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LCAR-B38M CAR T therapy appears durable in myeloma
SAN DIEGO – The chimeric antigen receptor (CAR) T-cell therapy LCAR-B38M is in the race for approval in multiple myeloma following encouraging phase 1 results reported at the annual meeting of the American Society of Hematology.
In the LEGEND-2 phase 1/2 open study of 57 patients with advanced relapsed/refractory multiple myeloma treated with the investigational CAR T therapy, the overall response rate was 88% and the complete response rate was 74%. Among 42 patients who achieved complete response, 39 (68%) were negative for minimal residual disease (MRD).
With a median follow-up of 12 months, the median duration of response was 16 months and progression-free survival was 15 months. But in patients who achieved MRD-negative complete response, the median progression-free survival was extended to 24 months.
Pyrexia and cytokine release syndrome were reported in 90% or more of patients. Thrombocytopenia and leukopenia were reported in nearly half of patients.
The phase 1 study was conducted by researchers from the Second Affiliated Hospital of Xi’an Jiaotong University in Xi’an, China. The B-cell maturation antigen (BCMA)–directed CAR T-cell therapy is being jointly developed by Nanjing Legend Biotech and Janssen. A phase 2 study is currently being planned in China for LCAR-B38M. In parallel, Janssen and Legend are enrolling patients in a phase 1b/2 trial of the agent (also known as JNJ-68284528) in the United States.
The therapy joins a growing field of anti-BCMA CAR T-cell agents with promising initial trial results, including bb2121.
In a video interview at ASH, Sen Zhuang, MD, PhD, vice president of oncology clinical development at Janssen Research & Development, said this class of CAR T agents offers the potential for “very long remissions” and possibly even a “cure” for myeloma.
The LEGEND-2 study is sponsored by Nanjing Legend Biotech and two of the investigators reported employment with the company.
SAN DIEGO – The chimeric antigen receptor (CAR) T-cell therapy LCAR-B38M is in the race for approval in multiple myeloma following encouraging phase 1 results reported at the annual meeting of the American Society of Hematology.
In the LEGEND-2 phase 1/2 open study of 57 patients with advanced relapsed/refractory multiple myeloma treated with the investigational CAR T therapy, the overall response rate was 88% and the complete response rate was 74%. Among 42 patients who achieved complete response, 39 (68%) were negative for minimal residual disease (MRD).
With a median follow-up of 12 months, the median duration of response was 16 months and progression-free survival was 15 months. But in patients who achieved MRD-negative complete response, the median progression-free survival was extended to 24 months.
Pyrexia and cytokine release syndrome were reported in 90% or more of patients. Thrombocytopenia and leukopenia were reported in nearly half of patients.
The phase 1 study was conducted by researchers from the Second Affiliated Hospital of Xi’an Jiaotong University in Xi’an, China. The B-cell maturation antigen (BCMA)–directed CAR T-cell therapy is being jointly developed by Nanjing Legend Biotech and Janssen. A phase 2 study is currently being planned in China for LCAR-B38M. In parallel, Janssen and Legend are enrolling patients in a phase 1b/2 trial of the agent (also known as JNJ-68284528) in the United States.
The therapy joins a growing field of anti-BCMA CAR T-cell agents with promising initial trial results, including bb2121.
In a video interview at ASH, Sen Zhuang, MD, PhD, vice president of oncology clinical development at Janssen Research & Development, said this class of CAR T agents offers the potential for “very long remissions” and possibly even a “cure” for myeloma.
The LEGEND-2 study is sponsored by Nanjing Legend Biotech and two of the investigators reported employment with the company.
SAN DIEGO – The chimeric antigen receptor (CAR) T-cell therapy LCAR-B38M is in the race for approval in multiple myeloma following encouraging phase 1 results reported at the annual meeting of the American Society of Hematology.
In the LEGEND-2 phase 1/2 open study of 57 patients with advanced relapsed/refractory multiple myeloma treated with the investigational CAR T therapy, the overall response rate was 88% and the complete response rate was 74%. Among 42 patients who achieved complete response, 39 (68%) were negative for minimal residual disease (MRD).
With a median follow-up of 12 months, the median duration of response was 16 months and progression-free survival was 15 months. But in patients who achieved MRD-negative complete response, the median progression-free survival was extended to 24 months.
Pyrexia and cytokine release syndrome were reported in 90% or more of patients. Thrombocytopenia and leukopenia were reported in nearly half of patients.
The phase 1 study was conducted by researchers from the Second Affiliated Hospital of Xi’an Jiaotong University in Xi’an, China. The B-cell maturation antigen (BCMA)–directed CAR T-cell therapy is being jointly developed by Nanjing Legend Biotech and Janssen. A phase 2 study is currently being planned in China for LCAR-B38M. In parallel, Janssen and Legend are enrolling patients in a phase 1b/2 trial of the agent (also known as JNJ-68284528) in the United States.
The therapy joins a growing field of anti-BCMA CAR T-cell agents with promising initial trial results, including bb2121.
In a video interview at ASH, Sen Zhuang, MD, PhD, vice president of oncology clinical development at Janssen Research & Development, said this class of CAR T agents offers the potential for “very long remissions” and possibly even a “cure” for myeloma.
The LEGEND-2 study is sponsored by Nanjing Legend Biotech and two of the investigators reported employment with the company.
REPORTING FROM ASH 2018
Key clinical point:
Major finding: The complete response rate was 74% with median progression-free survival of 15 months.
Study details: A phase 1/2 study of 57 patients with advanced relapsed/refractory multiple myeloma.
Disclosures: The study is sponsored by Nanjing Legend Biotech. Two of the investigators reported employment with the company.
2018: A banner year for hematology drug approvals
SAN DIEGO – It was banner year for new hematology drug approvals, according to R. Angelo de Claro, MD, of the Food and Drug Administration.
, including 12 first-time approvals, 5 new biosimilars, and 15 new indications for previously approved drugs, Dr. de Claro, clinical team leader in the FDA’s division of hematology products in Silver Spring, Md., said during an overview of the approvals at the annual meeting of the American Society of Hematology.
These include six new approvals for first-line treatment, and eight for pediatric indications, he said.
Highlights were discussed at two ASH-FDA joint symposia at the meeting, including one focused on the malignant hematology approvals, and another on the nonmalignant hematology approvals. In a video interview, Dr. de Claro provides some additional insight into their importance and about what might lie ahead.
“I think what’s exciting is that you have drug development occurring in more common conditions such as chronic lymphocytic leukemia, as well as in rare conditions, including hairy cell leukemia – and the first-ever approval in hemophagocytic lymphohistiocytosis,” he said. “It’s been very busy at the FDA; stay tuned ... the year’s not done yet. There could be more coming and we certainly anticipate more applications in the future.”
Dr. de Claro is an FDA employee. He reported having no other relevant disclosures.
SAN DIEGO – It was banner year for new hematology drug approvals, according to R. Angelo de Claro, MD, of the Food and Drug Administration.
, including 12 first-time approvals, 5 new biosimilars, and 15 new indications for previously approved drugs, Dr. de Claro, clinical team leader in the FDA’s division of hematology products in Silver Spring, Md., said during an overview of the approvals at the annual meeting of the American Society of Hematology.
These include six new approvals for first-line treatment, and eight for pediatric indications, he said.
Highlights were discussed at two ASH-FDA joint symposia at the meeting, including one focused on the malignant hematology approvals, and another on the nonmalignant hematology approvals. In a video interview, Dr. de Claro provides some additional insight into their importance and about what might lie ahead.
“I think what’s exciting is that you have drug development occurring in more common conditions such as chronic lymphocytic leukemia, as well as in rare conditions, including hairy cell leukemia – and the first-ever approval in hemophagocytic lymphohistiocytosis,” he said. “It’s been very busy at the FDA; stay tuned ... the year’s not done yet. There could be more coming and we certainly anticipate more applications in the future.”
Dr. de Claro is an FDA employee. He reported having no other relevant disclosures.
SAN DIEGO – It was banner year for new hematology drug approvals, according to R. Angelo de Claro, MD, of the Food and Drug Administration.
, including 12 first-time approvals, 5 new biosimilars, and 15 new indications for previously approved drugs, Dr. de Claro, clinical team leader in the FDA’s division of hematology products in Silver Spring, Md., said during an overview of the approvals at the annual meeting of the American Society of Hematology.
These include six new approvals for first-line treatment, and eight for pediatric indications, he said.
Highlights were discussed at two ASH-FDA joint symposia at the meeting, including one focused on the malignant hematology approvals, and another on the nonmalignant hematology approvals. In a video interview, Dr. de Claro provides some additional insight into their importance and about what might lie ahead.
“I think what’s exciting is that you have drug development occurring in more common conditions such as chronic lymphocytic leukemia, as well as in rare conditions, including hairy cell leukemia – and the first-ever approval in hemophagocytic lymphohistiocytosis,” he said. “It’s been very busy at the FDA; stay tuned ... the year’s not done yet. There could be more coming and we certainly anticipate more applications in the future.”
Dr. de Claro is an FDA employee. He reported having no other relevant disclosures.
REPORTING FROM ASH 2018
Phase 3 study confirms biosimilarity of PF-05280586 with rituximab
SAN DIEGO – The potential rituximab biosimilar drug PF-05280586 showed efficacy, safety, immunogenicity, pharmacokinetics, and pharmacodynamics similar to those of rituximab at up to 26 weeks in a randomized phase 3 study of treatment-naive patients with CD20-positive low tumor burden follicular lymphoma (LTB-FL).
The primary endpoint of overall response rate at 26 weeks was 75.5% in 196 patients randomized to receive PF-05280586, and 70.7% in 198 patients who received a rituximab reference product sourced from the European Union (MabThera; rituximab‑EU), Jeff Sharman, MD, reported at the annual meeting of the American Society of Hematology.
“This resulted in a difference between the two arms of 4.66%,” said Dr. Sharman of Willamette Valley Cancer Institute and Research Center, Springfield, Ore.
The 95% confidence interval for this difference ... was entirely contained within the prespecified equivalence margin, he said.
“Depth of response was a key secondary endpoint, and rates of complete response were 29.3% and 30.4%, respectively,” he said, noting that rates of partial response, stable response, and progressive disease were also similar between the two study arms.
Estimated 1-year progression-free survival (PFS) rates were also highly similar at 76.4% and 81.2% in the PF-05280586 and rituximab-EU arms.
Rapid depletion in CD19-positive B-cell counts was observed in both groups after initial dosing, with recovery by week 39 and a sustained increase until the end of week 52.
Treatment-emergent adverse events (TEAEs) occurred in 78.6% vs. 72.1% of patients in the PF‑05280586 vs. rituximab‑EU arms, respectively, and the rates of serious adverse events and grade 3 events were similar in the groups, as were rates of infusion interruptions or infusion-related reactions (IRRs), Dr. Sharman said.
IRRs occurred in about 25% of patients in each arm, and most were grade 1 or 2. Grade 3 IRRs occurred in 2.6% vs. 0.5% of patients in the groups, respectively, and no grade 4 IRRs occurred.
Rates of anti-drug antibodies were also similar in the two groups, as were serum drug concentrations – regardless of anti-drug antibody status, he noted.
Study subjects were adults with a mean age of 60 years and histologically confirmed CD20-positive grade 1-3a follicular lymphoma with no prior rituximab or system therapy for B-cell non-Hodgkin lymphoma (NHL). They had Ann Arbor disease stages II (26.9%), III (44.2%) or IV (28.9%), ECOG performance status of 0-1, and at least 1 measurable disease lesion identifiable on imaging.
Risk level as assessed by the Follicular Lymphoma International Prognostic Index–2 was low in 28.4%, medium in 66%, and high in 5.6% of patients.
Treatment with each agent was given at intravenous doses of 375 mg/m2 weekly for 4 weeks at days 1, 8, 15, and 22.
PF-05280586 is being developed by Pfizer, and in this 52-week double-blind study – the largest study to date of the early use of the potential rituximab biosimilar in patients with previously untreated CD20-positive LTB-FL – the primary endpoint was met, demonstrating its therapeutic equivalence with rituximab-EU for overall response rate at week 26, Dr. Sharman said.
“These results therefore confirm the biosimilarity of PF-05280586 with rituximab-EU,” he concluded.
Of note, the reporting of these findings comes on the heels of the first Food and Drug Administration approval of a biosimilar rituximab product for the treatment of NHL; Celltrion’s product Truxima (formerly CT-P10), a biosimilar of Genentech’s Rituxan (rituximab), was approved Nov. 28 to treat adults with CD20-positive, B-cell NHL, either as a single agent or in combination with chemotherapy.
The PF-0528056 study was sponsored by Pfizer. Dr. Sharman has been a consultant for, and/or received research funding and honoraria from Acerta, Pharmacyclics (an AbbVie Company), Pfizer, TG Therapeutics, Abbvie, and Genentech.
SOURCE: Sharman J et al. ASH 2018: Abstract 394.
SAN DIEGO – The potential rituximab biosimilar drug PF-05280586 showed efficacy, safety, immunogenicity, pharmacokinetics, and pharmacodynamics similar to those of rituximab at up to 26 weeks in a randomized phase 3 study of treatment-naive patients with CD20-positive low tumor burden follicular lymphoma (LTB-FL).
The primary endpoint of overall response rate at 26 weeks was 75.5% in 196 patients randomized to receive PF-05280586, and 70.7% in 198 patients who received a rituximab reference product sourced from the European Union (MabThera; rituximab‑EU), Jeff Sharman, MD, reported at the annual meeting of the American Society of Hematology.
“This resulted in a difference between the two arms of 4.66%,” said Dr. Sharman of Willamette Valley Cancer Institute and Research Center, Springfield, Ore.
The 95% confidence interval for this difference ... was entirely contained within the prespecified equivalence margin, he said.
“Depth of response was a key secondary endpoint, and rates of complete response were 29.3% and 30.4%, respectively,” he said, noting that rates of partial response, stable response, and progressive disease were also similar between the two study arms.
Estimated 1-year progression-free survival (PFS) rates were also highly similar at 76.4% and 81.2% in the PF-05280586 and rituximab-EU arms.
Rapid depletion in CD19-positive B-cell counts was observed in both groups after initial dosing, with recovery by week 39 and a sustained increase until the end of week 52.
Treatment-emergent adverse events (TEAEs) occurred in 78.6% vs. 72.1% of patients in the PF‑05280586 vs. rituximab‑EU arms, respectively, and the rates of serious adverse events and grade 3 events were similar in the groups, as were rates of infusion interruptions or infusion-related reactions (IRRs), Dr. Sharman said.
IRRs occurred in about 25% of patients in each arm, and most were grade 1 or 2. Grade 3 IRRs occurred in 2.6% vs. 0.5% of patients in the groups, respectively, and no grade 4 IRRs occurred.
Rates of anti-drug antibodies were also similar in the two groups, as were serum drug concentrations – regardless of anti-drug antibody status, he noted.
Study subjects were adults with a mean age of 60 years and histologically confirmed CD20-positive grade 1-3a follicular lymphoma with no prior rituximab or system therapy for B-cell non-Hodgkin lymphoma (NHL). They had Ann Arbor disease stages II (26.9%), III (44.2%) or IV (28.9%), ECOG performance status of 0-1, and at least 1 measurable disease lesion identifiable on imaging.
Risk level as assessed by the Follicular Lymphoma International Prognostic Index–2 was low in 28.4%, medium in 66%, and high in 5.6% of patients.
Treatment with each agent was given at intravenous doses of 375 mg/m2 weekly for 4 weeks at days 1, 8, 15, and 22.
PF-05280586 is being developed by Pfizer, and in this 52-week double-blind study – the largest study to date of the early use of the potential rituximab biosimilar in patients with previously untreated CD20-positive LTB-FL – the primary endpoint was met, demonstrating its therapeutic equivalence with rituximab-EU for overall response rate at week 26, Dr. Sharman said.
“These results therefore confirm the biosimilarity of PF-05280586 with rituximab-EU,” he concluded.
Of note, the reporting of these findings comes on the heels of the first Food and Drug Administration approval of a biosimilar rituximab product for the treatment of NHL; Celltrion’s product Truxima (formerly CT-P10), a biosimilar of Genentech’s Rituxan (rituximab), was approved Nov. 28 to treat adults with CD20-positive, B-cell NHL, either as a single agent or in combination with chemotherapy.
The PF-0528056 study was sponsored by Pfizer. Dr. Sharman has been a consultant for, and/or received research funding and honoraria from Acerta, Pharmacyclics (an AbbVie Company), Pfizer, TG Therapeutics, Abbvie, and Genentech.
SOURCE: Sharman J et al. ASH 2018: Abstract 394.
SAN DIEGO – The potential rituximab biosimilar drug PF-05280586 showed efficacy, safety, immunogenicity, pharmacokinetics, and pharmacodynamics similar to those of rituximab at up to 26 weeks in a randomized phase 3 study of treatment-naive patients with CD20-positive low tumor burden follicular lymphoma (LTB-FL).
The primary endpoint of overall response rate at 26 weeks was 75.5% in 196 patients randomized to receive PF-05280586, and 70.7% in 198 patients who received a rituximab reference product sourced from the European Union (MabThera; rituximab‑EU), Jeff Sharman, MD, reported at the annual meeting of the American Society of Hematology.
“This resulted in a difference between the two arms of 4.66%,” said Dr. Sharman of Willamette Valley Cancer Institute and Research Center, Springfield, Ore.
The 95% confidence interval for this difference ... was entirely contained within the prespecified equivalence margin, he said.
“Depth of response was a key secondary endpoint, and rates of complete response were 29.3% and 30.4%, respectively,” he said, noting that rates of partial response, stable response, and progressive disease were also similar between the two study arms.
Estimated 1-year progression-free survival (PFS) rates were also highly similar at 76.4% and 81.2% in the PF-05280586 and rituximab-EU arms.
Rapid depletion in CD19-positive B-cell counts was observed in both groups after initial dosing, with recovery by week 39 and a sustained increase until the end of week 52.
Treatment-emergent adverse events (TEAEs) occurred in 78.6% vs. 72.1% of patients in the PF‑05280586 vs. rituximab‑EU arms, respectively, and the rates of serious adverse events and grade 3 events were similar in the groups, as were rates of infusion interruptions or infusion-related reactions (IRRs), Dr. Sharman said.
IRRs occurred in about 25% of patients in each arm, and most were grade 1 or 2. Grade 3 IRRs occurred in 2.6% vs. 0.5% of patients in the groups, respectively, and no grade 4 IRRs occurred.
Rates of anti-drug antibodies were also similar in the two groups, as were serum drug concentrations – regardless of anti-drug antibody status, he noted.
Study subjects were adults with a mean age of 60 years and histologically confirmed CD20-positive grade 1-3a follicular lymphoma with no prior rituximab or system therapy for B-cell non-Hodgkin lymphoma (NHL). They had Ann Arbor disease stages II (26.9%), III (44.2%) or IV (28.9%), ECOG performance status of 0-1, and at least 1 measurable disease lesion identifiable on imaging.
Risk level as assessed by the Follicular Lymphoma International Prognostic Index–2 was low in 28.4%, medium in 66%, and high in 5.6% of patients.
Treatment with each agent was given at intravenous doses of 375 mg/m2 weekly for 4 weeks at days 1, 8, 15, and 22.
PF-05280586 is being developed by Pfizer, and in this 52-week double-blind study – the largest study to date of the early use of the potential rituximab biosimilar in patients with previously untreated CD20-positive LTB-FL – the primary endpoint was met, demonstrating its therapeutic equivalence with rituximab-EU for overall response rate at week 26, Dr. Sharman said.
“These results therefore confirm the biosimilarity of PF-05280586 with rituximab-EU,” he concluded.
Of note, the reporting of these findings comes on the heels of the first Food and Drug Administration approval of a biosimilar rituximab product for the treatment of NHL; Celltrion’s product Truxima (formerly CT-P10), a biosimilar of Genentech’s Rituxan (rituximab), was approved Nov. 28 to treat adults with CD20-positive, B-cell NHL, either as a single agent or in combination with chemotherapy.
The PF-0528056 study was sponsored by Pfizer. Dr. Sharman has been a consultant for, and/or received research funding and honoraria from Acerta, Pharmacyclics (an AbbVie Company), Pfizer, TG Therapeutics, Abbvie, and Genentech.
SOURCE: Sharman J et al. ASH 2018: Abstract 394.
REPORTING FROM ASH 2018
Key clinical point: PF-05280586 shows biosimilarity to rituximab at up to 26 weeks.
Major finding: ORR at 26 weeks was 75.5% vs. 70.7% with PF-05280586 vs. rituximab, respectively.
Study details: A phase 3 study of 394 patients.
Disclosures: This study was sponsored by Pfizer. Dr. Sharman has been a consultant for, and/or received research funding and honoraria from Acerta, Pharmacyclics (an AbbVie Company), Pfizer, TG Therapeutics, Abbvie, and Genentech.
Source: Sharman J et al. ASH 2018: Abstract 394.
Factor IX expression stable at up to 8 years with gene therapy
SAN DIEGO – according to interim follow-up data from a phase 1/2 dose-escalation study.
The therapy – a self-complementary adeno-associated virus vector containing a codon-optimized factor IX gene, under control of a synthetic liver specific promoter and pseudotyped with serotype 8 capsid (scAAV2/8-LP1-hFIXco) – was previously shown to result in a dose-dependent increase in plasma factor IX levels in all 10 patients enrolled in the study, and an earlier update showed stable factor IX activity for at least 3 years, Ulrike M. Reiss, MD, reported at the annual meeting of the American Society of Hematology.
However, declining factor IX expression over time remains a concern, because AAV-mediated transgene expression is mediated mainly by episomally retained viral genomes, which may be lost with natural turnover of hepatocytes, noted Dr. Reiss, director of the clinical hematology division and the Hemophilia Treatment Center at St. Jude Children’s Research Hospital in Memphis.
At the “halfway mark,” with a median follow-up of 6.7 years in 10 patients aged 18-64 years who were treated with doses of either 2 x 1011, 6 x 1011, or 2 x 1012 vector genomes per kg (in 2, 2, and 6 patients, respectively), “factor IX expression has been persistent and stable in all participants after vector infusion,” she said.
“Factor IX expression was vector-dose dependent, achieving average levels of 1.9%-2.3% at the lower doses, and 5.1% at the high vector dose. All patients converted from having severe hemophilia to mild-moderate hemophilia,” she added.
The single significant adverse event observed during annual follow-up evaluations in the patients was a vector-related, immune-mediated liver inflammation occurring within 2-3 months of infusion in four of the six high-dose participants.
“There was complete resolution in all cases after a short course of corticosteroids over 8-12 weeks, including the taper. There were no late sequelae or any recurrence of transaminitis over time,” Dr. Reiss said. “We did not observe any new factor IX inhibitor or any late toxicity in any of these participants.”
Additionally, a comparison of average data across 3 years prior to gene therapy with the average data at 6.7 years after gene therapy showed that the annualized bleed rate decreased by 82% in the 10 participants and factor IX use decreased by 66%. In the high-dose group, the bleed rate decreased from 21 bleeds to 2 bleeds per year, and vector consumption was markedly reduced to a mean of 500 IU/kg per year from a mean of more than 2800 IU/kg per year. “Only one of the six patients in the high-dose group currently continues on prophylaxis treatment, whereas three in the low- and mid-dose groups are currently on prophylaxis,” she said. “In all [patients], the interval between prophylactic infusions has lengthened.”
Of note, Dr. Reiss and her colleagues explored the ability of using a modified, empty capsid-reduced vector preparation of the gene therapy to prevent the transaminitis seen in the 2-3 months after infusion. A new clinical preparation of scAAV2/8-LP1-hFIXco was manufactured with most of the empty particles removed by cesium chloride density centrifugation, but this approach provided no benefit in that regard.
“This further supports the observation that the anticapsid immune response is vector-dose dependent,” she said.
Additionally, the pattern of humoral response to AAV8 capsid was consistent with the primary immune response in participants.
“High IgG antibody titers have persisted for over 6 years; this finding is important because it will preclude these patients from any retreatment with the same vector or even potentially alternative AAV vectors of other serotypes with cross-reactive antigenicity,” she said.
Dr. Reiss reported having no relevant disclosures
SOURCE: Reiss UM et al. ASH 2018, Abstract 491.
SAN DIEGO – according to interim follow-up data from a phase 1/2 dose-escalation study.
The therapy – a self-complementary adeno-associated virus vector containing a codon-optimized factor IX gene, under control of a synthetic liver specific promoter and pseudotyped with serotype 8 capsid (scAAV2/8-LP1-hFIXco) – was previously shown to result in a dose-dependent increase in plasma factor IX levels in all 10 patients enrolled in the study, and an earlier update showed stable factor IX activity for at least 3 years, Ulrike M. Reiss, MD, reported at the annual meeting of the American Society of Hematology.
However, declining factor IX expression over time remains a concern, because AAV-mediated transgene expression is mediated mainly by episomally retained viral genomes, which may be lost with natural turnover of hepatocytes, noted Dr. Reiss, director of the clinical hematology division and the Hemophilia Treatment Center at St. Jude Children’s Research Hospital in Memphis.
At the “halfway mark,” with a median follow-up of 6.7 years in 10 patients aged 18-64 years who were treated with doses of either 2 x 1011, 6 x 1011, or 2 x 1012 vector genomes per kg (in 2, 2, and 6 patients, respectively), “factor IX expression has been persistent and stable in all participants after vector infusion,” she said.
“Factor IX expression was vector-dose dependent, achieving average levels of 1.9%-2.3% at the lower doses, and 5.1% at the high vector dose. All patients converted from having severe hemophilia to mild-moderate hemophilia,” she added.
The single significant adverse event observed during annual follow-up evaluations in the patients was a vector-related, immune-mediated liver inflammation occurring within 2-3 months of infusion in four of the six high-dose participants.
“There was complete resolution in all cases after a short course of corticosteroids over 8-12 weeks, including the taper. There were no late sequelae or any recurrence of transaminitis over time,” Dr. Reiss said. “We did not observe any new factor IX inhibitor or any late toxicity in any of these participants.”
Additionally, a comparison of average data across 3 years prior to gene therapy with the average data at 6.7 years after gene therapy showed that the annualized bleed rate decreased by 82% in the 10 participants and factor IX use decreased by 66%. In the high-dose group, the bleed rate decreased from 21 bleeds to 2 bleeds per year, and vector consumption was markedly reduced to a mean of 500 IU/kg per year from a mean of more than 2800 IU/kg per year. “Only one of the six patients in the high-dose group currently continues on prophylaxis treatment, whereas three in the low- and mid-dose groups are currently on prophylaxis,” she said. “In all [patients], the interval between prophylactic infusions has lengthened.”
Of note, Dr. Reiss and her colleagues explored the ability of using a modified, empty capsid-reduced vector preparation of the gene therapy to prevent the transaminitis seen in the 2-3 months after infusion. A new clinical preparation of scAAV2/8-LP1-hFIXco was manufactured with most of the empty particles removed by cesium chloride density centrifugation, but this approach provided no benefit in that regard.
“This further supports the observation that the anticapsid immune response is vector-dose dependent,” she said.
Additionally, the pattern of humoral response to AAV8 capsid was consistent with the primary immune response in participants.
“High IgG antibody titers have persisted for over 6 years; this finding is important because it will preclude these patients from any retreatment with the same vector or even potentially alternative AAV vectors of other serotypes with cross-reactive antigenicity,” she said.
Dr. Reiss reported having no relevant disclosures
SOURCE: Reiss UM et al. ASH 2018, Abstract 491.
SAN DIEGO – according to interim follow-up data from a phase 1/2 dose-escalation study.
The therapy – a self-complementary adeno-associated virus vector containing a codon-optimized factor IX gene, under control of a synthetic liver specific promoter and pseudotyped with serotype 8 capsid (scAAV2/8-LP1-hFIXco) – was previously shown to result in a dose-dependent increase in plasma factor IX levels in all 10 patients enrolled in the study, and an earlier update showed stable factor IX activity for at least 3 years, Ulrike M. Reiss, MD, reported at the annual meeting of the American Society of Hematology.
However, declining factor IX expression over time remains a concern, because AAV-mediated transgene expression is mediated mainly by episomally retained viral genomes, which may be lost with natural turnover of hepatocytes, noted Dr. Reiss, director of the clinical hematology division and the Hemophilia Treatment Center at St. Jude Children’s Research Hospital in Memphis.
At the “halfway mark,” with a median follow-up of 6.7 years in 10 patients aged 18-64 years who were treated with doses of either 2 x 1011, 6 x 1011, or 2 x 1012 vector genomes per kg (in 2, 2, and 6 patients, respectively), “factor IX expression has been persistent and stable in all participants after vector infusion,” she said.
“Factor IX expression was vector-dose dependent, achieving average levels of 1.9%-2.3% at the lower doses, and 5.1% at the high vector dose. All patients converted from having severe hemophilia to mild-moderate hemophilia,” she added.
The single significant adverse event observed during annual follow-up evaluations in the patients was a vector-related, immune-mediated liver inflammation occurring within 2-3 months of infusion in four of the six high-dose participants.
“There was complete resolution in all cases after a short course of corticosteroids over 8-12 weeks, including the taper. There were no late sequelae or any recurrence of transaminitis over time,” Dr. Reiss said. “We did not observe any new factor IX inhibitor or any late toxicity in any of these participants.”
Additionally, a comparison of average data across 3 years prior to gene therapy with the average data at 6.7 years after gene therapy showed that the annualized bleed rate decreased by 82% in the 10 participants and factor IX use decreased by 66%. In the high-dose group, the bleed rate decreased from 21 bleeds to 2 bleeds per year, and vector consumption was markedly reduced to a mean of 500 IU/kg per year from a mean of more than 2800 IU/kg per year. “Only one of the six patients in the high-dose group currently continues on prophylaxis treatment, whereas three in the low- and mid-dose groups are currently on prophylaxis,” she said. “In all [patients], the interval between prophylactic infusions has lengthened.”
Of note, Dr. Reiss and her colleagues explored the ability of using a modified, empty capsid-reduced vector preparation of the gene therapy to prevent the transaminitis seen in the 2-3 months after infusion. A new clinical preparation of scAAV2/8-LP1-hFIXco was manufactured with most of the empty particles removed by cesium chloride density centrifugation, but this approach provided no benefit in that regard.
“This further supports the observation that the anticapsid immune response is vector-dose dependent,” she said.
Additionally, the pattern of humoral response to AAV8 capsid was consistent with the primary immune response in participants.
“High IgG antibody titers have persisted for over 6 years; this finding is important because it will preclude these patients from any retreatment with the same vector or even potentially alternative AAV vectors of other serotypes with cross-reactive antigenicity,” she said.
Dr. Reiss reported having no relevant disclosures
SOURCE: Reiss UM et al. ASH 2018, Abstract 491.
REPORTING FROM ASH 2018
Key clinical point: With a median follow-up of 6.7 years in 10 patients aged 18-64 years who were treated with scAAV2/8-LP1-hFIX–comediated gene therapy, factor IX expression has been persistent and stable.
Major finding: Factor IX expression averaged 1.9%-2.3% at the lower doses, and 5.1% at the high dose at up to 8.6 years.
Study details: An interim follow-up data for 10 patients in a phase 1/2 study.
Disclosures: Dr. Reiss reported having no disclosures.
Source: Reiss UM et al. ASH 2018, Abstract 491.
CLL resistance mechanism to venetoclax identified
SAN DIEGO – A recurrent mutation in BCL2, the therapeutic target of venetoclax (Venclexta), appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.
The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, said lead author Piers Blombery, MBBS, from the Peter MacCallum Cancer Center in Melbourne.
“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said in a late-breaking oral abstract session at the annual meeting of the American Society of Hematology.
The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” he added.
The paper was published online in Cancer Discovery (2018 Dec 4. doi: 10.1158/2159-8290.CD-18-1119) to coincide with the presentation at ASH.
Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.
To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.
In seven of the patients, they identified a novel mutation that showed up at the time of progression, but was absent from the pre-venetoclax samples. The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.
They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found that the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies. Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.
In other experiments, they determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and that in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage, compared with wild type cells.
Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.
“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.
In an interview, Dr. Blombery said that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.
The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation. Dr. Blombery reported having no relevant disclosures.
SOURCE: Blombery P et al. ASH 2018, Abstract LBA-7.
SAN DIEGO – A recurrent mutation in BCL2, the therapeutic target of venetoclax (Venclexta), appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.
The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, said lead author Piers Blombery, MBBS, from the Peter MacCallum Cancer Center in Melbourne.
“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said in a late-breaking oral abstract session at the annual meeting of the American Society of Hematology.
The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” he added.
The paper was published online in Cancer Discovery (2018 Dec 4. doi: 10.1158/2159-8290.CD-18-1119) to coincide with the presentation at ASH.
Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.
To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.
In seven of the patients, they identified a novel mutation that showed up at the time of progression, but was absent from the pre-venetoclax samples. The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.
They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found that the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies. Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.
In other experiments, they determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and that in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage, compared with wild type cells.
Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.
“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.
In an interview, Dr. Blombery said that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.
The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation. Dr. Blombery reported having no relevant disclosures.
SOURCE: Blombery P et al. ASH 2018, Abstract LBA-7.
SAN DIEGO – A recurrent mutation in BCL2, the therapeutic target of venetoclax (Venclexta), appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.
The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, said lead author Piers Blombery, MBBS, from the Peter MacCallum Cancer Center in Melbourne.
“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said in a late-breaking oral abstract session at the annual meeting of the American Society of Hematology.
The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” he added.
The paper was published online in Cancer Discovery (2018 Dec 4. doi: 10.1158/2159-8290.CD-18-1119) to coincide with the presentation at ASH.
Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.
To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.
In seven of the patients, they identified a novel mutation that showed up at the time of progression, but was absent from the pre-venetoclax samples. The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.
They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found that the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies. Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.
In other experiments, they determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and that in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage, compared with wild type cells.
Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.
“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.
In an interview, Dr. Blombery said that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.
The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation. Dr. Blombery reported having no relevant disclosures.
SOURCE: Blombery P et al. ASH 2018, Abstract LBA-7.
REPORTING FROM ASH 2018
Key clinical point:
Major finding: The mutation was identified in samples from seven patients after venetoclax therapy, but not in any of the pretherapy samples.
Study details: Genetic analysis of CLL mutations in 15 patients enrolled in clinical trials of venetoclax.
Disclosures: The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation. Dr. Blombery reported having no relevant disclosures.
Source: Blombery P et al. ASH 2018, Abstract LBA-7.
In IDH-mutated AML, first-line IDH inhibitors plus chemo may boost remission
SAN DIEGO – In patients with newly diagnosed acute myeloid leukemia (AML) bearing IDH1 or IDH2 mutations, combinations of either ivosidenib (Tibsovo, for IDH1) or enasidenib (Idhifa, for IDH2) with standard induction and consolidation regimens are safe and well tolerated and are associated with encouraging remission rates, results of a phase 1 trial indicate.
In the open-label, phase 1 trial, ivosidenib plus chemotherapy was associated with elimination of minimal residual disease (MRD) by flow cytometry in 88% of treated patients and with IDH1-mutation clearance in 41% of patients.
Enasidenib plus chemotherapy was associated with elimination of MRD in 45% of patients and with IDH2-mutation clearance in 25% of patients, said Eytan M. Stein, MD, from Memorial Sloan Kettering Cancer Center in New York.
“The overall survival rates are robust, with greater than 75% 1-year survival in both ivosidenib- and enasidenib-treated patients,” he said at the annual meeting of the American Society of Hematology.
Both ivosidenib and enasidenib are approved in the United States for treatment of patients with relapsed or refractory AML bearing either IDH1 or IDH2 mutations, respectively. In this trial, the investigators explored the therapeutic potential of the IDH inhibitors in patients with previously untreated disease.
Dr. Stein and his colleagues investigated combining each of the agents with standard induction therapy with either daunorubicin 60 mg/m2 per day or idarubicin 12 mg/m2 per day for 3 days, plus cytarabine 200 mg/m2 per day for 7 days. Patients with IDH1 mutations received ivosidenib 500 mg once daily, and those with IDH2 mutations received enasidenib 100 mg once daily.
After induction, patients with a complete remission (CR), CR with incomplete recovery of hematologic counts (CRi), or CR with incomplete recovery of platelets (CRp) could receive up to four cycles of consolidation therapy while continuing the IDH inhibitor. Patients who completed consolidation or were ineligible for consolidation could continue on maintenance therapy with their assigned drug until the end of the study.
The drugs were discontinued in patients who went on to hematopoietic stem cell transplant.
The most frequent co-occurring baseline mutations were DNMT3A, NPM1, and NRAS for patients with IDH1 mutations, and DNMT3A, SRSF2, and ASXL1 for patients with IDH2 mutations.
A total of 60 patients were assigned to ivosidenib and chemotherapy and 93 were assigned to enasidenib/chemotherapy. The median patient age was about 63 years in each arm.
All patients in each arm received a least one induction dose and about 48% in each arm received at least some consolidation dosing. In all, 18% of patients in the ivosidenib arm and 19% in the enasidenib arm went on to maintenance.
Treatment discontinuations occurred in 55% of patients in the ivosidenib group and 84% in the enasidenib group. The primary reason for discontinuation included HSCT, adverse events, progressive disease, and death (one and four patients in the respective arms).
Adverse events of interest, regardless of attribution, included the IDH differentiation syndrome in two patients on ivosidenib and one on enasidenib, leukocytosis, QT interval prolongation, and increased blood bilirubin.
The 30-day and 60-day mortality rates were 5% and 8% in the ivosidenib arm and 5% and 9% in the enasidenib arm, respectively.
Best overall response rates (CR+CRi+CRp) among all patients were 80% in the ivosidenib arm and 72% in the enasidenib arm. In each trial arm, the response rates were higher among patients with de novo AML, compared with secondary AML.
Of 12 ivosidenib-treated patients who had IDH1-mutation clearance, 10 had clearance at the end of induction therapy, and 2 achieved clearance during or after consolidation. Of 15 ivosidenib-treated patients who became MRD negative, 12 had achieved it by the end of induction, and 3 became MRD negative during consolidation.
In the enasidenib arm, 15 patients had IDH2 mutation clearance (11 after induction, 4 during consolidation) and 9 became MRD negative (7 after induction and 2 during or after consolidation).
The probability of surviving to 1 year after the start of induction among ivosidenib-treated patients was 79%; the median overall survival had not been reached and was not estimable at the time of data cutoff. The probability of surviving to 1 year among patients in the enasidenib arm was 75%. In this group, too, median overall survival had not been reached.
The clinical benefit of adding either IDH inhibitor to induction, consolidation, and maintenance therapy for patients with newly diagnosed AML with IDH mutations will be further evaluated in a randomized, phase 3 trial, Dr. Stein said.
The study was funded by Agios Pharmaceuticals and Celgene. Dr. Stein reported consulting with those companies and others.
SOURCE: Stein EM et al. ASH 2018, Abstract 560.
SAN DIEGO – In patients with newly diagnosed acute myeloid leukemia (AML) bearing IDH1 or IDH2 mutations, combinations of either ivosidenib (Tibsovo, for IDH1) or enasidenib (Idhifa, for IDH2) with standard induction and consolidation regimens are safe and well tolerated and are associated with encouraging remission rates, results of a phase 1 trial indicate.
In the open-label, phase 1 trial, ivosidenib plus chemotherapy was associated with elimination of minimal residual disease (MRD) by flow cytometry in 88% of treated patients and with IDH1-mutation clearance in 41% of patients.
Enasidenib plus chemotherapy was associated with elimination of MRD in 45% of patients and with IDH2-mutation clearance in 25% of patients, said Eytan M. Stein, MD, from Memorial Sloan Kettering Cancer Center in New York.
“The overall survival rates are robust, with greater than 75% 1-year survival in both ivosidenib- and enasidenib-treated patients,” he said at the annual meeting of the American Society of Hematology.
Both ivosidenib and enasidenib are approved in the United States for treatment of patients with relapsed or refractory AML bearing either IDH1 or IDH2 mutations, respectively. In this trial, the investigators explored the therapeutic potential of the IDH inhibitors in patients with previously untreated disease.
Dr. Stein and his colleagues investigated combining each of the agents with standard induction therapy with either daunorubicin 60 mg/m2 per day or idarubicin 12 mg/m2 per day for 3 days, plus cytarabine 200 mg/m2 per day for 7 days. Patients with IDH1 mutations received ivosidenib 500 mg once daily, and those with IDH2 mutations received enasidenib 100 mg once daily.
After induction, patients with a complete remission (CR), CR with incomplete recovery of hematologic counts (CRi), or CR with incomplete recovery of platelets (CRp) could receive up to four cycles of consolidation therapy while continuing the IDH inhibitor. Patients who completed consolidation or were ineligible for consolidation could continue on maintenance therapy with their assigned drug until the end of the study.
The drugs were discontinued in patients who went on to hematopoietic stem cell transplant.
The most frequent co-occurring baseline mutations were DNMT3A, NPM1, and NRAS for patients with IDH1 mutations, and DNMT3A, SRSF2, and ASXL1 for patients with IDH2 mutations.
A total of 60 patients were assigned to ivosidenib and chemotherapy and 93 were assigned to enasidenib/chemotherapy. The median patient age was about 63 years in each arm.
All patients in each arm received a least one induction dose and about 48% in each arm received at least some consolidation dosing. In all, 18% of patients in the ivosidenib arm and 19% in the enasidenib arm went on to maintenance.
Treatment discontinuations occurred in 55% of patients in the ivosidenib group and 84% in the enasidenib group. The primary reason for discontinuation included HSCT, adverse events, progressive disease, and death (one and four patients in the respective arms).
Adverse events of interest, regardless of attribution, included the IDH differentiation syndrome in two patients on ivosidenib and one on enasidenib, leukocytosis, QT interval prolongation, and increased blood bilirubin.
The 30-day and 60-day mortality rates were 5% and 8% in the ivosidenib arm and 5% and 9% in the enasidenib arm, respectively.
Best overall response rates (CR+CRi+CRp) among all patients were 80% in the ivosidenib arm and 72% in the enasidenib arm. In each trial arm, the response rates were higher among patients with de novo AML, compared with secondary AML.
Of 12 ivosidenib-treated patients who had IDH1-mutation clearance, 10 had clearance at the end of induction therapy, and 2 achieved clearance during or after consolidation. Of 15 ivosidenib-treated patients who became MRD negative, 12 had achieved it by the end of induction, and 3 became MRD negative during consolidation.
In the enasidenib arm, 15 patients had IDH2 mutation clearance (11 after induction, 4 during consolidation) and 9 became MRD negative (7 after induction and 2 during or after consolidation).
The probability of surviving to 1 year after the start of induction among ivosidenib-treated patients was 79%; the median overall survival had not been reached and was not estimable at the time of data cutoff. The probability of surviving to 1 year among patients in the enasidenib arm was 75%. In this group, too, median overall survival had not been reached.
The clinical benefit of adding either IDH inhibitor to induction, consolidation, and maintenance therapy for patients with newly diagnosed AML with IDH mutations will be further evaluated in a randomized, phase 3 trial, Dr. Stein said.
The study was funded by Agios Pharmaceuticals and Celgene. Dr. Stein reported consulting with those companies and others.
SOURCE: Stein EM et al. ASH 2018, Abstract 560.
SAN DIEGO – In patients with newly diagnosed acute myeloid leukemia (AML) bearing IDH1 or IDH2 mutations, combinations of either ivosidenib (Tibsovo, for IDH1) or enasidenib (Idhifa, for IDH2) with standard induction and consolidation regimens are safe and well tolerated and are associated with encouraging remission rates, results of a phase 1 trial indicate.
In the open-label, phase 1 trial, ivosidenib plus chemotherapy was associated with elimination of minimal residual disease (MRD) by flow cytometry in 88% of treated patients and with IDH1-mutation clearance in 41% of patients.
Enasidenib plus chemotherapy was associated with elimination of MRD in 45% of patients and with IDH2-mutation clearance in 25% of patients, said Eytan M. Stein, MD, from Memorial Sloan Kettering Cancer Center in New York.
“The overall survival rates are robust, with greater than 75% 1-year survival in both ivosidenib- and enasidenib-treated patients,” he said at the annual meeting of the American Society of Hematology.
Both ivosidenib and enasidenib are approved in the United States for treatment of patients with relapsed or refractory AML bearing either IDH1 or IDH2 mutations, respectively. In this trial, the investigators explored the therapeutic potential of the IDH inhibitors in patients with previously untreated disease.
Dr. Stein and his colleagues investigated combining each of the agents with standard induction therapy with either daunorubicin 60 mg/m2 per day or idarubicin 12 mg/m2 per day for 3 days, plus cytarabine 200 mg/m2 per day for 7 days. Patients with IDH1 mutations received ivosidenib 500 mg once daily, and those with IDH2 mutations received enasidenib 100 mg once daily.
After induction, patients with a complete remission (CR), CR with incomplete recovery of hematologic counts (CRi), or CR with incomplete recovery of platelets (CRp) could receive up to four cycles of consolidation therapy while continuing the IDH inhibitor. Patients who completed consolidation or were ineligible for consolidation could continue on maintenance therapy with their assigned drug until the end of the study.
The drugs were discontinued in patients who went on to hematopoietic stem cell transplant.
The most frequent co-occurring baseline mutations were DNMT3A, NPM1, and NRAS for patients with IDH1 mutations, and DNMT3A, SRSF2, and ASXL1 for patients with IDH2 mutations.
A total of 60 patients were assigned to ivosidenib and chemotherapy and 93 were assigned to enasidenib/chemotherapy. The median patient age was about 63 years in each arm.
All patients in each arm received a least one induction dose and about 48% in each arm received at least some consolidation dosing. In all, 18% of patients in the ivosidenib arm and 19% in the enasidenib arm went on to maintenance.
Treatment discontinuations occurred in 55% of patients in the ivosidenib group and 84% in the enasidenib group. The primary reason for discontinuation included HSCT, adverse events, progressive disease, and death (one and four patients in the respective arms).
Adverse events of interest, regardless of attribution, included the IDH differentiation syndrome in two patients on ivosidenib and one on enasidenib, leukocytosis, QT interval prolongation, and increased blood bilirubin.
The 30-day and 60-day mortality rates were 5% and 8% in the ivosidenib arm and 5% and 9% in the enasidenib arm, respectively.
Best overall response rates (CR+CRi+CRp) among all patients were 80% in the ivosidenib arm and 72% in the enasidenib arm. In each trial arm, the response rates were higher among patients with de novo AML, compared with secondary AML.
Of 12 ivosidenib-treated patients who had IDH1-mutation clearance, 10 had clearance at the end of induction therapy, and 2 achieved clearance during or after consolidation. Of 15 ivosidenib-treated patients who became MRD negative, 12 had achieved it by the end of induction, and 3 became MRD negative during consolidation.
In the enasidenib arm, 15 patients had IDH2 mutation clearance (11 after induction, 4 during consolidation) and 9 became MRD negative (7 after induction and 2 during or after consolidation).
The probability of surviving to 1 year after the start of induction among ivosidenib-treated patients was 79%; the median overall survival had not been reached and was not estimable at the time of data cutoff. The probability of surviving to 1 year among patients in the enasidenib arm was 75%. In this group, too, median overall survival had not been reached.
The clinical benefit of adding either IDH inhibitor to induction, consolidation, and maintenance therapy for patients with newly diagnosed AML with IDH mutations will be further evaluated in a randomized, phase 3 trial, Dr. Stein said.
The study was funded by Agios Pharmaceuticals and Celgene. Dr. Stein reported consulting with those companies and others.
SOURCE: Stein EM et al. ASH 2018, Abstract 560.
REPORTING FROM ASH 2018
Key clinical point: The IDH1 inhibitor ivosidenib and IDH2 inhibitor enasidenib combined with induction and consolidation therapy showed promising efficacy against newly diagnosed acute myeloid leukemia.
Major finding: The 1-year survival rates were greater than 75% for patients with previously untreated acute myeloid leukemia who received either of the IDH-mutated inhibitors.
Study details: An open-label, prospective trial in 153 patients with newly diagnosed acute myeloid leukemia.
Disclosures: The study was funded by Agios Pharmaceuticals and Celgene. Dr. Stein reported consulting with those companies and others.
Source: Stein EM et al. ASH 2018, Abstract 560.
DOAC pause yields favorable outcomes for AF patients
San Diego – In patients with atrial fibrillation who had direct oral anticoagulant (DOAC) interruption for an elective surgery, a simple and standardized management strategy yielded low rates of bleeding and thromboembolism, according to results of a prospective study of more than 3,000 patients.
Rates of major bleeding were less than 2% and rates of arterial thromboembolism were less than 1% in patients managed in accordance with the strategy, which foregoes heparin bridging and preoperative coagulation testing, according to investigator James D. Douketis, MD, of St. Joseph’s Healthcare and McMaster University, Hamilton, Ont.
“This is the first study to demonstrate the safety of a standardized perioperative management approach in a patients with atrial fibrillation who are taking a DOAC, and we hope will establish a standard and will have an effect on our clinical practice guidelines,” Dr. Douketis said during a press briefing at the annual meeting of the American Society of Hematology.
This trial offers the “most definitive evidence to date” that atrial fibrillation patients can – in an organized fashion based on bleeding risk – safely stop taking DOACs, said Mark Crowther, MD, chair and professor of medicine at McMaster University.
“This study will almost instantaneously establish a treatment practice and a treatment standard for the vast number of patients in North America and around the world who take these drugs,” added Dr. Crowther, who moderated the press briefing.
The PAUSE study included three parallel cohorts of atrial fibrillation patients taking DOACs (apixaban, dabigatran, or rivaroxaban) who required anticoagulant interruption for an elective surgery or procedure.
The DOAC interruptions were done using standardized protocols based on the pharmacokinetic properties of each DOAC, procedure-associated bleeding risk, and creatinine clearance, the investigators reported.
The interruptions occurred 1 day before and after low bleeding risk surgeries, and 2 days before and after high bleeding risk surgeries, while longer interruptions were used in patients receiving dabigatran who had a creatinine clearance below 50 mL/min.
A total of 3,007 patients at 23 sites in Canada, the United States, and Europe were managed by this approach in the PAUSE study – 1,257 patients receiving apixaban, 668 receiving dabigatran, and 1,082 receiving rivaroxaban – and were evaluated weekly for 30 days post-procedure.
PAUSE is the largest study to date that addresses how to manage the common problem of perioperative DOAC management. It is likely to have a practice-changing impact and will inform future practice guidelines in perioperative care.
The 30-day postoperative rate of major bleeding was low, according to investigators, at 1.35% (95% confidence interval, 0-2.00%) for apixaban, 0.90% (95% CI, 0-1.73%) for dabigatran, and 1.85% (95% CI, 0-2.65%) for rivaroxaban, Dr. Douketis reported.
Likewise, the rate of arterial thromboembolism was low at 0.16% (95% CI, 0-0.48%) for apixaban, 0.6% (95% CI, 0-1.33%) for dabigatran, and 0.37% (95% CI, 0-0.82%) for rivaroxaban, he said.
Most patients (greater than 90%) had minimal to no residual DOAC levels at the time of surgery, the investigator added.
The study was funded by the Canadian Institutes of Health Research and the H&S Foundation of Canada. Dr. Douketis reported disclosures related to Janssen, which makes rivaroxaban; Boehringer-Ingelheim, which makes dabigatran; and other companies. Dr. Crowther reported financial relationships with Bristol-Myers Squibb and other companies.
SOURCE: Douketis J et al. ASH 2018, Abstract LBA-5.
San Diego – In patients with atrial fibrillation who had direct oral anticoagulant (DOAC) interruption for an elective surgery, a simple and standardized management strategy yielded low rates of bleeding and thromboembolism, according to results of a prospective study of more than 3,000 patients.
Rates of major bleeding were less than 2% and rates of arterial thromboembolism were less than 1% in patients managed in accordance with the strategy, which foregoes heparin bridging and preoperative coagulation testing, according to investigator James D. Douketis, MD, of St. Joseph’s Healthcare and McMaster University, Hamilton, Ont.
“This is the first study to demonstrate the safety of a standardized perioperative management approach in a patients with atrial fibrillation who are taking a DOAC, and we hope will establish a standard and will have an effect on our clinical practice guidelines,” Dr. Douketis said during a press briefing at the annual meeting of the American Society of Hematology.
This trial offers the “most definitive evidence to date” that atrial fibrillation patients can – in an organized fashion based on bleeding risk – safely stop taking DOACs, said Mark Crowther, MD, chair and professor of medicine at McMaster University.
“This study will almost instantaneously establish a treatment practice and a treatment standard for the vast number of patients in North America and around the world who take these drugs,” added Dr. Crowther, who moderated the press briefing.
The PAUSE study included three parallel cohorts of atrial fibrillation patients taking DOACs (apixaban, dabigatran, or rivaroxaban) who required anticoagulant interruption for an elective surgery or procedure.
The DOAC interruptions were done using standardized protocols based on the pharmacokinetic properties of each DOAC, procedure-associated bleeding risk, and creatinine clearance, the investigators reported.
The interruptions occurred 1 day before and after low bleeding risk surgeries, and 2 days before and after high bleeding risk surgeries, while longer interruptions were used in patients receiving dabigatran who had a creatinine clearance below 50 mL/min.
A total of 3,007 patients at 23 sites in Canada, the United States, and Europe were managed by this approach in the PAUSE study – 1,257 patients receiving apixaban, 668 receiving dabigatran, and 1,082 receiving rivaroxaban – and were evaluated weekly for 30 days post-procedure.
PAUSE is the largest study to date that addresses how to manage the common problem of perioperative DOAC management. It is likely to have a practice-changing impact and will inform future practice guidelines in perioperative care.
The 30-day postoperative rate of major bleeding was low, according to investigators, at 1.35% (95% confidence interval, 0-2.00%) for apixaban, 0.90% (95% CI, 0-1.73%) for dabigatran, and 1.85% (95% CI, 0-2.65%) for rivaroxaban, Dr. Douketis reported.
Likewise, the rate of arterial thromboembolism was low at 0.16% (95% CI, 0-0.48%) for apixaban, 0.6% (95% CI, 0-1.33%) for dabigatran, and 0.37% (95% CI, 0-0.82%) for rivaroxaban, he said.
Most patients (greater than 90%) had minimal to no residual DOAC levels at the time of surgery, the investigator added.
The study was funded by the Canadian Institutes of Health Research and the H&S Foundation of Canada. Dr. Douketis reported disclosures related to Janssen, which makes rivaroxaban; Boehringer-Ingelheim, which makes dabigatran; and other companies. Dr. Crowther reported financial relationships with Bristol-Myers Squibb and other companies.
SOURCE: Douketis J et al. ASH 2018, Abstract LBA-5.
San Diego – In patients with atrial fibrillation who had direct oral anticoagulant (DOAC) interruption for an elective surgery, a simple and standardized management strategy yielded low rates of bleeding and thromboembolism, according to results of a prospective study of more than 3,000 patients.
Rates of major bleeding were less than 2% and rates of arterial thromboembolism were less than 1% in patients managed in accordance with the strategy, which foregoes heparin bridging and preoperative coagulation testing, according to investigator James D. Douketis, MD, of St. Joseph’s Healthcare and McMaster University, Hamilton, Ont.
“This is the first study to demonstrate the safety of a standardized perioperative management approach in a patients with atrial fibrillation who are taking a DOAC, and we hope will establish a standard and will have an effect on our clinical practice guidelines,” Dr. Douketis said during a press briefing at the annual meeting of the American Society of Hematology.
This trial offers the “most definitive evidence to date” that atrial fibrillation patients can – in an organized fashion based on bleeding risk – safely stop taking DOACs, said Mark Crowther, MD, chair and professor of medicine at McMaster University.
“This study will almost instantaneously establish a treatment practice and a treatment standard for the vast number of patients in North America and around the world who take these drugs,” added Dr. Crowther, who moderated the press briefing.
The PAUSE study included three parallel cohorts of atrial fibrillation patients taking DOACs (apixaban, dabigatran, or rivaroxaban) who required anticoagulant interruption for an elective surgery or procedure.
The DOAC interruptions were done using standardized protocols based on the pharmacokinetic properties of each DOAC, procedure-associated bleeding risk, and creatinine clearance, the investigators reported.
The interruptions occurred 1 day before and after low bleeding risk surgeries, and 2 days before and after high bleeding risk surgeries, while longer interruptions were used in patients receiving dabigatran who had a creatinine clearance below 50 mL/min.
A total of 3,007 patients at 23 sites in Canada, the United States, and Europe were managed by this approach in the PAUSE study – 1,257 patients receiving apixaban, 668 receiving dabigatran, and 1,082 receiving rivaroxaban – and were evaluated weekly for 30 days post-procedure.
PAUSE is the largest study to date that addresses how to manage the common problem of perioperative DOAC management. It is likely to have a practice-changing impact and will inform future practice guidelines in perioperative care.
The 30-day postoperative rate of major bleeding was low, according to investigators, at 1.35% (95% confidence interval, 0-2.00%) for apixaban, 0.90% (95% CI, 0-1.73%) for dabigatran, and 1.85% (95% CI, 0-2.65%) for rivaroxaban, Dr. Douketis reported.
Likewise, the rate of arterial thromboembolism was low at 0.16% (95% CI, 0-0.48%) for apixaban, 0.6% (95% CI, 0-1.33%) for dabigatran, and 0.37% (95% CI, 0-0.82%) for rivaroxaban, he said.
Most patients (greater than 90%) had minimal to no residual DOAC levels at the time of surgery, the investigator added.
The study was funded by the Canadian Institutes of Health Research and the H&S Foundation of Canada. Dr. Douketis reported disclosures related to Janssen, which makes rivaroxaban; Boehringer-Ingelheim, which makes dabigatran; and other companies. Dr. Crowther reported financial relationships with Bristol-Myers Squibb and other companies.
SOURCE: Douketis J et al. ASH 2018, Abstract LBA-5.
REPORTING FROM ASH 2018
Key clinical point:
Major finding: The 30-day postoperative rate of major bleeding was 1.35% (95% CI, 0-2.00%) for apixaban, 0.90% (95% CI, 0-1.73%) for dabigatran, and 1.85% (95% CI, 0-2.65%) for rivaroxaban.
Study details: A prospective study of more than 3,000 subjects with atrial fibrillation who underwent DOAC interruption due to an elective surgery or procedure.
Disclosures: The study was funded by the Canadian Institutes of Health Research and H&S Foundation of Canada. Dr. Douketis reported disclosures related to Janssen, which makes rivaroxaban; Boehringer-Ingelheim, which makes dabigatran; and other companies.
Source: Douketis J et al. ASH 2018, Abstract LBA-5.
Sickle cell disease guidelines release set for early 2019
, according to Robert Liem, MD, chair of the American Society of Hematology coordination panel for the initiative.
The new clinical practice recommendations will expand on 2014 guidelines published by the National Heart, Lung, and Blood Institute in a way that will help both hematologists and nonhematologists who take care of patients with sickle cell disease, Dr. Liem said in a video interview at the annual meeting of the American Society of Hematology.
Five different guidelines are under development to cover different aspects of acute and chronic complications of sickle cell disease, including pain, cardiopulmonary and kidney disease, cerebrovascular disease, transfusion support, and stem cell transplantation.
Watch the video to learn more about the guideline effort from the perspective of Dr. Liem, who is also the director of the Comprehensive Sickle Cell Program at the Ann & Robert H. Lurie Children’s Hospital of Chicago.
, according to Robert Liem, MD, chair of the American Society of Hematology coordination panel for the initiative.
The new clinical practice recommendations will expand on 2014 guidelines published by the National Heart, Lung, and Blood Institute in a way that will help both hematologists and nonhematologists who take care of patients with sickle cell disease, Dr. Liem said in a video interview at the annual meeting of the American Society of Hematology.
Five different guidelines are under development to cover different aspects of acute and chronic complications of sickle cell disease, including pain, cardiopulmonary and kidney disease, cerebrovascular disease, transfusion support, and stem cell transplantation.
Watch the video to learn more about the guideline effort from the perspective of Dr. Liem, who is also the director of the Comprehensive Sickle Cell Program at the Ann & Robert H. Lurie Children’s Hospital of Chicago.
, according to Robert Liem, MD, chair of the American Society of Hematology coordination panel for the initiative.
The new clinical practice recommendations will expand on 2014 guidelines published by the National Heart, Lung, and Blood Institute in a way that will help both hematologists and nonhematologists who take care of patients with sickle cell disease, Dr. Liem said in a video interview at the annual meeting of the American Society of Hematology.
Five different guidelines are under development to cover different aspects of acute and chronic complications of sickle cell disease, including pain, cardiopulmonary and kidney disease, cerebrovascular disease, transfusion support, and stem cell transplantation.
Watch the video to learn more about the guideline effort from the perspective of Dr. Liem, who is also the director of the Comprehensive Sickle Cell Program at the Ann & Robert H. Lurie Children’s Hospital of Chicago.
FROM ASH 2018
Emapalumab safe, effective in pediatric primary hemophagocytic lymphohistiocytosis
, according to Franco Locatelli, MD, of the department of pediatric hematology and oncology at Ospedale Pediatrico Bambino Gesù, Rome.
The recently approved agent should be considered a new therapeutic option for this rare and life-threatening syndrome because of its targeted mode of action, Dr. Locatelli and his coinvestigators reported at the annual meeting of the American Society of Hematology.
Multiple lines of evidence have pointed to interferon gamma as a “rational target” in this disease, and elevated levels of interferon gamma are consistently observed in patients with HLH, Dr. Locatelli said in a press conference at the meeting.
Emapalumab binds to its target with high affinity, recognizing both free and receptor-bound interferon gamma, he added.
Primary HLH is a rare, life-threatening syndrome of hyperinflammation, characterized by prolonged fever, cytopenias, and splenomegaly and hepatomegaly, among other clinical manifestations, Dr. Locatelli said.
In the open-label, single-arm, pivotal study, 34 children with primary HLH were treated: 7 who were treatment naive and 27 who had failed conventional HLH therapy.
The patients received emapalumab intravenously with concomitant dexamethasone for up to 8 weeks, or extended to the point of allogeneic hematopoietic stem cell transplantation (HSCT), if needed.
The study met its primary endpoint of overall response rate higher than 40%, Dr. Locatelli reported. The overall response rate was 64.7% for all 34 treated patients (95% confidence interval, 46% to 80%; P = .0031), and 63% for the 27 patients who had failed prior therapy (95% CI, 42% to 81%; P = .0134), reported data show.
Response was rapid, occurring at a median of 8 days after starting emapalumab, and patients were in response for a median of 75% of days during treatment, Dr. Locatelli said.
Common adverse events in the study included infections, infusion-related reactions, pyrexia, and hypertension, while one patient had disseminated histoplasmosis that resolved with appropriate treatment, according to investigators.
In light of these results, the Food and Drug Administration approved emapalumab on Nov. 20, 2018, for the treatment of pediatric and adult patients with primary HLH with refractory, recurrent or progressive disease, or intolerance to conventional HLH treatments.
There is “certainly room for enlarging the indication” to first-line treatment of HLH once a sufficient number of previously untreated patients have been treated with the monoclonal antibody, Dr. Locatelli said.
However, a randomized trial would not be feasible, he said. “It’s a very rare disease, and it would be almost impossible to run a prospective, randomized trial in a reasonable period of time.”
The study described by Dr. Locatelli was sponsored by Novimmune. Study authors provided disclosures related to Sobi, Novimmune, Rocket Pharmaceuticals, Inc., AB2Bio, Novartis, Eli Lilly, Sanofi, UCB, Pfizer, and Abbvie. Two authors reported employment with Novimmune.
SOURCE: Locatelli F et al. ASH 2018; Abstract LBA-6.
, according to Franco Locatelli, MD, of the department of pediatric hematology and oncology at Ospedale Pediatrico Bambino Gesù, Rome.
The recently approved agent should be considered a new therapeutic option for this rare and life-threatening syndrome because of its targeted mode of action, Dr. Locatelli and his coinvestigators reported at the annual meeting of the American Society of Hematology.
Multiple lines of evidence have pointed to interferon gamma as a “rational target” in this disease, and elevated levels of interferon gamma are consistently observed in patients with HLH, Dr. Locatelli said in a press conference at the meeting.
Emapalumab binds to its target with high affinity, recognizing both free and receptor-bound interferon gamma, he added.
Primary HLH is a rare, life-threatening syndrome of hyperinflammation, characterized by prolonged fever, cytopenias, and splenomegaly and hepatomegaly, among other clinical manifestations, Dr. Locatelli said.
In the open-label, single-arm, pivotal study, 34 children with primary HLH were treated: 7 who were treatment naive and 27 who had failed conventional HLH therapy.
The patients received emapalumab intravenously with concomitant dexamethasone for up to 8 weeks, or extended to the point of allogeneic hematopoietic stem cell transplantation (HSCT), if needed.
The study met its primary endpoint of overall response rate higher than 40%, Dr. Locatelli reported. The overall response rate was 64.7% for all 34 treated patients (95% confidence interval, 46% to 80%; P = .0031), and 63% for the 27 patients who had failed prior therapy (95% CI, 42% to 81%; P = .0134), reported data show.
Response was rapid, occurring at a median of 8 days after starting emapalumab, and patients were in response for a median of 75% of days during treatment, Dr. Locatelli said.
Common adverse events in the study included infections, infusion-related reactions, pyrexia, and hypertension, while one patient had disseminated histoplasmosis that resolved with appropriate treatment, according to investigators.
In light of these results, the Food and Drug Administration approved emapalumab on Nov. 20, 2018, for the treatment of pediatric and adult patients with primary HLH with refractory, recurrent or progressive disease, or intolerance to conventional HLH treatments.
There is “certainly room for enlarging the indication” to first-line treatment of HLH once a sufficient number of previously untreated patients have been treated with the monoclonal antibody, Dr. Locatelli said.
However, a randomized trial would not be feasible, he said. “It’s a very rare disease, and it would be almost impossible to run a prospective, randomized trial in a reasonable period of time.”
The study described by Dr. Locatelli was sponsored by Novimmune. Study authors provided disclosures related to Sobi, Novimmune, Rocket Pharmaceuticals, Inc., AB2Bio, Novartis, Eli Lilly, Sanofi, UCB, Pfizer, and Abbvie. Two authors reported employment with Novimmune.
SOURCE: Locatelli F et al. ASH 2018; Abstract LBA-6.
, according to Franco Locatelli, MD, of the department of pediatric hematology and oncology at Ospedale Pediatrico Bambino Gesù, Rome.
The recently approved agent should be considered a new therapeutic option for this rare and life-threatening syndrome because of its targeted mode of action, Dr. Locatelli and his coinvestigators reported at the annual meeting of the American Society of Hematology.
Multiple lines of evidence have pointed to interferon gamma as a “rational target” in this disease, and elevated levels of interferon gamma are consistently observed in patients with HLH, Dr. Locatelli said in a press conference at the meeting.
Emapalumab binds to its target with high affinity, recognizing both free and receptor-bound interferon gamma, he added.
Primary HLH is a rare, life-threatening syndrome of hyperinflammation, characterized by prolonged fever, cytopenias, and splenomegaly and hepatomegaly, among other clinical manifestations, Dr. Locatelli said.
In the open-label, single-arm, pivotal study, 34 children with primary HLH were treated: 7 who were treatment naive and 27 who had failed conventional HLH therapy.
The patients received emapalumab intravenously with concomitant dexamethasone for up to 8 weeks, or extended to the point of allogeneic hematopoietic stem cell transplantation (HSCT), if needed.
The study met its primary endpoint of overall response rate higher than 40%, Dr. Locatelli reported. The overall response rate was 64.7% for all 34 treated patients (95% confidence interval, 46% to 80%; P = .0031), and 63% for the 27 patients who had failed prior therapy (95% CI, 42% to 81%; P = .0134), reported data show.
Response was rapid, occurring at a median of 8 days after starting emapalumab, and patients were in response for a median of 75% of days during treatment, Dr. Locatelli said.
Common adverse events in the study included infections, infusion-related reactions, pyrexia, and hypertension, while one patient had disseminated histoplasmosis that resolved with appropriate treatment, according to investigators.
In light of these results, the Food and Drug Administration approved emapalumab on Nov. 20, 2018, for the treatment of pediatric and adult patients with primary HLH with refractory, recurrent or progressive disease, or intolerance to conventional HLH treatments.
There is “certainly room for enlarging the indication” to first-line treatment of HLH once a sufficient number of previously untreated patients have been treated with the monoclonal antibody, Dr. Locatelli said.
However, a randomized trial would not be feasible, he said. “It’s a very rare disease, and it would be almost impossible to run a prospective, randomized trial in a reasonable period of time.”
The study described by Dr. Locatelli was sponsored by Novimmune. Study authors provided disclosures related to Sobi, Novimmune, Rocket Pharmaceuticals, Inc., AB2Bio, Novartis, Eli Lilly, Sanofi, UCB, Pfizer, and Abbvie. Two authors reported employment with Novimmune.
SOURCE: Locatelli F et al. ASH 2018; Abstract LBA-6.
FROM ASH 2018
Key clinical point: Emapalumab, an interferon gamma-blocking antibody, controls disease activity and has a favorable safety profile in patients with primary hemophagocytic lymphohistiocytosis.
Major finding: The overall response rate was 64.7% for all 34 treated patients (95% CI, 46%-80%; P = .0031), and 63% for the 27 patients who had failed prior therapy (95% CI, 42%-81%; P = .0134).
Study details: In the open-label, single-arm, pivotal study, 34 children with primary HLH were treated: 7 who were treatment naive and 27 who had failed conventional HLH therapy.
Disclosures: The study described by Dr. Locatelli was sponsored by Novimmune. Study authors provided disclosures related to Sobi, Novimmune, Rocket Pharmaceuticals, AB2Bio, Novartis, Eli Lilly, Sanofi, UCB, Pfizer, and Abbvie. Two authors reported employment with Novimmune.
Source: Locatelli F et al. ASH 2018; Abstract LBA-6.
Lower-dose rituximab may be enough in acquired TTP
SAN DIEGO – Lower-than-usual doses of rituximab may be sufficient in patients with acquired thrombotic thrombocytopenic purpura (TTP), results of a recent pilot safety and efficacy study suggest.
Patients receiving just 100 mg/week for 4 weeks had rates of relapse and exacerbation that were favorable, compared with historical controls, according to investigator Jeffrey I. Zwicker, MD, of Beth Israel Deaconess Medical Center and Harvard Medical School, both in Boston. He presented the findings at the annual meeting of the American Society of Hematology.
However, the low-dose treatment was not without side effects, according to Dr. Zwicker, who described one case of acute respiratory failure out of the 19 patients enrolled in the ART (Adjuvant Rituximab in TTP) study.
“The likely benefit is cost savings, rather than less toxicity,” Dr. Zwicker said of the low-dose rituximab regimen.
Out of 19 patients enrolled in ART, 18 were eligible to receive the study treatment, which included low-dose rituximab plus standard plasma exchange and corticosteroids.
Following this initial therapy, all patients had a response, defined as a platelet count 150,000/mcL or greater for 2 consecutive days, with a median time to response of 5 days.
There were two exacerbations (12%) at 30 days after stopping plasma exchange and no cases of refractory TTP, which compared favorably to historical controls, Dr. Zwicker said.
The rate of relapse at 2 years was 28%, which again compared favorably with a historical control data repository in which the rate of relapse at 2 years was 51%.
One patient in the study suffered a case of acute respiratory failure requiring intubation during the third rituximab infusion and was ultimately placed on extracorporeal membrane oxygenation.
“The patient did survive, but this is just a reminder that there are potential side effects, even with lower doses of rituximab,” Dr. Zwicker said.
A few other serious adverse events – including central line infection and bacteremia in one patient – were more likely related to the plasma exchange, he added.
These results with low-dose rituximab are consistent with findings that rituximab 375 mg/m2 for four doses reduces the incidence of exacerbation and refractory disease and prevents or delays relapses, according to Dr. Zwicker and his coinvestigators, including J. Evan Sadler, MD, PhD, of Washington University, St. Louis, who initiated the study.
The typical TTP regimen of rituximab 375 mg/m2 for four weekly doses is borrowed from protocols for B-cell lymphomas; however, the B-cell mass in nonmalignant disease is likely to be much less than in lymphoproliferative disorders, Dr. Zwicker told attendees.
“The benefit, principally, of lower-dose rituximab is saving of thousands upon thousands of dollars,” Dr. Zwicker said.
This is not the only data set to suggest a potential role for lower-dose rituximab, he added, noting that a recently published retrospective analysis showed “fairly similar” treatment-free survival rates for standard rituximab and a reduced-dose regimen. There also are case series in other autoimmune cytopenias, namely idiopathic thrombocytopenic purpura and pure red cell aplasia, that provide evidence in support of low-dose rituximab, he added.
Dr. Zwicker reported research funding with Incyte and Quercegen, and consultancy with Parexel. Dr. Sadler reported consultancy with Ablynx.
SOURCE: Zwicker JI et al. ASH 2018, Abstract 374.
SAN DIEGO – Lower-than-usual doses of rituximab may be sufficient in patients with acquired thrombotic thrombocytopenic purpura (TTP), results of a recent pilot safety and efficacy study suggest.
Patients receiving just 100 mg/week for 4 weeks had rates of relapse and exacerbation that were favorable, compared with historical controls, according to investigator Jeffrey I. Zwicker, MD, of Beth Israel Deaconess Medical Center and Harvard Medical School, both in Boston. He presented the findings at the annual meeting of the American Society of Hematology.
However, the low-dose treatment was not without side effects, according to Dr. Zwicker, who described one case of acute respiratory failure out of the 19 patients enrolled in the ART (Adjuvant Rituximab in TTP) study.
“The likely benefit is cost savings, rather than less toxicity,” Dr. Zwicker said of the low-dose rituximab regimen.
Out of 19 patients enrolled in ART, 18 were eligible to receive the study treatment, which included low-dose rituximab plus standard plasma exchange and corticosteroids.
Following this initial therapy, all patients had a response, defined as a platelet count 150,000/mcL or greater for 2 consecutive days, with a median time to response of 5 days.
There were two exacerbations (12%) at 30 days after stopping plasma exchange and no cases of refractory TTP, which compared favorably to historical controls, Dr. Zwicker said.
The rate of relapse at 2 years was 28%, which again compared favorably with a historical control data repository in which the rate of relapse at 2 years was 51%.
One patient in the study suffered a case of acute respiratory failure requiring intubation during the third rituximab infusion and was ultimately placed on extracorporeal membrane oxygenation.
“The patient did survive, but this is just a reminder that there are potential side effects, even with lower doses of rituximab,” Dr. Zwicker said.
A few other serious adverse events – including central line infection and bacteremia in one patient – were more likely related to the plasma exchange, he added.
These results with low-dose rituximab are consistent with findings that rituximab 375 mg/m2 for four doses reduces the incidence of exacerbation and refractory disease and prevents or delays relapses, according to Dr. Zwicker and his coinvestigators, including J. Evan Sadler, MD, PhD, of Washington University, St. Louis, who initiated the study.
The typical TTP regimen of rituximab 375 mg/m2 for four weekly doses is borrowed from protocols for B-cell lymphomas; however, the B-cell mass in nonmalignant disease is likely to be much less than in lymphoproliferative disorders, Dr. Zwicker told attendees.
“The benefit, principally, of lower-dose rituximab is saving of thousands upon thousands of dollars,” Dr. Zwicker said.
This is not the only data set to suggest a potential role for lower-dose rituximab, he added, noting that a recently published retrospective analysis showed “fairly similar” treatment-free survival rates for standard rituximab and a reduced-dose regimen. There also are case series in other autoimmune cytopenias, namely idiopathic thrombocytopenic purpura and pure red cell aplasia, that provide evidence in support of low-dose rituximab, he added.
Dr. Zwicker reported research funding with Incyte and Quercegen, and consultancy with Parexel. Dr. Sadler reported consultancy with Ablynx.
SOURCE: Zwicker JI et al. ASH 2018, Abstract 374.
SAN DIEGO – Lower-than-usual doses of rituximab may be sufficient in patients with acquired thrombotic thrombocytopenic purpura (TTP), results of a recent pilot safety and efficacy study suggest.
Patients receiving just 100 mg/week for 4 weeks had rates of relapse and exacerbation that were favorable, compared with historical controls, according to investigator Jeffrey I. Zwicker, MD, of Beth Israel Deaconess Medical Center and Harvard Medical School, both in Boston. He presented the findings at the annual meeting of the American Society of Hematology.
However, the low-dose treatment was not without side effects, according to Dr. Zwicker, who described one case of acute respiratory failure out of the 19 patients enrolled in the ART (Adjuvant Rituximab in TTP) study.
“The likely benefit is cost savings, rather than less toxicity,” Dr. Zwicker said of the low-dose rituximab regimen.
Out of 19 patients enrolled in ART, 18 were eligible to receive the study treatment, which included low-dose rituximab plus standard plasma exchange and corticosteroids.
Following this initial therapy, all patients had a response, defined as a platelet count 150,000/mcL or greater for 2 consecutive days, with a median time to response of 5 days.
There were two exacerbations (12%) at 30 days after stopping plasma exchange and no cases of refractory TTP, which compared favorably to historical controls, Dr. Zwicker said.
The rate of relapse at 2 years was 28%, which again compared favorably with a historical control data repository in which the rate of relapse at 2 years was 51%.
One patient in the study suffered a case of acute respiratory failure requiring intubation during the third rituximab infusion and was ultimately placed on extracorporeal membrane oxygenation.
“The patient did survive, but this is just a reminder that there are potential side effects, even with lower doses of rituximab,” Dr. Zwicker said.
A few other serious adverse events – including central line infection and bacteremia in one patient – were more likely related to the plasma exchange, he added.
These results with low-dose rituximab are consistent with findings that rituximab 375 mg/m2 for four doses reduces the incidence of exacerbation and refractory disease and prevents or delays relapses, according to Dr. Zwicker and his coinvestigators, including J. Evan Sadler, MD, PhD, of Washington University, St. Louis, who initiated the study.
The typical TTP regimen of rituximab 375 mg/m2 for four weekly doses is borrowed from protocols for B-cell lymphomas; however, the B-cell mass in nonmalignant disease is likely to be much less than in lymphoproliferative disorders, Dr. Zwicker told attendees.
“The benefit, principally, of lower-dose rituximab is saving of thousands upon thousands of dollars,” Dr. Zwicker said.
This is not the only data set to suggest a potential role for lower-dose rituximab, he added, noting that a recently published retrospective analysis showed “fairly similar” treatment-free survival rates for standard rituximab and a reduced-dose regimen. There also are case series in other autoimmune cytopenias, namely idiopathic thrombocytopenic purpura and pure red cell aplasia, that provide evidence in support of low-dose rituximab, he added.
Dr. Zwicker reported research funding with Incyte and Quercegen, and consultancy with Parexel. Dr. Sadler reported consultancy with Ablynx.
SOURCE: Zwicker JI et al. ASH 2018, Abstract 374.
REPORTING FROM ASH 2018
Key clinical point:
Major finding: After low-dose rituximab plus standard plasma exchange and corticosteroids, the rate of relapse at 2 years was 28%, versus 51% in a historical control data set.
Study details: Findings of the ART (Adjuvant Rituximab in TTP) study including 19 patients with acquired TTP.
Disclosures: Dr. Zwicker reported research funding with Incyte and Quercegen, and consultancy with Parexel. Dr. Sadler reported consultancy with Ablynx.
Source: Zwicker JI et al. ASH 2018, Abstract 374.