with a significant increase in risk of heart failure, cautioned a specialist in plasma cell disorders.
In addition, immunomodulating agents such as lenalidomide (Revlimid) and pomalidomide (Pomalyst) are associated with increased risk for thromboembolic events, said R. Frank Cornell, MD, clinical director of plasma cell disorders at Vanderbilt University Medical Center in Nashville, Tenn.
In an ongoing, prospective study comparing rates of cardiac adverse events in patients receiving carfilzomib or another proteasome inhibitor, bortezomib (Velcade), Dr. Cornell and his colleagues found that while there were no significant differences in progression-free survival (PFS) or overall survival (OS) between the treatments, “patients who experienced a cardiovascular event had significantly worse progression-free and overall survival compared to those that did not have a cardiovascular event,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
The Prospective Observation of Cardiac Safety With Proteasome Inhibition (PROTECT) trial, scheduled for completion in August 2019, enrolled 95 patients with relapsed multiple myeloma and randomly assigned them on a 2:1 basis to receive carfilzomib or bortezomib.
The investigators found that cardiovascular adverse events occurred in 33 of the 65 patients (51%) randomized to carfilzomib, compared with 5 of 30 patients (17%) assigned to bortezomib.
The events included grade 1 or 2 heart failure (HF) in 12 patients on carfilzomib vs. 2 on bortezomib, and grade 3 or 4 HF in 11 vs. 1, respectively. Hypertension was significantly more frequent among patients on carfilzomib, and one patient on carfilzomib died from the acute coronary syndrome 24 hours after receiving carfilzomib in the second week of treatment.
The investigators found that both B-type natriuretic peptide (BNP) and N-terminal pro b-type natriuretic peptide (NT-proBNP) were highly predictive of cardiovascular adverse events. Patients on carfilzomib who had levels of the markers above normal at baseline had an odds ratio (OR) for cardiovascular events of 7.39 (P less than .0001), and those with BNP or NT-proBNP increases at week 2 or 3 during cycle 1 had an OR for a cardiovascular adverse event of 63.5 (P less than .001).
In multivariate analysis, the risk for cardiovascular events for patients treated with carfilzomib was significantly lower for patients with one or no traditional cardiovascular risk factors, compared with patients with two or more.
“Prospective monitoring with natriuretic peptides should be considered, particularly early in treatment,” Dr. Cornell said.
IMiDs and thromboembolism
In early clinical trials of immunomodulators (IMiDs) for multiple myeloma, investigators saw that the incidence of thromboembolic events was lower among patients who received thromboprophylaxis than among those who did not, Dr. Cornell noted.
“From this, certain guidelines have been developed such that all patients considered to be at risk should at least receive an aspirin, 81-325 mg, and patients at higher risk for thromboembolism should receive low-molecular-weight heparin or therapeutic-dose warfarin,” he said.
There is little guidance, however, about the use of direct oral anticoagulants in this population, he added, a fact that prompted him and his colleagues in oncology and cardiology to perform a pilot study of apixaban (Eliquis) for primary prevention of venous thromboembolism (VTE) in patients with multiple myeloma who were receiving immunodulatory drugs.
Results of the pilot study, reported in a poster session at the 2018 annual meeting of the American Society of Hematology, showed that among 50 patients who received apixaban 2.5 mg twice daily for 6 months during IMiD therapy, there were no VTEs, stroke, or myocardial infarction, and no episodes of major bleeding. There were just three nonmajor bleeding events, and one early withdrawal from apixaban due to an allergic reaction manifesting as generalized edema.
“Further study is needed to validate this as a potential primary prophylaxis in patients receiving IMiDs for multiple myeloma,” Dr. Cornell said.
He reported having no financial disclosures. Millennium Pharmaceuticals is a sponsor of the PROTECT trial.
REPORTING FROM ACC CARDIO-ONCOLOGY
Think duration, not dose, when managing bleeding with non–factor replacements
PRAGUE – Clinicians should prioritize treatment duration with factors or bypassing agents – not dose level – when managing breakthrough bleeds in patients with hemophilia who are on non–factor replacement therapy, according to a leading expert.
Duration of treatment is more strongly associated with thromboembolism than dose magnitude, said Andreas Tiede, MD, PhD, head of hemostaseology at Hannover (Germany) Medical School in Germany, noting that recommendations vary by non–factor replacement agent.
These remarks were part of a presentation about novel agents for treatment of hemophilia with inhibitors delivered at the annual congress of the European Association for Haemophilia and Allied Disorders.
“Concomitant use of factor products, both factor VIII and IX, and the bypassing agents, have usually preceded thromboembolic events in clinical trials [for non–factor replacement therapies] so this [topic] is crucial,” Dr. Tiede said.
Other experts recommend lower doses and shorter treatment durations. “I think that’s reasonable, but with some question mark behind the low doses,” he said. “I think it depends a little bit on the interaction between the non–factor replacement therapy and the bypassing agent in your patient.”
With a busy pipeline of non–factor replacement agents for hemophilia, such interactions are becoming increasingly relevant for clinicians and their patients.
Emicizumab, for instance, which is now approved for hemophilia with or without inhibitors, has synergistic activity with activated prothrombin complex concentrates (APCC). This was demonstrated by an emicizumab prophylaxis trial in which five out of eight patients with breakthrough bleeding who were treated with APPC at a dose higher than 100 IU/kg per day for more than 24 hours developed thrombotic microangiopathy. (N Engl J Med. 2017;377:809-18).
Other patients who received multiple infusions of APCC developed skin necrosis, cavernous vein thrombosis, and thrombophlebitis. Consequently, it is now recommended that APCC be avoided in patients taking emicizumab, and if unavoidable, given at the lowest dose possible. However, Dr. Tiede advised that this recommendation for APCC should not be extrapolated to encompass all factors and bypassing agents, based on existing data.
“Regarding higher or lower doses for initial treatment, I would be a little bit more careful,” he said. “That obviously depends on [whether] there is a synergistic effect with the non–factor replacement therapy and the bypassing agent. Synergistic effects have clearly been shown for the interaction of emicizumab and APCC, but when it comes to the interaction between emicizumab and VIIa, I’m not so sure. I don’t think that we have enough evidence to recommend lower doses of VIIa.”
Dr. Tiede also suggested that lower doses of factor VIII are probably unnecessary. “At high doses or high concentrations of factor VIII, emicizumab’s low affinity to the targets will not result in any significant action anymore,” he said. “So I think we have to wait for more data from basic research and also more clinical data.”
Regarding concern for duration of therapy, Dr. Tiede explained that, when treating breakthrough bleeding in a patient on non–factor replacement therapy, “the patient’s hemostatic protection level will never fall to zero, as it would have done in a patient treated previously, on demand with bypassing agents only.” Since hemostatic protection levels never return to zero, it is easier to enter the thromboembolic danger zone.
This risk was recently demonstrated by an emerging non-factor replacement therapy. In a phase 3 trial for fitusiran – a small interfering RNA therapy that targets antithrombin – a patient with hemophilia A developed a breakthrough bleed and 31-46 IU/kg of factor VIII was given, resulting in fatal cerebral sinus thrombosis. After a temporary hold, the study restarted with new limits on factor and bypassing agent doses.
Dr. Tiede reported financial relationships with Bayer, Biotest, CSL Behring, Novo Nordisk, Pfizer, and other companies.
PRAGUE – Clinicians should prioritize treatment duration with factors or bypassing agents – not dose level – when managing breakthrough bleeds in patients with hemophilia who are on non–factor replacement therapy, according to a leading expert.
Duration of treatment is more strongly associated with thromboembolism than dose magnitude, said Andreas Tiede, MD, PhD, head of hemostaseology at Hannover (Germany) Medical School in Germany, noting that recommendations vary by non–factor replacement agent.
These remarks were part of a presentation about novel agents for treatment of hemophilia with inhibitors delivered at the annual congress of the European Association for Haemophilia and Allied Disorders.
“Concomitant use of factor products, both factor VIII and IX, and the bypassing agents, have usually preceded thromboembolic events in clinical trials [for non–factor replacement therapies] so this [topic] is crucial,” Dr. Tiede said.
Other experts recommend lower doses and shorter treatment durations. “I think that’s reasonable, but with some question mark behind the low doses,” he said. “I think it depends a little bit on the interaction between the non–factor replacement therapy and the bypassing agent in your patient.”
With a busy pipeline of non–factor replacement agents for hemophilia, such interactions are becoming increasingly relevant for clinicians and their patients.
Emicizumab, for instance, which is now approved for hemophilia with or without inhibitors, has synergistic activity with activated prothrombin complex concentrates (APCC). This was demonstrated by an emicizumab prophylaxis trial in which five out of eight patients with breakthrough bleeding who were treated with APPC at a dose higher than 100 IU/kg per day for more than 24 hours developed thrombotic microangiopathy. (N Engl J Med. 2017;377:809-18).
Other patients who received multiple infusions of APCC developed skin necrosis, cavernous vein thrombosis, and thrombophlebitis. Consequently, it is now recommended that APCC be avoided in patients taking emicizumab, and if unavoidable, given at the lowest dose possible. However, Dr. Tiede advised that this recommendation for APCC should not be extrapolated to encompass all factors and bypassing agents, based on existing data.
“Regarding higher or lower doses for initial treatment, I would be a little bit more careful,” he said. “That obviously depends on [whether] there is a synergistic effect with the non–factor replacement therapy and the bypassing agent. Synergistic effects have clearly been shown for the interaction of emicizumab and APCC, but when it comes to the interaction between emicizumab and VIIa, I’m not so sure. I don’t think that we have enough evidence to recommend lower doses of VIIa.”
Dr. Tiede also suggested that lower doses of factor VIII are probably unnecessary. “At high doses or high concentrations of factor VIII, emicizumab’s low affinity to the targets will not result in any significant action anymore,” he said. “So I think we have to wait for more data from basic research and also more clinical data.”
Regarding concern for duration of therapy, Dr. Tiede explained that, when treating breakthrough bleeding in a patient on non–factor replacement therapy, “the patient’s hemostatic protection level will never fall to zero, as it would have done in a patient treated previously, on demand with bypassing agents only.” Since hemostatic protection levels never return to zero, it is easier to enter the thromboembolic danger zone.
This risk was recently demonstrated by an emerging non-factor replacement therapy. In a phase 3 trial for fitusiran – a small interfering RNA therapy that targets antithrombin – a patient with hemophilia A developed a breakthrough bleed and 31-46 IU/kg of factor VIII was given, resulting in fatal cerebral sinus thrombosis. After a temporary hold, the study restarted with new limits on factor and bypassing agent doses.
Dr. Tiede reported financial relationships with Bayer, Biotest, CSL Behring, Novo Nordisk, Pfizer, and other companies.
PRAGUE – Clinicians should prioritize treatment duration with factors or bypassing agents – not dose level – when managing breakthrough bleeds in patients with hemophilia who are on non–factor replacement therapy, according to a leading expert.
Duration of treatment is more strongly associated with thromboembolism than dose magnitude, said Andreas Tiede, MD, PhD, head of hemostaseology at Hannover (Germany) Medical School in Germany, noting that recommendations vary by non–factor replacement agent.
These remarks were part of a presentation about novel agents for treatment of hemophilia with inhibitors delivered at the annual congress of the European Association for Haemophilia and Allied Disorders.
“Concomitant use of factor products, both factor VIII and IX, and the bypassing agents, have usually preceded thromboembolic events in clinical trials [for non–factor replacement therapies] so this [topic] is crucial,” Dr. Tiede said.
Other experts recommend lower doses and shorter treatment durations. “I think that’s reasonable, but with some question mark behind the low doses,” he said. “I think it depends a little bit on the interaction between the non–factor replacement therapy and the bypassing agent in your patient.”
With a busy pipeline of non–factor replacement agents for hemophilia, such interactions are becoming increasingly relevant for clinicians and their patients.
Emicizumab, for instance, which is now approved for hemophilia with or without inhibitors, has synergistic activity with activated prothrombin complex concentrates (APCC). This was demonstrated by an emicizumab prophylaxis trial in which five out of eight patients with breakthrough bleeding who were treated with APPC at a dose higher than 100 IU/kg per day for more than 24 hours developed thrombotic microangiopathy. (N Engl J Med. 2017;377:809-18).
Other patients who received multiple infusions of APCC developed skin necrosis, cavernous vein thrombosis, and thrombophlebitis. Consequently, it is now recommended that APCC be avoided in patients taking emicizumab, and if unavoidable, given at the lowest dose possible. However, Dr. Tiede advised that this recommendation for APCC should not be extrapolated to encompass all factors and bypassing agents, based on existing data.
“Regarding higher or lower doses for initial treatment, I would be a little bit more careful,” he said. “That obviously depends on [whether] there is a synergistic effect with the non–factor replacement therapy and the bypassing agent. Synergistic effects have clearly been shown for the interaction of emicizumab and APCC, but when it comes to the interaction between emicizumab and VIIa, I’m not so sure. I don’t think that we have enough evidence to recommend lower doses of VIIa.”
Dr. Tiede also suggested that lower doses of factor VIII are probably unnecessary. “At high doses or high concentrations of factor VIII, emicizumab’s low affinity to the targets will not result in any significant action anymore,” he said. “So I think we have to wait for more data from basic research and also more clinical data.”
Regarding concern for duration of therapy, Dr. Tiede explained that, when treating breakthrough bleeding in a patient on non–factor replacement therapy, “the patient’s hemostatic protection level will never fall to zero, as it would have done in a patient treated previously, on demand with bypassing agents only.” Since hemostatic protection levels never return to zero, it is easier to enter the thromboembolic danger zone.
This risk was recently demonstrated by an emerging non-factor replacement therapy. In a phase 3 trial for fitusiran – a small interfering RNA therapy that targets antithrombin – a patient with hemophilia A developed a breakthrough bleed and 31-46 IU/kg of factor VIII was given, resulting in fatal cerebral sinus thrombosis. After a temporary hold, the study restarted with new limits on factor and bypassing agent doses.
Dr. Tiede reported financial relationships with Bayer, Biotest, CSL Behring, Novo Nordisk, Pfizer, and other companies.
EXPERT ANALYSIS FROM EAHAD 2019