Leukemia, Myelodysplasia, Transplantation

Image by Difu Wu

The US Food and Drug Administration (FDA) has granted priority review to a supplemental new drug application (sNDA) for the tyrosine kinase inhibitor (TKI) bosutinib (Bosulif®).

If approved, the sNDA would expand the use of bosutinib to include patients with newly diagnosed, chronic phase, Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML).

Bosutinib is currently FDA-approved to treat adults with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA plans to make a decision on the sNDA for bosutinib by the end of this year.

Meanwhile, the European Medicines Agency (EMA) has validated for review a type II variation application for bosutinib in patients with newly diagnosed, chronic phase Ph+ CML.

Bosutinib already has conditional marketing authorization in the European Economic Area for the treatment of adults with Ph+ CML who previously received at least 1 TKI and adults with Ph+ CML for whom imatinib, nilotinib, and dasatinib are not considered appropriate.

Phase 3 trial

The applications submitted to the EMA and FDA are both supported by early results from the phase 3 BFORE trial. Results from this trial were presented at the ASCO Annual Meeting in May.

In this ongoing study, researchers are comparing bosutinib and imatinib as first-line treatment of chronic phase CML.

As of the ASCO presentation, the trial had enrolled 536 patients who were randomized 1:1 to receive bosutinib (n=268) or imatinib (n=268).

The presentation included results in a modified intent-to-treat population of Ph+ patients with e13a2/e14a2 transcripts who had at least 12 months of follow-up. In this group, there were 246 patients in the bosutinib arm and 241 in the imatinib arm.

Most of the patients were still on therapy at the 12-month mark or beyond—78% in the bosutinib arm and 73.2% in the imatinib arm. The median treatment duration was 14.1 months and 13.8 months, respectively.

At 12 months, the rate of major molecular response was 47.2% in the bosutinib arm and 36.9% in the imatinib arm (P= 0.02). The rate of complete cytogenetic response was 77.2% and 66.4%, respectively (P<0.008).

One patient in the bosutinib arm and 4 in the imatinib arm discontinued treatment due to disease progression, while 12.7% and 8.7%, respectively, discontinued treatment due to drug-related toxicity.

Adverse events that were more common in the bosutinib arm than the imatinib arm included grade 3 or higher diarrhea (7.8% vs 0.8%), increased alanine levels (19% vs 1.5%), increased aspartate levels (9.7% vs 1.9%), cardiovascular events (3% vs 0.4%), and peripheral vascular events (1.5% vs 1.1%). Cerebrovascular events were more common with imatinib than bosutinib (0.4% and 0%, respectively).

Image by Difu Wu

The US Food and Drug Administration (FDA) has granted priority review to a supplemental new drug application (sNDA) for the tyrosine kinase inhibitor (TKI) bosutinib (Bosulif®).

If approved, the sNDA would expand the use of bosutinib to include patients with newly diagnosed, chronic phase, Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML).

Bosutinib is currently FDA-approved to treat adults with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA plans to make a decision on the sNDA for bosutinib by the end of this year.

Meanwhile, the European Medicines Agency (EMA) has validated for review a type II variation application for bosutinib in patients with newly diagnosed, chronic phase Ph+ CML.

Bosutinib already has conditional marketing authorization in the European Economic Area for the treatment of adults with Ph+ CML who previously received at least 1 TKI and adults with Ph+ CML for whom imatinib, nilotinib, and dasatinib are not considered appropriate.

Phase 3 trial

The applications submitted to the EMA and FDA are both supported by early results from the phase 3 BFORE trial. Results from this trial were presented at the ASCO Annual Meeting in May.

In this ongoing study, researchers are comparing bosutinib and imatinib as first-line treatment of chronic phase CML.

As of the ASCO presentation, the trial had enrolled 536 patients who were randomized 1:1 to receive bosutinib (n=268) or imatinib (n=268).

The presentation included results in a modified intent-to-treat population of Ph+ patients with e13a2/e14a2 transcripts who had at least 12 months of follow-up. In this group, there were 246 patients in the bosutinib arm and 241 in the imatinib arm.

Most of the patients were still on therapy at the 12-month mark or beyond—78% in the bosutinib arm and 73.2% in the imatinib arm. The median treatment duration was 14.1 months and 13.8 months, respectively.

At 12 months, the rate of major molecular response was 47.2% in the bosutinib arm and 36.9% in the imatinib arm (P= 0.02). The rate of complete cytogenetic response was 77.2% and 66.4%, respectively (P<0.008).

One patient in the bosutinib arm and 4 in the imatinib arm discontinued treatment due to disease progression, while 12.7% and 8.7%, respectively, discontinued treatment due to drug-related toxicity.

Adverse events that were more common in the bosutinib arm than the imatinib arm included grade 3 or higher diarrhea (7.8% vs 0.8%), increased alanine levels (19% vs 1.5%), increased aspartate levels (9.7% vs 1.9%), cardiovascular events (3% vs 0.4%), and peripheral vascular events (1.5% vs 1.1%). Cerebrovascular events were more common with imatinib than bosutinib (0.4% and 0%, respectively).

Image by Difu Wu

The US Food and Drug Administration (FDA) has granted priority review to a supplemental new drug application (sNDA) for the tyrosine kinase inhibitor (TKI) bosutinib (Bosulif®).

If approved, the sNDA would expand the use of bosutinib to include patients with newly diagnosed, chronic phase, Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML).

Bosutinib is currently FDA-approved to treat adults with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA plans to make a decision on the sNDA for bosutinib by the end of this year.

Meanwhile, the European Medicines Agency (EMA) has validated for review a type II variation application for bosutinib in patients with newly diagnosed, chronic phase Ph+ CML.

Bosutinib already has conditional marketing authorization in the European Economic Area for the treatment of adults with Ph+ CML who previously received at least 1 TKI and adults with Ph+ CML for whom imatinib, nilotinib, and dasatinib are not considered appropriate.

Phase 3 trial

The applications submitted to the EMA and FDA are both supported by early results from the phase 3 BFORE trial. Results from this trial were presented at the ASCO Annual Meeting in May.

In this ongoing study, researchers are comparing bosutinib and imatinib as first-line treatment of chronic phase CML.

As of the ASCO presentation, the trial had enrolled 536 patients who were randomized 1:1 to receive bosutinib (n=268) or imatinib (n=268).

The presentation included results in a modified intent-to-treat population of Ph+ patients with e13a2/e14a2 transcripts who had at least 12 months of follow-up. In this group, there were 246 patients in the bosutinib arm and 241 in the imatinib arm.

Most of the patients were still on therapy at the 12-month mark or beyond—78% in the bosutinib arm and 73.2% in the imatinib arm. The median treatment duration was 14.1 months and 13.8 months, respectively.

At 12 months, the rate of major molecular response was 47.2% in the bosutinib arm and 36.9% in the imatinib arm (P= 0.02). The rate of complete cytogenetic response was 77.2% and 66.4%, respectively (P<0.008).

One patient in the bosutinib arm and 4 in the imatinib arm discontinued treatment due to disease progression, while 12.7% and 8.7%, respectively, discontinued treatment due to drug-related toxicity.

Adverse events that were more common in the bosutinib arm than the imatinib arm included grade 3 or higher diarrhea (7.8% vs 0.8%), increased alanine levels (19% vs 1.5%), increased aspartate levels (9.7% vs 1.9%), cardiovascular events (3% vs 0.4%), and peripheral vascular events (1.5% vs 1.1%). Cerebrovascular events were more common with imatinib than bosutinib (0.4% and 0%, respectively).

Red and white blood cells

New research suggests that bacterial infection activates hematopoietic stem cells (HSCs) and significantly reduces their ability to produce blood by forcibly inducing proliferation.

These findings indicate that bacterial infections might cause dysregulated hematopoiesis like that which occurs in patients with anemias and leukemias.

Hitoshi Takizawa, PhD, of Kumamoto University’s International Research Center for Medical Sciences in Kumamoto, Japan, and his colleagues reported these findings in Cell Stem Cell.

The researchers gave lipopolysaccharide to mice to generate a bacterial infection model and analyzed the role of Toll-like receptors (TLRs) in HSCs.

The team found that lipopolysaccharides spread throughout the body, with some eventually reaching the bone marrow. This stimulated TLR4 and induced HSCs to proliferate.

However, the stimulus also induced stress on the HSCs.

So although HSCs proliferate temporarily upon TLR4 stimulation, their ability to successfully self-replicate decreases, resulting in diminished blood production.

The researchers observed similar results after infecting mice with Salmonella Typhimurium.

“Fortunately, we were able to confirm that this molecular reaction can be inhibited by drugs,” Dr Takizawa said.

Specifically, the researchers found that activation of reactive oxygen species and p38 through TLR4 ligation is key to HSC dysfunction.

And small-molecule inhibitors of reactive oxygen species and p38 were able to prevent HSC dysfunction.

“The medication maintains the production of blood and immune cells without weakening the immune reaction against pathogenic bacteria,” Dr Takizawa said. “It might be possible to simultaneously prevent blood diseases and many bacterial infections in the future.” 

Red and white blood cells

New research suggests that bacterial infection activates hematopoietic stem cells (HSCs) and significantly reduces their ability to produce blood by forcibly inducing proliferation.

These findings indicate that bacterial infections might cause dysregulated hematopoiesis like that which occurs in patients with anemias and leukemias.

Hitoshi Takizawa, PhD, of Kumamoto University’s International Research Center for Medical Sciences in Kumamoto, Japan, and his colleagues reported these findings in Cell Stem Cell.

The researchers gave lipopolysaccharide to mice to generate a bacterial infection model and analyzed the role of Toll-like receptors (TLRs) in HSCs.

The team found that lipopolysaccharides spread throughout the body, with some eventually reaching the bone marrow. This stimulated TLR4 and induced HSCs to proliferate.

However, the stimulus also induced stress on the HSCs.

So although HSCs proliferate temporarily upon TLR4 stimulation, their ability to successfully self-replicate decreases, resulting in diminished blood production.

The researchers observed similar results after infecting mice with Salmonella Typhimurium.

“Fortunately, we were able to confirm that this molecular reaction can be inhibited by drugs,” Dr Takizawa said.

Specifically, the researchers found that activation of reactive oxygen species and p38 through TLR4 ligation is key to HSC dysfunction.

And small-molecule inhibitors of reactive oxygen species and p38 were able to prevent HSC dysfunction.

“The medication maintains the production of blood and immune cells without weakening the immune reaction against pathogenic bacteria,” Dr Takizawa said. “It might be possible to simultaneously prevent blood diseases and many bacterial infections in the future.” 

Red and white blood cells

New research suggests that bacterial infection activates hematopoietic stem cells (HSCs) and significantly reduces their ability to produce blood by forcibly inducing proliferation.

These findings indicate that bacterial infections might cause dysregulated hematopoiesis like that which occurs in patients with anemias and leukemias.

Hitoshi Takizawa, PhD, of Kumamoto University’s International Research Center for Medical Sciences in Kumamoto, Japan, and his colleagues reported these findings in Cell Stem Cell.

The researchers gave lipopolysaccharide to mice to generate a bacterial infection model and analyzed the role of Toll-like receptors (TLRs) in HSCs.

The team found that lipopolysaccharides spread throughout the body, with some eventually reaching the bone marrow. This stimulated TLR4 and induced HSCs to proliferate.

However, the stimulus also induced stress on the HSCs.

So although HSCs proliferate temporarily upon TLR4 stimulation, their ability to successfully self-replicate decreases, resulting in diminished blood production.

The researchers observed similar results after infecting mice with Salmonella Typhimurium.

“Fortunately, we were able to confirm that this molecular reaction can be inhibited by drugs,” Dr Takizawa said.

Specifically, the researchers found that activation of reactive oxygen species and p38 through TLR4 ligation is key to HSC dysfunction.

And small-molecule inhibitors of reactive oxygen species and p38 were able to prevent HSC dysfunction.

“The medication maintains the production of blood and immune cells without weakening the immune reaction against pathogenic bacteria,” Dr Takizawa said. “It might be possible to simultaneously prevent blood diseases and many bacterial infections in the future.” 

Enasidenib was a well-tolerated, efficacious alternative to cytotoxic chemotherapy for patients with IDH2-mutated relapsed or refractory acute myeloid leukemia (AML), the results of a phase 1/2 study showed.

The Food and Drug Administration recently approved enasidenib (Idhifa, formerly AG-221; Celgene) for the treatment of adult patients with relapsed or refractory AML having an IDH2 mutation as detected by a companion diagnostic test (RealTime IDH2 Assay; Abbott Molecular Inc.). The drug was generally safe and well tolerated, according to reported trial results (Blood. 2017 Aug. 10;130[6]:722-31). The main grade 3-4 enasidenib-related adverse events were hyperbilirubinemia (12%) and IDH inhibitor–associated differentiation syndrome (6%).

The drug is an oral selective inhibitor of mutant isocitrate dehydrogenase 2 (IDH2) enzymes that is not myeloablative. Although enasidenib appears to work by inducing myeloblast differentiation, predictors of response to the drug generally remain elusive, according to Eytan M. Stein, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center, New York, and his coauthors.

About 12% of patients with AML have an IDH2 mutation. This genetic defect leads to accumulation of the metabolite 2-hydroxyglutarate (2-HG), causing DNA and histone hypermethylation. Hypermethylation, in turn, blocks hematopoietic cellular differentiation.

In a phase 1/2 trial sponsored by Celgene and Agios Pharmaceuticals, the investigators tested daily enasidenib monotherapy among 239 patients with IDH2-mutated advanced myeloid malignancies.

Among the 176 patients with relapsed or refractory AML (more than half of whom had already received at least two regimens directed against the disease), the overall response rate was 40.3%, and the complete response/remission rate was 19.3%. The median duration of response was 5.8 months.

Evaluation of serial bone marrow aspirates showed that responses were associated with myeloid cellular differentiation and maturation, generally without evidence of aplasia or hypoplasia.

With a median follow-up of 7.7 months, median overall survival was 9.3 months in the entire AML cohort and 19.7 months in the subset achieving complete response/remission. Ten percent of patients went on to allogeneic stem cell transplantation.

Although nearly all patients had a marked reduction in plasma levels of 2-HG, the extent of reduction did not predict response, suggesting that this metabolite is not a biomarker for benefit, and additional mechanisms are at play.

“Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed,” Dr. Stein and his coinvestigators wrote. “Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.”

They noted that an ongoing multicenter, randomized phase 3 trial, called IDHENTIFY (NCT02577406), is testing enasidenib against conventional regimens in older adults with late-stage AML harboring an IDH2 mutation.

In a companion translational study, investigators led by Michael D. Amatangelo, PhD, a scientist with Celgene in Summit, N.J., further explored mechanisms of enasidenib response and sought to identify alternative biomarkers for benefit in the AML cohort. They measured 2-HG levels, mutant IDH2 allele burden, and co-occurring somatic mutations in samples serially collected during the trial, and used flow cytometry to assess inhibition of mutant IDH2 on hematopoietic differentiation.

Enasidenib therapy induced 2-HG suppression regardless of whether patients’ IDH2 mutation affected the R140 or the R172 residue, according to reported results (Blood. 2017 Aug. 10;130[6]:732-41). However, analyses confirmed that 2-HG suppression alone did not predict response, as most nonresponders also had suppression.

In some patients with complete remission, mutant IDH2 persisted, but there was normalization of hematopoietic stem and progenitor compartments, and emergence of functional neutrophils having the IDH2 mutation. And some patients saw a reduction in mutant IDH2 allele burden, with levels remaining undetectable during response.

Analyses failed to identify any single mutation predictive of response to enasidenib. However, patients who did not achieve a response more commonly had mutations in NRAS and other MAPK pathway effectors, suggesting that RAS signaling plays a role in primary resistance to the drug.

“Although this is only a subgroup analysis of a large single-arm experience, taken together, the clinical response and translational data demonstrate that single-agent [mutant IDH2] inhibition by enasidenib in [relapsed or refractory AML] represents a critical and novel differentiation therapy,” Dr. Amatangelo and his coinvestigators wrote.

“Although enasidenib responses are clinically durable, the genetic heterogeneity observed in our patients suggests that combination with other therapies may be required to achieve long-term disease remission in more patients,” they added. “Current clinical studies combining enasidenib with combination chemotherapy or azacitidine (NCT02677922 and NCT02632708) and future orthogonal targeted therapies will address this question.”

Dr. Stein disclosed that he received grants and personal fees from Celgene and Agios Pharmaceuticals. Dr. Amatangelo disclosed that he is employed by and owns equity in Celgene.

Enasidenib was a well-tolerated, efficacious alternative to cytotoxic chemotherapy for patients with IDH2-mutated relapsed or refractory acute myeloid leukemia (AML), the results of a phase 1/2 study showed.

The Food and Drug Administration recently approved enasidenib (Idhifa, formerly AG-221; Celgene) for the treatment of adult patients with relapsed or refractory AML having an IDH2 mutation as detected by a companion diagnostic test (RealTime IDH2 Assay; Abbott Molecular Inc.). The drug was generally safe and well tolerated, according to reported trial results (Blood. 2017 Aug. 10;130[6]:722-31). The main grade 3-4 enasidenib-related adverse events were hyperbilirubinemia (12%) and IDH inhibitor–associated differentiation syndrome (6%).

The drug is an oral selective inhibitor of mutant isocitrate dehydrogenase 2 (IDH2) enzymes that is not myeloablative. Although enasidenib appears to work by inducing myeloblast differentiation, predictors of response to the drug generally remain elusive, according to Eytan M. Stein, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center, New York, and his coauthors.

About 12% of patients with AML have an IDH2 mutation. This genetic defect leads to accumulation of the metabolite 2-hydroxyglutarate (2-HG), causing DNA and histone hypermethylation. Hypermethylation, in turn, blocks hematopoietic cellular differentiation.

In a phase 1/2 trial sponsored by Celgene and Agios Pharmaceuticals, the investigators tested daily enasidenib monotherapy among 239 patients with IDH2-mutated advanced myeloid malignancies.

Among the 176 patients with relapsed or refractory AML (more than half of whom had already received at least two regimens directed against the disease), the overall response rate was 40.3%, and the complete response/remission rate was 19.3%. The median duration of response was 5.8 months.

Evaluation of serial bone marrow aspirates showed that responses were associated with myeloid cellular differentiation and maturation, generally without evidence of aplasia or hypoplasia.

With a median follow-up of 7.7 months, median overall survival was 9.3 months in the entire AML cohort and 19.7 months in the subset achieving complete response/remission. Ten percent of patients went on to allogeneic stem cell transplantation.

Although nearly all patients had a marked reduction in plasma levels of 2-HG, the extent of reduction did not predict response, suggesting that this metabolite is not a biomarker for benefit, and additional mechanisms are at play.

“Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed,” Dr. Stein and his coinvestigators wrote. “Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.”

They noted that an ongoing multicenter, randomized phase 3 trial, called IDHENTIFY (NCT02577406), is testing enasidenib against conventional regimens in older adults with late-stage AML harboring an IDH2 mutation.

In a companion translational study, investigators led by Michael D. Amatangelo, PhD, a scientist with Celgene in Summit, N.J., further explored mechanisms of enasidenib response and sought to identify alternative biomarkers for benefit in the AML cohort. They measured 2-HG levels, mutant IDH2 allele burden, and co-occurring somatic mutations in samples serially collected during the trial, and used flow cytometry to assess inhibition of mutant IDH2 on hematopoietic differentiation.

Enasidenib therapy induced 2-HG suppression regardless of whether patients’ IDH2 mutation affected the R140 or the R172 residue, according to reported results (Blood. 2017 Aug. 10;130[6]:732-41). However, analyses confirmed that 2-HG suppression alone did not predict response, as most nonresponders also had suppression.

In some patients with complete remission, mutant IDH2 persisted, but there was normalization of hematopoietic stem and progenitor compartments, and emergence of functional neutrophils having the IDH2 mutation. And some patients saw a reduction in mutant IDH2 allele burden, with levels remaining undetectable during response.

Analyses failed to identify any single mutation predictive of response to enasidenib. However, patients who did not achieve a response more commonly had mutations in NRAS and other MAPK pathway effectors, suggesting that RAS signaling plays a role in primary resistance to the drug.

“Although this is only a subgroup analysis of a large single-arm experience, taken together, the clinical response and translational data demonstrate that single-agent [mutant IDH2] inhibition by enasidenib in [relapsed or refractory AML] represents a critical and novel differentiation therapy,” Dr. Amatangelo and his coinvestigators wrote.

“Although enasidenib responses are clinically durable, the genetic heterogeneity observed in our patients suggests that combination with other therapies may be required to achieve long-term disease remission in more patients,” they added. “Current clinical studies combining enasidenib with combination chemotherapy or azacitidine (NCT02677922 and NCT02632708) and future orthogonal targeted therapies will address this question.”

Dr. Stein disclosed that he received grants and personal fees from Celgene and Agios Pharmaceuticals. Dr. Amatangelo disclosed that he is employed by and owns equity in Celgene.

Enasidenib was a well-tolerated, efficacious alternative to cytotoxic chemotherapy for patients with IDH2-mutated relapsed or refractory acute myeloid leukemia (AML), the results of a phase 1/2 study showed.

The Food and Drug Administration recently approved enasidenib (Idhifa, formerly AG-221; Celgene) for the treatment of adult patients with relapsed or refractory AML having an IDH2 mutation as detected by a companion diagnostic test (RealTime IDH2 Assay; Abbott Molecular Inc.). The drug was generally safe and well tolerated, according to reported trial results (Blood. 2017 Aug. 10;130[6]:722-31). The main grade 3-4 enasidenib-related adverse events were hyperbilirubinemia (12%) and IDH inhibitor–associated differentiation syndrome (6%).

The drug is an oral selective inhibitor of mutant isocitrate dehydrogenase 2 (IDH2) enzymes that is not myeloablative. Although enasidenib appears to work by inducing myeloblast differentiation, predictors of response to the drug generally remain elusive, according to Eytan M. Stein, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center, New York, and his coauthors.

About 12% of patients with AML have an IDH2 mutation. This genetic defect leads to accumulation of the metabolite 2-hydroxyglutarate (2-HG), causing DNA and histone hypermethylation. Hypermethylation, in turn, blocks hematopoietic cellular differentiation.

In a phase 1/2 trial sponsored by Celgene and Agios Pharmaceuticals, the investigators tested daily enasidenib monotherapy among 239 patients with IDH2-mutated advanced myeloid malignancies.

Among the 176 patients with relapsed or refractory AML (more than half of whom had already received at least two regimens directed against the disease), the overall response rate was 40.3%, and the complete response/remission rate was 19.3%. The median duration of response was 5.8 months.

Evaluation of serial bone marrow aspirates showed that responses were associated with myeloid cellular differentiation and maturation, generally without evidence of aplasia or hypoplasia.

With a median follow-up of 7.7 months, median overall survival was 9.3 months in the entire AML cohort and 19.7 months in the subset achieving complete response/remission. Ten percent of patients went on to allogeneic stem cell transplantation.

Although nearly all patients had a marked reduction in plasma levels of 2-HG, the extent of reduction did not predict response, suggesting that this metabolite is not a biomarker for benefit, and additional mechanisms are at play.

“Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed,” Dr. Stein and his coinvestigators wrote. “Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.”

They noted that an ongoing multicenter, randomized phase 3 trial, called IDHENTIFY (NCT02577406), is testing enasidenib against conventional regimens in older adults with late-stage AML harboring an IDH2 mutation.

In a companion translational study, investigators led by Michael D. Amatangelo, PhD, a scientist with Celgene in Summit, N.J., further explored mechanisms of enasidenib response and sought to identify alternative biomarkers for benefit in the AML cohort. They measured 2-HG levels, mutant IDH2 allele burden, and co-occurring somatic mutations in samples serially collected during the trial, and used flow cytometry to assess inhibition of mutant IDH2 on hematopoietic differentiation.

Enasidenib therapy induced 2-HG suppression regardless of whether patients’ IDH2 mutation affected the R140 or the R172 residue, according to reported results (Blood. 2017 Aug. 10;130[6]:732-41). However, analyses confirmed that 2-HG suppression alone did not predict response, as most nonresponders also had suppression.

In some patients with complete remission, mutant IDH2 persisted, but there was normalization of hematopoietic stem and progenitor compartments, and emergence of functional neutrophils having the IDH2 mutation. And some patients saw a reduction in mutant IDH2 allele burden, with levels remaining undetectable during response.

Analyses failed to identify any single mutation predictive of response to enasidenib. However, patients who did not achieve a response more commonly had mutations in NRAS and other MAPK pathway effectors, suggesting that RAS signaling plays a role in primary resistance to the drug.

“Although this is only a subgroup analysis of a large single-arm experience, taken together, the clinical response and translational data demonstrate that single-agent [mutant IDH2] inhibition by enasidenib in [relapsed or refractory AML] represents a critical and novel differentiation therapy,” Dr. Amatangelo and his coinvestigators wrote.

“Although enasidenib responses are clinically durable, the genetic heterogeneity observed in our patients suggests that combination with other therapies may be required to achieve long-term disease remission in more patients,” they added. “Current clinical studies combining enasidenib with combination chemotherapy or azacitidine (NCT02677922 and NCT02632708) and future orthogonal targeted therapies will address this question.”

Dr. Stein disclosed that he received grants and personal fees from Celgene and Agios Pharmaceuticals. Dr. Amatangelo disclosed that he is employed by and owns equity in Celgene.

Photo by Bill Branson

New research suggests survivors of childhood cancer can incur high out-of-pocket medical costs into adulthood and may forgo healthcare to lessen this financial burden.

The study showed that childhood cancer survivors (CCSs) were more likely than non-CCSs to have out-of-pocket medical costs that were at least 10% of their annual income.

And these high costs were associated with delaying care or skipping it altogether.

These findings were published in the Journal of Clinical Oncology.

“Survivors who reported spending a higher percentage of their income on out-of-pocket medical costs were not only more likely to report financial burden, they also were at risk for undertaking behaviors potentially detrimental to their health in order to save money,” said study author Ryan Nipp, MD, of Massachusetts General Hospital Cancer Center in Boston.

“While studies have identified associations between financial burden and patients’ treatment outcomes, quality of life, and even survival among adults with cancer, as far as we know, this is the first to report these associations in survivors of childhood cancer.”

For this research, Dr Nipp and his colleagues surveyed participants in the Childhood Cancer Survivor Study. This included adults who had been treated for childhood cancers between 1970 and 1986 along with a control group of siblings not affected by cancer.

In 2011 and 2012, participants were asked to provide information about their health insurance, the out-of-pocket healthcare costs they paid during the previous year, and sociodemographic information such as annual income and employment status.

The researchers also asked participants whether medical costs posed a financial burden and, if so, what measures they had taken to deal with that burden.

Study population

The researchers received complete responses from 580 CCSs and 173 of their siblings without a history of cancer. The most common cancer diagnosis was leukemia (33%), followed by Hodgkin lymphoma (14%), while non-Hodgkin lymphoma was less common (7%).

CCSs were a mean of 30.2 years from diagnosis. Use of chemotherapy (77%), radiation (66%), and surgery (81%) were common. Few patients had cancer recurrence (13%) or second cancers (5%).

There was no significant difference between CCSs and their siblings with regard to age at the time of the survey (P=0.071), household income (P=0.053), education (P=0.345), health insurance status (P=0.317), or having at least 1 hospitalization in the past year (P=0.270).

However, CCSs were significantly more likely than siblings to have chronic health conditions (P<0.001). Forty percent of CCSs had severe or life-threatening chronic conditions, compared to 17% of siblings.

Seventy-six percent of CCSs and 80% of siblings were employed. Twenty-nine percent of CCSs and 39% of siblings had household incomes exceeding $100,000. Twelve percent of CCSs and 5% of siblings had household incomes below $20,000.

Ninety-one percent of CCSs and 93% of siblings were insured. Most subjects in both groups (81% and 87%, respectively) had employer-sponsored insurance.

Results

CCSs were significantly more likely than their siblings to have out-of-pocket medical costs that were at least 10% of their annual income—10% and 3%, respectively (P<0.001).

Among CCSs, those with higher out-of-pocket costs (≥10% vs <10% of income) were more likely to have household incomes below $50,000 (odds ratio [OR]=5.5) and to report being hospitalized in the past year (OR=2.3).

CCSs with a higher percentage of their income spent on out-of-pocket costs were also more likely to:

• Have problems paying their medical bills (OR=8.8)
• Report inability to pay for basic costs of living such as food, heat, or rent (OR=6.1)
• Defer healthcare for a medical problem (OR=3.1)
• Skip a test, treatment, or follow-up (OR=2.1)
• Consider filing for bankruptcy (OR=6.4).

“A more comprehensive understanding of the relationship between high out-of-pocket medical costs and the adverse effects of increased financial burden on cancer survivors could be instrumental in helping us identify those at risk for higher costs to help us address their financial challenges and improve health outcomes,” Dr Nipp said.

“It could also help inform policy changes to help meet the unique needs of cancer survivors and improve our understanding of how both higher costs and resulting financial burden influence patients’ approach to their medical care and decision-making.”

Photo by Bill Branson

New research suggests survivors of childhood cancer can incur high out-of-pocket medical costs into adulthood and may forgo healthcare to lessen this financial burden.

The study showed that childhood cancer survivors (CCSs) were more likely than non-CCSs to have out-of-pocket medical costs that were at least 10% of their annual income.

And these high costs were associated with delaying care or skipping it altogether.

These findings were published in the Journal of Clinical Oncology.

“Survivors who reported spending a higher percentage of their income on out-of-pocket medical costs were not only more likely to report financial burden, they also were at risk for undertaking behaviors potentially detrimental to their health in order to save money,” said study author Ryan Nipp, MD, of Massachusetts General Hospital Cancer Center in Boston.

“While studies have identified associations between financial burden and patients’ treatment outcomes, quality of life, and even survival among adults with cancer, as far as we know, this is the first to report these associations in survivors of childhood cancer.”

For this research, Dr Nipp and his colleagues surveyed participants in the Childhood Cancer Survivor Study. This included adults who had been treated for childhood cancers between 1970 and 1986 along with a control group of siblings not affected by cancer.

In 2011 and 2012, participants were asked to provide information about their health insurance, the out-of-pocket healthcare costs they paid during the previous year, and sociodemographic information such as annual income and employment status.

The researchers also asked participants whether medical costs posed a financial burden and, if so, what measures they had taken to deal with that burden.

Study population

The researchers received complete responses from 580 CCSs and 173 of their siblings without a history of cancer. The most common cancer diagnosis was leukemia (33%), followed by Hodgkin lymphoma (14%), while non-Hodgkin lymphoma was less common (7%).

CCSs were a mean of 30.2 years from diagnosis. Use of chemotherapy (77%), radiation (66%), and surgery (81%) were common. Few patients had cancer recurrence (13%) or second cancers (5%).

There was no significant difference between CCSs and their siblings with regard to age at the time of the survey (P=0.071), household income (P=0.053), education (P=0.345), health insurance status (P=0.317), or having at least 1 hospitalization in the past year (P=0.270).

However, CCSs were significantly more likely than siblings to have chronic health conditions (P<0.001). Forty percent of CCSs had severe or life-threatening chronic conditions, compared to 17% of siblings.

Seventy-six percent of CCSs and 80% of siblings were employed. Twenty-nine percent of CCSs and 39% of siblings had household incomes exceeding $100,000. Twelve percent of CCSs and 5% of siblings had household incomes below $20,000.

Ninety-one percent of CCSs and 93% of siblings were insured. Most subjects in both groups (81% and 87%, respectively) had employer-sponsored insurance.

Results

CCSs were significantly more likely than their siblings to have out-of-pocket medical costs that were at least 10% of their annual income—10% and 3%, respectively (P<0.001).

Among CCSs, those with higher out-of-pocket costs (≥10% vs <10% of income) were more likely to have household incomes below $50,000 (odds ratio [OR]=5.5) and to report being hospitalized in the past year (OR=2.3).

CCSs with a higher percentage of their income spent on out-of-pocket costs were also more likely to:

• Have problems paying their medical bills (OR=8.8)
• Report inability to pay for basic costs of living such as food, heat, or rent (OR=6.1)
• Defer healthcare for a medical problem (OR=3.1)
• Skip a test, treatment, or follow-up (OR=2.1)
• Consider filing for bankruptcy (OR=6.4).

“A more comprehensive understanding of the relationship between high out-of-pocket medical costs and the adverse effects of increased financial burden on cancer survivors could be instrumental in helping us identify those at risk for higher costs to help us address their financial challenges and improve health outcomes,” Dr Nipp said.

“It could also help inform policy changes to help meet the unique needs of cancer survivors and improve our understanding of how both higher costs and resulting financial burden influence patients’ approach to their medical care and decision-making.”

Photo by Bill Branson

New research suggests survivors of childhood cancer can incur high out-of-pocket medical costs into adulthood and may forgo healthcare to lessen this financial burden.

The study showed that childhood cancer survivors (CCSs) were more likely than non-CCSs to have out-of-pocket medical costs that were at least 10% of their annual income.

And these high costs were associated with delaying care or skipping it altogether.

These findings were published in the Journal of Clinical Oncology.

“Survivors who reported spending a higher percentage of their income on out-of-pocket medical costs were not only more likely to report financial burden, they also were at risk for undertaking behaviors potentially detrimental to their health in order to save money,” said study author Ryan Nipp, MD, of Massachusetts General Hospital Cancer Center in Boston.

“While studies have identified associations between financial burden and patients’ treatment outcomes, quality of life, and even survival among adults with cancer, as far as we know, this is the first to report these associations in survivors of childhood cancer.”

For this research, Dr Nipp and his colleagues surveyed participants in the Childhood Cancer Survivor Study. This included adults who had been treated for childhood cancers between 1970 and 1986 along with a control group of siblings not affected by cancer.

In 2011 and 2012, participants were asked to provide information about their health insurance, the out-of-pocket healthcare costs they paid during the previous year, and sociodemographic information such as annual income and employment status.

The researchers also asked participants whether medical costs posed a financial burden and, if so, what measures they had taken to deal with that burden.

Study population

The researchers received complete responses from 580 CCSs and 173 of their siblings without a history of cancer. The most common cancer diagnosis was leukemia (33%), followed by Hodgkin lymphoma (14%), while non-Hodgkin lymphoma was less common (7%).

CCSs were a mean of 30.2 years from diagnosis. Use of chemotherapy (77%), radiation (66%), and surgery (81%) were common. Few patients had cancer recurrence (13%) or second cancers (5%).

There was no significant difference between CCSs and their siblings with regard to age at the time of the survey (P=0.071), household income (P=0.053), education (P=0.345), health insurance status (P=0.317), or having at least 1 hospitalization in the past year (P=0.270).

However, CCSs were significantly more likely than siblings to have chronic health conditions (P<0.001). Forty percent of CCSs had severe or life-threatening chronic conditions, compared to 17% of siblings.

Seventy-six percent of CCSs and 80% of siblings were employed. Twenty-nine percent of CCSs and 39% of siblings had household incomes exceeding $100,000. Twelve percent of CCSs and 5% of siblings had household incomes below $20,000.

Ninety-one percent of CCSs and 93% of siblings were insured. Most subjects in both groups (81% and 87%, respectively) had employer-sponsored insurance.

Results

CCSs were significantly more likely than their siblings to have out-of-pocket medical costs that were at least 10% of their annual income—10% and 3%, respectively (P<0.001).

Among CCSs, those with higher out-of-pocket costs (≥10% vs <10% of income) were more likely to have household incomes below $50,000 (odds ratio [OR]=5.5) and to report being hospitalized in the past year (OR=2.3).

CCSs with a higher percentage of their income spent on out-of-pocket costs were also more likely to:

• Have problems paying their medical bills (OR=8.8)
• Report inability to pay for basic costs of living such as food, heat, or rent (OR=6.1)
• Defer healthcare for a medical problem (OR=3.1)
• Skip a test, treatment, or follow-up (OR=2.1)
• Consider filing for bankruptcy (OR=6.4).

“A more comprehensive understanding of the relationship between high out-of-pocket medical costs and the adverse effects of increased financial burden on cancer survivors could be instrumental in helping us identify those at risk for higher costs to help us address their financial challenges and improve health outcomes,” Dr Nipp said.

“It could also help inform policy changes to help meet the unique needs of cancer survivors and improve our understanding of how both higher costs and resulting financial burden influence patients’ approach to their medical care and decision-making.”

Image by Lance Liotta

Researchers have described a molecular mechanism that could help explain the link between low vitamin C (ascorbate) levels and acute myeloid leukemia (AML).

The team found that mice with low levels of ascorbate in their blood experience a notable increase in hematopoietic stem cell (HSC) frequency and function.

This, in turn, accelerates AML development, partly by inhibiting the tumor suppressor Tet2.

Sean Morrison, PhD, of the University of Texas Southwestern Medical Center in Dallas, and his colleagues reported these findings in Nature.

“We have known for a while that people with lower levels of ascorbate (vitamin C) are at increased cancer risk, but we haven’t fully understood why,” Dr Morrison said. “Our research provides part of the explanation, at least for the blood-forming system.”

Dr Morrison and his colleagues developed a technique for analyzing the metabolic profiles of rare cell populations and used it to compare HSCs to restricted hematopoietic progenitors.

The researchers found that each hematopoietic cell type had a “distinct metabolic signature,” and both human and mouse HSCs had “unusually high” levels of ascorbate, which decreased as the cells differentiated.

To determine if ascorbate is important for HSC function, the team studied mice that lacked gulonolactone oxidase (Gulo), an enzyme mice use to synthesize their own ascorbate. Loss of the enzyme requires Gulo-deficient mice to obtain ascorbate exclusively through their diet like humans do.

So when the researchers fed the mice a standard diet, which contains little ascorbate, the animals’ ascorbate levels were depleted.

The team expected ascorbate depletion might lead to loss of HSC function, but they found the opposite was true. HSCs actually gained function, and this increased the incidence of AML in the mice.

This increase is partly tied to how ascorbate affects Tet2. The researchers found that ascorbate depletion can limit Tet2 function in tissues in a way that increases the risk of AML.

In addition, ascorbate depletion cooperated with Flt3 internal tandem duplication mutations to accelerate leukemogenesis. But the researchers were able to suppress leukemogenesis by feeding animals higher levels of ascorbate.

“Stem cells use ascorbate to regulate the abundance of certain chemical modifications on DNA, which are part of the epigenome,” said study author Michalis Agathocleous, PhD, of the University of Texas Southwestern Medical Center.

“So when stem cells don’t receive enough vitamin C, the epigenome can become damaged in a way that increases stem cell function but also increases the risk of leukemia.”

The researchers said further studies are needed to better understand the potential clinical implications of these findings.

However, the findings may have implications for older patients with clonal hematopoiesis. This condition increases a person’s risk of developing leukemia, but it is not well understood why certain patients develop leukemia and others do not. The results of this study might offer an explanation.

“One of the most common mutations in patients with clonal hematopoiesis is a loss of one copy of TET2,” Dr Morrison said. “Our results suggest patients with clonal hematopoiesis and a TET2 mutation should be particularly careful to get 100% of their daily vitamin C requirement. Because these patients only have one good copy of TET2 left, they need to maximize the residual TET2 tumor-suppressor activity to protect themselves from cancer.” 

Image by Lance Liotta

Researchers have described a molecular mechanism that could help explain the link between low vitamin C (ascorbate) levels and acute myeloid leukemia (AML).

The team found that mice with low levels of ascorbate in their blood experience a notable increase in hematopoietic stem cell (HSC) frequency and function.

This, in turn, accelerates AML development, partly by inhibiting the tumor suppressor Tet2.

Sean Morrison, PhD, of the University of Texas Southwestern Medical Center in Dallas, and his colleagues reported these findings in Nature.

“We have known for a while that people with lower levels of ascorbate (vitamin C) are at increased cancer risk, but we haven’t fully understood why,” Dr Morrison said. “Our research provides part of the explanation, at least for the blood-forming system.”

Dr Morrison and his colleagues developed a technique for analyzing the metabolic profiles of rare cell populations and used it to compare HSCs to restricted hematopoietic progenitors.

The researchers found that each hematopoietic cell type had a “distinct metabolic signature,” and both human and mouse HSCs had “unusually high” levels of ascorbate, which decreased as the cells differentiated.

To determine if ascorbate is important for HSC function, the team studied mice that lacked gulonolactone oxidase (Gulo), an enzyme mice use to synthesize their own ascorbate. Loss of the enzyme requires Gulo-deficient mice to obtain ascorbate exclusively through their diet like humans do.

So when the researchers fed the mice a standard diet, which contains little ascorbate, the animals’ ascorbate levels were depleted.

The team expected ascorbate depletion might lead to loss of HSC function, but they found the opposite was true. HSCs actually gained function, and this increased the incidence of AML in the mice.

This increase is partly tied to how ascorbate affects Tet2. The researchers found that ascorbate depletion can limit Tet2 function in tissues in a way that increases the risk of AML.

In addition, ascorbate depletion cooperated with Flt3 internal tandem duplication mutations to accelerate leukemogenesis. But the researchers were able to suppress leukemogenesis by feeding animals higher levels of ascorbate.

“Stem cells use ascorbate to regulate the abundance of certain chemical modifications on DNA, which are part of the epigenome,” said study author Michalis Agathocleous, PhD, of the University of Texas Southwestern Medical Center.

“So when stem cells don’t receive enough vitamin C, the epigenome can become damaged in a way that increases stem cell function but also increases the risk of leukemia.”

The researchers said further studies are needed to better understand the potential clinical implications of these findings.

However, the findings may have implications for older patients with clonal hematopoiesis. This condition increases a person’s risk of developing leukemia, but it is not well understood why certain patients develop leukemia and others do not. The results of this study might offer an explanation.

“One of the most common mutations in patients with clonal hematopoiesis is a loss of one copy of TET2,” Dr Morrison said. “Our results suggest patients with clonal hematopoiesis and a TET2 mutation should be particularly careful to get 100% of their daily vitamin C requirement. Because these patients only have one good copy of TET2 left, they need to maximize the residual TET2 tumor-suppressor activity to protect themselves from cancer.” 

Image by Lance Liotta

Researchers have described a molecular mechanism that could help explain the link between low vitamin C (ascorbate) levels and acute myeloid leukemia (AML).

The team found that mice with low levels of ascorbate in their blood experience a notable increase in hematopoietic stem cell (HSC) frequency and function.

This, in turn, accelerates AML development, partly by inhibiting the tumor suppressor Tet2.

Sean Morrison, PhD, of the University of Texas Southwestern Medical Center in Dallas, and his colleagues reported these findings in Nature.

“We have known for a while that people with lower levels of ascorbate (vitamin C) are at increased cancer risk, but we haven’t fully understood why,” Dr Morrison said. “Our research provides part of the explanation, at least for the blood-forming system.”

Dr Morrison and his colleagues developed a technique for analyzing the metabolic profiles of rare cell populations and used it to compare HSCs to restricted hematopoietic progenitors.

The researchers found that each hematopoietic cell type had a “distinct metabolic signature,” and both human and mouse HSCs had “unusually high” levels of ascorbate, which decreased as the cells differentiated.

To determine if ascorbate is important for HSC function, the team studied mice that lacked gulonolactone oxidase (Gulo), an enzyme mice use to synthesize their own ascorbate. Loss of the enzyme requires Gulo-deficient mice to obtain ascorbate exclusively through their diet like humans do.

So when the researchers fed the mice a standard diet, which contains little ascorbate, the animals’ ascorbate levels were depleted.

The team expected ascorbate depletion might lead to loss of HSC function, but they found the opposite was true. HSCs actually gained function, and this increased the incidence of AML in the mice.

This increase is partly tied to how ascorbate affects Tet2. The researchers found that ascorbate depletion can limit Tet2 function in tissues in a way that increases the risk of AML.

In addition, ascorbate depletion cooperated with Flt3 internal tandem duplication mutations to accelerate leukemogenesis. But the researchers were able to suppress leukemogenesis by feeding animals higher levels of ascorbate.

“Stem cells use ascorbate to regulate the abundance of certain chemical modifications on DNA, which are part of the epigenome,” said study author Michalis Agathocleous, PhD, of the University of Texas Southwestern Medical Center.

“So when stem cells don’t receive enough vitamin C, the epigenome can become damaged in a way that increases stem cell function but also increases the risk of leukemia.”

The researchers said further studies are needed to better understand the potential clinical implications of these findings.

However, the findings may have implications for older patients with clonal hematopoiesis. This condition increases a person’s risk of developing leukemia, but it is not well understood why certain patients develop leukemia and others do not. The results of this study might offer an explanation.

“One of the most common mutations in patients with clonal hematopoiesis is a loss of one copy of TET2,” Dr Morrison said. “Our results suggest patients with clonal hematopoiesis and a TET2 mutation should be particularly careful to get 100% of their daily vitamin C requirement. Because these patients only have one good copy of TET2 left, they need to maximize the residual TET2 tumor-suppressor activity to protect themselves from cancer.” 

When doctors talk about a new leukemia drug from Novartis, they ooze enthusiasm, using words like “breakthrough,” “revolutionary” and “a watershed moment.”

But when they think about how much the therapy is likely to cost, their tone turns alarmist.

“It’s going to cost a fortune,” said Ivan Borrello, MD, at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore.

“From what we’re hearing, this will be a quantum leap more expensive than other cancer drugs,” said Leonard Saltz, MD, chief of gastrointestinal oncology at Memorial Sloan Kettering Cancer Center in New York.

Switzerland-based Novartis hasn’t announced a price for the medicine, but British health authorities have said a price of $649,000 for a one-time treatment would be justified given the significant benefits.

The cancer therapy was unanimously approved by a Food and Drug Administration advisory committee in July, and its approval seems all but certain.

The treatment, CTL019, belongs to a new class of medications called CAR T-cell therapies, which involve harvesting patients’ immune cells and genetically altering them to kill cancer. It’s been tested in patients whose leukemia has relapsed in spite of the best chemotherapy or a bone-marrow transplant.

The prognosis for these patients is normally bleak. But in a clinical trial, 83% of those treated with CAR T-cell therapy – described as a “living drug” because it derives from a patient’s own cells – have gone into remission.

CAR T cells have been successful only in a limited number of cancers, however, and are being suggested for use as a last resort when all else has failed. As a result, only a few hundred patients a year would be eligible for them, at least initially, said J. Leonard Lichtenfeld, MD, deputy chief medical officer for the American Cancer Society.

The FDA is scheduled to decide on approval by Oct. 3. The agency also is considering a CAR T-cell therapy from Kite Pharma.

A third company, Juno Therapeutics, halted the development of one its CAR T-cell therapies after five patients died from complications of the treatment.

Rather than wait for Novartis to announce a price, an advocacy group called Patients for Affordable Drugs has launched a preemptive strike, asking to meet with company officials to discuss a “fair” price for the therapy. The Novartis drug has the potential to be one of the most expensive drugs ever sold, said David Mitchell, the patients group’s president, who has been treated for multiple myeloma, a blood cancer, since 2010. (The Laura and John Arnold Foundation, which provides some funding for Kaiser Health News, supports Patients for Affordable Drugs.)

“Many people with cancer look forward with great hope to the potential of your new drug,” Mr. Mitchell wrote in a letter to Novartis. “But drugs don’t work if patients can’t afford them.”

Cancer drugs today routinely cost more than $100,000 a year. A combination therapy for melanoma sells for $250,000. Such prices are particularly outrageous, given that taxpayers fund many drugs’ early research, Mr. Mitchell said.

The federal government spent more than $200 million over 2 decades to support the basic research into CAR T-cell therapy, long before Novartis bought the rights.

The patients group urged Novartis to charge no more for the drug in the U.S. than in other developed countries.

Novartis has agreed to meet with the patients group. In a statement, Novartis said the company is “carefully considering the appropriate price for CTL019, taking into consideration the value that this treatment represents for patients, society and the healthcare system, both near-term and long-term.”

Novartis made a significant investment in CAR T-cell therapy, according to the statement.

“We employ hundreds of people around the world who work on CAR Ts, we are conducting ongoing U.S. and global clinical trials and have developed a sophisticated, FDA-validated manufacturing site and process for this personalized therapy.”

Soaring prices for cancer drugs have led many patients to cut back on treatment or skip pills, a recent Kaiser Health News analysis showed.

The effect of CAR T-cell therapies on overall health costs would initially be relatively small, because it would be used by relatively few people, Dr. Lichtenfeld said.

Health systems and insurers may struggle to pay for the treatment, however, if the FDA approves it for wider use, Dr. Lichtenfeld said. Researchers are studying CAR T cells in a number of cancers. So far, the technology seems more effective in blood cancers, such as leukemias and lymphomas.

Hidden costs could further add to patients’ financial burdens, Dr. Borrello said.

Beyond the cost of the procedure, patients would need to pay for traditional chemotherapy, which is given before CAR T-cell therapy to improve its odds of success. They would also have to foot the bill for travel and lodging to one of the 30-35 hospitals in the country equipped to provide the high-tech treatment, said Prakash Satwani, MD, a pediatric hematologist at New York-Presbyterian/Columbia University Medical Center, which plans to offer the therapy.

Because patients can develop life-threatening side effects weeks after the procedure, doctors will ask patients to stay within 2 hours of the hospital for up to a month. In New York, even budget hotels cost more than $200 a night – an expense not typically covered by insurance. Patients who develop a dangerous complication, in which the immune system overreacts and attacks vital organs, might need coverage for emergency room care, as well as lengthy stays in the ICU, Dr. Satwani said.

Doctors don’t yet know what the full range of long-term side effects will be. CAR T-cell therapies can damage healthy immune cells, including the cells that produce the antibodies that fight disease. Some patients will need long-term treatments with a product called intravenous immunoglobulin, which provides the antibodies that patients need to prevent infection, Dr. Lichtenfeld said.

Dr. Saltz, an oncologist who has long spoken out about high drug prices, said he applauded the patients group’s efforts. But he said he doubts their efforts will persuade Novartis to set a reasonably affordable price.

“I’m not optimistic that this will have much effect on the company,” said Dr. Saltz. “There’s no market pressure for the company to respond to.”

High drug prices don’t just hurt patients, Dr. Saltz said. They also drive up insurance premiums for everyone.

“They affect each and every one of us,” he said, “because these costs will be paid by anyone who has any kind of insurance coverage.”
 

KHN’s coverage of prescription drug development, costs and pricing is supported in part by the Laura and John Arnold Foundation. Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.

When doctors talk about a new leukemia drug from Novartis, they ooze enthusiasm, using words like “breakthrough,” “revolutionary” and “a watershed moment.”

But when they think about how much the therapy is likely to cost, their tone turns alarmist.

“It’s going to cost a fortune,” said Ivan Borrello, MD, at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore.

“From what we’re hearing, this will be a quantum leap more expensive than other cancer drugs,” said Leonard Saltz, MD, chief of gastrointestinal oncology at Memorial Sloan Kettering Cancer Center in New York.

Switzerland-based Novartis hasn’t announced a price for the medicine, but British health authorities have said a price of $649,000 for a one-time treatment would be justified given the significant benefits.

The cancer therapy was unanimously approved by a Food and Drug Administration advisory committee in July, and its approval seems all but certain.

The treatment, CTL019, belongs to a new class of medications called CAR T-cell therapies, which involve harvesting patients’ immune cells and genetically altering them to kill cancer. It’s been tested in patients whose leukemia has relapsed in spite of the best chemotherapy or a bone-marrow transplant.

The prognosis for these patients is normally bleak. But in a clinical trial, 83% of those treated with CAR T-cell therapy – described as a “living drug” because it derives from a patient’s own cells – have gone into remission.

CAR T cells have been successful only in a limited number of cancers, however, and are being suggested for use as a last resort when all else has failed. As a result, only a few hundred patients a year would be eligible for them, at least initially, said J. Leonard Lichtenfeld, MD, deputy chief medical officer for the American Cancer Society.

The FDA is scheduled to decide on approval by Oct. 3. The agency also is considering a CAR T-cell therapy from Kite Pharma.

A third company, Juno Therapeutics, halted the development of one its CAR T-cell therapies after five patients died from complications of the treatment.

Rather than wait for Novartis to announce a price, an advocacy group called Patients for Affordable Drugs has launched a preemptive strike, asking to meet with company officials to discuss a “fair” price for the therapy. The Novartis drug has the potential to be one of the most expensive drugs ever sold, said David Mitchell, the patients group’s president, who has been treated for multiple myeloma, a blood cancer, since 2010. (The Laura and John Arnold Foundation, which provides some funding for Kaiser Health News, supports Patients for Affordable Drugs.)

“Many people with cancer look forward with great hope to the potential of your new drug,” Mr. Mitchell wrote in a letter to Novartis. “But drugs don’t work if patients can’t afford them.”

Cancer drugs today routinely cost more than $100,000 a year. A combination therapy for melanoma sells for $250,000. Such prices are particularly outrageous, given that taxpayers fund many drugs’ early research, Mr. Mitchell said.

The federal government spent more than $200 million over 2 decades to support the basic research into CAR T-cell therapy, long before Novartis bought the rights.

The patients group urged Novartis to charge no more for the drug in the U.S. than in other developed countries.

Novartis has agreed to meet with the patients group. In a statement, Novartis said the company is “carefully considering the appropriate price for CTL019, taking into consideration the value that this treatment represents for patients, society and the healthcare system, both near-term and long-term.”

Novartis made a significant investment in CAR T-cell therapy, according to the statement.

“We employ hundreds of people around the world who work on CAR Ts, we are conducting ongoing U.S. and global clinical trials and have developed a sophisticated, FDA-validated manufacturing site and process for this personalized therapy.”

Soaring prices for cancer drugs have led many patients to cut back on treatment or skip pills, a recent Kaiser Health News analysis showed.

The effect of CAR T-cell therapies on overall health costs would initially be relatively small, because it would be used by relatively few people, Dr. Lichtenfeld said.

Health systems and insurers may struggle to pay for the treatment, however, if the FDA approves it for wider use, Dr. Lichtenfeld said. Researchers are studying CAR T cells in a number of cancers. So far, the technology seems more effective in blood cancers, such as leukemias and lymphomas.

Hidden costs could further add to patients’ financial burdens, Dr. Borrello said.

Beyond the cost of the procedure, patients would need to pay for traditional chemotherapy, which is given before CAR T-cell therapy to improve its odds of success. They would also have to foot the bill for travel and lodging to one of the 30-35 hospitals in the country equipped to provide the high-tech treatment, said Prakash Satwani, MD, a pediatric hematologist at New York-Presbyterian/Columbia University Medical Center, which plans to offer the therapy.

Because patients can develop life-threatening side effects weeks after the procedure, doctors will ask patients to stay within 2 hours of the hospital for up to a month. In New York, even budget hotels cost more than $200 a night – an expense not typically covered by insurance. Patients who develop a dangerous complication, in which the immune system overreacts and attacks vital organs, might need coverage for emergency room care, as well as lengthy stays in the ICU, Dr. Satwani said.

Doctors don’t yet know what the full range of long-term side effects will be. CAR T-cell therapies can damage healthy immune cells, including the cells that produce the antibodies that fight disease. Some patients will need long-term treatments with a product called intravenous immunoglobulin, which provides the antibodies that patients need to prevent infection, Dr. Lichtenfeld said.

Dr. Saltz, an oncologist who has long spoken out about high drug prices, said he applauded the patients group’s efforts. But he said he doubts their efforts will persuade Novartis to set a reasonably affordable price.

“I’m not optimistic that this will have much effect on the company,” said Dr. Saltz. “There’s no market pressure for the company to respond to.”

High drug prices don’t just hurt patients, Dr. Saltz said. They also drive up insurance premiums for everyone.

“They affect each and every one of us,” he said, “because these costs will be paid by anyone who has any kind of insurance coverage.”
 

KHN’s coverage of prescription drug development, costs and pricing is supported in part by the Laura and John Arnold Foundation. Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.

When doctors talk about a new leukemia drug from Novartis, they ooze enthusiasm, using words like “breakthrough,” “revolutionary” and “a watershed moment.”

But when they think about how much the therapy is likely to cost, their tone turns alarmist.

“It’s going to cost a fortune,” said Ivan Borrello, MD, at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore.

“From what we’re hearing, this will be a quantum leap more expensive than other cancer drugs,” said Leonard Saltz, MD, chief of gastrointestinal oncology at Memorial Sloan Kettering Cancer Center in New York.

Switzerland-based Novartis hasn’t announced a price for the medicine, but British health authorities have said a price of $649,000 for a one-time treatment would be justified given the significant benefits.

The cancer therapy was unanimously approved by a Food and Drug Administration advisory committee in July, and its approval seems all but certain.

The treatment, CTL019, belongs to a new class of medications called CAR T-cell therapies, which involve harvesting patients’ immune cells and genetically altering them to kill cancer. It’s been tested in patients whose leukemia has relapsed in spite of the best chemotherapy or a bone-marrow transplant.

The prognosis for these patients is normally bleak. But in a clinical trial, 83% of those treated with CAR T-cell therapy – described as a “living drug” because it derives from a patient’s own cells – have gone into remission.

CAR T cells have been successful only in a limited number of cancers, however, and are being suggested for use as a last resort when all else has failed. As a result, only a few hundred patients a year would be eligible for them, at least initially, said J. Leonard Lichtenfeld, MD, deputy chief medical officer for the American Cancer Society.

The FDA is scheduled to decide on approval by Oct. 3. The agency also is considering a CAR T-cell therapy from Kite Pharma.

A third company, Juno Therapeutics, halted the development of one its CAR T-cell therapies after five patients died from complications of the treatment.

Rather than wait for Novartis to announce a price, an advocacy group called Patients for Affordable Drugs has launched a preemptive strike, asking to meet with company officials to discuss a “fair” price for the therapy. The Novartis drug has the potential to be one of the most expensive drugs ever sold, said David Mitchell, the patients group’s president, who has been treated for multiple myeloma, a blood cancer, since 2010. (The Laura and John Arnold Foundation, which provides some funding for Kaiser Health News, supports Patients for Affordable Drugs.)

“Many people with cancer look forward with great hope to the potential of your new drug,” Mr. Mitchell wrote in a letter to Novartis. “But drugs don’t work if patients can’t afford them.”

Cancer drugs today routinely cost more than $100,000 a year. A combination therapy for melanoma sells for $250,000. Such prices are particularly outrageous, given that taxpayers fund many drugs’ early research, Mr. Mitchell said.

The federal government spent more than $200 million over 2 decades to support the basic research into CAR T-cell therapy, long before Novartis bought the rights.

The patients group urged Novartis to charge no more for the drug in the U.S. than in other developed countries.

Novartis has agreed to meet with the patients group. In a statement, Novartis said the company is “carefully considering the appropriate price for CTL019, taking into consideration the value that this treatment represents for patients, society and the healthcare system, both near-term and long-term.”

Novartis made a significant investment in CAR T-cell therapy, according to the statement.

“We employ hundreds of people around the world who work on CAR Ts, we are conducting ongoing U.S. and global clinical trials and have developed a sophisticated, FDA-validated manufacturing site and process for this personalized therapy.”

Soaring prices for cancer drugs have led many patients to cut back on treatment or skip pills, a recent Kaiser Health News analysis showed.

The effect of CAR T-cell therapies on overall health costs would initially be relatively small, because it would be used by relatively few people, Dr. Lichtenfeld said.

Health systems and insurers may struggle to pay for the treatment, however, if the FDA approves it for wider use, Dr. Lichtenfeld said. Researchers are studying CAR T cells in a number of cancers. So far, the technology seems more effective in blood cancers, such as leukemias and lymphomas.

Hidden costs could further add to patients’ financial burdens, Dr. Borrello said.

Beyond the cost of the procedure, patients would need to pay for traditional chemotherapy, which is given before CAR T-cell therapy to improve its odds of success. They would also have to foot the bill for travel and lodging to one of the 30-35 hospitals in the country equipped to provide the high-tech treatment, said Prakash Satwani, MD, a pediatric hematologist at New York-Presbyterian/Columbia University Medical Center, which plans to offer the therapy.

Because patients can develop life-threatening side effects weeks after the procedure, doctors will ask patients to stay within 2 hours of the hospital for up to a month. In New York, even budget hotels cost more than $200 a night – an expense not typically covered by insurance. Patients who develop a dangerous complication, in which the immune system overreacts and attacks vital organs, might need coverage for emergency room care, as well as lengthy stays in the ICU, Dr. Satwani said.

Doctors don’t yet know what the full range of long-term side effects will be. CAR T-cell therapies can damage healthy immune cells, including the cells that produce the antibodies that fight disease. Some patients will need long-term treatments with a product called intravenous immunoglobulin, which provides the antibodies that patients need to prevent infection, Dr. Lichtenfeld said.

Dr. Saltz, an oncologist who has long spoken out about high drug prices, said he applauded the patients group’s efforts. But he said he doubts their efforts will persuade Novartis to set a reasonably affordable price.

“I’m not optimistic that this will have much effect on the company,” said Dr. Saltz. “There’s no market pressure for the company to respond to.”

High drug prices don’t just hurt patients, Dr. Saltz said. They also drive up insurance premiums for everyone.

“They affect each and every one of us,” he said, “because these costs will be paid by anyone who has any kind of insurance coverage.”
 

KHN’s coverage of prescription drug development, costs and pricing is supported in part by the Laura and John Arnold Foundation. Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.

Lab mouse

A 3-drug combination has demonstrated long-term efficacy against acute lymphoblastic leukemia (ALL) in mice, according to research published in Nature Communications.

Researchers found that when the production of nucleotides is stopped, a DNA replication stress response is activated, and this allows ALL cells to survive.

The team used these findings to devise a 3-drug regimen that blocks both of the nucleotide biosynthetic pathways and inhibits the replication stress response.

One of the drugs is triapine (3-AP), which inhibits ribonucleotide reductase (RNR) and enhances salvage nucleotide biosynthesis.

Another drug is DI-82, which inhibits the nucleoside salvage kinase deoxycytidine kinase (dCK).

And the third drug is VE-822, which inhibits the replication stress-sensing kinase ataxia telangiectasia and Rad3-related protein (ATR).

The researchers tested these 3 drugs in a mouse model of pre-B-ALL. Starting on day 7 after inoculation of pre-B-ALL, the mice received 3-AP and DI-82 twice a day and VE-822 once a day.

The team said mice in the control group succumbed to their disease within 17 days. However, all of the mice that received the 3-drug combination were still disease-free 442 days after they had stopped treatment (on day 42).

The researchers said the combination was well-tolerated, as mice maintained their body weight and enjoyed long-term survival without any detectable pathology.

The team also tested a dosing regimen in which all 3 drugs were given once a day.

Although this was less effective than the first regimen, 4 of 5 mice had no detectable disease 313 days after stopping treatment.

Two of the researchers involved in this study are co-founders and equity holders of Trethera Corp, a company developing a dCK inhibitor known as TRE-515.

The University of California (where most of the study authors work) has patented intellectual property for small-molecule dCK inhibitors, and it was licensed by Trethera.

Lab mouse

A 3-drug combination has demonstrated long-term efficacy against acute lymphoblastic leukemia (ALL) in mice, according to research published in Nature Communications.

Researchers found that when the production of nucleotides is stopped, a DNA replication stress response is activated, and this allows ALL cells to survive.

The team used these findings to devise a 3-drug regimen that blocks both of the nucleotide biosynthetic pathways and inhibits the replication stress response.

One of the drugs is triapine (3-AP), which inhibits ribonucleotide reductase (RNR) and enhances salvage nucleotide biosynthesis.

Another drug is DI-82, which inhibits the nucleoside salvage kinase deoxycytidine kinase (dCK).

And the third drug is VE-822, which inhibits the replication stress-sensing kinase ataxia telangiectasia and Rad3-related protein (ATR).

The researchers tested these 3 drugs in a mouse model of pre-B-ALL. Starting on day 7 after inoculation of pre-B-ALL, the mice received 3-AP and DI-82 twice a day and VE-822 once a day.

The team said mice in the control group succumbed to their disease within 17 days. However, all of the mice that received the 3-drug combination were still disease-free 442 days after they had stopped treatment (on day 42).

The researchers said the combination was well-tolerated, as mice maintained their body weight and enjoyed long-term survival without any detectable pathology.

The team also tested a dosing regimen in which all 3 drugs were given once a day.

Although this was less effective than the first regimen, 4 of 5 mice had no detectable disease 313 days after stopping treatment.

Two of the researchers involved in this study are co-founders and equity holders of Trethera Corp, a company developing a dCK inhibitor known as TRE-515.

The University of California (where most of the study authors work) has patented intellectual property for small-molecule dCK inhibitors, and it was licensed by Trethera.

Lab mouse

A 3-drug combination has demonstrated long-term efficacy against acute lymphoblastic leukemia (ALL) in mice, according to research published in Nature Communications.

Researchers found that when the production of nucleotides is stopped, a DNA replication stress response is activated, and this allows ALL cells to survive.

The team used these findings to devise a 3-drug regimen that blocks both of the nucleotide biosynthetic pathways and inhibits the replication stress response.

One of the drugs is triapine (3-AP), which inhibits ribonucleotide reductase (RNR) and enhances salvage nucleotide biosynthesis.

Another drug is DI-82, which inhibits the nucleoside salvage kinase deoxycytidine kinase (dCK).

And the third drug is VE-822, which inhibits the replication stress-sensing kinase ataxia telangiectasia and Rad3-related protein (ATR).

The researchers tested these 3 drugs in a mouse model of pre-B-ALL. Starting on day 7 after inoculation of pre-B-ALL, the mice received 3-AP and DI-82 twice a day and VE-822 once a day.

The team said mice in the control group succumbed to their disease within 17 days. However, all of the mice that received the 3-drug combination were still disease-free 442 days after they had stopped treatment (on day 42).

The researchers said the combination was well-tolerated, as mice maintained their body weight and enjoyed long-term survival without any detectable pathology.

The team also tested a dosing regimen in which all 3 drugs were given once a day.

Although this was less effective than the first regimen, 4 of 5 mice had no detectable disease 313 days after stopping treatment.

Two of the researchers involved in this study are co-founders and equity holders of Trethera Corp, a company developing a dCK inhibitor known as TRE-515.

The University of California (where most of the study authors work) has patented intellectual property for small-molecule dCK inhibitors, and it was licensed by Trethera.

Image by Ed Uthman

An investigational antibody has demonstrated activity against acute myeloid leukemia (AML), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL), according to researchers.

PF-06747143 is a humanized CXCR4 immunoglobulin G1 (IgG1) antibody that binds to CXCR4 and inhibits both CXCL12-mediated signaling pathways and cell migration.

Whether given alone or in combination with chemotherapy, PF-06747143 demonstrated efficacy in mouse models of NHL, MM, and AML.

Treatment involving PF-06747143—alone or in combination—eradicated more cancer cells than did standard treatment options.

These results were published in Blood Advances. The research was sponsored by Pfizer, Inc., the company developing PF-06747143.

“One of the major limitations we see in treating blood cancers is the failure to clear cancer cells from the bone marrow,” said study author Flavia Pernasetti, PhD, of Pfizer Oncology Research and Development.

“Because the bone marrow allows the cancer cells to flourish, removing these cells is an essential step in treating these malignancies effectively.”

With this goal in mind, Dr Pernasetti and her colleagues looked to the mechanisms that control the movement of cells into the bone marrow (BM) in the first place—the chemokine receptor CXCR4 and its ligand CXCL12.

The researchers created PF-06747143, which attacks and kills cancer cells directly but also removes cancer cells from the BM so they can be killed by other treatments.

Results in NHL

The researchers first tested PF-06747143 in an NHL Ramos xenograft model. Mice received PF-06747143 or a control IgG1 antibody at 10 mg/kg on days 1 and 8.

PF-06747143 significantly inhibited tumor growth compared to the control antibody (P<0.0001). Seventy percent of PF-06747143-treated mice had tumor volumes below their initial size at the end of the study.

PF-06747143 produced a dose-dependent response that was sustained until the end of the study, even after treatment was stopped.

Results in MM

The researchers tested PF-06747143 in a disseminated MM model, in which the OPM2-Luc tumor cells were implanted intravenously and migrated spontaneously to the BM.

Mice received PF-06747143 or IgG1 control at 10 mg/kg weekly for 5 doses. Other mice received melphalan at 1 mg/kg twice a week for a total of 4 cycles.

On day 30, PF-06747143 had significantly inhibited BM tumor growth compared to the control antibody or melphalan (P<0.0001).

PF-06747143-treated mice also had a significant survival benefit. The median survival was 33.5 days for mice that received the control antibody and 36 days for mice treated with melphalan. However, there were no deaths in the PF-06747143-treated mice by day 50, which marked the end of the study (P<0.0001).

The researchers also tested PF-06747143 at a lower dose (1 mg/kg weekly for a total of 7 doses), both alone and in combination with bortezomib (0.5 mg/kg twice a week for a total of 4 cycles).

The median survival was 34 days in the control mice, 44 days in mice that received bortezomib alone, and 47 days in mice that received PF-06747143 alone. However, there were no deaths in the combination arm at day 51, which was the end of the study (P<0.0003).

Results in AML

The researchers tested PF-06747143 in an AML disseminated tumor model using MV4-11 cells.

They compared PF-06747143 (given at 0.1, 1, or 10 mg/kg weekly for 4 doses) to the chemotherapeutic agent daunorubicin (2 mg/kg on days 1, 3, and 5), the FLT3 inhibitor crenolanib (7.5 mg/kg twice a day, on days 11-15 and 25-29), and a control IgG1 antibody (10 mg/kg weekly for 4 doses).

PF-06747143 (at 10 mg/kg), daunorubicin, and crenolanib all significantly reduced the number of tumor cells in the peripheral blood and BM when compared with the control antibody (P<0.05).

PF-06746143 treatment (at 10 mg/kg) reduced the number of AML cells in the BM by 95.9%, while daunorubicin reduced them by 84.5% and crenolanib by 80.5%.

The median survival was 36 days for mice that received PF-06747143 at 0.1 mg/kg, 41 days for mice that received the control antibody, 47 days for mice that received PF-06747143 at 1 mg/kg, and 63 days for mice that received PF-06747143 at 10 mg/kg.

The researchers also found that PF-06747143 had a “strong combinatorial effect” with daunorubicin and cytarabine in a chemotherapy-resistant model of AML. The team noted that only 36% of BM cells are positive for CXCR4 in this model.

Treatment with PF-06747143 alone reduced the percentage of AML cells in the BM to 80%, combination daunorubicin and cytarabine reduced it to 27%, and combination PF-06747143, daunorubicin, and cytarabine reduced the percentage of AML cells in the BM to 0.3%.

“Our preliminary preclinical results are encouraging,” Dr Pernasetti said, “and we are very excited to see how our antibody fares in clinical testing.”

PF-06747143 is currently being evaluated in a phase 1 trial of AML patients.

Image by Ed Uthman

An investigational antibody has demonstrated activity against acute myeloid leukemia (AML), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL), according to researchers.

PF-06747143 is a humanized CXCR4 immunoglobulin G1 (IgG1) antibody that binds to CXCR4 and inhibits both CXCL12-mediated signaling pathways and cell migration.

Whether given alone or in combination with chemotherapy, PF-06747143 demonstrated efficacy in mouse models of NHL, MM, and AML.

Treatment involving PF-06747143—alone or in combination—eradicated more cancer cells than did standard treatment options.

These results were published in Blood Advances. The research was sponsored by Pfizer, Inc., the company developing PF-06747143.

“One of the major limitations we see in treating blood cancers is the failure to clear cancer cells from the bone marrow,” said study author Flavia Pernasetti, PhD, of Pfizer Oncology Research and Development.

“Because the bone marrow allows the cancer cells to flourish, removing these cells is an essential step in treating these malignancies effectively.”

With this goal in mind, Dr Pernasetti and her colleagues looked to the mechanisms that control the movement of cells into the bone marrow (BM) in the first place—the chemokine receptor CXCR4 and its ligand CXCL12.

The researchers created PF-06747143, which attacks and kills cancer cells directly but also removes cancer cells from the BM so they can be killed by other treatments.

Results in NHL

The researchers first tested PF-06747143 in an NHL Ramos xenograft model. Mice received PF-06747143 or a control IgG1 antibody at 10 mg/kg on days 1 and 8.

PF-06747143 significantly inhibited tumor growth compared to the control antibody (P<0.0001). Seventy percent of PF-06747143-treated mice had tumor volumes below their initial size at the end of the study.

PF-06747143 produced a dose-dependent response that was sustained until the end of the study, even after treatment was stopped.

Results in MM

The researchers tested PF-06747143 in a disseminated MM model, in which the OPM2-Luc tumor cells were implanted intravenously and migrated spontaneously to the BM.

Mice received PF-06747143 or IgG1 control at 10 mg/kg weekly for 5 doses. Other mice received melphalan at 1 mg/kg twice a week for a total of 4 cycles.

On day 30, PF-06747143 had significantly inhibited BM tumor growth compared to the control antibody or melphalan (P<0.0001).

PF-06747143-treated mice also had a significant survival benefit. The median survival was 33.5 days for mice that received the control antibody and 36 days for mice treated with melphalan. However, there were no deaths in the PF-06747143-treated mice by day 50, which marked the end of the study (P<0.0001).

The researchers also tested PF-06747143 at a lower dose (1 mg/kg weekly for a total of 7 doses), both alone and in combination with bortezomib (0.5 mg/kg twice a week for a total of 4 cycles).

The median survival was 34 days in the control mice, 44 days in mice that received bortezomib alone, and 47 days in mice that received PF-06747143 alone. However, there were no deaths in the combination arm at day 51, which was the end of the study (P<0.0003).

Results in AML

The researchers tested PF-06747143 in an AML disseminated tumor model using MV4-11 cells.

They compared PF-06747143 (given at 0.1, 1, or 10 mg/kg weekly for 4 doses) to the chemotherapeutic agent daunorubicin (2 mg/kg on days 1, 3, and 5), the FLT3 inhibitor crenolanib (7.5 mg/kg twice a day, on days 11-15 and 25-29), and a control IgG1 antibody (10 mg/kg weekly for 4 doses).

PF-06747143 (at 10 mg/kg), daunorubicin, and crenolanib all significantly reduced the number of tumor cells in the peripheral blood and BM when compared with the control antibody (P<0.05).

PF-06746143 treatment (at 10 mg/kg) reduced the number of AML cells in the BM by 95.9%, while daunorubicin reduced them by 84.5% and crenolanib by 80.5%.

The median survival was 36 days for mice that received PF-06747143 at 0.1 mg/kg, 41 days for mice that received the control antibody, 47 days for mice that received PF-06747143 at 1 mg/kg, and 63 days for mice that received PF-06747143 at 10 mg/kg.

The researchers also found that PF-06747143 had a “strong combinatorial effect” with daunorubicin and cytarabine in a chemotherapy-resistant model of AML. The team noted that only 36% of BM cells are positive for CXCR4 in this model.

Treatment with PF-06747143 alone reduced the percentage of AML cells in the BM to 80%, combination daunorubicin and cytarabine reduced it to 27%, and combination PF-06747143, daunorubicin, and cytarabine reduced the percentage of AML cells in the BM to 0.3%.

“Our preliminary preclinical results are encouraging,” Dr Pernasetti said, “and we are very excited to see how our antibody fares in clinical testing.”

PF-06747143 is currently being evaluated in a phase 1 trial of AML patients.

Image by Ed Uthman

An investigational antibody has demonstrated activity against acute myeloid leukemia (AML), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL), according to researchers.

PF-06747143 is a humanized CXCR4 immunoglobulin G1 (IgG1) antibody that binds to CXCR4 and inhibits both CXCL12-mediated signaling pathways and cell migration.

Whether given alone or in combination with chemotherapy, PF-06747143 demonstrated efficacy in mouse models of NHL, MM, and AML.

Treatment involving PF-06747143—alone or in combination—eradicated more cancer cells than did standard treatment options.

These results were published in Blood Advances. The research was sponsored by Pfizer, Inc., the company developing PF-06747143.

“One of the major limitations we see in treating blood cancers is the failure to clear cancer cells from the bone marrow,” said study author Flavia Pernasetti, PhD, of Pfizer Oncology Research and Development.

“Because the bone marrow allows the cancer cells to flourish, removing these cells is an essential step in treating these malignancies effectively.”

With this goal in mind, Dr Pernasetti and her colleagues looked to the mechanisms that control the movement of cells into the bone marrow (BM) in the first place—the chemokine receptor CXCR4 and its ligand CXCL12.

The researchers created PF-06747143, which attacks and kills cancer cells directly but also removes cancer cells from the BM so they can be killed by other treatments.

Results in NHL

The researchers first tested PF-06747143 in an NHL Ramos xenograft model. Mice received PF-06747143 or a control IgG1 antibody at 10 mg/kg on days 1 and 8.

PF-06747143 significantly inhibited tumor growth compared to the control antibody (P<0.0001). Seventy percent of PF-06747143-treated mice had tumor volumes below their initial size at the end of the study.

PF-06747143 produced a dose-dependent response that was sustained until the end of the study, even after treatment was stopped.

Results in MM

The researchers tested PF-06747143 in a disseminated MM model, in which the OPM2-Luc tumor cells were implanted intravenously and migrated spontaneously to the BM.

Mice received PF-06747143 or IgG1 control at 10 mg/kg weekly for 5 doses. Other mice received melphalan at 1 mg/kg twice a week for a total of 4 cycles.

On day 30, PF-06747143 had significantly inhibited BM tumor growth compared to the control antibody or melphalan (P<0.0001).

PF-06747143-treated mice also had a significant survival benefit. The median survival was 33.5 days for mice that received the control antibody and 36 days for mice treated with melphalan. However, there were no deaths in the PF-06747143-treated mice by day 50, which marked the end of the study (P<0.0001).

The researchers also tested PF-06747143 at a lower dose (1 mg/kg weekly for a total of 7 doses), both alone and in combination with bortezomib (0.5 mg/kg twice a week for a total of 4 cycles).

The median survival was 34 days in the control mice, 44 days in mice that received bortezomib alone, and 47 days in mice that received PF-06747143 alone. However, there were no deaths in the combination arm at day 51, which was the end of the study (P<0.0003).

Results in AML

The researchers tested PF-06747143 in an AML disseminated tumor model using MV4-11 cells.

They compared PF-06747143 (given at 0.1, 1, or 10 mg/kg weekly for 4 doses) to the chemotherapeutic agent daunorubicin (2 mg/kg on days 1, 3, and 5), the FLT3 inhibitor crenolanib (7.5 mg/kg twice a day, on days 11-15 and 25-29), and a control IgG1 antibody (10 mg/kg weekly for 4 doses).

PF-06747143 (at 10 mg/kg), daunorubicin, and crenolanib all significantly reduced the number of tumor cells in the peripheral blood and BM when compared with the control antibody (P<0.05).

PF-06746143 treatment (at 10 mg/kg) reduced the number of AML cells in the BM by 95.9%, while daunorubicin reduced them by 84.5% and crenolanib by 80.5%.

The median survival was 36 days for mice that received PF-06747143 at 0.1 mg/kg, 41 days for mice that received the control antibody, 47 days for mice that received PF-06747143 at 1 mg/kg, and 63 days for mice that received PF-06747143 at 10 mg/kg.

The researchers also found that PF-06747143 had a “strong combinatorial effect” with daunorubicin and cytarabine in a chemotherapy-resistant model of AML. The team noted that only 36% of BM cells are positive for CXCR4 in this model.

Treatment with PF-06747143 alone reduced the percentage of AML cells in the BM to 80%, combination daunorubicin and cytarabine reduced it to 27%, and combination PF-06747143, daunorubicin, and cytarabine reduced the percentage of AML cells in the BM to 0.3%.

“Our preliminary preclinical results are encouraging,” Dr Pernasetti said, “and we are very excited to see how our antibody fares in clinical testing.”

PF-06747143 is currently being evaluated in a phase 1 trial of AML patients.

AML cells

The US Food and Drug Administration (FDA) has granted orphan drug designation to SY-1425 for the treatment of acute myeloid leukemia (AML).

SY-1425 is an oral, first-in-class, selective retinoic acid receptor alpha (RARα) agonist. It is currently under investigation in a phase 2 trial of patients with AML and myelodysplastic syndromes (MDS).

“We believe that SY-1425 may provide a meaningful benefit for subsets of AML patients whose disease is driven by abnormally high expression of the RARA or IRF8 genes,” said David A. Roth, MD, chief medical officer at Syros Pharmaceuticals, the company developing SY-1425.

“Receiving orphan drug designation is an important regulatory milestone in the development of SY-1425. We’re pleased with the continued progress of the ongoing phase 2 clinical trial, and we look forward to presenting initial clinical data in the fourth quarter of this year.”

Using its gene control platform, Syros discovered subsets of AML and MDS patients with super-enhancers associated with RARA or IRF8. These super-enhancers are believed to drive overexpression of the RARA or IRF8 genes, locking cells in an immature, undifferentiated, and proliferative state and leading to disease.

In preclinical studies, SY-1425 promoted differentiation of AML cells with high RARA or IRF8 expression and inhibited tumor growth and prolonged survival in patient-derived xenograft models of AML with high RARA expression.

In the ongoing phase 2 trial, researchers are assessing the safety and efficacy of SY-1425 as a single agent in 4 AML and MDS patient populations, as well as SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.

All patients are prospectively selected using biomarkers for high expression of RARA or IRF8. Additional details about the trial can be found at https://clinicaltrials.gov/ct2/show/NCT02807558.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

AML cells

The US Food and Drug Administration (FDA) has granted orphan drug designation to SY-1425 for the treatment of acute myeloid leukemia (AML).

SY-1425 is an oral, first-in-class, selective retinoic acid receptor alpha (RARα) agonist. It is currently under investigation in a phase 2 trial of patients with AML and myelodysplastic syndromes (MDS).

“We believe that SY-1425 may provide a meaningful benefit for subsets of AML patients whose disease is driven by abnormally high expression of the RARA or IRF8 genes,” said David A. Roth, MD, chief medical officer at Syros Pharmaceuticals, the company developing SY-1425.

“Receiving orphan drug designation is an important regulatory milestone in the development of SY-1425. We’re pleased with the continued progress of the ongoing phase 2 clinical trial, and we look forward to presenting initial clinical data in the fourth quarter of this year.”

Using its gene control platform, Syros discovered subsets of AML and MDS patients with super-enhancers associated with RARA or IRF8. These super-enhancers are believed to drive overexpression of the RARA or IRF8 genes, locking cells in an immature, undifferentiated, and proliferative state and leading to disease.

In preclinical studies, SY-1425 promoted differentiation of AML cells with high RARA or IRF8 expression and inhibited tumor growth and prolonged survival in patient-derived xenograft models of AML with high RARA expression.

In the ongoing phase 2 trial, researchers are assessing the safety and efficacy of SY-1425 as a single agent in 4 AML and MDS patient populations, as well as SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.

All patients are prospectively selected using biomarkers for high expression of RARA or IRF8. Additional details about the trial can be found at https://clinicaltrials.gov/ct2/show/NCT02807558.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

AML cells

The US Food and Drug Administration (FDA) has granted orphan drug designation to SY-1425 for the treatment of acute myeloid leukemia (AML).

SY-1425 is an oral, first-in-class, selective retinoic acid receptor alpha (RARα) agonist. It is currently under investigation in a phase 2 trial of patients with AML and myelodysplastic syndromes (MDS).

“We believe that SY-1425 may provide a meaningful benefit for subsets of AML patients whose disease is driven by abnormally high expression of the RARA or IRF8 genes,” said David A. Roth, MD, chief medical officer at Syros Pharmaceuticals, the company developing SY-1425.

“Receiving orphan drug designation is an important regulatory milestone in the development of SY-1425. We’re pleased with the continued progress of the ongoing phase 2 clinical trial, and we look forward to presenting initial clinical data in the fourth quarter of this year.”

Using its gene control platform, Syros discovered subsets of AML and MDS patients with super-enhancers associated with RARA or IRF8. These super-enhancers are believed to drive overexpression of the RARA or IRF8 genes, locking cells in an immature, undifferentiated, and proliferative state and leading to disease.

In preclinical studies, SY-1425 promoted differentiation of AML cells with high RARA or IRF8 expression and inhibited tumor growth and prolonged survival in patient-derived xenograft models of AML with high RARA expression.

In the ongoing phase 2 trial, researchers are assessing the safety and efficacy of SY-1425 as a single agent in 4 AML and MDS patient populations, as well as SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.

All patients are prospectively selected using biomarkers for high expression of RARA or IRF8. Additional details about the trial can be found at https://clinicaltrials.gov/ct2/show/NCT02807558.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Inotuzumab ozogamicin therapy significantly increased the risk of sinusoidal obstruction syndrome (veno-occlusive disease) among adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), especially when they also received follow-up hematopoietic stem cell transplantation, according to a safety analysis from the INO-VATE trial.

After a median of 9 weeks of treatment, 13% of 164 patients who received inotuzumab ozogamicin (Besponsa, Wyeth/Pfizer) developed sinusoidal obstruction syndrome, compared with less than 1% of 143 patients who received standard care, reported Hagop M. Kantarjian, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his associates (Lancet Haematol. 2017 Jul 4. doi: 10.1016/ S2352-3026[17]30103-5).

Follow-up treatment with HSCT increased the risk of sinusoidal obstruction syndrome in both the intervention (22%) and standard-care (3%) groups. Among patients who did not undergo HSCT, rates of this adverse event were 3% and 0%, respectively. Five patients died from sinusoidal obstruction syndrome, all of whom received both inotuzumab ozogamicin and HSCT. The findings earned the newly approved regimen a boxed warning for severe hepatotoxicity.

The open-label, phase 3, multicenter INO-VATE study included 326 adults with CD22-positive, Philadelphia chromosome–negative or Philadelphia chromosome–positive relapsed or refractory B-cell precursor ALL. The safety analysis included 305 patients. Rates of treatment-emergent hepatotoxicities, of all grades, were 51% with inotuzumab ozogamicin and 34% with standard care. Most adverse hepatic events were grade 1-2 liver-related laboratory abnormalities, but 8% of inotuzumab ozogamicin recipients developed grade 3 or higher sinusoidal obstruction syndrome, versus less than 1% of the control group.

“After follow-up HSCT, the frequency of sinusoidal obstruction syndrome was 50% or higher in the following subgroups: patients aged 65 years or older, patients with last available pre-HSCT serum bilirubin concentration more than or equal to the upper limit of normal, and patients who received conditioning regimens with two alkylating agents,” Dr. Kantarjian and his fellow investigators wrote. Conditioning regimens that included thiotepa markedly increased the risk of sinusoidal obstruction syndrome. Additional risk factors included HSCT before study enrollment, history of liver disease, and a final pre-HSCT platelet count of less than 100 × 109 platelets per L.

Rates of sinusoidal obstruction syndrome were 42% with four to six cycles of inotuzumab ozogamicin, 23% with three cycles, 19% with two cycles, and 8% with one cycle, said the investigators. In multivariate analysis, conditioning with two alkylating agents (P = .02 compared with one alkylating agent) and pre-HSCT bilirubin of at least the upper limit of normal (P = .01) significantly increased the risk of sinusoidal obstruction syndrome during or after treatment with inotuzumab ozogamicin.

Notably, inotuzumab ozogamicin did not significantly increase the chances of survival compared with standard care among patients who also received follow-up HSCT (hazard ratio, 1.3; 97.5% confidence interval, 0.66 to 2.3; P = 0.77). Among HSCT recipients, the chances of surviving to 24 months were 39% (95% CI, 28%-50%) with inotuzumab ozogamicin and 29% (11%-49%) with standard care. Nonetheless, HSCT “offers possibility of cure in the relapsed or recurrent [ALL] setting,” the researchers wrote. Clinicians should be especially wary of sinusoidal obstruction syndrome if patients are 65 years or older, received HSCT before inotuzumab ozogamicin treatment, or have a baseline history of liver disease, they said. Strategies to minimize risk include shortening the duration of inotuzumab ozogamicin treatment and avoiding conditioning regimens that contain two alkylating agents.

Pfizer funded and collaborated in the trial. Dr. Kantarjian disclosed ties to Pfizer and numerous other pharmaceutical companies.

Inotuzumab ozogamicin therapy significantly increased the risk of sinusoidal obstruction syndrome (veno-occlusive disease) among adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), especially when they also received follow-up hematopoietic stem cell transplantation, according to a safety analysis from the INO-VATE trial.

After a median of 9 weeks of treatment, 13% of 164 patients who received inotuzumab ozogamicin (Besponsa, Wyeth/Pfizer) developed sinusoidal obstruction syndrome, compared with less than 1% of 143 patients who received standard care, reported Hagop M. Kantarjian, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his associates (Lancet Haematol. 2017 Jul 4. doi: 10.1016/ S2352-3026[17]30103-5).

Follow-up treatment with HSCT increased the risk of sinusoidal obstruction syndrome in both the intervention (22%) and standard-care (3%) groups. Among patients who did not undergo HSCT, rates of this adverse event were 3% and 0%, respectively. Five patients died from sinusoidal obstruction syndrome, all of whom received both inotuzumab ozogamicin and HSCT. The findings earned the newly approved regimen a boxed warning for severe hepatotoxicity.

The open-label, phase 3, multicenter INO-VATE study included 326 adults with CD22-positive, Philadelphia chromosome–negative or Philadelphia chromosome–positive relapsed or refractory B-cell precursor ALL. The safety analysis included 305 patients. Rates of treatment-emergent hepatotoxicities, of all grades, were 51% with inotuzumab ozogamicin and 34% with standard care. Most adverse hepatic events were grade 1-2 liver-related laboratory abnormalities, but 8% of inotuzumab ozogamicin recipients developed grade 3 or higher sinusoidal obstruction syndrome, versus less than 1% of the control group.

“After follow-up HSCT, the frequency of sinusoidal obstruction syndrome was 50% or higher in the following subgroups: patients aged 65 years or older, patients with last available pre-HSCT serum bilirubin concentration more than or equal to the upper limit of normal, and patients who received conditioning regimens with two alkylating agents,” Dr. Kantarjian and his fellow investigators wrote. Conditioning regimens that included thiotepa markedly increased the risk of sinusoidal obstruction syndrome. Additional risk factors included HSCT before study enrollment, history of liver disease, and a final pre-HSCT platelet count of less than 100 × 109 platelets per L.

Rates of sinusoidal obstruction syndrome were 42% with four to six cycles of inotuzumab ozogamicin, 23% with three cycles, 19% with two cycles, and 8% with one cycle, said the investigators. In multivariate analysis, conditioning with two alkylating agents (P = .02 compared with one alkylating agent) and pre-HSCT bilirubin of at least the upper limit of normal (P = .01) significantly increased the risk of sinusoidal obstruction syndrome during or after treatment with inotuzumab ozogamicin.

Notably, inotuzumab ozogamicin did not significantly increase the chances of survival compared with standard care among patients who also received follow-up HSCT (hazard ratio, 1.3; 97.5% confidence interval, 0.66 to 2.3; P = 0.77). Among HSCT recipients, the chances of surviving to 24 months were 39% (95% CI, 28%-50%) with inotuzumab ozogamicin and 29% (11%-49%) with standard care. Nonetheless, HSCT “offers possibility of cure in the relapsed or recurrent [ALL] setting,” the researchers wrote. Clinicians should be especially wary of sinusoidal obstruction syndrome if patients are 65 years or older, received HSCT before inotuzumab ozogamicin treatment, or have a baseline history of liver disease, they said. Strategies to minimize risk include shortening the duration of inotuzumab ozogamicin treatment and avoiding conditioning regimens that contain two alkylating agents.

Pfizer funded and collaborated in the trial. Dr. Kantarjian disclosed ties to Pfizer and numerous other pharmaceutical companies.

Inotuzumab ozogamicin therapy significantly increased the risk of sinusoidal obstruction syndrome (veno-occlusive disease) among adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), especially when they also received follow-up hematopoietic stem cell transplantation, according to a safety analysis from the INO-VATE trial.

After a median of 9 weeks of treatment, 13% of 164 patients who received inotuzumab ozogamicin (Besponsa, Wyeth/Pfizer) developed sinusoidal obstruction syndrome, compared with less than 1% of 143 patients who received standard care, reported Hagop M. Kantarjian, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his associates (Lancet Haematol. 2017 Jul 4. doi: 10.1016/ S2352-3026[17]30103-5).

Follow-up treatment with HSCT increased the risk of sinusoidal obstruction syndrome in both the intervention (22%) and standard-care (3%) groups. Among patients who did not undergo HSCT, rates of this adverse event were 3% and 0%, respectively. Five patients died from sinusoidal obstruction syndrome, all of whom received both inotuzumab ozogamicin and HSCT. The findings earned the newly approved regimen a boxed warning for severe hepatotoxicity.

The open-label, phase 3, multicenter INO-VATE study included 326 adults with CD22-positive, Philadelphia chromosome–negative or Philadelphia chromosome–positive relapsed or refractory B-cell precursor ALL. The safety analysis included 305 patients. Rates of treatment-emergent hepatotoxicities, of all grades, were 51% with inotuzumab ozogamicin and 34% with standard care. Most adverse hepatic events were grade 1-2 liver-related laboratory abnormalities, but 8% of inotuzumab ozogamicin recipients developed grade 3 or higher sinusoidal obstruction syndrome, versus less than 1% of the control group.

“After follow-up HSCT, the frequency of sinusoidal obstruction syndrome was 50% or higher in the following subgroups: patients aged 65 years or older, patients with last available pre-HSCT serum bilirubin concentration more than or equal to the upper limit of normal, and patients who received conditioning regimens with two alkylating agents,” Dr. Kantarjian and his fellow investigators wrote. Conditioning regimens that included thiotepa markedly increased the risk of sinusoidal obstruction syndrome. Additional risk factors included HSCT before study enrollment, history of liver disease, and a final pre-HSCT platelet count of less than 100 × 109 platelets per L.

Rates of sinusoidal obstruction syndrome were 42% with four to six cycles of inotuzumab ozogamicin, 23% with three cycles, 19% with two cycles, and 8% with one cycle, said the investigators. In multivariate analysis, conditioning with two alkylating agents (P = .02 compared with one alkylating agent) and pre-HSCT bilirubin of at least the upper limit of normal (P = .01) significantly increased the risk of sinusoidal obstruction syndrome during or after treatment with inotuzumab ozogamicin.

Notably, inotuzumab ozogamicin did not significantly increase the chances of survival compared with standard care among patients who also received follow-up HSCT (hazard ratio, 1.3; 97.5% confidence interval, 0.66 to 2.3; P = 0.77). Among HSCT recipients, the chances of surviving to 24 months were 39% (95% CI, 28%-50%) with inotuzumab ozogamicin and 29% (11%-49%) with standard care. Nonetheless, HSCT “offers possibility of cure in the relapsed or recurrent [ALL] setting,” the researchers wrote. Clinicians should be especially wary of sinusoidal obstruction syndrome if patients are 65 years or older, received HSCT before inotuzumab ozogamicin treatment, or have a baseline history of liver disease, they said. Strategies to minimize risk include shortening the duration of inotuzumab ozogamicin treatment and avoiding conditioning regimens that contain two alkylating agents.

Pfizer funded and collaborated in the trial. Dr. Kantarjian disclosed ties to Pfizer and numerous other pharmaceutical companies.