AML

Photo by Rhoda Baer

Adding an experimental compound to chemotherapy is a “promising” treatment approach for certain patients with acute myeloid leukemia (AML), according to researchers.

They tested the compound, CPI-613, in combination with high-dose cytarabine and mitoxantrone in a phase 1 trial of patients with relapsed or refractory AML.

The combination produced similar response rates in the overall patient population (50%), patients age 60 and older (47%), and those with poor-risk cytogenetics (46%).

The most common grade 3/4 adverse events (AEs) were hematologic toxicities, and there was 1 fatal AE—hypotension.

Mortality rates in this trial were similar to those observed in historical controls treated with high-dose cytarabine, mitoxantrone, and asparaginase.

“These data are very encouraging, especially for patients 60 years of age or older who have historically done very poorly with this disease,” said Timothy Pardee, MD, PhD, a professor at Wake Forest Baptist Health in Winston-Salem, North Carolina, and chief medical officer of Rafael Pharmaceuticals, Inc., the company developing CPI-613.

Dr Pardee and his colleagues reported these results in Clinical Cancer Research.

The researchers noted that CPI-613 is designed to target mitochondrial metabolism in cancer cells, and preclinical research showed that CPI-613 sensitized AML cells to chemotherapy.

To investigate this further, the team tested CPI-613 in combination with high-dose cytarabine and mitoxantrone in the phase 1 trial. The study included 66 patients with relapsed or refractory AML, as well as a patient with advanced-phase chronic myeloid leukemia (CML) who was mistakenly enrolled.

The patients’ median age was 60 (range, 21-79), and 54% were age 60 and older. Their median percentage of marrow blasts was 43%. Forty percent of patients had poor-risk cytogenetics, and 49% had intermediate-risk cytogenetics.

Most patients (72%) had no prior salvage therapy, 13% had 1 prior line of salvage, 10% had 2 prior lines, and 4% had more than 2. Thirty-one percent of patients had refractory disease.

Seven percent of patients had previously received high-dose cytarabine and mitoxantrone, and 25% had previous salvage including high-dose or intermediate-dose cytarabine.

Treatment

Patients received CPI-613, given over 2 hours, on days 1 to 5 of cycle 1. Doses ranged from 500 mg/m² to 2750 mg/m².

Starting on day 3, patients received 5 doses of cytarabine at 3 gm/m² (for patients younger than 60) or 1.5 gm/m² (for older patients) in 500 mL normal saline, over 3 hours, every 12 hours.

Patients also received 3 daily doses of mitoxantrone at 6 mg/m² in 50 mL normal saline, given over 15 minutes, after the first, third, and fifth doses of cytarabine.

Patients were initially assigned to receive 1 cycle of treatment. Those with at least 5% blasts after the first cycle could receive a second course—either a full course or a 3-day course. And patients who responded to the first course could receive up to 2 cycles of the 3-day course.

Safety

There were 2 dose-limiting toxicities when CPI-613 was given at the 2750 mg/m² dose. One of these toxicities was grade 3 diarrhea that didn’t respond to anti-diarrheals, and the other was grade 3 nausea that didn’t respond to antiemetics.

Because of these events, 2500 mg/m² was deemed the maximum-tolerated dose. However, the recommended phase 2 dose is 2000 mg/m².

The most common AEs—occurring in at least 50% of all patients who received CPI-613 (n=67)—included hemoglobin decrease (67%), hyperglycemia (67%), neutropenia (67%), thrombocytopenia (67%), hypomagnesemia (66%), leukopenia (66%), lymphopenia (66%), hypoalbuminemia (65%), hypokalemia (60%), hypocalcemia (57%), and diarrhea (55%).

All cases of neutropenia, thrombocytopenia, leukopenia, and lymphopenia were grade 3/4. Other common grade 3/4 AEs (occurring in at least 20% of patients) included hemoglobin decrease (62%), febrile neutropenia (28%), hypophosphatemia (24%), and hypokalemia (23%).

The only grade 5 AE was hypotension.

The mortality rate was 12% (n=8) at 30 days and 19% (n=13) at 60 days. The researchers said this was similar to the historical experience with high-dose cytarabine, mitoxantrone, and asparaginase. Mortality rates with this regimen were 13% at 30 days and 22% at 60 days.

Efficacy

Sixty-two patients were evaluable for response. Of the 5 patients who were not evaluable, 1 didn’t complete the first cycle of treatment, 1 was the CML patient, and 3 died before assessment.

The overall response rate was 50% (31/62). This included 26 patients with a complete response (CR) and 5 patients who had a CR with incomplete count recovery (CRi).

The rate of CR/CRi was 47% (15/32) in patients older than 60 years of age, 46% (11/24) in patients who had poor-risk cytogenetics, and 53% (8/15) when CPI-613 was given at the recommended phase 2 dose—2000 mg/m².

The median overall survival (OS) was 6.7 months for all evaluable patients and 13.2 months for patients who achieved a CR/CRi.

The median OS was 6.9 months for patients age 60 and older, which was not significantly different from the median OS in younger patients (P=0.9642).

This study was sponsored by Wake Forest University Health Sciences and the National Cancer Institute.

Photo by Rhoda Baer

Adding an experimental compound to chemotherapy is a “promising” treatment approach for certain patients with acute myeloid leukemia (AML), according to researchers.

They tested the compound, CPI-613, in combination with high-dose cytarabine and mitoxantrone in a phase 1 trial of patients with relapsed or refractory AML.

The combination produced similar response rates in the overall patient population (50%), patients age 60 and older (47%), and those with poor-risk cytogenetics (46%).

The most common grade 3/4 adverse events (AEs) were hematologic toxicities, and there was 1 fatal AE—hypotension.

Mortality rates in this trial were similar to those observed in historical controls treated with high-dose cytarabine, mitoxantrone, and asparaginase.

“These data are very encouraging, especially for patients 60 years of age or older who have historically done very poorly with this disease,” said Timothy Pardee, MD, PhD, a professor at Wake Forest Baptist Health in Winston-Salem, North Carolina, and chief medical officer of Rafael Pharmaceuticals, Inc., the company developing CPI-613.

Dr Pardee and his colleagues reported these results in Clinical Cancer Research.

The researchers noted that CPI-613 is designed to target mitochondrial metabolism in cancer cells, and preclinical research showed that CPI-613 sensitized AML cells to chemotherapy.

To investigate this further, the team tested CPI-613 in combination with high-dose cytarabine and mitoxantrone in the phase 1 trial. The study included 66 patients with relapsed or refractory AML, as well as a patient with advanced-phase chronic myeloid leukemia (CML) who was mistakenly enrolled.

The patients’ median age was 60 (range, 21-79), and 54% were age 60 and older. Their median percentage of marrow blasts was 43%. Forty percent of patients had poor-risk cytogenetics, and 49% had intermediate-risk cytogenetics.

Most patients (72%) had no prior salvage therapy, 13% had 1 prior line of salvage, 10% had 2 prior lines, and 4% had more than 2. Thirty-one percent of patients had refractory disease.

Seven percent of patients had previously received high-dose cytarabine and mitoxantrone, and 25% had previous salvage including high-dose or intermediate-dose cytarabine.

Treatment

Patients received CPI-613, given over 2 hours, on days 1 to 5 of cycle 1. Doses ranged from 500 mg/m² to 2750 mg/m².

Starting on day 3, patients received 5 doses of cytarabine at 3 gm/m² (for patients younger than 60) or 1.5 gm/m² (for older patients) in 500 mL normal saline, over 3 hours, every 12 hours.

Patients also received 3 daily doses of mitoxantrone at 6 mg/m² in 50 mL normal saline, given over 15 minutes, after the first, third, and fifth doses of cytarabine.

Patients were initially assigned to receive 1 cycle of treatment. Those with at least 5% blasts after the first cycle could receive a second course—either a full course or a 3-day course. And patients who responded to the first course could receive up to 2 cycles of the 3-day course.

Safety

There were 2 dose-limiting toxicities when CPI-613 was given at the 2750 mg/m² dose. One of these toxicities was grade 3 diarrhea that didn’t respond to anti-diarrheals, and the other was grade 3 nausea that didn’t respond to antiemetics.

Because of these events, 2500 mg/m² was deemed the maximum-tolerated dose. However, the recommended phase 2 dose is 2000 mg/m².

The most common AEs—occurring in at least 50% of all patients who received CPI-613 (n=67)—included hemoglobin decrease (67%), hyperglycemia (67%), neutropenia (67%), thrombocytopenia (67%), hypomagnesemia (66%), leukopenia (66%), lymphopenia (66%), hypoalbuminemia (65%), hypokalemia (60%), hypocalcemia (57%), and diarrhea (55%).

All cases of neutropenia, thrombocytopenia, leukopenia, and lymphopenia were grade 3/4. Other common grade 3/4 AEs (occurring in at least 20% of patients) included hemoglobin decrease (62%), febrile neutropenia (28%), hypophosphatemia (24%), and hypokalemia (23%).

The only grade 5 AE was hypotension.

The mortality rate was 12% (n=8) at 30 days and 19% (n=13) at 60 days. The researchers said this was similar to the historical experience with high-dose cytarabine, mitoxantrone, and asparaginase. Mortality rates with this regimen were 13% at 30 days and 22% at 60 days.

Efficacy

Sixty-two patients were evaluable for response. Of the 5 patients who were not evaluable, 1 didn’t complete the first cycle of treatment, 1 was the CML patient, and 3 died before assessment.

The overall response rate was 50% (31/62). This included 26 patients with a complete response (CR) and 5 patients who had a CR with incomplete count recovery (CRi).

The rate of CR/CRi was 47% (15/32) in patients older than 60 years of age, 46% (11/24) in patients who had poor-risk cytogenetics, and 53% (8/15) when CPI-613 was given at the recommended phase 2 dose—2000 mg/m².

The median overall survival (OS) was 6.7 months for all evaluable patients and 13.2 months for patients who achieved a CR/CRi.

The median OS was 6.9 months for patients age 60 and older, which was not significantly different from the median OS in younger patients (P=0.9642).

This study was sponsored by Wake Forest University Health Sciences and the National Cancer Institute.

Photo by Rhoda Baer

Adding an experimental compound to chemotherapy is a “promising” treatment approach for certain patients with acute myeloid leukemia (AML), according to researchers.

They tested the compound, CPI-613, in combination with high-dose cytarabine and mitoxantrone in a phase 1 trial of patients with relapsed or refractory AML.

The combination produced similar response rates in the overall patient population (50%), patients age 60 and older (47%), and those with poor-risk cytogenetics (46%).

The most common grade 3/4 adverse events (AEs) were hematologic toxicities, and there was 1 fatal AE—hypotension.

Mortality rates in this trial were similar to those observed in historical controls treated with high-dose cytarabine, mitoxantrone, and asparaginase.

“These data are very encouraging, especially for patients 60 years of age or older who have historically done very poorly with this disease,” said Timothy Pardee, MD, PhD, a professor at Wake Forest Baptist Health in Winston-Salem, North Carolina, and chief medical officer of Rafael Pharmaceuticals, Inc., the company developing CPI-613.

Dr Pardee and his colleagues reported these results in Clinical Cancer Research.

The researchers noted that CPI-613 is designed to target mitochondrial metabolism in cancer cells, and preclinical research showed that CPI-613 sensitized AML cells to chemotherapy.

To investigate this further, the team tested CPI-613 in combination with high-dose cytarabine and mitoxantrone in the phase 1 trial. The study included 66 patients with relapsed or refractory AML, as well as a patient with advanced-phase chronic myeloid leukemia (CML) who was mistakenly enrolled.

The patients’ median age was 60 (range, 21-79), and 54% were age 60 and older. Their median percentage of marrow blasts was 43%. Forty percent of patients had poor-risk cytogenetics, and 49% had intermediate-risk cytogenetics.

Most patients (72%) had no prior salvage therapy, 13% had 1 prior line of salvage, 10% had 2 prior lines, and 4% had more than 2. Thirty-one percent of patients had refractory disease.

Seven percent of patients had previously received high-dose cytarabine and mitoxantrone, and 25% had previous salvage including high-dose or intermediate-dose cytarabine.

Treatment

Patients received CPI-613, given over 2 hours, on days 1 to 5 of cycle 1. Doses ranged from 500 mg/m² to 2750 mg/m².

Starting on day 3, patients received 5 doses of cytarabine at 3 gm/m² (for patients younger than 60) or 1.5 gm/m² (for older patients) in 500 mL normal saline, over 3 hours, every 12 hours.

Patients also received 3 daily doses of mitoxantrone at 6 mg/m² in 50 mL normal saline, given over 15 minutes, after the first, third, and fifth doses of cytarabine.

Patients were initially assigned to receive 1 cycle of treatment. Those with at least 5% blasts after the first cycle could receive a second course—either a full course or a 3-day course. And patients who responded to the first course could receive up to 2 cycles of the 3-day course.

Safety

There were 2 dose-limiting toxicities when CPI-613 was given at the 2750 mg/m² dose. One of these toxicities was grade 3 diarrhea that didn’t respond to anti-diarrheals, and the other was grade 3 nausea that didn’t respond to antiemetics.

Because of these events, 2500 mg/m² was deemed the maximum-tolerated dose. However, the recommended phase 2 dose is 2000 mg/m².

The most common AEs—occurring in at least 50% of all patients who received CPI-613 (n=67)—included hemoglobin decrease (67%), hyperglycemia (67%), neutropenia (67%), thrombocytopenia (67%), hypomagnesemia (66%), leukopenia (66%), lymphopenia (66%), hypoalbuminemia (65%), hypokalemia (60%), hypocalcemia (57%), and diarrhea (55%).

All cases of neutropenia, thrombocytopenia, leukopenia, and lymphopenia were grade 3/4. Other common grade 3/4 AEs (occurring in at least 20% of patients) included hemoglobin decrease (62%), febrile neutropenia (28%), hypophosphatemia (24%), and hypokalemia (23%).

The only grade 5 AE was hypotension.

The mortality rate was 12% (n=8) at 30 days and 19% (n=13) at 60 days. The researchers said this was similar to the historical experience with high-dose cytarabine, mitoxantrone, and asparaginase. Mortality rates with this regimen were 13% at 30 days and 22% at 60 days.

Efficacy

Sixty-two patients were evaluable for response. Of the 5 patients who were not evaluable, 1 didn’t complete the first cycle of treatment, 1 was the CML patient, and 3 died before assessment.

The overall response rate was 50% (31/62). This included 26 patients with a complete response (CR) and 5 patients who had a CR with incomplete count recovery (CRi).

The rate of CR/CRi was 47% (15/32) in patients older than 60 years of age, 46% (11/24) in patients who had poor-risk cytogenetics, and 53% (8/15) when CPI-613 was given at the recommended phase 2 dose—2000 mg/m².

The median overall survival (OS) was 6.7 months for all evaluable patients and 13.2 months for patients who achieved a CR/CRi.

The median OS was 6.9 months for patients age 60 and older, which was not significantly different from the median OS in younger patients (P=0.9642).

This study was sponsored by Wake Forest University Health Sciences and the National Cancer Institute.

Lab mouse

Preclinical results support clinical testing of an experimental agent in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to researchers.

The agent, ALRN-6924, was shown to combat AML and MDS by restoring activity of the tumor-suppressing protein p53.

ALRN-6924 exhibited antileukemic activity in AML cells and mouse models of the disease, as well as in a patient with MDS and excess leukemic blasts who received the drug on a compassionate-use basis.

These results, published in Science Translational Medicine, have led to a phase 1 trial of ALRN-6924 in patients with AML or MDS.

ALRN-6924 was developed by Aileron Therapeutics Inc., to target p53 by inhibiting 2 naturally occurring proteins, MDMX and MDM2. Overexpression of these proteins inactivates p53, allowing cancer cells to multiply unchecked.

In the current study, researchers set out to confirm ALRN-6924’s mechanism of action and determine the efficacy of the drug in AML/MDS. This work was supported, in part, by grants from Aileron Therapeutics Inc., and the National Institutes of Health.

The researchers did find that ALRN-6924 targets both MDMX and MDM2, blocking their interaction with p53 in AML cells.

The team said ALRN-6924 inhibited proliferation by inducing cell-cycle arrest and apoptosis in AML cell lines and AML patient cells, including leukemic stem cell-enriched populations.

“This is important because AML is driven by stem cells, and, if you don’t target stem cells, the disease will come back very quickly,” said study author Ulrich Steidl, MD, PhD, of Albert Einstein College of Medicine in Bronx, New York.

The researchers also found that ALRN-6924 greatly increased survival in a mouse model of AML. The median survival was 34 days in vehicle-treated control mice, 83 days in mice that received ALRN-6924 at 20 mg/kg twice a week, and 151 days in mice that received ALRN-6924 at 20 mg/kg three times a week.

“This is a very striking response,” Dr Steidl said. “Most experimental drugs for leukemia achieve an increase in survival of only a few days in these preclinical models. Even more importantly, ALRN-6924 effectively cured about 40% of the treated mice, meaning they were disease-free more than 1 year after treatment, essentially a lifetime for a mouse.”

Finally, the researchers assessed the effects of ALRN-6924 in a patient who had high-risk MDS with excess leukemic blasts.

The team found the p53 protein “was rapidly induced” in CD34+ leukemic blasts but not in healthy lymphocytes. And ALRN-6924 reduced the number of malignant cells circulating in the blood.

“This test was not designed to assess the efficacy of the drug in humans,” Dr Steidl noted. “That has to be done in a proper clinical trial. Our goal was to determine whether it can hit the desired target in human cells in a clinical setting, which it did in this individual.”

ALRN-6924 is a stapled alpha-helical peptide, a class of drugs whose helical structure is stabilized using hydrocarbon “staples.” The stapling prevents the peptides from being degraded by enzymes before reaching their intended target. ALRN-6924 is the first stapled peptide therapeutic to be tested in patients.

In the phase 1 trial (NCT02909972), researchers are testing ALRN-6924 in patients with relapsed/refractory AML or advanced MDS.

Lab mouse

Preclinical results support clinical testing of an experimental agent in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to researchers.

The agent, ALRN-6924, was shown to combat AML and MDS by restoring activity of the tumor-suppressing protein p53.

ALRN-6924 exhibited antileukemic activity in AML cells and mouse models of the disease, as well as in a patient with MDS and excess leukemic blasts who received the drug on a compassionate-use basis.

These results, published in Science Translational Medicine, have led to a phase 1 trial of ALRN-6924 in patients with AML or MDS.

ALRN-6924 was developed by Aileron Therapeutics Inc., to target p53 by inhibiting 2 naturally occurring proteins, MDMX and MDM2. Overexpression of these proteins inactivates p53, allowing cancer cells to multiply unchecked.

In the current study, researchers set out to confirm ALRN-6924’s mechanism of action and determine the efficacy of the drug in AML/MDS. This work was supported, in part, by grants from Aileron Therapeutics Inc., and the National Institutes of Health.

The researchers did find that ALRN-6924 targets both MDMX and MDM2, blocking their interaction with p53 in AML cells.

The team said ALRN-6924 inhibited proliferation by inducing cell-cycle arrest and apoptosis in AML cell lines and AML patient cells, including leukemic stem cell-enriched populations.

“This is important because AML is driven by stem cells, and, if you don’t target stem cells, the disease will come back very quickly,” said study author Ulrich Steidl, MD, PhD, of Albert Einstein College of Medicine in Bronx, New York.

The researchers also found that ALRN-6924 greatly increased survival in a mouse model of AML. The median survival was 34 days in vehicle-treated control mice, 83 days in mice that received ALRN-6924 at 20 mg/kg twice a week, and 151 days in mice that received ALRN-6924 at 20 mg/kg three times a week.

“This is a very striking response,” Dr Steidl said. “Most experimental drugs for leukemia achieve an increase in survival of only a few days in these preclinical models. Even more importantly, ALRN-6924 effectively cured about 40% of the treated mice, meaning they were disease-free more than 1 year after treatment, essentially a lifetime for a mouse.”

Finally, the researchers assessed the effects of ALRN-6924 in a patient who had high-risk MDS with excess leukemic blasts.

The team found the p53 protein “was rapidly induced” in CD34+ leukemic blasts but not in healthy lymphocytes. And ALRN-6924 reduced the number of malignant cells circulating in the blood.

“This test was not designed to assess the efficacy of the drug in humans,” Dr Steidl noted. “That has to be done in a proper clinical trial. Our goal was to determine whether it can hit the desired target in human cells in a clinical setting, which it did in this individual.”

ALRN-6924 is a stapled alpha-helical peptide, a class of drugs whose helical structure is stabilized using hydrocarbon “staples.” The stapling prevents the peptides from being degraded by enzymes before reaching their intended target. ALRN-6924 is the first stapled peptide therapeutic to be tested in patients.

In the phase 1 trial (NCT02909972), researchers are testing ALRN-6924 in patients with relapsed/refractory AML or advanced MDS.

Lab mouse

Preclinical results support clinical testing of an experimental agent in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to researchers.

The agent, ALRN-6924, was shown to combat AML and MDS by restoring activity of the tumor-suppressing protein p53.

ALRN-6924 exhibited antileukemic activity in AML cells and mouse models of the disease, as well as in a patient with MDS and excess leukemic blasts who received the drug on a compassionate-use basis.

These results, published in Science Translational Medicine, have led to a phase 1 trial of ALRN-6924 in patients with AML or MDS.

ALRN-6924 was developed by Aileron Therapeutics Inc., to target p53 by inhibiting 2 naturally occurring proteins, MDMX and MDM2. Overexpression of these proteins inactivates p53, allowing cancer cells to multiply unchecked.

In the current study, researchers set out to confirm ALRN-6924’s mechanism of action and determine the efficacy of the drug in AML/MDS. This work was supported, in part, by grants from Aileron Therapeutics Inc., and the National Institutes of Health.

The researchers did find that ALRN-6924 targets both MDMX and MDM2, blocking their interaction with p53 in AML cells.

The team said ALRN-6924 inhibited proliferation by inducing cell-cycle arrest and apoptosis in AML cell lines and AML patient cells, including leukemic stem cell-enriched populations.

“This is important because AML is driven by stem cells, and, if you don’t target stem cells, the disease will come back very quickly,” said study author Ulrich Steidl, MD, PhD, of Albert Einstein College of Medicine in Bronx, New York.

The researchers also found that ALRN-6924 greatly increased survival in a mouse model of AML. The median survival was 34 days in vehicle-treated control mice, 83 days in mice that received ALRN-6924 at 20 mg/kg twice a week, and 151 days in mice that received ALRN-6924 at 20 mg/kg three times a week.

“This is a very striking response,” Dr Steidl said. “Most experimental drugs for leukemia achieve an increase in survival of only a few days in these preclinical models. Even more importantly, ALRN-6924 effectively cured about 40% of the treated mice, meaning they were disease-free more than 1 year after treatment, essentially a lifetime for a mouse.”

Finally, the researchers assessed the effects of ALRN-6924 in a patient who had high-risk MDS with excess leukemic blasts.

The team found the p53 protein “was rapidly induced” in CD34+ leukemic blasts but not in healthy lymphocytes. And ALRN-6924 reduced the number of malignant cells circulating in the blood.

“This test was not designed to assess the efficacy of the drug in humans,” Dr Steidl noted. “That has to be done in a proper clinical trial. Our goal was to determine whether it can hit the desired target in human cells in a clinical setting, which it did in this individual.”

ALRN-6924 is a stapled alpha-helical peptide, a class of drugs whose helical structure is stabilized using hydrocarbon “staples.” The stapling prevents the peptides from being degraded by enzymes before reaching their intended target. ALRN-6924 is the first stapled peptide therapeutic to be tested in patients.

In the phase 1 trial (NCT02909972), researchers are testing ALRN-6924 in patients with relapsed/refractory AML or advanced MDS.

Image by Spencer Phillips

New research has revealed a link between rare gene variants and survival after hematopoietic stem cell transplant (HSCT).

Researchers performed exome sequencing in nearly 2500 HSCT recipients and their matched, unrelated donors.

The sequencing revealed several gene variants—in both donors and recipients—that were significantly associated with overall survival (OS), transplant-related mortality (TRM), and disease-related mortality (DRM) after HSCT.

Qianqian Zhu, PhD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, and her colleagues described these findings in Blood.

The team performed exome sequencing—using the Illumina HumanExome BeadChip—in patients who participated in the DISCOVeRY-BMT study.

This included 2473 HSCT recipients who had acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndromes. It also included 2221 donors who were a 10/10 human leukocyte antigen match for each recipient.

The researchers looked at genetic variants in donors and recipients and assessed the variants’ associations with OS, TRM, and DRM.

Variants in recipients

Analyses revealed an increased risk of TRM when there was a mismatch between donors and recipients for a variant in TEX38—rs200092801. The increased risk was even more pronounced when either the recipient or the donor was female.

Among the recipients mismatched with their donors at rs200092801, every female recipient and every recipient with a female donor died from TRM. In comparison, 44% of the male recipients with male donors died from TRM.

The researchers said the rs200092801 variant may prompt the production of a mutant peptide that can be presented by MHC-I molecules to immune cells to trigger downstream immune response and TRM.

Dr Zhu and her colleagues also identified variants that appeared to have a positive impact on TRM and OS.

Recipients who had any of 6 variants in the gene OR51D1 had a decreased risk of TRM and improved OS.

The variants (rs138224979, rs148606808, rs141786655, rs61745314, rs200394876, and rs149135276) were not associated with DRM, so the researchers concluded that the improvement in OS was driven by protection against TRM.

Donor variants linked to OS

Donors had variants in 4 genes—ALPP, EMID1, SLC44A5, and LRP1—that were associated with OS but not TRM or DRM.

The 3 variants identified in ALPP (rs144454460, rs140078460, and rs142493383) were associated with improved OS.

And the 2 variants in SLC44A5 (rs143004355 and rs149696907) were associated with worse OS.

There were 2 variants in EMID1. One was associated with improved OS (rs34772704), and the other was associated with decreased OS (rs139996840).

And there were 27 variants in LRP1. Some had a positive association with OS, and others had a negative association.

Donor variants linked to TRM and DRM

Six variants in the HHAT gene were associated with TRM. Five of the variants appeared to have a protective effect against TRM (rs145455128, rs146916002, rs61744143, rs149597734, and rs145943928). For the other variant (rs141591165), the apparent effect was inconsistent between patient cohorts.

There were 3 variants in LYZL4 associated with DRM. Two were associated with an increased risk of DRM (rs147770623 and rs76947105), and 1 appeared to have a protective effect (rs181886204).

Six variants in NT5E appeared to have a protective effect against DRM (rs200250022, rs200369370, rs41271617, rs200648774, rs144719925, and rs145505137).

The researchers said the variants in NT5E probably reduce the enzyme activity of the gene. This supports preclinical findings showing that targeted blockade of NT5E can slow tumor growth.

“We have just started to uncover the biological relevance of these new and unexpected genes to a patient’s survival after [HSCT],” Dr Zhu said.

“Our findings shed light on new areas that were not considered before, but we need to further replicate and test our findings. We’re hoping that additional studies of this type will continue to discover novel genes leading to improved outcomes for patients.”

Image by Spencer Phillips

New research has revealed a link between rare gene variants and survival after hematopoietic stem cell transplant (HSCT).

Researchers performed exome sequencing in nearly 2500 HSCT recipients and their matched, unrelated donors.

The sequencing revealed several gene variants—in both donors and recipients—that were significantly associated with overall survival (OS), transplant-related mortality (TRM), and disease-related mortality (DRM) after HSCT.

Qianqian Zhu, PhD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, and her colleagues described these findings in Blood.

The team performed exome sequencing—using the Illumina HumanExome BeadChip—in patients who participated in the DISCOVeRY-BMT study.

This included 2473 HSCT recipients who had acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndromes. It also included 2221 donors who were a 10/10 human leukocyte antigen match for each recipient.

The researchers looked at genetic variants in donors and recipients and assessed the variants’ associations with OS, TRM, and DRM.

Variants in recipients

Analyses revealed an increased risk of TRM when there was a mismatch between donors and recipients for a variant in TEX38—rs200092801. The increased risk was even more pronounced when either the recipient or the donor was female.

Among the recipients mismatched with their donors at rs200092801, every female recipient and every recipient with a female donor died from TRM. In comparison, 44% of the male recipients with male donors died from TRM.

The researchers said the rs200092801 variant may prompt the production of a mutant peptide that can be presented by MHC-I molecules to immune cells to trigger downstream immune response and TRM.

Dr Zhu and her colleagues also identified variants that appeared to have a positive impact on TRM and OS.

Recipients who had any of 6 variants in the gene OR51D1 had a decreased risk of TRM and improved OS.

The variants (rs138224979, rs148606808, rs141786655, rs61745314, rs200394876, and rs149135276) were not associated with DRM, so the researchers concluded that the improvement in OS was driven by protection against TRM.

Donor variants linked to OS

Donors had variants in 4 genes—ALPP, EMID1, SLC44A5, and LRP1—that were associated with OS but not TRM or DRM.

The 3 variants identified in ALPP (rs144454460, rs140078460, and rs142493383) were associated with improved OS.

And the 2 variants in SLC44A5 (rs143004355 and rs149696907) were associated with worse OS.

There were 2 variants in EMID1. One was associated with improved OS (rs34772704), and the other was associated with decreased OS (rs139996840).

And there were 27 variants in LRP1. Some had a positive association with OS, and others had a negative association.

Donor variants linked to TRM and DRM

Six variants in the HHAT gene were associated with TRM. Five of the variants appeared to have a protective effect against TRM (rs145455128, rs146916002, rs61744143, rs149597734, and rs145943928). For the other variant (rs141591165), the apparent effect was inconsistent between patient cohorts.

There were 3 variants in LYZL4 associated with DRM. Two were associated with an increased risk of DRM (rs147770623 and rs76947105), and 1 appeared to have a protective effect (rs181886204).

Six variants in NT5E appeared to have a protective effect against DRM (rs200250022, rs200369370, rs41271617, rs200648774, rs144719925, and rs145505137).

The researchers said the variants in NT5E probably reduce the enzyme activity of the gene. This supports preclinical findings showing that targeted blockade of NT5E can slow tumor growth.

“We have just started to uncover the biological relevance of these new and unexpected genes to a patient’s survival after [HSCT],” Dr Zhu said.

“Our findings shed light on new areas that were not considered before, but we need to further replicate and test our findings. We’re hoping that additional studies of this type will continue to discover novel genes leading to improved outcomes for patients.”

Image by Spencer Phillips

New research has revealed a link between rare gene variants and survival after hematopoietic stem cell transplant (HSCT).

Researchers performed exome sequencing in nearly 2500 HSCT recipients and their matched, unrelated donors.

The sequencing revealed several gene variants—in both donors and recipients—that were significantly associated with overall survival (OS), transplant-related mortality (TRM), and disease-related mortality (DRM) after HSCT.

Qianqian Zhu, PhD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, and her colleagues described these findings in Blood.

The team performed exome sequencing—using the Illumina HumanExome BeadChip—in patients who participated in the DISCOVeRY-BMT study.

This included 2473 HSCT recipients who had acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndromes. It also included 2221 donors who were a 10/10 human leukocyte antigen match for each recipient.

The researchers looked at genetic variants in donors and recipients and assessed the variants’ associations with OS, TRM, and DRM.

Variants in recipients

Analyses revealed an increased risk of TRM when there was a mismatch between donors and recipients for a variant in TEX38—rs200092801. The increased risk was even more pronounced when either the recipient or the donor was female.

Among the recipients mismatched with their donors at rs200092801, every female recipient and every recipient with a female donor died from TRM. In comparison, 44% of the male recipients with male donors died from TRM.

The researchers said the rs200092801 variant may prompt the production of a mutant peptide that can be presented by MHC-I molecules to immune cells to trigger downstream immune response and TRM.

Dr Zhu and her colleagues also identified variants that appeared to have a positive impact on TRM and OS.

Recipients who had any of 6 variants in the gene OR51D1 had a decreased risk of TRM and improved OS.

The variants (rs138224979, rs148606808, rs141786655, rs61745314, rs200394876, and rs149135276) were not associated with DRM, so the researchers concluded that the improvement in OS was driven by protection against TRM.

Donor variants linked to OS

Donors had variants in 4 genes—ALPP, EMID1, SLC44A5, and LRP1—that were associated with OS but not TRM or DRM.

The 3 variants identified in ALPP (rs144454460, rs140078460, and rs142493383) were associated with improved OS.

And the 2 variants in SLC44A5 (rs143004355 and rs149696907) were associated with worse OS.

There were 2 variants in EMID1. One was associated with improved OS (rs34772704), and the other was associated with decreased OS (rs139996840).

And there were 27 variants in LRP1. Some had a positive association with OS, and others had a negative association.

Donor variants linked to TRM and DRM

Six variants in the HHAT gene were associated with TRM. Five of the variants appeared to have a protective effect against TRM (rs145455128, rs146916002, rs61744143, rs149597734, and rs145943928). For the other variant (rs141591165), the apparent effect was inconsistent between patient cohorts.

There were 3 variants in LYZL4 associated with DRM. Two were associated with an increased risk of DRM (rs147770623 and rs76947105), and 1 appeared to have a protective effect (rs181886204).

Six variants in NT5E appeared to have a protective effect against DRM (rs200250022, rs200369370, rs41271617, rs200648774, rs144719925, and rs145505137).

The researchers said the variants in NT5E probably reduce the enzyme activity of the gene. This supports preclinical findings showing that targeted blockade of NT5E can slow tumor growth.

“We have just started to uncover the biological relevance of these new and unexpected genes to a patient’s survival after [HSCT],” Dr Zhu said.

“Our findings shed light on new areas that were not considered before, but we need to further replicate and test our findings. We’re hoping that additional studies of this type will continue to discover novel genes leading to improved outcomes for patients.”

Image from Darryl Leja, NHGRI

Through extensive analyses of data from The Cancer Genome Atlas (TCGA), researchers have produced a new resource known as the Pan-Cancer Atlas.

Multiple research groups analyzed data on more than 10,000 tumors spanning 33 types of cancer, including acute myeloid leukemia and diffuse large B-cell lymphoma.

The work revealed new insights regarding cells of origin, oncogenic processes, and signaling pathways.

These insights make up the Pan-Cancer Atlas and are described in 27 papers published in Cell Press journals. The entire collection of papers is available through a portal on cell.com.

The Pan-Cancer Atlas is the final output of TCGA, a joint effort of the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) to “collect, select, and analyze human tissues for genomic alterations on a very large scale.”

“This project is the culmination of more than a decade of ground-breaking work,” said Francis S. Collins, MD, PhD, director of the National Institutes of Health.

“This analysis provides cancer researchers with unprecedented understanding of how, where, and why tumors arise in humans, enabling better informed clinical trials and future treatments.”

The project focused on genome sequencing as well as other analyses, such as investigating gene and protein expression profiles and associating them with clinical and imaging data.

“The Pan-Cancer Atlas effort complements the over 30 tumor-specific papers that have been published by TCGA in the last decade and expands upon earlier pan-cancer work that was published in 2013,” said Jean Claude Zenklusen, PhD, director of the TCGA Program Office at NCI.

The Pan-Cancer Atlas is divided into 3 main categories—cell of origin, oncogenic processes, and signaling pathways—each anchored by a summary paper that recaps the core findings for the topic. Companion papers report in-depth explorations of individual topics within these categories.

Cell of origin

In the first Pan-Cancer Atlas summary paper, the authors review the findings from analyses using a technique called molecular clustering, which groups tumors by parameters such as genes being expressed, abnormality of chromosome numbers in tumor cells, and DNA modifications.

The analyses suggest that tumor types cluster by their possible cells of origin, a finding that has implications for the classification and treatment of various cancers.

“Rather than the organ of origin, we can now use molecular features to identify the cancer’s cell of origin,” said Li Ding, PhD, of Washington University School of Medicine in St. Louis, Missouri.

“We are looking at what genes are turned on in the tumor, and that brings us to a particular cell type. For example, squamous cell cancers can arise in the lung, bladder, cervix, and some tumors of the head and neck. We traditionally have treated cancers in these areas as completely different diseases, but, [by] studying their molecular features, we now know such cancers are closely related.”

“This new molecular-based classification system should greatly help in the clinic, where it is already explaining some of the similar clinical behavior of what we thought were different tumor types,” said Charles Perou, PhD, of UNC Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina.

“These findings also provide many new therapeutic opportunities, which can and will be tested in the next phase of human clinical trials.”

Oncogenic processes

The second Pan-Cancer Atlas summary paper presents a broad view of the TCGA findings on the processes that lead to cancer development and progression.

The research revealed insights into 3 critical oncogenic processes—germline and somatic mutations, the influence of the tumor’s underlying genome and epigenome on gene and protein expression, and the interplay of tumor and immune cells.

“For the 10,000 tumors we analyzed, we now know—in detail—the inherited mutations driving cancer and the genetic errors that accumulate as people age, increasing the risk of cancer,” Dr Ding said. “This is the first definitive summary of the genetics behind 33 major types of cancer.”

“TCGA has created a catalogue of alterations that occur in a variety of cancer types,” said Katherine Hoadley, PhD, of University of North Carolina at Chapel Hill.

“Having this catalogue of alterations is really important for us to look, in future studies, at why these alterations are there and to predict outcomes for patients.”

Signaling pathways

The final Pan-Cancer Atlas summary paper details TCGA research on the genomic alterations in the signaling pathways that control cell-cycle progression, cell death, and cell growth. The work highlights the similarities and differences in these processes across a range of cancers.

The researchers believe these studies have revealed new patterns of potential vulnerabilities that might aid the development of targeted and combination therapies.

Image from Darryl Leja, NHGRI

Through extensive analyses of data from The Cancer Genome Atlas (TCGA), researchers have produced a new resource known as the Pan-Cancer Atlas.

Multiple research groups analyzed data on more than 10,000 tumors spanning 33 types of cancer, including acute myeloid leukemia and diffuse large B-cell lymphoma.

The work revealed new insights regarding cells of origin, oncogenic processes, and signaling pathways.

These insights make up the Pan-Cancer Atlas and are described in 27 papers published in Cell Press journals. The entire collection of papers is available through a portal on cell.com.

The Pan-Cancer Atlas is the final output of TCGA, a joint effort of the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) to “collect, select, and analyze human tissues for genomic alterations on a very large scale.”

“This project is the culmination of more than a decade of ground-breaking work,” said Francis S. Collins, MD, PhD, director of the National Institutes of Health.

“This analysis provides cancer researchers with unprecedented understanding of how, where, and why tumors arise in humans, enabling better informed clinical trials and future treatments.”

The project focused on genome sequencing as well as other analyses, such as investigating gene and protein expression profiles and associating them with clinical and imaging data.

“The Pan-Cancer Atlas effort complements the over 30 tumor-specific papers that have been published by TCGA in the last decade and expands upon earlier pan-cancer work that was published in 2013,” said Jean Claude Zenklusen, PhD, director of the TCGA Program Office at NCI.

The Pan-Cancer Atlas is divided into 3 main categories—cell of origin, oncogenic processes, and signaling pathways—each anchored by a summary paper that recaps the core findings for the topic. Companion papers report in-depth explorations of individual topics within these categories.

Cell of origin

In the first Pan-Cancer Atlas summary paper, the authors review the findings from analyses using a technique called molecular clustering, which groups tumors by parameters such as genes being expressed, abnormality of chromosome numbers in tumor cells, and DNA modifications.

The analyses suggest that tumor types cluster by their possible cells of origin, a finding that has implications for the classification and treatment of various cancers.

“Rather than the organ of origin, we can now use molecular features to identify the cancer’s cell of origin,” said Li Ding, PhD, of Washington University School of Medicine in St. Louis, Missouri.

“We are looking at what genes are turned on in the tumor, and that brings us to a particular cell type. For example, squamous cell cancers can arise in the lung, bladder, cervix, and some tumors of the head and neck. We traditionally have treated cancers in these areas as completely different diseases, but, [by] studying their molecular features, we now know such cancers are closely related.”

“This new molecular-based classification system should greatly help in the clinic, where it is already explaining some of the similar clinical behavior of what we thought were different tumor types,” said Charles Perou, PhD, of UNC Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina.

“These findings also provide many new therapeutic opportunities, which can and will be tested in the next phase of human clinical trials.”

Oncogenic processes

The second Pan-Cancer Atlas summary paper presents a broad view of the TCGA findings on the processes that lead to cancer development and progression.

The research revealed insights into 3 critical oncogenic processes—germline and somatic mutations, the influence of the tumor’s underlying genome and epigenome on gene and protein expression, and the interplay of tumor and immune cells.

“For the 10,000 tumors we analyzed, we now know—in detail—the inherited mutations driving cancer and the genetic errors that accumulate as people age, increasing the risk of cancer,” Dr Ding said. “This is the first definitive summary of the genetics behind 33 major types of cancer.”

“TCGA has created a catalogue of alterations that occur in a variety of cancer types,” said Katherine Hoadley, PhD, of University of North Carolina at Chapel Hill.

“Having this catalogue of alterations is really important for us to look, in future studies, at why these alterations are there and to predict outcomes for patients.”

Signaling pathways

The final Pan-Cancer Atlas summary paper details TCGA research on the genomic alterations in the signaling pathways that control cell-cycle progression, cell death, and cell growth. The work highlights the similarities and differences in these processes across a range of cancers.

The researchers believe these studies have revealed new patterns of potential vulnerabilities that might aid the development of targeted and combination therapies.

Image from Darryl Leja, NHGRI

Through extensive analyses of data from The Cancer Genome Atlas (TCGA), researchers have produced a new resource known as the Pan-Cancer Atlas.

Multiple research groups analyzed data on more than 10,000 tumors spanning 33 types of cancer, including acute myeloid leukemia and diffuse large B-cell lymphoma.

The work revealed new insights regarding cells of origin, oncogenic processes, and signaling pathways.

These insights make up the Pan-Cancer Atlas and are described in 27 papers published in Cell Press journals. The entire collection of papers is available through a portal on cell.com.

The Pan-Cancer Atlas is the final output of TCGA, a joint effort of the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) to “collect, select, and analyze human tissues for genomic alterations on a very large scale.”

“This project is the culmination of more than a decade of ground-breaking work,” said Francis S. Collins, MD, PhD, director of the National Institutes of Health.

“This analysis provides cancer researchers with unprecedented understanding of how, where, and why tumors arise in humans, enabling better informed clinical trials and future treatments.”

The project focused on genome sequencing as well as other analyses, such as investigating gene and protein expression profiles and associating them with clinical and imaging data.

“The Pan-Cancer Atlas effort complements the over 30 tumor-specific papers that have been published by TCGA in the last decade and expands upon earlier pan-cancer work that was published in 2013,” said Jean Claude Zenklusen, PhD, director of the TCGA Program Office at NCI.

The Pan-Cancer Atlas is divided into 3 main categories—cell of origin, oncogenic processes, and signaling pathways—each anchored by a summary paper that recaps the core findings for the topic. Companion papers report in-depth explorations of individual topics within these categories.

Cell of origin

In the first Pan-Cancer Atlas summary paper, the authors review the findings from analyses using a technique called molecular clustering, which groups tumors by parameters such as genes being expressed, abnormality of chromosome numbers in tumor cells, and DNA modifications.

The analyses suggest that tumor types cluster by their possible cells of origin, a finding that has implications for the classification and treatment of various cancers.

“Rather than the organ of origin, we can now use molecular features to identify the cancer’s cell of origin,” said Li Ding, PhD, of Washington University School of Medicine in St. Louis, Missouri.

“We are looking at what genes are turned on in the tumor, and that brings us to a particular cell type. For example, squamous cell cancers can arise in the lung, bladder, cervix, and some tumors of the head and neck. We traditionally have treated cancers in these areas as completely different diseases, but, [by] studying their molecular features, we now know such cancers are closely related.”

“This new molecular-based classification system should greatly help in the clinic, where it is already explaining some of the similar clinical behavior of what we thought were different tumor types,” said Charles Perou, PhD, of UNC Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina.

“These findings also provide many new therapeutic opportunities, which can and will be tested in the next phase of human clinical trials.”

Oncogenic processes

The second Pan-Cancer Atlas summary paper presents a broad view of the TCGA findings on the processes that lead to cancer development and progression.

The research revealed insights into 3 critical oncogenic processes—germline and somatic mutations, the influence of the tumor’s underlying genome and epigenome on gene and protein expression, and the interplay of tumor and immune cells.

“For the 10,000 tumors we analyzed, we now know—in detail—the inherited mutations driving cancer and the genetic errors that accumulate as people age, increasing the risk of cancer,” Dr Ding said. “This is the first definitive summary of the genetics behind 33 major types of cancer.”

“TCGA has created a catalogue of alterations that occur in a variety of cancer types,” said Katherine Hoadley, PhD, of University of North Carolina at Chapel Hill.

“Having this catalogue of alterations is really important for us to look, in future studies, at why these alterations are there and to predict outcomes for patients.”

Signaling pathways

The final Pan-Cancer Atlas summary paper details TCGA research on the genomic alterations in the signaling pathways that control cell-cycle progression, cell death, and cell growth. The work highlights the similarities and differences in these processes across a range of cancers.

The researchers believe these studies have revealed new patterns of potential vulnerabilities that might aid the development of targeted and combination therapies.

AML cells

The experimental agent prexigebersen (formerly BP1001) was considered well-tolerated and demonstrated early evidence of activity against relapsed/refractory hematologic disorders in a phase 1/1b trial.

The drug reduced blasts in the bone marrow and peripheral blood for patients with acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS).

When given in combination with low-dose cytarabine, prexigebersen produced complete responses (CRs) in patients with AML.

Researchers said that, overall, the toxic effects of prexigebersen were manageable.

There was 1 patient who had dose-limiting toxicities, 1 who discontinued treatment due to possible drug-related toxic effects, and 1 treatment-related death.

Still, the maximum tolerated dose of prexigebersen was not established.

These results were published in The Lancet Haematology. The study was sponsored by Bio-Path Holdings, Inc., the company developing prexigebersen.

Prexigebersen is an anti-sense oligodeoxynucleotide developed to block Grb2 expression and function. Researchers tested the drug in a single-center, dose-escalation, phase 1/1b trial that enrolled and treated 39 patients.

In the phase 1 portion of the trial, patients received prexigebersen monotherapy. In the phase 1b portion, they received the drug in combination with low-dose cytarabine.

There were 32 patients in the phase 1 portion of the trial. Most (n=23) had AML, 5 had CML in blast phase, and 4 had MDS. The patients’ median age was 63 (range, 56-73), and they had received a median of 4 prior therapies.

All 7 patients in the phase 1b portion had AML. They had a median age of 72 (range, 70-76) and had all received 1 prior therapy.

For phase 1, prexigebersen was administered intravenously, twice weekly for 28 days at doses of 5 mg/m² in cohort 1 (n=13), 10 mg/m² in cohort 2 (n=6), 20 mg/m² in cohort 3 (n=3), 40 mg/m² in cohort 4 (n=3), 60 mg/m² in cohort 5 (n=3), and 90 mg/m² in cohort 6 (n=4).

In the phase 1b portion, patients received prexigebersen at 60 mg/m² (n=4) or 90 mg/m² (n=3) in combination with 20 mg of cytarabine (twice-daily subcutaneous injections).

Safety

Twenty-seven patients were evaluable for dose-limiting toxicity—21 from phase 1 and 6 from 1b.

One patient in cohort 1 developed mucositis and hand-foot syndrome, which were considered possibly related to prexigebersen and deemed dose-limiting toxicities. The patient was also receiving hydroxyurea (3 g/day) for CML and had a history of hydroxyurea-induced mucositis.

There were no other dose-limiting toxicities, and the researchers did not identify a maximum tolerated dose of prexigebersen.

The most common grade 3-4 adverse events (AEs) were cardiopulmonary disorders and fevers (including neutropenic fevers and infections).

In the monotherapy group, 17% of patients had grade 3-4 cardiopulmonary AEs, and 11% had fevers. In the prexigebersen-cytarabine combination group, 8% had grade 3-4 cardiopulmonary AEs, and 6% had fevers.

There were 5 grade 5 AEs in 4 patients, all of whom received monotherapy. These included cardiopulmonary disorders (n=2), fevers (n=2), and multi-organ failure (n=1). One patient had both fever (sepsis) and multi-organ failure.

Efficacy

According to the researchers’ assessments, 22% of phase 1 patients (7/32) benefited from prexigebersen monotherapy and therefore received more than 1 cycle of treatment. Five of these patients had AML, and 2 had MDS.

Single-agent activity was observed in other patients as well.

Thirty-three percent (9/27) of patients who had peripheral blood blasts at baseline saw their blasts reduced by 50% or more while receiving monotherapy. One of these patients had CML, and the rest had AML.

Ten percent (3/29) of patients with bone marrow blasts at baseline had a reduction in blasts of 50% or more while receiving monotherapy.  Two of these patients had AML, and 1 had MDS.

Of the 7 patients receiving prexigebersen with cytarabine, 2 achieved a CR, and 1 had a CR with incomplete hematological recovery.

Two of the patients had stable disease, and the remaining 2 patients progressed. One of the patients with progressive disease withdrew from the study, and the other died.

Deaths

There were a total of 8 deaths.

One death was considered treatment-related. This patient had progressive CML in blast phase and died of multiple organ failure. This was the first patient treated on the trial, who also had the only dose-limiting toxicities.

Two patients with AML and 1 with MDS died of disease progression. Three AML patients died of sepsis, pneumonia, and cardiac arrest. And a CML patient died of respiratory distress.

AML cells

The experimental agent prexigebersen (formerly BP1001) was considered well-tolerated and demonstrated early evidence of activity against relapsed/refractory hematologic disorders in a phase 1/1b trial.

The drug reduced blasts in the bone marrow and peripheral blood for patients with acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS).

When given in combination with low-dose cytarabine, prexigebersen produced complete responses (CRs) in patients with AML.

Researchers said that, overall, the toxic effects of prexigebersen were manageable.

There was 1 patient who had dose-limiting toxicities, 1 who discontinued treatment due to possible drug-related toxic effects, and 1 treatment-related death.

Still, the maximum tolerated dose of prexigebersen was not established.

These results were published in The Lancet Haematology. The study was sponsored by Bio-Path Holdings, Inc., the company developing prexigebersen.

Prexigebersen is an anti-sense oligodeoxynucleotide developed to block Grb2 expression and function. Researchers tested the drug in a single-center, dose-escalation, phase 1/1b trial that enrolled and treated 39 patients.

In the phase 1 portion of the trial, patients received prexigebersen monotherapy. In the phase 1b portion, they received the drug in combination with low-dose cytarabine.

There were 32 patients in the phase 1 portion of the trial. Most (n=23) had AML, 5 had CML in blast phase, and 4 had MDS. The patients’ median age was 63 (range, 56-73), and they had received a median of 4 prior therapies.

All 7 patients in the phase 1b portion had AML. They had a median age of 72 (range, 70-76) and had all received 1 prior therapy.

For phase 1, prexigebersen was administered intravenously, twice weekly for 28 days at doses of 5 mg/m² in cohort 1 (n=13), 10 mg/m² in cohort 2 (n=6), 20 mg/m² in cohort 3 (n=3), 40 mg/m² in cohort 4 (n=3), 60 mg/m² in cohort 5 (n=3), and 90 mg/m² in cohort 6 (n=4).

In the phase 1b portion, patients received prexigebersen at 60 mg/m² (n=4) or 90 mg/m² (n=3) in combination with 20 mg of cytarabine (twice-daily subcutaneous injections).

Safety

Twenty-seven patients were evaluable for dose-limiting toxicity—21 from phase 1 and 6 from 1b.

One patient in cohort 1 developed mucositis and hand-foot syndrome, which were considered possibly related to prexigebersen and deemed dose-limiting toxicities. The patient was also receiving hydroxyurea (3 g/day) for CML and had a history of hydroxyurea-induced mucositis.

There were no other dose-limiting toxicities, and the researchers did not identify a maximum tolerated dose of prexigebersen.

The most common grade 3-4 adverse events (AEs) were cardiopulmonary disorders and fevers (including neutropenic fevers and infections).

In the monotherapy group, 17% of patients had grade 3-4 cardiopulmonary AEs, and 11% had fevers. In the prexigebersen-cytarabine combination group, 8% had grade 3-4 cardiopulmonary AEs, and 6% had fevers.

There were 5 grade 5 AEs in 4 patients, all of whom received monotherapy. These included cardiopulmonary disorders (n=2), fevers (n=2), and multi-organ failure (n=1). One patient had both fever (sepsis) and multi-organ failure.

Efficacy

According to the researchers’ assessments, 22% of phase 1 patients (7/32) benefited from prexigebersen monotherapy and therefore received more than 1 cycle of treatment. Five of these patients had AML, and 2 had MDS.

Single-agent activity was observed in other patients as well.

Thirty-three percent (9/27) of patients who had peripheral blood blasts at baseline saw their blasts reduced by 50% or more while receiving monotherapy. One of these patients had CML, and the rest had AML.

Ten percent (3/29) of patients with bone marrow blasts at baseline had a reduction in blasts of 50% or more while receiving monotherapy.  Two of these patients had AML, and 1 had MDS.

Of the 7 patients receiving prexigebersen with cytarabine, 2 achieved a CR, and 1 had a CR with incomplete hematological recovery.

Two of the patients had stable disease, and the remaining 2 patients progressed. One of the patients with progressive disease withdrew from the study, and the other died.

Deaths

There were a total of 8 deaths.

One death was considered treatment-related. This patient had progressive CML in blast phase and died of multiple organ failure. This was the first patient treated on the trial, who also had the only dose-limiting toxicities.

Two patients with AML and 1 with MDS died of disease progression. Three AML patients died of sepsis, pneumonia, and cardiac arrest. And a CML patient died of respiratory distress.

AML cells

The experimental agent prexigebersen (formerly BP1001) was considered well-tolerated and demonstrated early evidence of activity against relapsed/refractory hematologic disorders in a phase 1/1b trial.

The drug reduced blasts in the bone marrow and peripheral blood for patients with acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS).

When given in combination with low-dose cytarabine, prexigebersen produced complete responses (CRs) in patients with AML.

Researchers said that, overall, the toxic effects of prexigebersen were manageable.

There was 1 patient who had dose-limiting toxicities, 1 who discontinued treatment due to possible drug-related toxic effects, and 1 treatment-related death.

Still, the maximum tolerated dose of prexigebersen was not established.

These results were published in The Lancet Haematology. The study was sponsored by Bio-Path Holdings, Inc., the company developing prexigebersen.

Prexigebersen is an anti-sense oligodeoxynucleotide developed to block Grb2 expression and function. Researchers tested the drug in a single-center, dose-escalation, phase 1/1b trial that enrolled and treated 39 patients.

In the phase 1 portion of the trial, patients received prexigebersen monotherapy. In the phase 1b portion, they received the drug in combination with low-dose cytarabine.

There were 32 patients in the phase 1 portion of the trial. Most (n=23) had AML, 5 had CML in blast phase, and 4 had MDS. The patients’ median age was 63 (range, 56-73), and they had received a median of 4 prior therapies.

All 7 patients in the phase 1b portion had AML. They had a median age of 72 (range, 70-76) and had all received 1 prior therapy.

For phase 1, prexigebersen was administered intravenously, twice weekly for 28 days at doses of 5 mg/m² in cohort 1 (n=13), 10 mg/m² in cohort 2 (n=6), 20 mg/m² in cohort 3 (n=3), 40 mg/m² in cohort 4 (n=3), 60 mg/m² in cohort 5 (n=3), and 90 mg/m² in cohort 6 (n=4).

In the phase 1b portion, patients received prexigebersen at 60 mg/m² (n=4) or 90 mg/m² (n=3) in combination with 20 mg of cytarabine (twice-daily subcutaneous injections).

Safety

Twenty-seven patients were evaluable for dose-limiting toxicity—21 from phase 1 and 6 from 1b.

One patient in cohort 1 developed mucositis and hand-foot syndrome, which were considered possibly related to prexigebersen and deemed dose-limiting toxicities. The patient was also receiving hydroxyurea (3 g/day) for CML and had a history of hydroxyurea-induced mucositis.

There were no other dose-limiting toxicities, and the researchers did not identify a maximum tolerated dose of prexigebersen.

The most common grade 3-4 adverse events (AEs) were cardiopulmonary disorders and fevers (including neutropenic fevers and infections).

In the monotherapy group, 17% of patients had grade 3-4 cardiopulmonary AEs, and 11% had fevers. In the prexigebersen-cytarabine combination group, 8% had grade 3-4 cardiopulmonary AEs, and 6% had fevers.

There were 5 grade 5 AEs in 4 patients, all of whom received monotherapy. These included cardiopulmonary disorders (n=2), fevers (n=2), and multi-organ failure (n=1). One patient had both fever (sepsis) and multi-organ failure.

Efficacy

According to the researchers’ assessments, 22% of phase 1 patients (7/32) benefited from prexigebersen monotherapy and therefore received more than 1 cycle of treatment. Five of these patients had AML, and 2 had MDS.

Single-agent activity was observed in other patients as well.

Thirty-three percent (9/27) of patients who had peripheral blood blasts at baseline saw their blasts reduced by 50% or more while receiving monotherapy. One of these patients had CML, and the rest had AML.

Ten percent (3/29) of patients with bone marrow blasts at baseline had a reduction in blasts of 50% or more while receiving monotherapy.  Two of these patients had AML, and 1 had MDS.

Of the 7 patients receiving prexigebersen with cytarabine, 2 achieved a CR, and 1 had a CR with incomplete hematological recovery.

Two of the patients had stable disease, and the remaining 2 patients progressed. One of the patients with progressive disease withdrew from the study, and the other died.

Deaths

There were a total of 8 deaths.

One death was considered treatment-related. This patient had progressive CML in blast phase and died of multiple organ failure. This was the first patient treated on the trial, who also had the only dose-limiting toxicities.

Two patients with AML and 1 with MDS died of disease progression. Three AML patients died of sepsis, pneumonia, and cardiac arrest. And a CML patient died of respiratory distress.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has granted orphan designation to MAX-40279 for the treatment of acute myeloid leukemia (AML).

MAX-40279 is a multi-target kinase inhibitor being developed by MaxiNovel Pharmaceuticals, Inc.

The drug mainly targets FMS-related tyrosine kinase 3 (FLT3) and fibroblast growth factor receptor (FGFR).

MAX-40279 demonstrated “potent” inhibition of FLT3 and FGFR in preclinical testing, according to MaxiNovel Pharmaceuticals, Inc.

The company is currently testing MAX-40279 in a phase 1 trial of patients with AML (NCT03412292).

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.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has granted orphan designation to MAX-40279 for the treatment of acute myeloid leukemia (AML).

MAX-40279 is a multi-target kinase inhibitor being developed by MaxiNovel Pharmaceuticals, Inc.

The drug mainly targets FMS-related tyrosine kinase 3 (FLT3) and fibroblast growth factor receptor (FGFR).

MAX-40279 demonstrated “potent” inhibition of FLT3 and FGFR in preclinical testing, according to MaxiNovel Pharmaceuticals, Inc.

The company is currently testing MAX-40279 in a phase 1 trial of patients with AML (NCT03412292).

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.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has granted orphan designation to MAX-40279 for the treatment of acute myeloid leukemia (AML).

MAX-40279 is a multi-target kinase inhibitor being developed by MaxiNovel Pharmaceuticals, Inc.

The drug mainly targets FMS-related tyrosine kinase 3 (FLT3) and fibroblast growth factor receptor (FGFR).

MAX-40279 demonstrated “potent” inhibition of FLT3 and FGFR in preclinical testing, according to MaxiNovel Pharmaceuticals, Inc.

The company is currently testing MAX-40279 in a phase 1 trial of patients with AML (NCT03412292).

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.

Detecting molecular minimal residual disease among patients in complete remission was a significant independent predictor of relapse and survival in acute myeloid leukemia (AML), findings from a new study suggest.

Mojca Jongen-Lavrencic, MD, PhD, of the Erasmus University in the Netherlands, and colleagues conducted targeted next-generation sequencing on bone marrow or peripheral blood samples to detect minimal residual disease in 482 newly diagnosed AML patients aged 18-65 years. The sampling was conducted at diagnosis and again after induction therapy. The study endpoints included 4-year rates of relapse, relapse-free survival, and overall survival. The findings are reported in the New England Journal of Medicine.

Overall, at least one mutation was found in 430 patients (89.2%). Persistent DTA mutations, which are associated with age-related hematopoiesis, were not significantly associated with higher 4-year relapse rates, compared with no detection of DTA mutations (P = .29). However, having a persistent DTA mutation and a coexisting persistent non-DTA mutation was a significant predictor of relapse, with a 4-year relapse rate of 66.7% versus 39.4% for no detection (P = .002).

Similarly, having a persistent non-DTA mutation at any allele frequency was linked to an increase risk of relapse at 4 years (55.7% with detection versus 34.6% without detection, P = .001). Non-DTA mutation was also significantly associated with reduced relapsed-free survival and reduced overall survival.

The study was funded by the Queen Wilhelmina Fund Foundation of the Dutch Cancer, among others. There was no commercial funding for the study.

[email protected]

SOURCE: Jongen-Lavrencic M et al. N Engl J Med. 2018 Mar 29;378:1189-99.

Detecting molecular minimal residual disease among patients in complete remission was a significant independent predictor of relapse and survival in acute myeloid leukemia (AML), findings from a new study suggest.

Mojca Jongen-Lavrencic, MD, PhD, of the Erasmus University in the Netherlands, and colleagues conducted targeted next-generation sequencing on bone marrow or peripheral blood samples to detect minimal residual disease in 482 newly diagnosed AML patients aged 18-65 years. The sampling was conducted at diagnosis and again after induction therapy. The study endpoints included 4-year rates of relapse, relapse-free survival, and overall survival. The findings are reported in the New England Journal of Medicine.

Overall, at least one mutation was found in 430 patients (89.2%). Persistent DTA mutations, which are associated with age-related hematopoiesis, were not significantly associated with higher 4-year relapse rates, compared with no detection of DTA mutations (P = .29). However, having a persistent DTA mutation and a coexisting persistent non-DTA mutation was a significant predictor of relapse, with a 4-year relapse rate of 66.7% versus 39.4% for no detection (P = .002).

Similarly, having a persistent non-DTA mutation at any allele frequency was linked to an increase risk of relapse at 4 years (55.7% with detection versus 34.6% without detection, P = .001). Non-DTA mutation was also significantly associated with reduced relapsed-free survival and reduced overall survival.

The study was funded by the Queen Wilhelmina Fund Foundation of the Dutch Cancer, among others. There was no commercial funding for the study.

[email protected]

SOURCE: Jongen-Lavrencic M et al. N Engl J Med. 2018 Mar 29;378:1189-99.

Detecting molecular minimal residual disease among patients in complete remission was a significant independent predictor of relapse and survival in acute myeloid leukemia (AML), findings from a new study suggest.

Mojca Jongen-Lavrencic, MD, PhD, of the Erasmus University in the Netherlands, and colleagues conducted targeted next-generation sequencing on bone marrow or peripheral blood samples to detect minimal residual disease in 482 newly diagnosed AML patients aged 18-65 years. The sampling was conducted at diagnosis and again after induction therapy. The study endpoints included 4-year rates of relapse, relapse-free survival, and overall survival. The findings are reported in the New England Journal of Medicine.

Overall, at least one mutation was found in 430 patients (89.2%). Persistent DTA mutations, which are associated with age-related hematopoiesis, were not significantly associated with higher 4-year relapse rates, compared with no detection of DTA mutations (P = .29). However, having a persistent DTA mutation and a coexisting persistent non-DTA mutation was a significant predictor of relapse, with a 4-year relapse rate of 66.7% versus 39.4% for no detection (P = .002).

Similarly, having a persistent non-DTA mutation at any allele frequency was linked to an increase risk of relapse at 4 years (55.7% with detection versus 34.6% without detection, P = .001). Non-DTA mutation was also significantly associated with reduced relapsed-free survival and reduced overall survival.

The study was funded by the Queen Wilhelmina Fund Foundation of the Dutch Cancer, among others. There was no commercial funding for the study.

[email protected]

SOURCE: Jongen-Lavrencic M et al. N Engl J Med. 2018 Mar 29;378:1189-99.

Library of Medicine

James F. Holland, MD, passed away last week, at the age of 92, due to complications of cardiovascular disease.

Dr Holland has been called a pioneer in the field of leukemia research.

He and his colleagues are credited with using combination chemotherapy to transform pediatric acute lymphoblastic leukemia from an incurable illness to one with a high survival rate.

Dr Holland and his colleagues also developed the 7+3 regimen—3 daily injections of daunorubicin and 7 days of intravenous cytarabine—for patients with acute myeloid leukemia.

Dr Holland was born on May 16, 1925, in Morristown, New Jersey. He graduated from Princeton University in 1944 and earned his medical degree from Columbia University College of Physicians and Surgeons in 1947.

Dr Holland was a captain in the US Army Medical Corps from 1949 to 1951. After that, he worked at Francis Delafield Hospital (which closed in 1975) in New York, New York. He joined the National Cancer Institute (NCI) in 1953. Two years later, he began working at Roswell Park Cancer Institute in Buffalo, New York.

Dr Holland became Roswell Park’s chief of medicine and director of the Cancer Clinical Research Center. But he continued to work with the NCI, conducting research as part of Acute Leukemia Group B, which later became Cancer and Leukemia Group B.

After spending a year on an oncology exchange program in the Soviet Union, Dr Holland started at Mount Sinai in New York, New York, in 1973. While there, he established the Department of Neoplastic Diseases at The Tisch Cancer Institute, Icahn School of Medicine.

Most recently, Dr Holland was a distinguished professor of neoplastic diseases at Mount Sinai. He saw patients but also conducted research on the human mammary tumor virus.

Dr Holland collaborated with Emil Frei III to publish the textbook Cancer Medicine, which is now in its ninth edition. Dr Holland served as president of the American Association for Cancer Research and the American Society of Clinical Oncology. He was a co-founder of the African Organization for Research and Training in Cancer as well.

Dr Holland was married to Jimmie C. Holland, MD, who is credited with founding the field of psycho-oncology. Jimmie passed away in December 2017. The couple is survived by 6 children and 9 grandchildren.

Library of Medicine

James F. Holland, MD, passed away last week, at the age of 92, due to complications of cardiovascular disease.

Dr Holland has been called a pioneer in the field of leukemia research.

He and his colleagues are credited with using combination chemotherapy to transform pediatric acute lymphoblastic leukemia from an incurable illness to one with a high survival rate.

Dr Holland and his colleagues also developed the 7+3 regimen—3 daily injections of daunorubicin and 7 days of intravenous cytarabine—for patients with acute myeloid leukemia.

Dr Holland was born on May 16, 1925, in Morristown, New Jersey. He graduated from Princeton University in 1944 and earned his medical degree from Columbia University College of Physicians and Surgeons in 1947.

Dr Holland was a captain in the US Army Medical Corps from 1949 to 1951. After that, he worked at Francis Delafield Hospital (which closed in 1975) in New York, New York. He joined the National Cancer Institute (NCI) in 1953. Two years later, he began working at Roswell Park Cancer Institute in Buffalo, New York.

Dr Holland became Roswell Park’s chief of medicine and director of the Cancer Clinical Research Center. But he continued to work with the NCI, conducting research as part of Acute Leukemia Group B, which later became Cancer and Leukemia Group B.

After spending a year on an oncology exchange program in the Soviet Union, Dr Holland started at Mount Sinai in New York, New York, in 1973. While there, he established the Department of Neoplastic Diseases at The Tisch Cancer Institute, Icahn School of Medicine.

Most recently, Dr Holland was a distinguished professor of neoplastic diseases at Mount Sinai. He saw patients but also conducted research on the human mammary tumor virus.

Dr Holland collaborated with Emil Frei III to publish the textbook Cancer Medicine, which is now in its ninth edition. Dr Holland served as president of the American Association for Cancer Research and the American Society of Clinical Oncology. He was a co-founder of the African Organization for Research and Training in Cancer as well.

Dr Holland was married to Jimmie C. Holland, MD, who is credited with founding the field of psycho-oncology. Jimmie passed away in December 2017. The couple is survived by 6 children and 9 grandchildren.

Library of Medicine

James F. Holland, MD, passed away last week, at the age of 92, due to complications of cardiovascular disease.

Dr Holland has been called a pioneer in the field of leukemia research.

He and his colleagues are credited with using combination chemotherapy to transform pediatric acute lymphoblastic leukemia from an incurable illness to one with a high survival rate.

Dr Holland and his colleagues also developed the 7+3 regimen—3 daily injections of daunorubicin and 7 days of intravenous cytarabine—for patients with acute myeloid leukemia.

Dr Holland was born on May 16, 1925, in Morristown, New Jersey. He graduated from Princeton University in 1944 and earned his medical degree from Columbia University College of Physicians and Surgeons in 1947.

Dr Holland was a captain in the US Army Medical Corps from 1949 to 1951. After that, he worked at Francis Delafield Hospital (which closed in 1975) in New York, New York. He joined the National Cancer Institute (NCI) in 1953. Two years later, he began working at Roswell Park Cancer Institute in Buffalo, New York.

Dr Holland became Roswell Park’s chief of medicine and director of the Cancer Clinical Research Center. But he continued to work with the NCI, conducting research as part of Acute Leukemia Group B, which later became Cancer and Leukemia Group B.

After spending a year on an oncology exchange program in the Soviet Union, Dr Holland started at Mount Sinai in New York, New York, in 1973. While there, he established the Department of Neoplastic Diseases at The Tisch Cancer Institute, Icahn School of Medicine.

Most recently, Dr Holland was a distinguished professor of neoplastic diseases at Mount Sinai. He saw patients but also conducted research on the human mammary tumor virus.

Dr Holland collaborated with Emil Frei III to publish the textbook Cancer Medicine, which is now in its ninth edition. Dr Holland served as president of the American Association for Cancer Research and the American Society of Clinical Oncology. He was a co-founder of the African Organization for Research and Training in Cancer as well.

Dr Holland was married to Jimmie C. Holland, MD, who is credited with founding the field of psycho-oncology. Jimmie passed away in December 2017. The couple is survived by 6 children and 9 grandchildren.

stem cell graft

LISBON—Phase 1 results suggest a programmed cellular therapy is safe for use in patients with hematologic malignancies.

The therapy, ProTmune, is being developed as a next-generation allogeneic graft intended to reduce the incidence and severity of acute graft-versus-host disease (GVHD) after hematopoietic stem cell transplant (HSCT).

Three of 7 patients who received ProTmune in this trial did develop acute GVHD, and 2 patients died.

However, the remaining 5 patients were still alive and disease-free at last follow-up.

There were no serious adverse events (AEs) attributed to ProTmune. The most common AEs were nausea, vomiting, and chest pain.

These results were presented at the 44th Annual Meeting of the EBMT (abstract A401*).

The trial, known as PROTECT, is sponsored by Fate Therapeutics, the company developing ProTmune.

The phase 1 portion of PROTECT enrolled 7 adults with hematologic malignancies—1 with myelodysplastic syndrome, 3 with acute lymphoblastic leukemia, and 3 with acute myeloid leukemia.

Patients were set to undergo matched, unrelated donor HSCT and received ProTmune as the graft. ProTmune is manufactured by modulating a mobilized peripheral blood graft with 2 small molecules, FT1050 and FT4145.

The patients ranged in age from 34 to 69, and most (n=5) were female. For conditioning, patients received fludarabine/busulfan (n=1), busulfan/cyclophosphamide (n=1), fludarabine/melphalan (n=3), or cyclophosphamide/total body irradiation (n=2).

Results

The data cut-off was February 26, 2018. The median time on study was 228 days (range, 151 to 353).

None of the patients had graft failure. The median time to neutrophil engraftment was 18 days (range, 14 to 22).

Three patients had acute GVHD at day 100 after HSCT. Two patients had grade 2 skin GVHD, and 1 had grade 3 GVHD in the skin and gut.

All 3 patients responded to steroid treatment. GVHD resolved in 5 days for the patient with grade 3 GVHD. For the grade 2 patients, GVHD resolved in 7 days and 8 days, respectively.

None of the patients relapsed, but 2 died—1 of pulmonary edema and 1 of atrial fibrillation.

AEs related to ProTmune included grade 1 vomiting (n=2), grade 2 nausea (n=2), and grade 2 chest pain (n=1).

Phase 2

The phase 2 portion of PROTECT is ongoing. This is a randomized, controlled, double-blinded trial designed to assess the safety and efficacy of ProTmune in up to 60 adults with hematologic malignancies undergoing matched, unrelated donor HSCT following myeloablative conditioning.

Patients are being randomized, in a 1:1 ratio, to receive either ProTmune or a conventional, mobilized peripheral blood cell graft from a matched, unrelated donor.

The primary efficacy endpoint is the cumulative incidence of grade 2-4 acute GVHD by day 100 post-HSCT. Rates of chronic GVHD, cancer relapse, disease-free survival, and overall survival are also being assessed.

*Some data in the abstract differ from the presentation.

stem cell graft

LISBON—Phase 1 results suggest a programmed cellular therapy is safe for use in patients with hematologic malignancies.

The therapy, ProTmune, is being developed as a next-generation allogeneic graft intended to reduce the incidence and severity of acute graft-versus-host disease (GVHD) after hematopoietic stem cell transplant (HSCT).

Three of 7 patients who received ProTmune in this trial did develop acute GVHD, and 2 patients died.

However, the remaining 5 patients were still alive and disease-free at last follow-up.

There were no serious adverse events (AEs) attributed to ProTmune. The most common AEs were nausea, vomiting, and chest pain.

These results were presented at the 44th Annual Meeting of the EBMT (abstract A401*).

The trial, known as PROTECT, is sponsored by Fate Therapeutics, the company developing ProTmune.

The phase 1 portion of PROTECT enrolled 7 adults with hematologic malignancies—1 with myelodysplastic syndrome, 3 with acute lymphoblastic leukemia, and 3 with acute myeloid leukemia.

Patients were set to undergo matched, unrelated donor HSCT and received ProTmune as the graft. ProTmune is manufactured by modulating a mobilized peripheral blood graft with 2 small molecules, FT1050 and FT4145.

The patients ranged in age from 34 to 69, and most (n=5) were female. For conditioning, patients received fludarabine/busulfan (n=1), busulfan/cyclophosphamide (n=1), fludarabine/melphalan (n=3), or cyclophosphamide/total body irradiation (n=2).

Results

The data cut-off was February 26, 2018. The median time on study was 228 days (range, 151 to 353).

None of the patients had graft failure. The median time to neutrophil engraftment was 18 days (range, 14 to 22).

Three patients had acute GVHD at day 100 after HSCT. Two patients had grade 2 skin GVHD, and 1 had grade 3 GVHD in the skin and gut.

All 3 patients responded to steroid treatment. GVHD resolved in 5 days for the patient with grade 3 GVHD. For the grade 2 patients, GVHD resolved in 7 days and 8 days, respectively.

None of the patients relapsed, but 2 died—1 of pulmonary edema and 1 of atrial fibrillation.

AEs related to ProTmune included grade 1 vomiting (n=2), grade 2 nausea (n=2), and grade 2 chest pain (n=1).

Phase 2

The phase 2 portion of PROTECT is ongoing. This is a randomized, controlled, double-blinded trial designed to assess the safety and efficacy of ProTmune in up to 60 adults with hematologic malignancies undergoing matched, unrelated donor HSCT following myeloablative conditioning.

Patients are being randomized, in a 1:1 ratio, to receive either ProTmune or a conventional, mobilized peripheral blood cell graft from a matched, unrelated donor.

The primary efficacy endpoint is the cumulative incidence of grade 2-4 acute GVHD by day 100 post-HSCT. Rates of chronic GVHD, cancer relapse, disease-free survival, and overall survival are also being assessed.

*Some data in the abstract differ from the presentation.

stem cell graft

LISBON—Phase 1 results suggest a programmed cellular therapy is safe for use in patients with hematologic malignancies.

The therapy, ProTmune, is being developed as a next-generation allogeneic graft intended to reduce the incidence and severity of acute graft-versus-host disease (GVHD) after hematopoietic stem cell transplant (HSCT).

Three of 7 patients who received ProTmune in this trial did develop acute GVHD, and 2 patients died.

However, the remaining 5 patients were still alive and disease-free at last follow-up.

There were no serious adverse events (AEs) attributed to ProTmune. The most common AEs were nausea, vomiting, and chest pain.

These results were presented at the 44th Annual Meeting of the EBMT (abstract A401*).

The trial, known as PROTECT, is sponsored by Fate Therapeutics, the company developing ProTmune.

The phase 1 portion of PROTECT enrolled 7 adults with hematologic malignancies—1 with myelodysplastic syndrome, 3 with acute lymphoblastic leukemia, and 3 with acute myeloid leukemia.

Patients were set to undergo matched, unrelated donor HSCT and received ProTmune as the graft. ProTmune is manufactured by modulating a mobilized peripheral blood graft with 2 small molecules, FT1050 and FT4145.

The patients ranged in age from 34 to 69, and most (n=5) were female. For conditioning, patients received fludarabine/busulfan (n=1), busulfan/cyclophosphamide (n=1), fludarabine/melphalan (n=3), or cyclophosphamide/total body irradiation (n=2).

Results

The data cut-off was February 26, 2018. The median time on study was 228 days (range, 151 to 353).

None of the patients had graft failure. The median time to neutrophil engraftment was 18 days (range, 14 to 22).

Three patients had acute GVHD at day 100 after HSCT. Two patients had grade 2 skin GVHD, and 1 had grade 3 GVHD in the skin and gut.

All 3 patients responded to steroid treatment. GVHD resolved in 5 days for the patient with grade 3 GVHD. For the grade 2 patients, GVHD resolved in 7 days and 8 days, respectively.

None of the patients relapsed, but 2 died—1 of pulmonary edema and 1 of atrial fibrillation.

AEs related to ProTmune included grade 1 vomiting (n=2), grade 2 nausea (n=2), and grade 2 chest pain (n=1).

Phase 2

The phase 2 portion of PROTECT is ongoing. This is a randomized, controlled, double-blinded trial designed to assess the safety and efficacy of ProTmune in up to 60 adults with hematologic malignancies undergoing matched, unrelated donor HSCT following myeloablative conditioning.

Patients are being randomized, in a 1:1 ratio, to receive either ProTmune or a conventional, mobilized peripheral blood cell graft from a matched, unrelated donor.

The primary efficacy endpoint is the cumulative incidence of grade 2-4 acute GVHD by day 100 post-HSCT. Rates of chronic GVHD, cancer relapse, disease-free survival, and overall survival are also being assessed.

*Some data in the abstract differ from the presentation.

Photo by Rhoda Baer

New research suggests patients with acute myeloid leukemia (AML) may have a lower risk of early mortality if they receive treatment at a National Cancer Institute (NCI) cancer center.

In a study of AML patients in California, the risk of 60-day mortality was 53% lower among patients treated at NCI cancer centers than among those treated at other centers.

These findings were reported in Cancer.

“We found the early mortality, deaths less than 60 days after diagnosis, was significantly lower at the NCI-designated cancer centers compared to non-NCI-designated cancer centers in California,” said study author Brian Jonas, MD, PhD, of the University of California at Davis School of Medicine in Sacramento, California.

To conduct this study, Dr Jonas and his colleagues analyzed data from the California Cancer Registry and the California Office of Statewide Health Planning and Development Patient Discharge Database.

The California Cancer Registry provides sociodemographic and clinical data for all California cancer patients. The California Office of Statewide Health Planning and Development Patient Discharge Database has data on diagnoses and procedures for all hospital patients in California, excluding 14 Veterans Affairs and military hospitals.

Patients

The study included data on AML patients 18 and older who received inpatient chemotherapy between 1999 and 2014. There were 7007 patients, 1762 (25%) of whom were treated at NCI-designated cancer centers.

The median number of new AML patients per year was 13.5 (range, 0-43) at the NCI centers and 2 (range, 1-17) at non-NCI centers that admitted at least 1 patient with AML. More than half of the non-NCI centers had a median of 0 new AML patients per year.

NCI patients were more likely to be younger (≤65) than non-NCI patients (P<0.0001), to live in neighborhoods with higher socioeconomic status (P<0.0001), have fewer comorbidities (P<0.0001), and have public health insurance (P<0.0001).

Results

There were several types of complications that differed significantly between center types.

Patients treated at NCI centers were significantly more likely to have leukapheresis (5.5% vs 2.7%; P<0.001) and renal failure (22.8% vs 19.9%; P=0.010).

But they were significantly less likely to have respiratory failure (11.6% vs 14.3%; P=0.003) and cardiac arrest (1.1% vs 2.0%; P=0.014).

Sixty-day survival was significantly higher among NCI patients (88.0% vs 76.3%; P<0.001).

In an inverse-probability-weighted analysis adjusted for sociodemographic factors and comorbidities, treatment at an NCI center was associated with significantly lower early mortality, with an odds ratio (OR) of 0.46 (P<0.001).

This analysis also revealed a significant association between increased early mortality and major bleeding (OR=1.79, P<0.001), renal failure (OR=2.33, P<0.001), respiratory failure (OR=6.46, P<0.001), and cardiac arrest (OR=13.33, P<0.001).

For the most part, the impact of complications on early mortality did not differ significantly by treatment center.

The exception was respiratory failure. Patients with respiratory failure had a significantly greater risk of early mortality if they were treated at a non-NCI center (OR=9.48) than at an NCI center (OR=4.20).

Potential explanations

The researchers believe the variations in early mortality they observed point to inconsistent supportive care. However, more work must be done to fully understand the differences in care driving these issues.

“This is clearly provocative data that makes you want to understand exactly why,” Dr Jonas said. “We’re going to have to dive into that question in a more significant way.”

In the absence of data that could identify the exact causes, the researchers noted that other studies have shown higher patient volumes may contribute to better care.

“I see 60 or more AML cases per year,” Dr Jonas said. “High volume/low volume must play a role.”

The researchers believe other potential contributing factors could be access to clinical trials, better nursing ratios, and more sophisticated intensive care units.

The team hopes this research will spawn more intensive efforts to identify the causes that underlie variations in early mortality between hospital sites.

“This is a provocative and hopeful paper in terms of improving outcomes,” Dr Jonas said. “It sends a positive message that there are things we could probably do that could help everyone.”

Photo by Rhoda Baer

New research suggests patients with acute myeloid leukemia (AML) may have a lower risk of early mortality if they receive treatment at a National Cancer Institute (NCI) cancer center.

In a study of AML patients in California, the risk of 60-day mortality was 53% lower among patients treated at NCI cancer centers than among those treated at other centers.

These findings were reported in Cancer.

“We found the early mortality, deaths less than 60 days after diagnosis, was significantly lower at the NCI-designated cancer centers compared to non-NCI-designated cancer centers in California,” said study author Brian Jonas, MD, PhD, of the University of California at Davis School of Medicine in Sacramento, California.

To conduct this study, Dr Jonas and his colleagues analyzed data from the California Cancer Registry and the California Office of Statewide Health Planning and Development Patient Discharge Database.

The California Cancer Registry provides sociodemographic and clinical data for all California cancer patients. The California Office of Statewide Health Planning and Development Patient Discharge Database has data on diagnoses and procedures for all hospital patients in California, excluding 14 Veterans Affairs and military hospitals.

Patients

The study included data on AML patients 18 and older who received inpatient chemotherapy between 1999 and 2014. There were 7007 patients, 1762 (25%) of whom were treated at NCI-designated cancer centers.

The median number of new AML patients per year was 13.5 (range, 0-43) at the NCI centers and 2 (range, 1-17) at non-NCI centers that admitted at least 1 patient with AML. More than half of the non-NCI centers had a median of 0 new AML patients per year.

NCI patients were more likely to be younger (≤65) than non-NCI patients (P<0.0001), to live in neighborhoods with higher socioeconomic status (P<0.0001), have fewer comorbidities (P<0.0001), and have public health insurance (P<0.0001).

Results

There were several types of complications that differed significantly between center types.

Patients treated at NCI centers were significantly more likely to have leukapheresis (5.5% vs 2.7%; P<0.001) and renal failure (22.8% vs 19.9%; P=0.010).

But they were significantly less likely to have respiratory failure (11.6% vs 14.3%; P=0.003) and cardiac arrest (1.1% vs 2.0%; P=0.014).

Sixty-day survival was significantly higher among NCI patients (88.0% vs 76.3%; P<0.001).

In an inverse-probability-weighted analysis adjusted for sociodemographic factors and comorbidities, treatment at an NCI center was associated with significantly lower early mortality, with an odds ratio (OR) of 0.46 (P<0.001).

This analysis also revealed a significant association between increased early mortality and major bleeding (OR=1.79, P<0.001), renal failure (OR=2.33, P<0.001), respiratory failure (OR=6.46, P<0.001), and cardiac arrest (OR=13.33, P<0.001).

For the most part, the impact of complications on early mortality did not differ significantly by treatment center.

The exception was respiratory failure. Patients with respiratory failure had a significantly greater risk of early mortality if they were treated at a non-NCI center (OR=9.48) than at an NCI center (OR=4.20).

Potential explanations

The researchers believe the variations in early mortality they observed point to inconsistent supportive care. However, more work must be done to fully understand the differences in care driving these issues.

“This is clearly provocative data that makes you want to understand exactly why,” Dr Jonas said. “We’re going to have to dive into that question in a more significant way.”

In the absence of data that could identify the exact causes, the researchers noted that other studies have shown higher patient volumes may contribute to better care.

“I see 60 or more AML cases per year,” Dr Jonas said. “High volume/low volume must play a role.”

The researchers believe other potential contributing factors could be access to clinical trials, better nursing ratios, and more sophisticated intensive care units.

The team hopes this research will spawn more intensive efforts to identify the causes that underlie variations in early mortality between hospital sites.

“This is a provocative and hopeful paper in terms of improving outcomes,” Dr Jonas said. “It sends a positive message that there are things we could probably do that could help everyone.”

Photo by Rhoda Baer

New research suggests patients with acute myeloid leukemia (AML) may have a lower risk of early mortality if they receive treatment at a National Cancer Institute (NCI) cancer center.

In a study of AML patients in California, the risk of 60-day mortality was 53% lower among patients treated at NCI cancer centers than among those treated at other centers.

These findings were reported in Cancer.

“We found the early mortality, deaths less than 60 days after diagnosis, was significantly lower at the NCI-designated cancer centers compared to non-NCI-designated cancer centers in California,” said study author Brian Jonas, MD, PhD, of the University of California at Davis School of Medicine in Sacramento, California.

To conduct this study, Dr Jonas and his colleagues analyzed data from the California Cancer Registry and the California Office of Statewide Health Planning and Development Patient Discharge Database.

The California Cancer Registry provides sociodemographic and clinical data for all California cancer patients. The California Office of Statewide Health Planning and Development Patient Discharge Database has data on diagnoses and procedures for all hospital patients in California, excluding 14 Veterans Affairs and military hospitals.

Patients

The study included data on AML patients 18 and older who received inpatient chemotherapy between 1999 and 2014. There were 7007 patients, 1762 (25%) of whom were treated at NCI-designated cancer centers.

The median number of new AML patients per year was 13.5 (range, 0-43) at the NCI centers and 2 (range, 1-17) at non-NCI centers that admitted at least 1 patient with AML. More than half of the non-NCI centers had a median of 0 new AML patients per year.

NCI patients were more likely to be younger (≤65) than non-NCI patients (P<0.0001), to live in neighborhoods with higher socioeconomic status (P<0.0001), have fewer comorbidities (P<0.0001), and have public health insurance (P<0.0001).

Results

There were several types of complications that differed significantly between center types.

Patients treated at NCI centers were significantly more likely to have leukapheresis (5.5% vs 2.7%; P<0.001) and renal failure (22.8% vs 19.9%; P=0.010).

But they were significantly less likely to have respiratory failure (11.6% vs 14.3%; P=0.003) and cardiac arrest (1.1% vs 2.0%; P=0.014).

Sixty-day survival was significantly higher among NCI patients (88.0% vs 76.3%; P<0.001).

In an inverse-probability-weighted analysis adjusted for sociodemographic factors and comorbidities, treatment at an NCI center was associated with significantly lower early mortality, with an odds ratio (OR) of 0.46 (P<0.001).

This analysis also revealed a significant association between increased early mortality and major bleeding (OR=1.79, P<0.001), renal failure (OR=2.33, P<0.001), respiratory failure (OR=6.46, P<0.001), and cardiac arrest (OR=13.33, P<0.001).

For the most part, the impact of complications on early mortality did not differ significantly by treatment center.

The exception was respiratory failure. Patients with respiratory failure had a significantly greater risk of early mortality if they were treated at a non-NCI center (OR=9.48) than at an NCI center (OR=4.20).

Potential explanations

The researchers believe the variations in early mortality they observed point to inconsistent supportive care. However, more work must be done to fully understand the differences in care driving these issues.

“This is clearly provocative data that makes you want to understand exactly why,” Dr Jonas said. “We’re going to have to dive into that question in a more significant way.”

In the absence of data that could identify the exact causes, the researchers noted that other studies have shown higher patient volumes may contribute to better care.

“I see 60 or more AML cases per year,” Dr Jonas said. “High volume/low volume must play a role.”

The researchers believe other potential contributing factors could be access to clinical trials, better nursing ratios, and more sophisticated intensive care units.

The team hopes this research will spawn more intensive efforts to identify the causes that underlie variations in early mortality between hospital sites.

“This is a provocative and hopeful paper in terms of improving outcomes,” Dr Jonas said. “It sends a positive message that there are things we could probably do that could help everyone.”