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Midostaurin improves survival in new AML
Adding the multitargeted kinase inhibitor midostaurin to standard chemotherapy led to significantly longer overall and event-free survival, compared with placebo and standard chemotherapy in newly diagnosed acute myeloid leukemia (AML) patients with FLT3 gene mutations, according to phase III trial results published in the New England Journal of Medicine.*
About 30% of AML patients have mutations to the FLT3 gene – with three-quarters of those internal tandem duplication (ITD) mutations, which involves duplication of between 3 and 100 amino acids in the juxtamembrane region. These mutations are linked with a high relapse rate and poor prognosis, especially when there is a high ratio of these mutations to wild-type FLT3. About 8% of patients with newly diagnosed AML have an FLT3 point mutation in the tyrosine kinase domain (TKD), but the effect of these on prognosis isn’t clear.
In the trial, called RATIFY and conducted at 225 sites in 17 countries, 360 patients were randomized to the midostaurin group and 357* to placebo, and they were treated from 2008 to 2013. In all, 29.8% of patients were “ITD high,” meaning their ITD FLT3 mutation to wild-type FLT3 ratio was higher than 0.7, and 47.6% were “ITD low,” with a mutation-to-wild-type FLT3 ratio of 0.5 to 0.7. A total of 22.6% of patients had TKD mutations.
Patients received standard induction chemotherapy, with daunorubicine and cytarabine, and on days 8 through 21 either 50 mg of midostaurin or placebo orally twice a day. Patients were given an identical second cycle of induction therapy, with midostaurin or placebo, if they showed definitive clinically significant residual leukemia after the first induction treatment.
Those who achieved complete remission after induction were given 4, 28-day cycles of consolidation treatment, with midostaurin or placebo on days 8 through 21. If they stayed in remission after that, they were given maintenance of 12, 28-day cycles of midostaurin or placebo.
They were not required to receive hematopoetic stem cell transplantation (HSCT), but it was performed at investigator discretion.
Midostaurin improved survival but not rates of complete remission as defined in the trial protocol, researchers reported.
The hazard ratio for death in the midostaurin group was 0.78 (95% CI, 0.63 to 0.96; one-sided P = .0009). The 4-year overall survival rate was 51.4% for the midostaurin group and 44.3% for the placebo group. Midostaurin was shown to benefit all mutation subgroups, but with no greater benefit in one group than another.
Patients in the midostaurin group had a 21.6% lower likelihood of having an event, defined as failure to achieve protocol-defined complete remission, relapse or death without relapse.
There was no significant difference between the groups in complete remission, which under protocol had to occur by day 60.
HSCT was performed in 57% of patients – during the first complete remission in 28.1% of the midostaurin group and in 22.7% during the first complete remission in the placebo group. For those who were transplanted after the first complete remission, no treatment effect was seen.
Researchers noted that there was a therapeutic benefit even among patients with ITD mutations but with a low allelic burden, in whom the disease might be due largely to mutations other than FLT3.
“It is possible that the benefit of midostaurin, which is a multitargeted kinase inhibitor, might lie beyond its ability to inhibit FLT3,” possibly through inhibition of KIT, researchers said.
They also noted that as the trial went on, more and more investigators decided to treat patients with hematopoietic stem cell transplantation, based on newly reported data elsewhere. Since midostaurin was discontinued at the time of transplant, that could have limited exposure to the drug and limited its effect.
*CORRECTION 7/5/2017: An earlier version of this article misstated the number of patients in the placebo group as well as where the study originally appeared.
Adding the multitargeted kinase inhibitor midostaurin to standard chemotherapy led to significantly longer overall and event-free survival, compared with placebo and standard chemotherapy in newly diagnosed acute myeloid leukemia (AML) patients with FLT3 gene mutations, according to phase III trial results published in the New England Journal of Medicine.*
About 30% of AML patients have mutations to the FLT3 gene – with three-quarters of those internal tandem duplication (ITD) mutations, which involves duplication of between 3 and 100 amino acids in the juxtamembrane region. These mutations are linked with a high relapse rate and poor prognosis, especially when there is a high ratio of these mutations to wild-type FLT3. About 8% of patients with newly diagnosed AML have an FLT3 point mutation in the tyrosine kinase domain (TKD), but the effect of these on prognosis isn’t clear.
In the trial, called RATIFY and conducted at 225 sites in 17 countries, 360 patients were randomized to the midostaurin group and 357* to placebo, and they were treated from 2008 to 2013. In all, 29.8% of patients were “ITD high,” meaning their ITD FLT3 mutation to wild-type FLT3 ratio was higher than 0.7, and 47.6% were “ITD low,” with a mutation-to-wild-type FLT3 ratio of 0.5 to 0.7. A total of 22.6% of patients had TKD mutations.
Patients received standard induction chemotherapy, with daunorubicine and cytarabine, and on days 8 through 21 either 50 mg of midostaurin or placebo orally twice a day. Patients were given an identical second cycle of induction therapy, with midostaurin or placebo, if they showed definitive clinically significant residual leukemia after the first induction treatment.
Those who achieved complete remission after induction were given 4, 28-day cycles of consolidation treatment, with midostaurin or placebo on days 8 through 21. If they stayed in remission after that, they were given maintenance of 12, 28-day cycles of midostaurin or placebo.
They were not required to receive hematopoetic stem cell transplantation (HSCT), but it was performed at investigator discretion.
Midostaurin improved survival but not rates of complete remission as defined in the trial protocol, researchers reported.
The hazard ratio for death in the midostaurin group was 0.78 (95% CI, 0.63 to 0.96; one-sided P = .0009). The 4-year overall survival rate was 51.4% for the midostaurin group and 44.3% for the placebo group. Midostaurin was shown to benefit all mutation subgroups, but with no greater benefit in one group than another.
Patients in the midostaurin group had a 21.6% lower likelihood of having an event, defined as failure to achieve protocol-defined complete remission, relapse or death without relapse.
There was no significant difference between the groups in complete remission, which under protocol had to occur by day 60.
HSCT was performed in 57% of patients – during the first complete remission in 28.1% of the midostaurin group and in 22.7% during the first complete remission in the placebo group. For those who were transplanted after the first complete remission, no treatment effect was seen.
Researchers noted that there was a therapeutic benefit even among patients with ITD mutations but with a low allelic burden, in whom the disease might be due largely to mutations other than FLT3.
“It is possible that the benefit of midostaurin, which is a multitargeted kinase inhibitor, might lie beyond its ability to inhibit FLT3,” possibly through inhibition of KIT, researchers said.
They also noted that as the trial went on, more and more investigators decided to treat patients with hematopoietic stem cell transplantation, based on newly reported data elsewhere. Since midostaurin was discontinued at the time of transplant, that could have limited exposure to the drug and limited its effect.
*CORRECTION 7/5/2017: An earlier version of this article misstated the number of patients in the placebo group as well as where the study originally appeared.
Adding the multitargeted kinase inhibitor midostaurin to standard chemotherapy led to significantly longer overall and event-free survival, compared with placebo and standard chemotherapy in newly diagnosed acute myeloid leukemia (AML) patients with FLT3 gene mutations, according to phase III trial results published in the New England Journal of Medicine.*
About 30% of AML patients have mutations to the FLT3 gene – with three-quarters of those internal tandem duplication (ITD) mutations, which involves duplication of between 3 and 100 amino acids in the juxtamembrane region. These mutations are linked with a high relapse rate and poor prognosis, especially when there is a high ratio of these mutations to wild-type FLT3. About 8% of patients with newly diagnosed AML have an FLT3 point mutation in the tyrosine kinase domain (TKD), but the effect of these on prognosis isn’t clear.
In the trial, called RATIFY and conducted at 225 sites in 17 countries, 360 patients were randomized to the midostaurin group and 357* to placebo, and they were treated from 2008 to 2013. In all, 29.8% of patients were “ITD high,” meaning their ITD FLT3 mutation to wild-type FLT3 ratio was higher than 0.7, and 47.6% were “ITD low,” with a mutation-to-wild-type FLT3 ratio of 0.5 to 0.7. A total of 22.6% of patients had TKD mutations.
Patients received standard induction chemotherapy, with daunorubicine and cytarabine, and on days 8 through 21 either 50 mg of midostaurin or placebo orally twice a day. Patients were given an identical second cycle of induction therapy, with midostaurin or placebo, if they showed definitive clinically significant residual leukemia after the first induction treatment.
Those who achieved complete remission after induction were given 4, 28-day cycles of consolidation treatment, with midostaurin or placebo on days 8 through 21. If they stayed in remission after that, they were given maintenance of 12, 28-day cycles of midostaurin or placebo.
They were not required to receive hematopoetic stem cell transplantation (HSCT), but it was performed at investigator discretion.
Midostaurin improved survival but not rates of complete remission as defined in the trial protocol, researchers reported.
The hazard ratio for death in the midostaurin group was 0.78 (95% CI, 0.63 to 0.96; one-sided P = .0009). The 4-year overall survival rate was 51.4% for the midostaurin group and 44.3% for the placebo group. Midostaurin was shown to benefit all mutation subgroups, but with no greater benefit in one group than another.
Patients in the midostaurin group had a 21.6% lower likelihood of having an event, defined as failure to achieve protocol-defined complete remission, relapse or death without relapse.
There was no significant difference between the groups in complete remission, which under protocol had to occur by day 60.
HSCT was performed in 57% of patients – during the first complete remission in 28.1% of the midostaurin group and in 22.7% during the first complete remission in the placebo group. For those who were transplanted after the first complete remission, no treatment effect was seen.
Researchers noted that there was a therapeutic benefit even among patients with ITD mutations but with a low allelic burden, in whom the disease might be due largely to mutations other than FLT3.
“It is possible that the benefit of midostaurin, which is a multitargeted kinase inhibitor, might lie beyond its ability to inhibit FLT3,” possibly through inhibition of KIT, researchers said.
They also noted that as the trial went on, more and more investigators decided to treat patients with hematopoietic stem cell transplantation, based on newly reported data elsewhere. Since midostaurin was discontinued at the time of transplant, that could have limited exposure to the drug and limited its effect.
*CORRECTION 7/5/2017: An earlier version of this article misstated the number of patients in the placebo group as well as where the study originally appeared.
FROM NEJM
Key clinical point: Multitargeted kinase inhibitor midostaurin combined with standard chemotherapy improved survival in newly diagnosed acute myeloid leukemia patients.
Major finding: The 4-year overall survival rate was 51.4% for the midostaurin group and 44.3% for the placebo group. Midostaurin was shown to benefit all mutation subgroups — internal tandem mutations and point mutations in the tyrosine kinase domain – but with no greater benefit in one group than another.
Data source: A multicenter, multinational, randomized, double-blind, placebo-controlled trial.
Disclosures: The trial was funded by the National Cancer Institute and Novartis. Researchers reported receiving personal fees from Novartis and other companies.
Gilteritinib shows safety, efficacy in relapsed/refractory AML
Gilteritinib, a tyrosine kinase inhibitor, had a generally favorable safety profile and inhibited FLT3 in a population enriched with relapsed/refractory acute myeloid leukemia (AML) patients who had the target mutations, based on results of a phase I/II trial.
The findings represent a step forward in treatment of AML with FLT3 inhibition, according to Alexander E. Perl, MD, of the University of Pennsylvania Abramson Comprehensive Cancer Center, Philadelphia, and his colleagues in the trial (NCT02014558), which is sponsored by Astellas Pharma Global Development.
Gilteritinib at 120 mg/day is being tested in phase III trials and in combination with chemotherapy regimens.
Initial entrants in the FLT3 inhibitor class had poor bioavailability, lacked potency and kinase specificity, and had low rates of response. While newer FLT3 inhibitors have had more potent effects, the proportions of patients who have responded have varied and their responses have often been transient, with resistance emerging within a few weeks of treatment.
Gilteritinib is attractive because it has in vitro activity against FLT3 internal tandem duplication mutations and tyrosine kinase domain mutations.
In the first-in-human, single-arm, open-label study — conducted at centers in the United States, Germany, France, and Italy — 252 patients were given one of seven gilteritinib doses, from 20 to 450 mg per day, either as part of a cohort to assess dose escalation or to expand a given dose.
FTL3 mutations were not required for study enrollment, but researchers did require 10 or more patients with confirmed FLT3 mutations to be enrolled in each of the dose expansion groups. Because they found that patients with the mutations were responding so much better than those with wild-type FLT3, they expanded the 120-mg and 200-mg dose cohorts to include only those with FLT3 mutations. In the end, 162 of 252 treated patients had internal tandem duplication mutations, 12 had codon D835 mutations, and 15 had both.
The most common grade 3 or 4 adverse events, regardless of relation to treatment, were neutropenia, seen in 39%, anemia (24%), thrombocytopenia (13%), sepsis (11%), and pneumonia (11%).
Commonly reported treatment-related adverse events were diarrhea (37%), anemia (34%), fatigue (33%), elevated aspartate aminotransferase (26%), and elevated alanine aminotransferase (19%).
Serious adverse events seen in at least 5% of patients included febrile neutropenia (39%; five cases of which were related to the treatment), progressive disease (17%), sepsis (14%; two of which were related to treatment), and pneumonia (11%), and acute renal failure (10%; five related to treatment), the researchers reported in The Lancet Oncology (doi: 10.1016/S1470-2045(17)30416-3).
Seven deaths were judged to be possibly or probably related to treatment, seen in the 20-mg, 80-mg, 120-mg, and 200-mg groups.
Of the 249 patients with data allowing a full analysis, 100 (40%) achieved a response, with 8% achieving a complete remission, 4% a complete remission with incomplete platelet recovery, 18% a complete remission with incomplete hematologic recovery, and 10% a partial remission.
At least 90% of the FLT3 inhibition was seen by the eighth day of treatment among those getting at least the 80-mg dose.
Median overall survival was 25 weeks, and leukemia-free survival will be reported in future data analyses, researchers said.
Only 19% of the patients with FLT3 mutations underwent a hematopoetic stem cell transplant after treatment, which was attributed in part to prior hematopioetic stem cell transplant and the advanced age of many of the patients. Among the patients who subsequently had transplants, the results did not have much effect. Median survival was 47 weeks for those with mutations who had an overall response to gilteritinib and had a transplant after treatment, compared to 42 weeks for those with mutations and an overall response but didn’t go on to transplant.
“Because gilteritinib as a single agent is likely to have limited curative capacity, even when used early in the disease course,” researchers wrote, “studies that integrate gilteritnib into frontline chemotherapy regimens are underway.”
Study authors reported receiving fees, grants, or nonfinancial support from Astellas, the sponsor of the trial, and other pharmaceutical companies.
Gilteritinib, a tyrosine kinase inhibitor, had a generally favorable safety profile and inhibited FLT3 in a population enriched with relapsed/refractory acute myeloid leukemia (AML) patients who had the target mutations, based on results of a phase I/II trial.
The findings represent a step forward in treatment of AML with FLT3 inhibition, according to Alexander E. Perl, MD, of the University of Pennsylvania Abramson Comprehensive Cancer Center, Philadelphia, and his colleagues in the trial (NCT02014558), which is sponsored by Astellas Pharma Global Development.
Gilteritinib at 120 mg/day is being tested in phase III trials and in combination with chemotherapy regimens.
Initial entrants in the FLT3 inhibitor class had poor bioavailability, lacked potency and kinase specificity, and had low rates of response. While newer FLT3 inhibitors have had more potent effects, the proportions of patients who have responded have varied and their responses have often been transient, with resistance emerging within a few weeks of treatment.
Gilteritinib is attractive because it has in vitro activity against FLT3 internal tandem duplication mutations and tyrosine kinase domain mutations.
In the first-in-human, single-arm, open-label study — conducted at centers in the United States, Germany, France, and Italy — 252 patients were given one of seven gilteritinib doses, from 20 to 450 mg per day, either as part of a cohort to assess dose escalation or to expand a given dose.
FTL3 mutations were not required for study enrollment, but researchers did require 10 or more patients with confirmed FLT3 mutations to be enrolled in each of the dose expansion groups. Because they found that patients with the mutations were responding so much better than those with wild-type FLT3, they expanded the 120-mg and 200-mg dose cohorts to include only those with FLT3 mutations. In the end, 162 of 252 treated patients had internal tandem duplication mutations, 12 had codon D835 mutations, and 15 had both.
The most common grade 3 or 4 adverse events, regardless of relation to treatment, were neutropenia, seen in 39%, anemia (24%), thrombocytopenia (13%), sepsis (11%), and pneumonia (11%).
Commonly reported treatment-related adverse events were diarrhea (37%), anemia (34%), fatigue (33%), elevated aspartate aminotransferase (26%), and elevated alanine aminotransferase (19%).
Serious adverse events seen in at least 5% of patients included febrile neutropenia (39%; five cases of which were related to the treatment), progressive disease (17%), sepsis (14%; two of which were related to treatment), and pneumonia (11%), and acute renal failure (10%; five related to treatment), the researchers reported in The Lancet Oncology (doi: 10.1016/S1470-2045(17)30416-3).
Seven deaths were judged to be possibly or probably related to treatment, seen in the 20-mg, 80-mg, 120-mg, and 200-mg groups.
Of the 249 patients with data allowing a full analysis, 100 (40%) achieved a response, with 8% achieving a complete remission, 4% a complete remission with incomplete platelet recovery, 18% a complete remission with incomplete hematologic recovery, and 10% a partial remission.
At least 90% of the FLT3 inhibition was seen by the eighth day of treatment among those getting at least the 80-mg dose.
Median overall survival was 25 weeks, and leukemia-free survival will be reported in future data analyses, researchers said.
Only 19% of the patients with FLT3 mutations underwent a hematopoetic stem cell transplant after treatment, which was attributed in part to prior hematopioetic stem cell transplant and the advanced age of many of the patients. Among the patients who subsequently had transplants, the results did not have much effect. Median survival was 47 weeks for those with mutations who had an overall response to gilteritinib and had a transplant after treatment, compared to 42 weeks for those with mutations and an overall response but didn’t go on to transplant.
“Because gilteritinib as a single agent is likely to have limited curative capacity, even when used early in the disease course,” researchers wrote, “studies that integrate gilteritnib into frontline chemotherapy regimens are underway.”
Study authors reported receiving fees, grants, or nonfinancial support from Astellas, the sponsor of the trial, and other pharmaceutical companies.
Gilteritinib, a tyrosine kinase inhibitor, had a generally favorable safety profile and inhibited FLT3 in a population enriched with relapsed/refractory acute myeloid leukemia (AML) patients who had the target mutations, based on results of a phase I/II trial.
The findings represent a step forward in treatment of AML with FLT3 inhibition, according to Alexander E. Perl, MD, of the University of Pennsylvania Abramson Comprehensive Cancer Center, Philadelphia, and his colleagues in the trial (NCT02014558), which is sponsored by Astellas Pharma Global Development.
Gilteritinib at 120 mg/day is being tested in phase III trials and in combination with chemotherapy regimens.
Initial entrants in the FLT3 inhibitor class had poor bioavailability, lacked potency and kinase specificity, and had low rates of response. While newer FLT3 inhibitors have had more potent effects, the proportions of patients who have responded have varied and their responses have often been transient, with resistance emerging within a few weeks of treatment.
Gilteritinib is attractive because it has in vitro activity against FLT3 internal tandem duplication mutations and tyrosine kinase domain mutations.
In the first-in-human, single-arm, open-label study — conducted at centers in the United States, Germany, France, and Italy — 252 patients were given one of seven gilteritinib doses, from 20 to 450 mg per day, either as part of a cohort to assess dose escalation or to expand a given dose.
FTL3 mutations were not required for study enrollment, but researchers did require 10 or more patients with confirmed FLT3 mutations to be enrolled in each of the dose expansion groups. Because they found that patients with the mutations were responding so much better than those with wild-type FLT3, they expanded the 120-mg and 200-mg dose cohorts to include only those with FLT3 mutations. In the end, 162 of 252 treated patients had internal tandem duplication mutations, 12 had codon D835 mutations, and 15 had both.
The most common grade 3 or 4 adverse events, regardless of relation to treatment, were neutropenia, seen in 39%, anemia (24%), thrombocytopenia (13%), sepsis (11%), and pneumonia (11%).
Commonly reported treatment-related adverse events were diarrhea (37%), anemia (34%), fatigue (33%), elevated aspartate aminotransferase (26%), and elevated alanine aminotransferase (19%).
Serious adverse events seen in at least 5% of patients included febrile neutropenia (39%; five cases of which were related to the treatment), progressive disease (17%), sepsis (14%; two of which were related to treatment), and pneumonia (11%), and acute renal failure (10%; five related to treatment), the researchers reported in The Lancet Oncology (doi: 10.1016/S1470-2045(17)30416-3).
Seven deaths were judged to be possibly or probably related to treatment, seen in the 20-mg, 80-mg, 120-mg, and 200-mg groups.
Of the 249 patients with data allowing a full analysis, 100 (40%) achieved a response, with 8% achieving a complete remission, 4% a complete remission with incomplete platelet recovery, 18% a complete remission with incomplete hematologic recovery, and 10% a partial remission.
At least 90% of the FLT3 inhibition was seen by the eighth day of treatment among those getting at least the 80-mg dose.
Median overall survival was 25 weeks, and leukemia-free survival will be reported in future data analyses, researchers said.
Only 19% of the patients with FLT3 mutations underwent a hematopoetic stem cell transplant after treatment, which was attributed in part to prior hematopioetic stem cell transplant and the advanced age of many of the patients. Among the patients who subsequently had transplants, the results did not have much effect. Median survival was 47 weeks for those with mutations who had an overall response to gilteritinib and had a transplant after treatment, compared to 42 weeks for those with mutations and an overall response but didn’t go on to transplant.
“Because gilteritinib as a single agent is likely to have limited curative capacity, even when used early in the disease course,” researchers wrote, “studies that integrate gilteritnib into frontline chemotherapy regimens are underway.”
Study authors reported receiving fees, grants, or nonfinancial support from Astellas, the sponsor of the trial, and other pharmaceutical companies.
FROM THE LANCET ONCOLOGY
Key clinical point: The highly selective tyrosine kinase inhibitor gilternitinib was generally safe and elicited responses in relapsed-refractory AML patients.
Major finding: Of the 249 patients with data allowing a full analysis, 100 (40%) achieved a response, with a median overall survival of 25 weeks.
Data source: Multicenter, single-arm, open-label study in Europe and the United States.
Disclosures: Astellas Pharma funded the study, and study authors reported receiving fees, grants or nonfinancial support from Astellas and other pharmaceutical companies.
Infections may trigger leukemia in the genetically susceptible
MADRID – The evidence thus far comes only from animal models, but commonly encountered childhood infections may be able to trigger the development of leukemia in those children with certain genetic predispositions to B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
Mice genetically modified to mimic BCP-ALL susceptibility and its most common subtype (ETV6-RUNX1 BCP-ALL) developed leukemia only after exposure to a common infectious environment.
“The mechanism that takes place in preleukemic cells after the mice were exposed to infection was different in the two mouse models,” she said at a briefing prior to her presentation of the data at the annual congress of the European Hematology Association.
“This is another piece that will, hopefully, contribute to the picture of how exposure to infection can contribute to leukemic development” and may lead to novel approaches for leukemia prevention, she added.
The possibility that exposure to infectious pathogens could trigger leukemia has been bandied about for a century, based in part on observations that leukemia is the most common malignancy in children, with a still unexplained peak incidence between the ages of 2 and 6 years, Dr. Hauer noted.
To explore a possible link, she and her colleagues developed and characterized the aforementioned mice mimicking BCP-ALL with the BCR-ABL1 transcription and ETV6-RUNX1 BCP-ALL, in addition to a previously described Pax5+/- infection model. Some of all three mouse models were exposed not to specific pathogens but to a common laboratory environment, where they could be expected to acquire various infections at 2-3 months of age, and some were kept in a sterile environment designed to reduce transmission of pathogens. Wild-type mice were used as controls.
They observed that the Pax5+/- and ETV6-RUNX1 mice developed BCP-ALL only after exposure to common pathogens. In contrast, the BCR-ABL1p190 mice developed BCP-ALL independent of exposure to common infection.
They also determined that the mechanism leading to leukemia in the Pax5+/- mice was related to constitutive activations of mutations in the Janus kinase (JAK)3 pathway in susceptible B cell precursors, whereas the ETV6-RUNX1 mice developed BCP-ALL at a low penetrance (10.75%, 10 of 93) with a CD19-positive, B220-positive, immunoglobulin M-negative cell surface phenotype, manifested by blast cells in peripheral blood and a clonal immature B-cell receptor rearrangement.
In mice, norovirus and hepatitis C virus may be some of the pathogens most closely linked to risk of leukemia, but it’s likely that other viruses and parasitic infections will turn out to be the culprits in humans, Dr. Hauer said.
The findings raise the possibility of an unexpected link between leukemia and the so-called “hygiene hypothesis” linking childhood asthma, allergies, and atopic skin conditions to a lack of early exposure to a multiplicity of pathogens. In many developed countries, children are relatively protected from exposure to many different pathogens and may not encounter infectious agents until entering preschool or kindergarten, Dr. Hauer commented.
The study was supported by German Cancer Aid, the Jose Carreras Leukemia Foundation, and other charitable agencies. Dr. Hauer reported no relevant disclosures.
MADRID – The evidence thus far comes only from animal models, but commonly encountered childhood infections may be able to trigger the development of leukemia in those children with certain genetic predispositions to B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
Mice genetically modified to mimic BCP-ALL susceptibility and its most common subtype (ETV6-RUNX1 BCP-ALL) developed leukemia only after exposure to a common infectious environment.
“The mechanism that takes place in preleukemic cells after the mice were exposed to infection was different in the two mouse models,” she said at a briefing prior to her presentation of the data at the annual congress of the European Hematology Association.
“This is another piece that will, hopefully, contribute to the picture of how exposure to infection can contribute to leukemic development” and may lead to novel approaches for leukemia prevention, she added.
The possibility that exposure to infectious pathogens could trigger leukemia has been bandied about for a century, based in part on observations that leukemia is the most common malignancy in children, with a still unexplained peak incidence between the ages of 2 and 6 years, Dr. Hauer noted.
To explore a possible link, she and her colleagues developed and characterized the aforementioned mice mimicking BCP-ALL with the BCR-ABL1 transcription and ETV6-RUNX1 BCP-ALL, in addition to a previously described Pax5+/- infection model. Some of all three mouse models were exposed not to specific pathogens but to a common laboratory environment, where they could be expected to acquire various infections at 2-3 months of age, and some were kept in a sterile environment designed to reduce transmission of pathogens. Wild-type mice were used as controls.
They observed that the Pax5+/- and ETV6-RUNX1 mice developed BCP-ALL only after exposure to common pathogens. In contrast, the BCR-ABL1p190 mice developed BCP-ALL independent of exposure to common infection.
They also determined that the mechanism leading to leukemia in the Pax5+/- mice was related to constitutive activations of mutations in the Janus kinase (JAK)3 pathway in susceptible B cell precursors, whereas the ETV6-RUNX1 mice developed BCP-ALL at a low penetrance (10.75%, 10 of 93) with a CD19-positive, B220-positive, immunoglobulin M-negative cell surface phenotype, manifested by blast cells in peripheral blood and a clonal immature B-cell receptor rearrangement.
In mice, norovirus and hepatitis C virus may be some of the pathogens most closely linked to risk of leukemia, but it’s likely that other viruses and parasitic infections will turn out to be the culprits in humans, Dr. Hauer said.
The findings raise the possibility of an unexpected link between leukemia and the so-called “hygiene hypothesis” linking childhood asthma, allergies, and atopic skin conditions to a lack of early exposure to a multiplicity of pathogens. In many developed countries, children are relatively protected from exposure to many different pathogens and may not encounter infectious agents until entering preschool or kindergarten, Dr. Hauer commented.
The study was supported by German Cancer Aid, the Jose Carreras Leukemia Foundation, and other charitable agencies. Dr. Hauer reported no relevant disclosures.
MADRID – The evidence thus far comes only from animal models, but commonly encountered childhood infections may be able to trigger the development of leukemia in those children with certain genetic predispositions to B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
Mice genetically modified to mimic BCP-ALL susceptibility and its most common subtype (ETV6-RUNX1 BCP-ALL) developed leukemia only after exposure to a common infectious environment.
“The mechanism that takes place in preleukemic cells after the mice were exposed to infection was different in the two mouse models,” she said at a briefing prior to her presentation of the data at the annual congress of the European Hematology Association.
“This is another piece that will, hopefully, contribute to the picture of how exposure to infection can contribute to leukemic development” and may lead to novel approaches for leukemia prevention, she added.
The possibility that exposure to infectious pathogens could trigger leukemia has been bandied about for a century, based in part on observations that leukemia is the most common malignancy in children, with a still unexplained peak incidence between the ages of 2 and 6 years, Dr. Hauer noted.
To explore a possible link, she and her colleagues developed and characterized the aforementioned mice mimicking BCP-ALL with the BCR-ABL1 transcription and ETV6-RUNX1 BCP-ALL, in addition to a previously described Pax5+/- infection model. Some of all three mouse models were exposed not to specific pathogens but to a common laboratory environment, where they could be expected to acquire various infections at 2-3 months of age, and some were kept in a sterile environment designed to reduce transmission of pathogens. Wild-type mice were used as controls.
They observed that the Pax5+/- and ETV6-RUNX1 mice developed BCP-ALL only after exposure to common pathogens. In contrast, the BCR-ABL1p190 mice developed BCP-ALL independent of exposure to common infection.
They also determined that the mechanism leading to leukemia in the Pax5+/- mice was related to constitutive activations of mutations in the Janus kinase (JAK)3 pathway in susceptible B cell precursors, whereas the ETV6-RUNX1 mice developed BCP-ALL at a low penetrance (10.75%, 10 of 93) with a CD19-positive, B220-positive, immunoglobulin M-negative cell surface phenotype, manifested by blast cells in peripheral blood and a clonal immature B-cell receptor rearrangement.
In mice, norovirus and hepatitis C virus may be some of the pathogens most closely linked to risk of leukemia, but it’s likely that other viruses and parasitic infections will turn out to be the culprits in humans, Dr. Hauer said.
The findings raise the possibility of an unexpected link between leukemia and the so-called “hygiene hypothesis” linking childhood asthma, allergies, and atopic skin conditions to a lack of early exposure to a multiplicity of pathogens. In many developed countries, children are relatively protected from exposure to many different pathogens and may not encounter infectious agents until entering preschool or kindergarten, Dr. Hauer commented.
The study was supported by German Cancer Aid, the Jose Carreras Leukemia Foundation, and other charitable agencies. Dr. Hauer reported no relevant disclosures.
AT EHA 2017
Key clinical point: This study suggests a link between acute lymphocytic leukemia development and infections in some genetically predisposed children.
Major finding: Mouse models of two types of B-cell precursor ALL developed leukemia only after exposure to infections.
Data source: A study of factors related to the development of childhood ALL using genetically modified mouse models.
Disclosures: The study was supported by German Cancer Aid, the Jose Carreras Leukemia Foundation, and other charitable agencies. Dr. Hauer reported no relevant disclosures.
Optimizing therapy in relapsed CLL: ibrutinib and beyond
CHICAGO – The efficacy of ibrutinib is durable for patients with relapsed chronic lymphocytic leukemia (CLL), and combination strategies are showing the potential to improve on this benefit, based on results from three studies reported in a poster discussion session at the annual meeting of the American Society of Clinical Oncology.
Ibrutinib monotherapy
In the phase III randomized RESONATE trial, funded by Pharmacyclics, investigators compared ibrutinib with ofatumumab (Arzerra), an anti-CD20 antibody, among 391 patients with CLL or small lymphocytic lymphoma (SLL), with cross-over allowed. Initial results favored ibrutinib.
Investigators led by John C. Byrd, MD, director of the division of hematology at the Ohio State University Comprehensive Cancer Center in Columbus, reported updated data in a poster session at the meeting, now with a median 44 months of follow-up in the ibrutinib arm.
Median progression-free survival was not reached with ibrutinib, compared with 8.1 months with ofatumumab (hazard ratio, 0.133). The 3-year rate of progression-free survival was 59% and 3%, respectively.
The pattern was generally similar across patients stratified by cytogenetics (deletion of 17p, deletion of 11q, or neither), IGHV and TP53 mutation status, and prior lines of therapy, reported Dr. Byrd, who disclosed that he receives research funding from Pharmacyclics, among other companies.
The 3-year overall survival rate for ibrutinib was 74%. In analyses adjusted for cross-over, patients given the inhibitor had a markedly lower risk of death than did peers given the antibody (HR, 0.37).
The overall response rate with ibrutinib was 91%. Although the rate of complete response increased with follow-up, it was still just 9%.
The most common grade 3 or worse adverse events were neutropenia (23%), pneumonia (17%), and anemia, thrombocytopenia, and hypertension (8% each). Of patients, 6% each had a major hemorrhage and grade 3 or worse atrial fibrillation.
“These long-term results from the international phase III RESONATE study show that extended treatment with ibrutinib is tolerable and continues to show sustained PFS in previously treated patients with CLL regardless of high-risk cytogenetics,” the investigators conclude. “Traditional poor prognostic factors for survival with chemoimmunotherapy, including del(17p) and del(11q), were not significant factors predictive of [progression-free survival] outcomes with ibrutinib therapy.”
Taken together, experience to date with ibrutinib highlights some issues and unmet needs, she said: greater treatment discontinuation in the real-world setting, early relapse in patients having higher-risk genetics or complex karyotypes, and an overall low rate of remission or minimal residual disease negativity.
These are important for several reasons, Dr. Brown maintained. “Persistent disease will lead to relapse eventually. If we have up to 40% discontinuation for adverse events, then, if people are in deeper remission at the time of discontinuation, they are likely to have a longer remission off drug. And, ultimately, of course, cure would require absence of disease,” she elaborated. “Then enhancing tolerability to keep patients on drug is an ongoing unmet need.”
Ibrutinib plus ublituximab and umbralisib
In a phase 1/1b trial funded by TG Therapeutics, investigators led by Loretta J. Nastoupil, MD, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center, Houston, tested a triplet consisting of ibrutinib with ublituximab – another anti-CD20 antibody – and umbralisib (TGR-1202) – an oral PI3 kinase–delta inhibitor.
A total of 38 patients with generally heavily pretreated leukemias and lymphomas were studied, including 20 with CLL or SLL. Notably, eight patients (50%) with CLL had a 17p or 11q deletion.
The median time on study was 11.1 months, reported Dr. Nastoupil, who disclosed that she receives honoraria and research funding from TG Therapeutics and that she has relationships with other companies. The overall response rate for the 19 evaluable patients with CLL or SLL was 100% (complete response in 32%, partial response in 68%).
The main grade 3 or 4 adverse events in the entire trial population were neutropenia (18%) and pyrexia (8%). Only two patients discontinued treatment because of adverse events.
“An expansion cohort is ongoing at the highest dose, and we will clearly need more patients treated and longer follow-up to really know the efficacy,” commented Dr. Brown, the discussant for the poster session. “But overall, I think the safety looks encouraging with this combination.”
“Novel agent combinations are feasible and hold promise for deeper remission and/or time-limited therapy. Most of the excitement is focused around BTK and BCL-2 inhibitors, but there is clearly a role for kinase-kinase combinations because we see here that it was safe to combine ibrutinib with a PI3 kinase inhibitor,” she noted. “So, we should continue to pursue other kinase-kinase combinations, as well as BCL-2–kinase combinations.”
Ibrutinib plus CAR-T cells
In a pilot trial funded by Novartis, investigators led by Saar Gill, MD, PhD, of the hospital of the University of Pennsylvania in Philadelphia, tested the combination of ibrutinib with chimeric antigen receptor–T cells (CAR-T cells) against CD19, on the basis of preclinical evidence of synergy.
Trial participants were 10 patients with CLL or SLL who had not achieved complete response with ibrutinib. All had a 17p deletion or a p53 mutation, or a complex karyotype, and some had a known ibrutinib resistance mutation.
At 3 months, eight (89%) of nine evaluable patients had no evidence of disease in bone marrow, reported Dr. Gill, who disclosed that he receives research funding from Novartis (institutional) and has patents for CAR-T cells for acute myeloid leukemia, among other disclosures. Seven patients (78%) achieved a complete or partial radiographic response in the spleen and lymph nodes.
Overall, the treatment was well tolerated. One patient developed grade 4 tumor lysis syndrome, and two developed grade 3 cytokine release syndrome. But, none required anticytokine therapy.
Most patients remain on ibrutinib and are being monitored. In addition, the researchers plan to treat 25 more patients with the same combination.
“We don’t know what will happen if the patients stop ibrutinib at some point, which is a question for the future,” commented Dr. Brown, the discussant.
“CAR-T cell therapy in CLL has historically had lower response rates than in ALL, but preclinical and early clinical data support ongoing investigation of combination therapy with ibrutinib as it appears that ibrutinib may enhance the production and engraftment of the T cells,” she noted. “Ultimately, of course, the role of CAR-T cell therapy in CLL will require a very clear, well-defined safety [protocol] if it is being used in comparison to some of the oral drugs that we can maintain many of the patients on for a long time.”
CHICAGO – The efficacy of ibrutinib is durable for patients with relapsed chronic lymphocytic leukemia (CLL), and combination strategies are showing the potential to improve on this benefit, based on results from three studies reported in a poster discussion session at the annual meeting of the American Society of Clinical Oncology.
Ibrutinib monotherapy
In the phase III randomized RESONATE trial, funded by Pharmacyclics, investigators compared ibrutinib with ofatumumab (Arzerra), an anti-CD20 antibody, among 391 patients with CLL or small lymphocytic lymphoma (SLL), with cross-over allowed. Initial results favored ibrutinib.
Investigators led by John C. Byrd, MD, director of the division of hematology at the Ohio State University Comprehensive Cancer Center in Columbus, reported updated data in a poster session at the meeting, now with a median 44 months of follow-up in the ibrutinib arm.
Median progression-free survival was not reached with ibrutinib, compared with 8.1 months with ofatumumab (hazard ratio, 0.133). The 3-year rate of progression-free survival was 59% and 3%, respectively.
The pattern was generally similar across patients stratified by cytogenetics (deletion of 17p, deletion of 11q, or neither), IGHV and TP53 mutation status, and prior lines of therapy, reported Dr. Byrd, who disclosed that he receives research funding from Pharmacyclics, among other companies.
The 3-year overall survival rate for ibrutinib was 74%. In analyses adjusted for cross-over, patients given the inhibitor had a markedly lower risk of death than did peers given the antibody (HR, 0.37).
The overall response rate with ibrutinib was 91%. Although the rate of complete response increased with follow-up, it was still just 9%.
The most common grade 3 or worse adverse events were neutropenia (23%), pneumonia (17%), and anemia, thrombocytopenia, and hypertension (8% each). Of patients, 6% each had a major hemorrhage and grade 3 or worse atrial fibrillation.
“These long-term results from the international phase III RESONATE study show that extended treatment with ibrutinib is tolerable and continues to show sustained PFS in previously treated patients with CLL regardless of high-risk cytogenetics,” the investigators conclude. “Traditional poor prognostic factors for survival with chemoimmunotherapy, including del(17p) and del(11q), were not significant factors predictive of [progression-free survival] outcomes with ibrutinib therapy.”
Taken together, experience to date with ibrutinib highlights some issues and unmet needs, she said: greater treatment discontinuation in the real-world setting, early relapse in patients having higher-risk genetics or complex karyotypes, and an overall low rate of remission or minimal residual disease negativity.
These are important for several reasons, Dr. Brown maintained. “Persistent disease will lead to relapse eventually. If we have up to 40% discontinuation for adverse events, then, if people are in deeper remission at the time of discontinuation, they are likely to have a longer remission off drug. And, ultimately, of course, cure would require absence of disease,” she elaborated. “Then enhancing tolerability to keep patients on drug is an ongoing unmet need.”
Ibrutinib plus ublituximab and umbralisib
In a phase 1/1b trial funded by TG Therapeutics, investigators led by Loretta J. Nastoupil, MD, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center, Houston, tested a triplet consisting of ibrutinib with ublituximab – another anti-CD20 antibody – and umbralisib (TGR-1202) – an oral PI3 kinase–delta inhibitor.
A total of 38 patients with generally heavily pretreated leukemias and lymphomas were studied, including 20 with CLL or SLL. Notably, eight patients (50%) with CLL had a 17p or 11q deletion.
The median time on study was 11.1 months, reported Dr. Nastoupil, who disclosed that she receives honoraria and research funding from TG Therapeutics and that she has relationships with other companies. The overall response rate for the 19 evaluable patients with CLL or SLL was 100% (complete response in 32%, partial response in 68%).
The main grade 3 or 4 adverse events in the entire trial population were neutropenia (18%) and pyrexia (8%). Only two patients discontinued treatment because of adverse events.
“An expansion cohort is ongoing at the highest dose, and we will clearly need more patients treated and longer follow-up to really know the efficacy,” commented Dr. Brown, the discussant for the poster session. “But overall, I think the safety looks encouraging with this combination.”
“Novel agent combinations are feasible and hold promise for deeper remission and/or time-limited therapy. Most of the excitement is focused around BTK and BCL-2 inhibitors, but there is clearly a role for kinase-kinase combinations because we see here that it was safe to combine ibrutinib with a PI3 kinase inhibitor,” she noted. “So, we should continue to pursue other kinase-kinase combinations, as well as BCL-2–kinase combinations.”
Ibrutinib plus CAR-T cells
In a pilot trial funded by Novartis, investigators led by Saar Gill, MD, PhD, of the hospital of the University of Pennsylvania in Philadelphia, tested the combination of ibrutinib with chimeric antigen receptor–T cells (CAR-T cells) against CD19, on the basis of preclinical evidence of synergy.
Trial participants were 10 patients with CLL or SLL who had not achieved complete response with ibrutinib. All had a 17p deletion or a p53 mutation, or a complex karyotype, and some had a known ibrutinib resistance mutation.
At 3 months, eight (89%) of nine evaluable patients had no evidence of disease in bone marrow, reported Dr. Gill, who disclosed that he receives research funding from Novartis (institutional) and has patents for CAR-T cells for acute myeloid leukemia, among other disclosures. Seven patients (78%) achieved a complete or partial radiographic response in the spleen and lymph nodes.
Overall, the treatment was well tolerated. One patient developed grade 4 tumor lysis syndrome, and two developed grade 3 cytokine release syndrome. But, none required anticytokine therapy.
Most patients remain on ibrutinib and are being monitored. In addition, the researchers plan to treat 25 more patients with the same combination.
“We don’t know what will happen if the patients stop ibrutinib at some point, which is a question for the future,” commented Dr. Brown, the discussant.
“CAR-T cell therapy in CLL has historically had lower response rates than in ALL, but preclinical and early clinical data support ongoing investigation of combination therapy with ibrutinib as it appears that ibrutinib may enhance the production and engraftment of the T cells,” she noted. “Ultimately, of course, the role of CAR-T cell therapy in CLL will require a very clear, well-defined safety [protocol] if it is being used in comparison to some of the oral drugs that we can maintain many of the patients on for a long time.”
CHICAGO – The efficacy of ibrutinib is durable for patients with relapsed chronic lymphocytic leukemia (CLL), and combination strategies are showing the potential to improve on this benefit, based on results from three studies reported in a poster discussion session at the annual meeting of the American Society of Clinical Oncology.
Ibrutinib monotherapy
In the phase III randomized RESONATE trial, funded by Pharmacyclics, investigators compared ibrutinib with ofatumumab (Arzerra), an anti-CD20 antibody, among 391 patients with CLL or small lymphocytic lymphoma (SLL), with cross-over allowed. Initial results favored ibrutinib.
Investigators led by John C. Byrd, MD, director of the division of hematology at the Ohio State University Comprehensive Cancer Center in Columbus, reported updated data in a poster session at the meeting, now with a median 44 months of follow-up in the ibrutinib arm.
Median progression-free survival was not reached with ibrutinib, compared with 8.1 months with ofatumumab (hazard ratio, 0.133). The 3-year rate of progression-free survival was 59% and 3%, respectively.
The pattern was generally similar across patients stratified by cytogenetics (deletion of 17p, deletion of 11q, or neither), IGHV and TP53 mutation status, and prior lines of therapy, reported Dr. Byrd, who disclosed that he receives research funding from Pharmacyclics, among other companies.
The 3-year overall survival rate for ibrutinib was 74%. In analyses adjusted for cross-over, patients given the inhibitor had a markedly lower risk of death than did peers given the antibody (HR, 0.37).
The overall response rate with ibrutinib was 91%. Although the rate of complete response increased with follow-up, it was still just 9%.
The most common grade 3 or worse adverse events were neutropenia (23%), pneumonia (17%), and anemia, thrombocytopenia, and hypertension (8% each). Of patients, 6% each had a major hemorrhage and grade 3 or worse atrial fibrillation.
“These long-term results from the international phase III RESONATE study show that extended treatment with ibrutinib is tolerable and continues to show sustained PFS in previously treated patients with CLL regardless of high-risk cytogenetics,” the investigators conclude. “Traditional poor prognostic factors for survival with chemoimmunotherapy, including del(17p) and del(11q), were not significant factors predictive of [progression-free survival] outcomes with ibrutinib therapy.”
Taken together, experience to date with ibrutinib highlights some issues and unmet needs, she said: greater treatment discontinuation in the real-world setting, early relapse in patients having higher-risk genetics or complex karyotypes, and an overall low rate of remission or minimal residual disease negativity.
These are important for several reasons, Dr. Brown maintained. “Persistent disease will lead to relapse eventually. If we have up to 40% discontinuation for adverse events, then, if people are in deeper remission at the time of discontinuation, they are likely to have a longer remission off drug. And, ultimately, of course, cure would require absence of disease,” she elaborated. “Then enhancing tolerability to keep patients on drug is an ongoing unmet need.”
Ibrutinib plus ublituximab and umbralisib
In a phase 1/1b trial funded by TG Therapeutics, investigators led by Loretta J. Nastoupil, MD, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center, Houston, tested a triplet consisting of ibrutinib with ublituximab – another anti-CD20 antibody – and umbralisib (TGR-1202) – an oral PI3 kinase–delta inhibitor.
A total of 38 patients with generally heavily pretreated leukemias and lymphomas were studied, including 20 with CLL or SLL. Notably, eight patients (50%) with CLL had a 17p or 11q deletion.
The median time on study was 11.1 months, reported Dr. Nastoupil, who disclosed that she receives honoraria and research funding from TG Therapeutics and that she has relationships with other companies. The overall response rate for the 19 evaluable patients with CLL or SLL was 100% (complete response in 32%, partial response in 68%).
The main grade 3 or 4 adverse events in the entire trial population were neutropenia (18%) and pyrexia (8%). Only two patients discontinued treatment because of adverse events.
“An expansion cohort is ongoing at the highest dose, and we will clearly need more patients treated and longer follow-up to really know the efficacy,” commented Dr. Brown, the discussant for the poster session. “But overall, I think the safety looks encouraging with this combination.”
“Novel agent combinations are feasible and hold promise for deeper remission and/or time-limited therapy. Most of the excitement is focused around BTK and BCL-2 inhibitors, but there is clearly a role for kinase-kinase combinations because we see here that it was safe to combine ibrutinib with a PI3 kinase inhibitor,” she noted. “So, we should continue to pursue other kinase-kinase combinations, as well as BCL-2–kinase combinations.”
Ibrutinib plus CAR-T cells
In a pilot trial funded by Novartis, investigators led by Saar Gill, MD, PhD, of the hospital of the University of Pennsylvania in Philadelphia, tested the combination of ibrutinib with chimeric antigen receptor–T cells (CAR-T cells) against CD19, on the basis of preclinical evidence of synergy.
Trial participants were 10 patients with CLL or SLL who had not achieved complete response with ibrutinib. All had a 17p deletion or a p53 mutation, or a complex karyotype, and some had a known ibrutinib resistance mutation.
At 3 months, eight (89%) of nine evaluable patients had no evidence of disease in bone marrow, reported Dr. Gill, who disclosed that he receives research funding from Novartis (institutional) and has patents for CAR-T cells for acute myeloid leukemia, among other disclosures. Seven patients (78%) achieved a complete or partial radiographic response in the spleen and lymph nodes.
Overall, the treatment was well tolerated. One patient developed grade 4 tumor lysis syndrome, and two developed grade 3 cytokine release syndrome. But, none required anticytokine therapy.
Most patients remain on ibrutinib and are being monitored. In addition, the researchers plan to treat 25 more patients with the same combination.
“We don’t know what will happen if the patients stop ibrutinib at some point, which is a question for the future,” commented Dr. Brown, the discussant.
“CAR-T cell therapy in CLL has historically had lower response rates than in ALL, but preclinical and early clinical data support ongoing investigation of combination therapy with ibrutinib as it appears that ibrutinib may enhance the production and engraftment of the T cells,” she noted. “Ultimately, of course, the role of CAR-T cell therapy in CLL will require a very clear, well-defined safety [protocol] if it is being used in comparison to some of the oral drugs that we can maintain many of the patients on for a long time.”
AT ASCO 2017
Key clinical point:
Major finding: Long-term progression-free survival was better with ibrutinib than with ofatumumab (hazard ratio, 0.133). The overall response rate with the triplet of ibrutinib, ublituximab, and umbralisib was 100%. Fully 89% of patients achieved no evidence of disease in marrow when anti-CD19 CAR-T cells were added to ibrutinib.
Data source: An update of a phase III randomized trial among 391 patients with previously treated CLL or SLL (RESONATE). A phase 1/1b trial including 19 patients with mainly relapsed or refractory CLL or SLL. A pilot trial among 10 patients with previously treated, mainly higher-risk, CLL or SLL.
Disclosures: Dr. Byrd disclosed that he receives research funding from Genentech, Acerta, and Pharmacyclics. The RESONATE trial was funded by Pharmacyclics. Dr. Nastoupil disclosed that she receives honoraria from Abbvie, Celgene, Genentech/Roche, Gilead Sciences, Pharmacyclics, and TG Therapeutics; receives research funding from Abbvie, Celgene, Janssen Biotech, and TG Therapeutics; and receives travel, accommodations, and/or expenses from Janssen Biotech. The trial was funded by TG Therapeutics. Dr. Gill disclosed that he receives honoraria from Alexion Pharmaceuticals, receives research funding from Novartis (institutional), and has patents for CAR-T cells for acute myeloid leukemia. The trial was funded by Novartis.
Patch is early indicator of temperature rise after HSCT
A fever-monitoring patch was well tolerated in hospitalized patients undergoing stem cell transplant or intensive chemotherapy for leukemia, and alerted physicians to the presence of a fever much earlier than did standard temperature-taking procedures, according to findings from a study abstract that was published in conjunction with the annual meeting of the American Society of Clinical Oncology.
The patch can transmit data via Bluetooth to an iPad or smartphone, and it attempts to bring temperature recording in line with other vital signs. “It’s the only vital sign that’s not continuously monitored outside of the ICU,” said John Gannon, CEO of Blue Spark, which markets the TempTraq underarm patch used in the study.
The units are constructed with thin batteries that can be “printed” on to any surface. “Being disposable makes it a very usable work flow device,” said Mr. Gannon.
The researchers tested the TempTraq in 10 patients who had been admitted for stem cell transplant or high dose chemotherapy for leukemia.
In addition to wearing the patch, patients had their temperature measured in standard fashion every 4 hours. The researchers defined a temperature rise as a spike above 100.4° F. The device measured body temperature every 10 minutes (14,342 temperature measurements).
Standard of care measurement identified 23 temperature rise episodes, 21 of which were recorded by the TempTraq patch. The device caught temperature spikes much sooner than did standard of care measures – a median of 140.1 minutes earlier (range, 30-180 minutes).
All 10 patients continued to wear the patch throughout the hospital stay, with 9 of 10 reporting that the patch was comfortable and didn’t produce any skin irritation. Eight patients indicated interest in using the patch again, and 8 said they were completely satisfied with the patch.
The next step is to determine if the patch could be used successfully in an outpatient stem cell transplant setting.
The device could also be integrated directly with hospital central monitoring systems using Blue Spark’s TempTraq Connect, which is a HIPAA-compliant service supported by the Google Healthcare Cloud Platform, though this was not tested in the current study.
The TempTraq could be used to monitor patients for the onset of sepsis and allow faster interventions, according to Mr. Gannon. Also, patients who are susceptible to infections could be sent home with a TempTraq monitor, which would send signals to a central monitoring station.
A fever-monitoring patch was well tolerated in hospitalized patients undergoing stem cell transplant or intensive chemotherapy for leukemia, and alerted physicians to the presence of a fever much earlier than did standard temperature-taking procedures, according to findings from a study abstract that was published in conjunction with the annual meeting of the American Society of Clinical Oncology.
The patch can transmit data via Bluetooth to an iPad or smartphone, and it attempts to bring temperature recording in line with other vital signs. “It’s the only vital sign that’s not continuously monitored outside of the ICU,” said John Gannon, CEO of Blue Spark, which markets the TempTraq underarm patch used in the study.
The units are constructed with thin batteries that can be “printed” on to any surface. “Being disposable makes it a very usable work flow device,” said Mr. Gannon.
The researchers tested the TempTraq in 10 patients who had been admitted for stem cell transplant or high dose chemotherapy for leukemia.
In addition to wearing the patch, patients had their temperature measured in standard fashion every 4 hours. The researchers defined a temperature rise as a spike above 100.4° F. The device measured body temperature every 10 minutes (14,342 temperature measurements).
Standard of care measurement identified 23 temperature rise episodes, 21 of which were recorded by the TempTraq patch. The device caught temperature spikes much sooner than did standard of care measures – a median of 140.1 minutes earlier (range, 30-180 minutes).
All 10 patients continued to wear the patch throughout the hospital stay, with 9 of 10 reporting that the patch was comfortable and didn’t produce any skin irritation. Eight patients indicated interest in using the patch again, and 8 said they were completely satisfied with the patch.
The next step is to determine if the patch could be used successfully in an outpatient stem cell transplant setting.
The device could also be integrated directly with hospital central monitoring systems using Blue Spark’s TempTraq Connect, which is a HIPAA-compliant service supported by the Google Healthcare Cloud Platform, though this was not tested in the current study.
The TempTraq could be used to monitor patients for the onset of sepsis and allow faster interventions, according to Mr. Gannon. Also, patients who are susceptible to infections could be sent home with a TempTraq monitor, which would send signals to a central monitoring station.
A fever-monitoring patch was well tolerated in hospitalized patients undergoing stem cell transplant or intensive chemotherapy for leukemia, and alerted physicians to the presence of a fever much earlier than did standard temperature-taking procedures, according to findings from a study abstract that was published in conjunction with the annual meeting of the American Society of Clinical Oncology.
The patch can transmit data via Bluetooth to an iPad or smartphone, and it attempts to bring temperature recording in line with other vital signs. “It’s the only vital sign that’s not continuously monitored outside of the ICU,” said John Gannon, CEO of Blue Spark, which markets the TempTraq underarm patch used in the study.
The units are constructed with thin batteries that can be “printed” on to any surface. “Being disposable makes it a very usable work flow device,” said Mr. Gannon.
The researchers tested the TempTraq in 10 patients who had been admitted for stem cell transplant or high dose chemotherapy for leukemia.
In addition to wearing the patch, patients had their temperature measured in standard fashion every 4 hours. The researchers defined a temperature rise as a spike above 100.4° F. The device measured body temperature every 10 minutes (14,342 temperature measurements).
Standard of care measurement identified 23 temperature rise episodes, 21 of which were recorded by the TempTraq patch. The device caught temperature spikes much sooner than did standard of care measures – a median of 140.1 minutes earlier (range, 30-180 minutes).
All 10 patients continued to wear the patch throughout the hospital stay, with 9 of 10 reporting that the patch was comfortable and didn’t produce any skin irritation. Eight patients indicated interest in using the patch again, and 8 said they were completely satisfied with the patch.
The next step is to determine if the patch could be used successfully in an outpatient stem cell transplant setting.
The device could also be integrated directly with hospital central monitoring systems using Blue Spark’s TempTraq Connect, which is a HIPAA-compliant service supported by the Google Healthcare Cloud Platform, though this was not tested in the current study.
The TempTraq could be used to monitor patients for the onset of sepsis and allow faster interventions, according to Mr. Gannon. Also, patients who are susceptible to infections could be sent home with a TempTraq monitor, which would send signals to a central monitoring station.
FROM ASCO 2017
Key clinical point: The device has the potential to detect infections as well as sepsis.
Major finding: The device detected fevers a median of 140 minutes sooner than did standard hospital testing.
Data source: Prospective study of 10 patients.
Disclosures: Mr. Gannon is an employee of Blue Spark Technologies, which sponsored the study.
Antibody from AML survivor may prove therapeutic
CHICAGO – A therapeutic target and possibly a treatment for acute myeloid leukemia and myelodysplastic syndrome may lie in the immortalized B cells of a patient whose acute myeloid leukemia was cured after allogeneic stem cell transplantation.
A B cell clone isolated from this patient makes a hypermutated immunoglobulin G1 antibody that binds leukemic blasts of all World Health Organization 2008 AML and myelodysplastic syndrome (MDS) types, based on cells obtained from 60 AML or MDS patients, but does not target healthy cells and lymphoid tissue, Mette D. Hazenberg, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.
“CD43 is broadly expressed on AML and MDS and, therefore, is a highly interesting target for immunotherapy,” said Dr. Hazenberg of AIMM Therapeutics and Academic Medical Center, Amsterdam.
The growth of luciferase-labeled AML cells expressing CD43s was inhibited in highly immunodeficient NOD scid-gamma mice that were reconstituted with human hematopoietic stem cells injected with AT1413. Healthy human hematopoietic cells, which express low levels of the target, were not affected by the treatment.
Next steps include further in vivo preclinical studies, according to Dr. Hazenberg.
AIMM Therapeutics is a biotech company comprising a joint venture between Immpact and the Academic Medical Center (AMC) at the University of Amsterdam. The study was supported by an AMC PhD scholarship and the KWF Dutch Cancer Society.
[email protected]
On Twitter @maryjodales
CHICAGO – A therapeutic target and possibly a treatment for acute myeloid leukemia and myelodysplastic syndrome may lie in the immortalized B cells of a patient whose acute myeloid leukemia was cured after allogeneic stem cell transplantation.
A B cell clone isolated from this patient makes a hypermutated immunoglobulin G1 antibody that binds leukemic blasts of all World Health Organization 2008 AML and myelodysplastic syndrome (MDS) types, based on cells obtained from 60 AML or MDS patients, but does not target healthy cells and lymphoid tissue, Mette D. Hazenberg, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.
“CD43 is broadly expressed on AML and MDS and, therefore, is a highly interesting target for immunotherapy,” said Dr. Hazenberg of AIMM Therapeutics and Academic Medical Center, Amsterdam.
The growth of luciferase-labeled AML cells expressing CD43s was inhibited in highly immunodeficient NOD scid-gamma mice that were reconstituted with human hematopoietic stem cells injected with AT1413. Healthy human hematopoietic cells, which express low levels of the target, were not affected by the treatment.
Next steps include further in vivo preclinical studies, according to Dr. Hazenberg.
AIMM Therapeutics is a biotech company comprising a joint venture between Immpact and the Academic Medical Center (AMC) at the University of Amsterdam. The study was supported by an AMC PhD scholarship and the KWF Dutch Cancer Society.
[email protected]
On Twitter @maryjodales
CHICAGO – A therapeutic target and possibly a treatment for acute myeloid leukemia and myelodysplastic syndrome may lie in the immortalized B cells of a patient whose acute myeloid leukemia was cured after allogeneic stem cell transplantation.
A B cell clone isolated from this patient makes a hypermutated immunoglobulin G1 antibody that binds leukemic blasts of all World Health Organization 2008 AML and myelodysplastic syndrome (MDS) types, based on cells obtained from 60 AML or MDS patients, but does not target healthy cells and lymphoid tissue, Mette D. Hazenberg, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.
“CD43 is broadly expressed on AML and MDS and, therefore, is a highly interesting target for immunotherapy,” said Dr. Hazenberg of AIMM Therapeutics and Academic Medical Center, Amsterdam.
The growth of luciferase-labeled AML cells expressing CD43s was inhibited in highly immunodeficient NOD scid-gamma mice that were reconstituted with human hematopoietic stem cells injected with AT1413. Healthy human hematopoietic cells, which express low levels of the target, were not affected by the treatment.
Next steps include further in vivo preclinical studies, according to Dr. Hazenberg.
AIMM Therapeutics is a biotech company comprising a joint venture between Immpact and the Academic Medical Center (AMC) at the University of Amsterdam. The study was supported by an AMC PhD scholarship and the KWF Dutch Cancer Society.
[email protected]
On Twitter @maryjodales
AT ASCO 2017
Key clinical point:
Major finding: The growth of luciferase-labeled SH2 cells was inhibited in highly immunodeficient NSG (NOD scid-gamma) mice that were reconstituted with human hematopoietic stem cells injected with AT1413.
Data source: Cellular studies and studies in severely immunodeficient mice.
Disclosures: Dr. Hazenberg is with AIMM Therapeutics and Academic Medical Center, Amsterdam. AIMM Therapeutics is a biotech company comprising a joint venture between Immpact and the Academic Medical Center (AMC) at the University of Amsterdam. The study was supported by an AMC PhD scholarship and the KWF Dutch Cancer Society.
FDA approves rituximab + hyaluronidase human for FL, DLBCL, and CLL
The Food and Drug Administration has approved rituximab plus hyaluronidase human for adult patients with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL).
The combination product, to be marketed as Rituxan Hycela, is administered subcutaneously, shortening administration time to 5 to 7 minutes as compared with the several hours needed for intravenous infusion, the FDA said in a statement.
Approval was based on noninferior rituximab trough concentrations for the subcutaneously administered combination, compared with intravenous rituximab, and comparable efficacy and safety results as shown in multiple randomized clinical trials.
The most common adverse events seen with the combination in patients with FL included infections, neutropenia, nausea, constipation, cough, and fatigue. In patients with DLBCL, the most common adverse events were infections, neutropenia, alopecia, nausea, and anemia; in CLL patients, infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and injection site erythema occurred most commonly.
The combination is indicated for the following previously approved indications for rituximab:
- Relapsed or refractory FL as a single agent.
- Previously untreated FL in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy.
- Nonprogressing (including stable disease) FL as a single agent after first-line cyclophosphamide, vincristine, and prednisone chemotherapy.
- Previously untreated DLBCL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone or other anthracycline-based chemotherapy regimens.
- Previously untreated and previously treated CLL in combination with fludarabine and cyclophosphamide.
The recommended doses are 1,400 mg rituximab and 23,400 units hyaluronidase human for FL and DLBCL and 1,600 mg rituximab and 26,800 units hyaluronidase human for CLL. The combination treatment should be initiated only after patients have received at least one full dose of a rituximab product by intravenous infusion, according to the prescribing information.
Rituxan Hycela is marketed by Genentech.
The Food and Drug Administration has approved rituximab plus hyaluronidase human for adult patients with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL).
The combination product, to be marketed as Rituxan Hycela, is administered subcutaneously, shortening administration time to 5 to 7 minutes as compared with the several hours needed for intravenous infusion, the FDA said in a statement.
Approval was based on noninferior rituximab trough concentrations for the subcutaneously administered combination, compared with intravenous rituximab, and comparable efficacy and safety results as shown in multiple randomized clinical trials.
The most common adverse events seen with the combination in patients with FL included infections, neutropenia, nausea, constipation, cough, and fatigue. In patients with DLBCL, the most common adverse events were infections, neutropenia, alopecia, nausea, and anemia; in CLL patients, infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and injection site erythema occurred most commonly.
The combination is indicated for the following previously approved indications for rituximab:
- Relapsed or refractory FL as a single agent.
- Previously untreated FL in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy.
- Nonprogressing (including stable disease) FL as a single agent after first-line cyclophosphamide, vincristine, and prednisone chemotherapy.
- Previously untreated DLBCL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone or other anthracycline-based chemotherapy regimens.
- Previously untreated and previously treated CLL in combination with fludarabine and cyclophosphamide.
The recommended doses are 1,400 mg rituximab and 23,400 units hyaluronidase human for FL and DLBCL and 1,600 mg rituximab and 26,800 units hyaluronidase human for CLL. The combination treatment should be initiated only after patients have received at least one full dose of a rituximab product by intravenous infusion, according to the prescribing information.
Rituxan Hycela is marketed by Genentech.
The Food and Drug Administration has approved rituximab plus hyaluronidase human for adult patients with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL).
The combination product, to be marketed as Rituxan Hycela, is administered subcutaneously, shortening administration time to 5 to 7 minutes as compared with the several hours needed for intravenous infusion, the FDA said in a statement.
Approval was based on noninferior rituximab trough concentrations for the subcutaneously administered combination, compared with intravenous rituximab, and comparable efficacy and safety results as shown in multiple randomized clinical trials.
The most common adverse events seen with the combination in patients with FL included infections, neutropenia, nausea, constipation, cough, and fatigue. In patients with DLBCL, the most common adverse events were infections, neutropenia, alopecia, nausea, and anemia; in CLL patients, infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and injection site erythema occurred most commonly.
The combination is indicated for the following previously approved indications for rituximab:
- Relapsed or refractory FL as a single agent.
- Previously untreated FL in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy.
- Nonprogressing (including stable disease) FL as a single agent after first-line cyclophosphamide, vincristine, and prednisone chemotherapy.
- Previously untreated DLBCL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone or other anthracycline-based chemotherapy regimens.
- Previously untreated and previously treated CLL in combination with fludarabine and cyclophosphamide.
The recommended doses are 1,400 mg rituximab and 23,400 units hyaluronidase human for FL and DLBCL and 1,600 mg rituximab and 26,800 units hyaluronidase human for CLL. The combination treatment should be initiated only after patients have received at least one full dose of a rituximab product by intravenous infusion, according to the prescribing information.
Rituxan Hycela is marketed by Genentech.
Lenalidomide consolidation linked to extended overall survival in non-del(11q) CLL
CHICAGO – Lenalidomide consolidation therapy was associated with an extended survival plateau for patients with non-del(11q) chronic lymphocytic leukemia (CLL), based on results from the phase 2 CALGB 10404 trial.
This unique survival plateau indicates future studies should continue to examine the role of lenalidomide, compared with fludarabine plus rituximab therapy, as well as the incorporation of lenalidomide into other novel treatment regimens, Amy Ruppert, MAS, said at the annual meeting of the American Society of Clinical Oncology.
All patients received 6 months of FR or FCR therapy, then patients underwent full staging. At 10 months, patients who had been randomized to the FR + lenalidomide group received lenalidomide 5 mg on days 1-21 of the first 28 day cycle and lenalidomide 10 mg on days 1-21 of the subsequent 5 cycles. At 18 months, patients in the FR+L group underwent full staging, and all patients underwent full staging at 24 months.
Based on pretreatment central interphase cytogenetic screening, patients who had del(11q22.3) in at least 20% of their cells were excluded from the primary analysis of 2-year progression-free survival.
Median progression-free survival was significantly shorter with FR, compared with FR+L (P = .03) and FCR (P less than .01), at 43 months (95% CI, 33-50), 66 months (95% CI, 45-not reached), and 78 months (95% CI, 58-not reached), respectively.
Median overall survival has not been reached for any arm of the study. While overall survival was similar across all arms at 1, 2, and 3 years of follow-up, there was a plateau in overall survival with no events seen beyond 41 months in the FR+L arm. Events continued to occur in the FR and FCR arms, reported Ms. Ruppert of the Comprehensive Cancer Center at Ohio State University, Columbus. At 48 months, the hazard ratio for overall survival in FR+L vs. FR was 0.27 (95% CI, 0.10-0.70; P = .01).
Ms. Ruppert had no financial disclosures. The study is sponsored by the National Cancer Institute and Celgene.
[email protected]
On Twitter @maryjodales
CHICAGO – Lenalidomide consolidation therapy was associated with an extended survival plateau for patients with non-del(11q) chronic lymphocytic leukemia (CLL), based on results from the phase 2 CALGB 10404 trial.
This unique survival plateau indicates future studies should continue to examine the role of lenalidomide, compared with fludarabine plus rituximab therapy, as well as the incorporation of lenalidomide into other novel treatment regimens, Amy Ruppert, MAS, said at the annual meeting of the American Society of Clinical Oncology.
All patients received 6 months of FR or FCR therapy, then patients underwent full staging. At 10 months, patients who had been randomized to the FR + lenalidomide group received lenalidomide 5 mg on days 1-21 of the first 28 day cycle and lenalidomide 10 mg on days 1-21 of the subsequent 5 cycles. At 18 months, patients in the FR+L group underwent full staging, and all patients underwent full staging at 24 months.
Based on pretreatment central interphase cytogenetic screening, patients who had del(11q22.3) in at least 20% of their cells were excluded from the primary analysis of 2-year progression-free survival.
Median progression-free survival was significantly shorter with FR, compared with FR+L (P = .03) and FCR (P less than .01), at 43 months (95% CI, 33-50), 66 months (95% CI, 45-not reached), and 78 months (95% CI, 58-not reached), respectively.
Median overall survival has not been reached for any arm of the study. While overall survival was similar across all arms at 1, 2, and 3 years of follow-up, there was a plateau in overall survival with no events seen beyond 41 months in the FR+L arm. Events continued to occur in the FR and FCR arms, reported Ms. Ruppert of the Comprehensive Cancer Center at Ohio State University, Columbus. At 48 months, the hazard ratio for overall survival in FR+L vs. FR was 0.27 (95% CI, 0.10-0.70; P = .01).
Ms. Ruppert had no financial disclosures. The study is sponsored by the National Cancer Institute and Celgene.
[email protected]
On Twitter @maryjodales
CHICAGO – Lenalidomide consolidation therapy was associated with an extended survival plateau for patients with non-del(11q) chronic lymphocytic leukemia (CLL), based on results from the phase 2 CALGB 10404 trial.
This unique survival plateau indicates future studies should continue to examine the role of lenalidomide, compared with fludarabine plus rituximab therapy, as well as the incorporation of lenalidomide into other novel treatment regimens, Amy Ruppert, MAS, said at the annual meeting of the American Society of Clinical Oncology.
All patients received 6 months of FR or FCR therapy, then patients underwent full staging. At 10 months, patients who had been randomized to the FR + lenalidomide group received lenalidomide 5 mg on days 1-21 of the first 28 day cycle and lenalidomide 10 mg on days 1-21 of the subsequent 5 cycles. At 18 months, patients in the FR+L group underwent full staging, and all patients underwent full staging at 24 months.
Based on pretreatment central interphase cytogenetic screening, patients who had del(11q22.3) in at least 20% of their cells were excluded from the primary analysis of 2-year progression-free survival.
Median progression-free survival was significantly shorter with FR, compared with FR+L (P = .03) and FCR (P less than .01), at 43 months (95% CI, 33-50), 66 months (95% CI, 45-not reached), and 78 months (95% CI, 58-not reached), respectively.
Median overall survival has not been reached for any arm of the study. While overall survival was similar across all arms at 1, 2, and 3 years of follow-up, there was a plateau in overall survival with no events seen beyond 41 months in the FR+L arm. Events continued to occur in the FR and FCR arms, reported Ms. Ruppert of the Comprehensive Cancer Center at Ohio State University, Columbus. At 48 months, the hazard ratio for overall survival in FR+L vs. FR was 0.27 (95% CI, 0.10-0.70; P = .01).
Ms. Ruppert had no financial disclosures. The study is sponsored by the National Cancer Institute and Celgene.
[email protected]
On Twitter @maryjodales
AT ASCO 2017
Key clinical point:
Major finding: At 48 months, the hazard ratio for overall survival in FR+L vs. FR was 0.27 (95% CI, 0.10-0.70; P = .01).
Data source: Results from 342 patients in the phase 2 CALGB 10404 trial.
Disclosures: Ms. Ruppert had no financial disclosures. The study is sponsored by the National Cancer Institute and Celgene.
Sequential triple therapy produces high response rates in CLL
Lugano, Switzerland– It’s in the BAG: For patients with treatment-naive or relapsed/refractory chronic lymphocytic leukemia, a regimen consisting of debulking with bendamustine (Treanda) followed sequentially by obinutuzumab (Gazyva) and venetoclax (Venclexta) was associated with a high overall response rate and a large majority of patients being negative for minimal residual disease (MRD) in peripheral blood.
In the open-label, phase II CLL2-BAG study in 66 patients, the overall response rate at the end of induction was 95%, and 87% of patients were negative for MRD, reported Paula Cramer, MD, of the University of Cologne (Germany).
“This sequential treatment of bendamustine followed by obinutuzumab and venetoclax does not lead to any cumulative or unexpected toxicity. As compared to other trials, it’s important to point out that only one laboratory TLS [tumor lysis syndrome] occurred with venetoclax. Maybe that’s explained by the sequential start of all three drugs,” she said at the International Conference on Malignant Lymphoma.
The trial is based on a concept the investigators call “sequential triple-T” (tailored and targeted treatment) aimed at complete eradication of MRD.
The 66 patients (median age, 59 years) had either previously untreated or relapsed/refractory CLL; 34 of the treatment-naive and 29 of the relapsed/refractory patients were evaluable for response.
At enrollment, patients who had an absolute lymphocyte count of 25,000/mcL or greater and/or lymph nodes 5 cm or larger received two cycles of debulking with bendamustine 70 mg/m2 on days 1 and 2 every 28 days, unless this was contraindicated.
The induction phase consisted of obinutuzumab 1,000 mg administered three times in cycle 1, then every 4 weeks for cycles 2 through 6. Venetoclax was started during cycle 2 with a dose escalation to 400 mg daily over a period of 5 weeks.
Maintenance therapy consisted of daily venetoclax and obinutuzumab every 3 months until MRD negativity or up to 24 months.
A total of 45 patients (31 who were treatment naive and 14 with relapsed/refractory disease) underwent debulking. Of this group 36 patients received both cycles, and 9 discontinued early because of either adverse events (5 patients), disease progression (1), or unknown reasons (3).
Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.
Responses
In all, 24 patients (53%) who had debulking had a response during that phase based on International Workshop on CLL (IWCLL) criteria, for an overall response rate (ORR) of 53%. Thirteen patients had stable disease after debulking, and four had disease progression.
Responses after induction according to IWCLL criteria, the primary endpoint, included five patients with a complete response (three treatment-naive and two relapsed/refractory patients), and 20 patients (14 treatment-naive and six relapsed/refractory patients) with an unconfirmed or clinical complete response or a complete response with incomplete recovery of counts.
In addition, 35 patients (17 who were treatment naive and 18 with relapsed/refractory disease) had a partial response. No patients had stable disease, and three patients, all with relapsed/refractory disease, had disease progression.
Of the 63 patients who had at least two cycles of therapy, 87% were MRD negative. Eight patients had MRD assessments by bone marrow, and all eight were MRD negative.
The maintenance phase of the trial is ongoing and the data are not mature, but 56 patients (30 who were treatment naive and 26 with relapsed/refractory disease) have started on maintenance therapy. Of this group, 28 have stopped maintenance, including 21 patients who stopped because they achieved MRD negativity, 5 who discontinued because of adverse events, and 2 with disease progression or Richter’s transformation.
At 15 months of follow-up, progression-free survival was 100% in patients who received the combination as the frontline therapy, and 83% in the patients with relapsed/refractory disease.
Adverse events
In the debulking phase, 34 patients (72%) experienced adverse events of any grade, including 16 patients with grade 3 or 4 events
Adverse events associated with debulking included neutropenia and anemia, each seen in five patients, thrombocytopenia and infection each seen in three patients, and coronary artery disorders, rash, tumor lysis syndrome, vomiting, and pyrexia in one patient each.
Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.
All but 3 of the 63 patients had an adverse event, and 44 patients had at least one grade 3 or 4 adverse event.
Cytopenias, infections, infusion-related reactions, and neoplasms were the most common adverse events.
There were three grade 3 laboratory-confirmed cases of tumor lysis syndrome, one each occurring during bendamustine debulking, obinutuzumab administration, and venetoclax administration.
Something other than venetoclax?
Davide Rossi, MD, PhD, of the Oncology Institute of Southern Switzerland in Bellinzona, the invited discussant, questioned whether venetoclax is the best agent to use in sequential triple-T therapy.
“We know that venetoclax is more active in blood and bone marrow than in lymph nodes and, indeed, a proportion of cases achieving all the criteria for a CR [complete response] in the bone marrow and the peripheral blood, including MRD negativity, may still have some residual [disease in] lymph nodes,” he said.
Drugs that inhibit the B-cell receptor pathway may be more effective at eradicating MRD in the lymph node compartment, Dr. Cramer said.
The study was sponsored by the German CLL study group. Dr. Cramer disclosed financial ties to multiple entities. Dr. Rossi did not report disclosures.
Lugano, Switzerland– It’s in the BAG: For patients with treatment-naive or relapsed/refractory chronic lymphocytic leukemia, a regimen consisting of debulking with bendamustine (Treanda) followed sequentially by obinutuzumab (Gazyva) and venetoclax (Venclexta) was associated with a high overall response rate and a large majority of patients being negative for minimal residual disease (MRD) in peripheral blood.
In the open-label, phase II CLL2-BAG study in 66 patients, the overall response rate at the end of induction was 95%, and 87% of patients were negative for MRD, reported Paula Cramer, MD, of the University of Cologne (Germany).
“This sequential treatment of bendamustine followed by obinutuzumab and venetoclax does not lead to any cumulative or unexpected toxicity. As compared to other trials, it’s important to point out that only one laboratory TLS [tumor lysis syndrome] occurred with venetoclax. Maybe that’s explained by the sequential start of all three drugs,” she said at the International Conference on Malignant Lymphoma.
The trial is based on a concept the investigators call “sequential triple-T” (tailored and targeted treatment) aimed at complete eradication of MRD.
The 66 patients (median age, 59 years) had either previously untreated or relapsed/refractory CLL; 34 of the treatment-naive and 29 of the relapsed/refractory patients were evaluable for response.
At enrollment, patients who had an absolute lymphocyte count of 25,000/mcL or greater and/or lymph nodes 5 cm or larger received two cycles of debulking with bendamustine 70 mg/m2 on days 1 and 2 every 28 days, unless this was contraindicated.
The induction phase consisted of obinutuzumab 1,000 mg administered three times in cycle 1, then every 4 weeks for cycles 2 through 6. Venetoclax was started during cycle 2 with a dose escalation to 400 mg daily over a period of 5 weeks.
Maintenance therapy consisted of daily venetoclax and obinutuzumab every 3 months until MRD negativity or up to 24 months.
A total of 45 patients (31 who were treatment naive and 14 with relapsed/refractory disease) underwent debulking. Of this group 36 patients received both cycles, and 9 discontinued early because of either adverse events (5 patients), disease progression (1), or unknown reasons (3).
Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.
Responses
In all, 24 patients (53%) who had debulking had a response during that phase based on International Workshop on CLL (IWCLL) criteria, for an overall response rate (ORR) of 53%. Thirteen patients had stable disease after debulking, and four had disease progression.
Responses after induction according to IWCLL criteria, the primary endpoint, included five patients with a complete response (three treatment-naive and two relapsed/refractory patients), and 20 patients (14 treatment-naive and six relapsed/refractory patients) with an unconfirmed or clinical complete response or a complete response with incomplete recovery of counts.
In addition, 35 patients (17 who were treatment naive and 18 with relapsed/refractory disease) had a partial response. No patients had stable disease, and three patients, all with relapsed/refractory disease, had disease progression.
Of the 63 patients who had at least two cycles of therapy, 87% were MRD negative. Eight patients had MRD assessments by bone marrow, and all eight were MRD negative.
The maintenance phase of the trial is ongoing and the data are not mature, but 56 patients (30 who were treatment naive and 26 with relapsed/refractory disease) have started on maintenance therapy. Of this group, 28 have stopped maintenance, including 21 patients who stopped because they achieved MRD negativity, 5 who discontinued because of adverse events, and 2 with disease progression or Richter’s transformation.
At 15 months of follow-up, progression-free survival was 100% in patients who received the combination as the frontline therapy, and 83% in the patients with relapsed/refractory disease.
Adverse events
In the debulking phase, 34 patients (72%) experienced adverse events of any grade, including 16 patients with grade 3 or 4 events
Adverse events associated with debulking included neutropenia and anemia, each seen in five patients, thrombocytopenia and infection each seen in three patients, and coronary artery disorders, rash, tumor lysis syndrome, vomiting, and pyrexia in one patient each.
Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.
All but 3 of the 63 patients had an adverse event, and 44 patients had at least one grade 3 or 4 adverse event.
Cytopenias, infections, infusion-related reactions, and neoplasms were the most common adverse events.
There were three grade 3 laboratory-confirmed cases of tumor lysis syndrome, one each occurring during bendamustine debulking, obinutuzumab administration, and venetoclax administration.
Something other than venetoclax?
Davide Rossi, MD, PhD, of the Oncology Institute of Southern Switzerland in Bellinzona, the invited discussant, questioned whether venetoclax is the best agent to use in sequential triple-T therapy.
“We know that venetoclax is more active in blood and bone marrow than in lymph nodes and, indeed, a proportion of cases achieving all the criteria for a CR [complete response] in the bone marrow and the peripheral blood, including MRD negativity, may still have some residual [disease in] lymph nodes,” he said.
Drugs that inhibit the B-cell receptor pathway may be more effective at eradicating MRD in the lymph node compartment, Dr. Cramer said.
The study was sponsored by the German CLL study group. Dr. Cramer disclosed financial ties to multiple entities. Dr. Rossi did not report disclosures.
Lugano, Switzerland– It’s in the BAG: For patients with treatment-naive or relapsed/refractory chronic lymphocytic leukemia, a regimen consisting of debulking with bendamustine (Treanda) followed sequentially by obinutuzumab (Gazyva) and venetoclax (Venclexta) was associated with a high overall response rate and a large majority of patients being negative for minimal residual disease (MRD) in peripheral blood.
In the open-label, phase II CLL2-BAG study in 66 patients, the overall response rate at the end of induction was 95%, and 87% of patients were negative for MRD, reported Paula Cramer, MD, of the University of Cologne (Germany).
“This sequential treatment of bendamustine followed by obinutuzumab and venetoclax does not lead to any cumulative or unexpected toxicity. As compared to other trials, it’s important to point out that only one laboratory TLS [tumor lysis syndrome] occurred with venetoclax. Maybe that’s explained by the sequential start of all three drugs,” she said at the International Conference on Malignant Lymphoma.
The trial is based on a concept the investigators call “sequential triple-T” (tailored and targeted treatment) aimed at complete eradication of MRD.
The 66 patients (median age, 59 years) had either previously untreated or relapsed/refractory CLL; 34 of the treatment-naive and 29 of the relapsed/refractory patients were evaluable for response.
At enrollment, patients who had an absolute lymphocyte count of 25,000/mcL or greater and/or lymph nodes 5 cm or larger received two cycles of debulking with bendamustine 70 mg/m2 on days 1 and 2 every 28 days, unless this was contraindicated.
The induction phase consisted of obinutuzumab 1,000 mg administered three times in cycle 1, then every 4 weeks for cycles 2 through 6. Venetoclax was started during cycle 2 with a dose escalation to 400 mg daily over a period of 5 weeks.
Maintenance therapy consisted of daily venetoclax and obinutuzumab every 3 months until MRD negativity or up to 24 months.
A total of 45 patients (31 who were treatment naive and 14 with relapsed/refractory disease) underwent debulking. Of this group 36 patients received both cycles, and 9 discontinued early because of either adverse events (5 patients), disease progression (1), or unknown reasons (3).
Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.
Responses
In all, 24 patients (53%) who had debulking had a response during that phase based on International Workshop on CLL (IWCLL) criteria, for an overall response rate (ORR) of 53%. Thirteen patients had stable disease after debulking, and four had disease progression.
Responses after induction according to IWCLL criteria, the primary endpoint, included five patients with a complete response (three treatment-naive and two relapsed/refractory patients), and 20 patients (14 treatment-naive and six relapsed/refractory patients) with an unconfirmed or clinical complete response or a complete response with incomplete recovery of counts.
In addition, 35 patients (17 who were treatment naive and 18 with relapsed/refractory disease) had a partial response. No patients had stable disease, and three patients, all with relapsed/refractory disease, had disease progression.
Of the 63 patients who had at least two cycles of therapy, 87% were MRD negative. Eight patients had MRD assessments by bone marrow, and all eight were MRD negative.
The maintenance phase of the trial is ongoing and the data are not mature, but 56 patients (30 who were treatment naive and 26 with relapsed/refractory disease) have started on maintenance therapy. Of this group, 28 have stopped maintenance, including 21 patients who stopped because they achieved MRD negativity, 5 who discontinued because of adverse events, and 2 with disease progression or Richter’s transformation.
At 15 months of follow-up, progression-free survival was 100% in patients who received the combination as the frontline therapy, and 83% in the patients with relapsed/refractory disease.
Adverse events
In the debulking phase, 34 patients (72%) experienced adverse events of any grade, including 16 patients with grade 3 or 4 events
Adverse events associated with debulking included neutropenia and anemia, each seen in five patients, thrombocytopenia and infection each seen in three patients, and coronary artery disorders, rash, tumor lysis syndrome, vomiting, and pyrexia in one patient each.
Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.
All but 3 of the 63 patients had an adverse event, and 44 patients had at least one grade 3 or 4 adverse event.
Cytopenias, infections, infusion-related reactions, and neoplasms were the most common adverse events.
There were three grade 3 laboratory-confirmed cases of tumor lysis syndrome, one each occurring during bendamustine debulking, obinutuzumab administration, and venetoclax administration.
Something other than venetoclax?
Davide Rossi, MD, PhD, of the Oncology Institute of Southern Switzerland in Bellinzona, the invited discussant, questioned whether venetoclax is the best agent to use in sequential triple-T therapy.
“We know that venetoclax is more active in blood and bone marrow than in lymph nodes and, indeed, a proportion of cases achieving all the criteria for a CR [complete response] in the bone marrow and the peripheral blood, including MRD negativity, may still have some residual [disease in] lymph nodes,” he said.
Drugs that inhibit the B-cell receptor pathway may be more effective at eradicating MRD in the lymph node compartment, Dr. Cramer said.
The study was sponsored by the German CLL study group. Dr. Cramer disclosed financial ties to multiple entities. Dr. Rossi did not report disclosures.
AT 14-ICML
Key clinical point: Sequential therapy with bendamustine, obinutuzumab, and venetoclax was associated with high response rates in patients with both treatment-naive and relapsed/refractory chronic lymphocytic leukemia.
Major finding: The overall response rate at the end of induction was 95%.
Data source: An open-label prospective study in 66 patients with CLL.
Disclosures: The study was sponsored by the German CLL study group. Dr. Cramer and her coauthors disclosed financial ties to multiple entities. Dr. Rossi did not report disclosures.
Company discontinues phase 3 trial of vadastuximab talirine in AML
Update as of June 21: The US Food and Drug Administration (FDA) has placed the Investigational New Drug (IND) application for vadastuximab talirine on hold. No clinical trial may resume under the IND until the FDA lifts the clinical hold.
On the advice of the Independent Data Monitoring Committee, Seattle Genetics is discontinuing the phase 3 CASCADE clinical trial of vadastuximab talirine as frontline treatment in older patients with acute myeloid leukemia (AML).
The company is also suspending patient enrollment and treatment in all its vadastuximab trials, including the ongoing phase 1/2 trial in frontline high-risk myelodysplastic syndromes (MDS).
In December last year, the US Food and Drug Administration (FDA) had placed the trials of vadastuximab on full and partial clinical holds due to the potential risk of hepatotoxicity.
The FDA lifted the hold in March of this year. However, concerns regarding a higher rate of deaths, including fatal infections but not liver toxicity, in the vadastuximab arm compared to control prompted the company to discontinue the phase 3 trial.
Vadastuximab talirene is an antibody-drug conjugate (ADC) targeted to CD33, which is expressed on most AML and MDS blasts. The ADC technology links anti-cancer compounds with targeting antibodies to precisely kill cancer cells and spare healthy ones.
Seattle Genetics’ ADC for Hodgkin lymphoma, brentuximab vedotin, was granted accelerated approval by the FDA in 2011.
The CASCADE trial was evaluating vadastuximab in combination with the hypomethylating agents (HMAs) azacytidine or decitabine compared to an HMA alone in older patients with newly diagnosed AML.
In addition to the MDS trial, the company is stopping enrollment onto the trial of vadastuximab in combination with 7+3 chemotherapy in newly diagnosed, younger AML patients and vadastuximab given prior to or after allogeneic hematopoietic stem cell transplant in AML patients.
Calling the decision “disappointing and unexpected,” Clay Siegall, PhD, president and CEO of Seattle Genetics, said, “Patient safety is our highest priority, and we will closely review the data and evaluate next steps.” 
Update as of June 21: The US Food and Drug Administration (FDA) has placed the Investigational New Drug (IND) application for vadastuximab talirine on hold. No clinical trial may resume under the IND until the FDA lifts the clinical hold.
On the advice of the Independent Data Monitoring Committee, Seattle Genetics is discontinuing the phase 3 CASCADE clinical trial of vadastuximab talirine as frontline treatment in older patients with acute myeloid leukemia (AML).
The company is also suspending patient enrollment and treatment in all its vadastuximab trials, including the ongoing phase 1/2 trial in frontline high-risk myelodysplastic syndromes (MDS).
In December last year, the US Food and Drug Administration (FDA) had placed the trials of vadastuximab on full and partial clinical holds due to the potential risk of hepatotoxicity.
The FDA lifted the hold in March of this year. However, concerns regarding a higher rate of deaths, including fatal infections but not liver toxicity, in the vadastuximab arm compared to control prompted the company to discontinue the phase 3 trial.
Vadastuximab talirene is an antibody-drug conjugate (ADC) targeted to CD33, which is expressed on most AML and MDS blasts. The ADC technology links anti-cancer compounds with targeting antibodies to precisely kill cancer cells and spare healthy ones.
Seattle Genetics’ ADC for Hodgkin lymphoma, brentuximab vedotin, was granted accelerated approval by the FDA in 2011.
The CASCADE trial was evaluating vadastuximab in combination with the hypomethylating agents (HMAs) azacytidine or decitabine compared to an HMA alone in older patients with newly diagnosed AML.
In addition to the MDS trial, the company is stopping enrollment onto the trial of vadastuximab in combination with 7+3 chemotherapy in newly diagnosed, younger AML patients and vadastuximab given prior to or after allogeneic hematopoietic stem cell transplant in AML patients.
Calling the decision “disappointing and unexpected,” Clay Siegall, PhD, president and CEO of Seattle Genetics, said, “Patient safety is our highest priority, and we will closely review the data and evaluate next steps.”
Update as of June 21: The US Food and Drug Administration (FDA) has placed the Investigational New Drug (IND) application for vadastuximab talirine on hold. No clinical trial may resume under the IND until the FDA lifts the clinical hold.
On the advice of the Independent Data Monitoring Committee, Seattle Genetics is discontinuing the phase 3 CASCADE clinical trial of vadastuximab talirine as frontline treatment in older patients with acute myeloid leukemia (AML).
The company is also suspending patient enrollment and treatment in all its vadastuximab trials, including the ongoing phase 1/2 trial in frontline high-risk myelodysplastic syndromes (MDS).
In December last year, the US Food and Drug Administration (FDA) had placed the trials of vadastuximab on full and partial clinical holds due to the potential risk of hepatotoxicity.
The FDA lifted the hold in March of this year. However, concerns regarding a higher rate of deaths, including fatal infections but not liver toxicity, in the vadastuximab arm compared to control prompted the company to discontinue the phase 3 trial.
Vadastuximab talirene is an antibody-drug conjugate (ADC) targeted to CD33, which is expressed on most AML and MDS blasts. The ADC technology links anti-cancer compounds with targeting antibodies to precisely kill cancer cells and spare healthy ones.
Seattle Genetics’ ADC for Hodgkin lymphoma, brentuximab vedotin, was granted accelerated approval by the FDA in 2011.
The CASCADE trial was evaluating vadastuximab in combination with the hypomethylating agents (HMAs) azacytidine or decitabine compared to an HMA alone in older patients with newly diagnosed AML.
In addition to the MDS trial, the company is stopping enrollment onto the trial of vadastuximab in combination with 7+3 chemotherapy in newly diagnosed, younger AML patients and vadastuximab given prior to or after allogeneic hematopoietic stem cell transplant in AML patients.
Calling the decision “disappointing and unexpected,” Clay Siegall, PhD, president and CEO of Seattle Genetics, said, “Patient safety is our highest priority, and we will closely review the data and evaluate next steps.”