AML

ATLANTA – In older patients with acute myeloid leukemia (AML) in complete remission after intensive chemotherapy, the addition of maintenance therapy with azacitidine significantly improved disease-free survival (DFS), according to results of a randomized, placebo-controlled phase 3 study.

Compared with observation, DFS was significantly improved in the maintenance azacitidine arm, according to results from the 116-patient HOVON97 trial presented at the annual meeting of the American Society of Hematology.

Overall survival was not significantly different between arms, possibly because of an excess of allogeneic transplant in the observation arm, according to Geert Huls, MD, PhD, of the department of hematology, University Medical Center Groningen, the Netherlands.

“When censored for allogeneic transplant, maintenance with azacitidine improves overall survival,” Dr. Huls said during an oral presentation on the findings.

The randomized maintenance therapy trial was designed to include 126 patients aged 60 years or older who had a confirmed diagnosis of AML and refractory anemia with excess of blasts (RAEB, RAEB-t) and who were in complete remission or in complete remission with incomplete blood count recovery after two cycles of therapy.

Investigators randomly assigned 116 patients to maintenance versus observation. Researchers intended to assign a total of 126 patients, but the trial was stopped early because of slow accrual, Dr. Huls said.

Maintenance treatment with azacitidine was given until relapse for no more than 12 cycles, according to the study protocol. Disease-free survival, the primary endpoint, was measured from the date of randomization to relapse or death from any cause.

Azacitidine maintenance therapy significantly improved DFS (P = .03), Dr. Huls said. After researchers adjusted for poor risk cytogenetic abnormalities at diagnosis and platelet count at study entry, the DFS difference remained significant (hazard ratio, 0.61; 95% confidence interval, 0.4-0.92; P = .019).

Overall survival, a secondary endpoint of the trial, was not significantly different between arms, even after adjustment for cytogenetic abnormalities and platelet counts, Dr. Huls said.

However, investigators found an excess of allogeneic transplant in the observation arm (11 patients, vs. 3 in the azacitidine arm). After they censored those 14 patients, they saw a difference in overall survival favoring azacitidine maintenance that approached significance (P = .07).

Dr. Huls speculated that the excess of transplant may have been related to “the psychology of the doctors.” In the maintenance arm, the physician’s thought process may have been that “ ‘this patient has now had two lines of treatment and has a relapse, and we are done,’ and in the [observation] arm he says, ‘well, the patient has had one arm of treatment, let’s go for another,’ ” Dr. Huls said.

Tolerability data showed that 14 adverse events were reported in the azacitidine maintenance arm, versus 4 for observation. One serious adverse event of grade 3 was reported in the azacitidine arm. The proportion of patients without platelet transfusions during the study was 86% for azacitidine and 93% for observation, and the proportion of patients without red blood cell transfusions was similarly 86% and 92% for the azacitidine and observation arms, respectively.

Dr. Huls reported financial relationships with Janssen and Celgene.

SOURCE: Huls G et al. ASH 2017 Abstract 463.

ATLANTA – In older patients with acute myeloid leukemia (AML) in complete remission after intensive chemotherapy, the addition of maintenance therapy with azacitidine significantly improved disease-free survival (DFS), according to results of a randomized, placebo-controlled phase 3 study.

Compared with observation, DFS was significantly improved in the maintenance azacitidine arm, according to results from the 116-patient HOVON97 trial presented at the annual meeting of the American Society of Hematology.

Overall survival was not significantly different between arms, possibly because of an excess of allogeneic transplant in the observation arm, according to Geert Huls, MD, PhD, of the department of hematology, University Medical Center Groningen, the Netherlands.

“When censored for allogeneic transplant, maintenance with azacitidine improves overall survival,” Dr. Huls said during an oral presentation on the findings.

The randomized maintenance therapy trial was designed to include 126 patients aged 60 years or older who had a confirmed diagnosis of AML and refractory anemia with excess of blasts (RAEB, RAEB-t) and who were in complete remission or in complete remission with incomplete blood count recovery after two cycles of therapy.

Investigators randomly assigned 116 patients to maintenance versus observation. Researchers intended to assign a total of 126 patients, but the trial was stopped early because of slow accrual, Dr. Huls said.

Maintenance treatment with azacitidine was given until relapse for no more than 12 cycles, according to the study protocol. Disease-free survival, the primary endpoint, was measured from the date of randomization to relapse or death from any cause.

Azacitidine maintenance therapy significantly improved DFS (P = .03), Dr. Huls said. After researchers adjusted for poor risk cytogenetic abnormalities at diagnosis and platelet count at study entry, the DFS difference remained significant (hazard ratio, 0.61; 95% confidence interval, 0.4-0.92; P = .019).

Overall survival, a secondary endpoint of the trial, was not significantly different between arms, even after adjustment for cytogenetic abnormalities and platelet counts, Dr. Huls said.

However, investigators found an excess of allogeneic transplant in the observation arm (11 patients, vs. 3 in the azacitidine arm). After they censored those 14 patients, they saw a difference in overall survival favoring azacitidine maintenance that approached significance (P = .07).

Dr. Huls speculated that the excess of transplant may have been related to “the psychology of the doctors.” In the maintenance arm, the physician’s thought process may have been that “ ‘this patient has now had two lines of treatment and has a relapse, and we are done,’ and in the [observation] arm he says, ‘well, the patient has had one arm of treatment, let’s go for another,’ ” Dr. Huls said.

Tolerability data showed that 14 adverse events were reported in the azacitidine maintenance arm, versus 4 for observation. One serious adverse event of grade 3 was reported in the azacitidine arm. The proportion of patients without platelet transfusions during the study was 86% for azacitidine and 93% for observation, and the proportion of patients without red blood cell transfusions was similarly 86% and 92% for the azacitidine and observation arms, respectively.

Dr. Huls reported financial relationships with Janssen and Celgene.

SOURCE: Huls G et al. ASH 2017 Abstract 463.

ATLANTA – In older patients with acute myeloid leukemia (AML) in complete remission after intensive chemotherapy, the addition of maintenance therapy with azacitidine significantly improved disease-free survival (DFS), according to results of a randomized, placebo-controlled phase 3 study.

Compared with observation, DFS was significantly improved in the maintenance azacitidine arm, according to results from the 116-patient HOVON97 trial presented at the annual meeting of the American Society of Hematology.

Overall survival was not significantly different between arms, possibly because of an excess of allogeneic transplant in the observation arm, according to Geert Huls, MD, PhD, of the department of hematology, University Medical Center Groningen, the Netherlands.

“When censored for allogeneic transplant, maintenance with azacitidine improves overall survival,” Dr. Huls said during an oral presentation on the findings.

The randomized maintenance therapy trial was designed to include 126 patients aged 60 years or older who had a confirmed diagnosis of AML and refractory anemia with excess of blasts (RAEB, RAEB-t) and who were in complete remission or in complete remission with incomplete blood count recovery after two cycles of therapy.

Investigators randomly assigned 116 patients to maintenance versus observation. Researchers intended to assign a total of 126 patients, but the trial was stopped early because of slow accrual, Dr. Huls said.

Maintenance treatment with azacitidine was given until relapse for no more than 12 cycles, according to the study protocol. Disease-free survival, the primary endpoint, was measured from the date of randomization to relapse or death from any cause.

Azacitidine maintenance therapy significantly improved DFS (P = .03), Dr. Huls said. After researchers adjusted for poor risk cytogenetic abnormalities at diagnosis and platelet count at study entry, the DFS difference remained significant (hazard ratio, 0.61; 95% confidence interval, 0.4-0.92; P = .019).

Overall survival, a secondary endpoint of the trial, was not significantly different between arms, even after adjustment for cytogenetic abnormalities and platelet counts, Dr. Huls said.

However, investigators found an excess of allogeneic transplant in the observation arm (11 patients, vs. 3 in the azacitidine arm). After they censored those 14 patients, they saw a difference in overall survival favoring azacitidine maintenance that approached significance (P = .07).

Dr. Huls speculated that the excess of transplant may have been related to “the psychology of the doctors.” In the maintenance arm, the physician’s thought process may have been that “ ‘this patient has now had two lines of treatment and has a relapse, and we are done,’ and in the [observation] arm he says, ‘well, the patient has had one arm of treatment, let’s go for another,’ ” Dr. Huls said.

Tolerability data showed that 14 adverse events were reported in the azacitidine maintenance arm, versus 4 for observation. One serious adverse event of grade 3 was reported in the azacitidine arm. The proportion of patients without platelet transfusions during the study was 86% for azacitidine and 93% for observation, and the proportion of patients without red blood cell transfusions was similarly 86% and 92% for the azacitidine and observation arms, respectively.

Dr. Huls reported financial relationships with Janssen and Celgene.

SOURCE: Huls G et al. ASH 2017 Abstract 463.

Receiving a trivalent inactivated influenza vaccine (TIV) did not protect children and adolescents with acute leukemia from developing the flu, said April Sykes of St. Jude Children’s Research Hospital in Carmel, Ind., and her associates.

Patients aged 1-21 years being treated for acute leukemia during three successive influenza seasons (2011-2012, 2012-2013, and 2013-2014) were identified by a retrospective review of EHRs; of those patients, 354 (71%) patients received TIV, and 98 (20%) received a booster dose of flu vaccine.

luiscar/Thinkstock

Receiving a trivalent inactivated influenza vaccine (TIV) did not protect children and adolescents with acute leukemia from developing the flu, said April Sykes of St. Jude Children’s Research Hospital in Carmel, Ind., and her associates.

Patients aged 1-21 years being treated for acute leukemia during three successive influenza seasons (2011-2012, 2012-2013, and 2013-2014) were identified by a retrospective review of EHRs; of those patients, 354 (71%) patients received TIV, and 98 (20%) received a booster dose of flu vaccine.

luiscar/Thinkstock

Receiving a trivalent inactivated influenza vaccine (TIV) did not protect children and adolescents with acute leukemia from developing the flu, said April Sykes of St. Jude Children’s Research Hospital in Carmel, Ind., and her associates.

Patients aged 1-21 years being treated for acute leukemia during three successive influenza seasons (2011-2012, 2012-2013, and 2013-2014) were identified by a retrospective review of EHRs; of those patients, 354 (71%) patients received TIV, and 98 (20%) received a booster dose of flu vaccine.

luiscar/Thinkstock

Photo courtesy of Novartis

Health Canada has approved use of the multi-targeted kinase inhibitor midostaurin (Rydapt™).

This makes midostaurin the first targeted therapy approved to treat FLT3-mutated acute myeloid leukemia (AML) in Canada.

Midostaurin is approved for use with standard cytarabine and daunorubicin induction and cytarabine consolidation for the treatment of adults with newly diagnosed FLT3-mutated AML.

Health Canada’s approval of midostaurin is based on results from the phase 3 RATIFY trial, which were published in NEJM in August.

In RATIFY, researchers compared midostaurin plus standard chemotherapy to placebo plus standard chemotherapy in 717 adults younger than age 60 who had FLT3-mutated AML.

The median overall survival was significantly longer in the midostaurin arm than the placebo arm—74.7 months and 25.6 months, respectively (hazard ratio=0.77, P=0.016).

And the median event-free survival was significantly longer in the midostaurin arm than the placebo arm—8.2 months and 3.0 months, respectively (hazard ratio=0.78, P=0.004).

The most frequent adverse events (AEs) in the midostaurin arm (occurring in at least 20% of patients) were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae, device-related infection, epistaxis, hyperglycemia, and upper respiratory tract infection.

The most frequent grade 3/4 AEs (occurring in at least 10% of patients) were febrile neutropenia, device-related infection, and mucositis.

Nine percent of patients in the midostaurin arm stopped treatment due to AEs, as did 6% in the placebo arm.

Photo courtesy of Novartis

Health Canada has approved use of the multi-targeted kinase inhibitor midostaurin (Rydapt™).

This makes midostaurin the first targeted therapy approved to treat FLT3-mutated acute myeloid leukemia (AML) in Canada.

Midostaurin is approved for use with standard cytarabine and daunorubicin induction and cytarabine consolidation for the treatment of adults with newly diagnosed FLT3-mutated AML.

Health Canada’s approval of midostaurin is based on results from the phase 3 RATIFY trial, which were published in NEJM in August.

In RATIFY, researchers compared midostaurin plus standard chemotherapy to placebo plus standard chemotherapy in 717 adults younger than age 60 who had FLT3-mutated AML.

The median overall survival was significantly longer in the midostaurin arm than the placebo arm—74.7 months and 25.6 months, respectively (hazard ratio=0.77, P=0.016).

And the median event-free survival was significantly longer in the midostaurin arm than the placebo arm—8.2 months and 3.0 months, respectively (hazard ratio=0.78, P=0.004).

The most frequent adverse events (AEs) in the midostaurin arm (occurring in at least 20% of patients) were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae, device-related infection, epistaxis, hyperglycemia, and upper respiratory tract infection.

The most frequent grade 3/4 AEs (occurring in at least 10% of patients) were febrile neutropenia, device-related infection, and mucositis.

Nine percent of patients in the midostaurin arm stopped treatment due to AEs, as did 6% in the placebo arm.

Photo courtesy of Novartis

Health Canada has approved use of the multi-targeted kinase inhibitor midostaurin (Rydapt™).

This makes midostaurin the first targeted therapy approved to treat FLT3-mutated acute myeloid leukemia (AML) in Canada.

Midostaurin is approved for use with standard cytarabine and daunorubicin induction and cytarabine consolidation for the treatment of adults with newly diagnosed FLT3-mutated AML.

Health Canada’s approval of midostaurin is based on results from the phase 3 RATIFY trial, which were published in NEJM in August.

In RATIFY, researchers compared midostaurin plus standard chemotherapy to placebo plus standard chemotherapy in 717 adults younger than age 60 who had FLT3-mutated AML.

The median overall survival was significantly longer in the midostaurin arm than the placebo arm—74.7 months and 25.6 months, respectively (hazard ratio=0.77, P=0.016).

And the median event-free survival was significantly longer in the midostaurin arm than the placebo arm—8.2 months and 3.0 months, respectively (hazard ratio=0.78, P=0.004).

The most frequent adverse events (AEs) in the midostaurin arm (occurring in at least 20% of patients) were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae, device-related infection, epistaxis, hyperglycemia, and upper respiratory tract infection.

The most frequent grade 3/4 AEs (occurring in at least 10% of patients) were febrile neutropenia, device-related infection, and mucositis.

Nine percent of patients in the midostaurin arm stopped treatment due to AEs, as did 6% in the placebo arm.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has granted fast track designation to crenolanib for the treatment of patients with FLT3 mutation-positive relapsed or refractory acute myeloid leukemia (AML).

Crenolanib is a benzimidazole type I tyrosine kinase inhibitor (TKI) that selectively inhibits signaling of wild-type and mutant isoforms of FLT3 and PDGFRα/β.

Crenolanib is being developed by Arog Pharmaceuticals, Inc.

The company is preparing for a phase 3, randomized, double-blind trial of crenolanib versus placebo in combination with best supportive care in patients with FLT3+ relapsed or refractory AML.

Results from a phase 2 trial of crenolanib in relapsed/refractory FLT3+ AML were presented at the 2016 ASCO Annual Meeting (abstract 7008).

The trial enrolled 69 patients who had a median age of 60 (range, 21-87). Twenty-nine patients had FLT3 ITD, 29 had ITD and D835, and 11 had D835.

Nineteen patients were TKI-naïve, 39 had received a prior TKI, and 11 had secondary AML.

Patients received crenolanib at 100 mg three times a day (n=43) or 66 mg/m² three times a day (n=26).

In the TKI-naïve patients, the overall response rate (ORR) was 47% (n=9), and 37% of patients had a complete response (CR) or CR with incomplete count recovery (CRi). The median overall survival (OS) was 238 days (range, 25-547).

In patients who previously received a TKI, the ORR was 28% (n=11), and the CR/CRi rate was 15% (n=6). The median OS was 94 days (range, 8-338).

In patients with secondary AML, the ORR was 9% (n=1, partial response). The median OS in this group was 64 days (range, 27-221).

Treatment-emergent adverse events (all grades and grade 3/4, respectively) included nausea (70%, 9%), vomiting (58%, 9%), diarrhea (56%, 2%), fatigue (36%, 11%), febrile neutropenia (35%, 35%), pneumonia (32%, 23%), peripheral edema (30%, 2%), pleural effusion (21%, 8%), dyspnea (20%, 5%), and epistaxis (20%, 8%).

Two patients discontinued crenolanib due to adverse events. One patient discontinued due to grade 3 fatigue, abdominal pain, and headache. The other discontinued due to grade 3 pneumonia.

There were 2 neutropenic septic deaths, which occurred 2 days and 21 days after the discontinuation of crenolanib.

About fast track designation

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has granted fast track designation to crenolanib for the treatment of patients with FLT3 mutation-positive relapsed or refractory acute myeloid leukemia (AML).

Crenolanib is a benzimidazole type I tyrosine kinase inhibitor (TKI) that selectively inhibits signaling of wild-type and mutant isoforms of FLT3 and PDGFRα/β.

Crenolanib is being developed by Arog Pharmaceuticals, Inc.

The company is preparing for a phase 3, randomized, double-blind trial of crenolanib versus placebo in combination with best supportive care in patients with FLT3+ relapsed or refractory AML.

Results from a phase 2 trial of crenolanib in relapsed/refractory FLT3+ AML were presented at the 2016 ASCO Annual Meeting (abstract 7008).

The trial enrolled 69 patients who had a median age of 60 (range, 21-87). Twenty-nine patients had FLT3 ITD, 29 had ITD and D835, and 11 had D835.

Nineteen patients were TKI-naïve, 39 had received a prior TKI, and 11 had secondary AML.

Patients received crenolanib at 100 mg three times a day (n=43) or 66 mg/m² three times a day (n=26).

In the TKI-naïve patients, the overall response rate (ORR) was 47% (n=9), and 37% of patients had a complete response (CR) or CR with incomplete count recovery (CRi). The median overall survival (OS) was 238 days (range, 25-547).

In patients who previously received a TKI, the ORR was 28% (n=11), and the CR/CRi rate was 15% (n=6). The median OS was 94 days (range, 8-338).

In patients with secondary AML, the ORR was 9% (n=1, partial response). The median OS in this group was 64 days (range, 27-221).

Treatment-emergent adverse events (all grades and grade 3/4, respectively) included nausea (70%, 9%), vomiting (58%, 9%), diarrhea (56%, 2%), fatigue (36%, 11%), febrile neutropenia (35%, 35%), pneumonia (32%, 23%), peripheral edema (30%, 2%), pleural effusion (21%, 8%), dyspnea (20%, 5%), and epistaxis (20%, 8%).

Two patients discontinued crenolanib due to adverse events. One patient discontinued due to grade 3 fatigue, abdominal pain, and headache. The other discontinued due to grade 3 pneumonia.

There were 2 neutropenic septic deaths, which occurred 2 days and 21 days after the discontinuation of crenolanib.

About fast track designation

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has granted fast track designation to crenolanib for the treatment of patients with FLT3 mutation-positive relapsed or refractory acute myeloid leukemia (AML).

Crenolanib is a benzimidazole type I tyrosine kinase inhibitor (TKI) that selectively inhibits signaling of wild-type and mutant isoforms of FLT3 and PDGFRα/β.

Crenolanib is being developed by Arog Pharmaceuticals, Inc.

The company is preparing for a phase 3, randomized, double-blind trial of crenolanib versus placebo in combination with best supportive care in patients with FLT3+ relapsed or refractory AML.

Results from a phase 2 trial of crenolanib in relapsed/refractory FLT3+ AML were presented at the 2016 ASCO Annual Meeting (abstract 7008).

The trial enrolled 69 patients who had a median age of 60 (range, 21-87). Twenty-nine patients had FLT3 ITD, 29 had ITD and D835, and 11 had D835.

Nineteen patients were TKI-naïve, 39 had received a prior TKI, and 11 had secondary AML.

Patients received crenolanib at 100 mg three times a day (n=43) or 66 mg/m² three times a day (n=26).

In the TKI-naïve patients, the overall response rate (ORR) was 47% (n=9), and 37% of patients had a complete response (CR) or CR with incomplete count recovery (CRi). The median overall survival (OS) was 238 days (range, 25-547).

In patients who previously received a TKI, the ORR was 28% (n=11), and the CR/CRi rate was 15% (n=6). The median OS was 94 days (range, 8-338).

In patients with secondary AML, the ORR was 9% (n=1, partial response). The median OS in this group was 64 days (range, 27-221).

Treatment-emergent adverse events (all grades and grade 3/4, respectively) included nausea (70%, 9%), vomiting (58%, 9%), diarrhea (56%, 2%), fatigue (36%, 11%), febrile neutropenia (35%, 35%), pneumonia (32%, 23%), peripheral edema (30%, 2%), pleural effusion (21%, 8%), dyspnea (20%, 5%), and epistaxis (20%, 8%).

Two patients discontinued crenolanib due to adverse events. One patient discontinued due to grade 3 fatigue, abdominal pain, and headache. The other discontinued due to grade 3 pneumonia.

There were 2 neutropenic septic deaths, which occurred 2 days and 21 days after the discontinuation of crenolanib.

About fast track designation

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

In patients with acute myeloid leukemia (AML), giving levofloxacin for febrile neutropenia prophylaxis reduced hospital admissions due to this complication by about one-quarter, according to results of a retrospective cohort study.

“Multiple studies have demonstrated the use of an oral fluoroquinolone antibiotic to prevent febrile neutropenia readmission to hospital after receiving consolidation chemotherapy,” Samantha S. F. Lee, PharmD, a clinical pharmacist at St. Michael’s Hospital in Toronto, and her colleagues wrote. “However, this is the first study to demonstrate a positive outcome specific to the AML population.”

The results support recommendations made by the Infectious Diseases Society of America and the National Comprehensive Cancer Network related to treatment of AML after receiving consolidation chemotherapy.

For the study, the investigators retrospectively reviewed the charts of consecutive patients with AML treated at London Health Sciences Centre, a tertiary academic medical center, between 2006 and 2013. They compared outcomes between 50 patients who were prescribed prophylactic levofloxacin (Levaquin) after consolidation therapy and 50 patients who were not prescribed any antibiotics.

Overall, patients given levofloxacin had a lower rate of hospital readmission due to febrile neutropenia whether given the antibiotic after the first chemotherapy consolidation cycle (42% vs. 72%, P = .002) or after all cycles (51.4% vs. 67%, P = .023).

None of the patients in the levofloxacin group developed Clostridium difficile–associated diarrhea within 30 days from discharge after receiving the first cycle of consolidation chemotherapy, compared with one patient in the group not given the antibiotic (Support Care Cancer. 2017 Nov 23. doi: 10.1007/s00520-017-3976-1).

The use of levofloxacin did not significantly impact secondary outcomes, including total days of antibiotic treatment provided to febrile neutropenic patients, days to readmission for febrile neutropenia, or the rate of positive bacterial cultures returned in febrile neutropenic patients.

It was not possible to assess differences in the rate of fluoroquinolone resistance in positive bacterial cultures because fluoroquinolone susceptibilities were infrequently reported.

“This study provides evidence of a strong association between prophylaxis with oral levofloxacin and the rate of febrile neutropenia, but further study is required to evaluate the impact of fluoroquinolone use on antibiotic resistance and [Clostridium difficile–associated diarrhea] rates in this patient setting,” the investigators wrote.

The study was limited by the small sample size, which precluded accurate ascertainment of some outcomes, including safety outcomes, they noted. Additionally, adherence to oral therapy was unknown, and some data, such as fluoroquinolone resistance, were missing for patients admitted for febrile neutropenia to outside hospitals.

Dr. Lee reported having no relevant conflicts of interest.

In patients with acute myeloid leukemia (AML), giving levofloxacin for febrile neutropenia prophylaxis reduced hospital admissions due to this complication by about one-quarter, according to results of a retrospective cohort study.

“Multiple studies have demonstrated the use of an oral fluoroquinolone antibiotic to prevent febrile neutropenia readmission to hospital after receiving consolidation chemotherapy,” Samantha S. F. Lee, PharmD, a clinical pharmacist at St. Michael’s Hospital in Toronto, and her colleagues wrote. “However, this is the first study to demonstrate a positive outcome specific to the AML population.”

The results support recommendations made by the Infectious Diseases Society of America and the National Comprehensive Cancer Network related to treatment of AML after receiving consolidation chemotherapy.

For the study, the investigators retrospectively reviewed the charts of consecutive patients with AML treated at London Health Sciences Centre, a tertiary academic medical center, between 2006 and 2013. They compared outcomes between 50 patients who were prescribed prophylactic levofloxacin (Levaquin) after consolidation therapy and 50 patients who were not prescribed any antibiotics.

Overall, patients given levofloxacin had a lower rate of hospital readmission due to febrile neutropenia whether given the antibiotic after the first chemotherapy consolidation cycle (42% vs. 72%, P = .002) or after all cycles (51.4% vs. 67%, P = .023).

None of the patients in the levofloxacin group developed Clostridium difficile–associated diarrhea within 30 days from discharge after receiving the first cycle of consolidation chemotherapy, compared with one patient in the group not given the antibiotic (Support Care Cancer. 2017 Nov 23. doi: 10.1007/s00520-017-3976-1).

The use of levofloxacin did not significantly impact secondary outcomes, including total days of antibiotic treatment provided to febrile neutropenic patients, days to readmission for febrile neutropenia, or the rate of positive bacterial cultures returned in febrile neutropenic patients.

It was not possible to assess differences in the rate of fluoroquinolone resistance in positive bacterial cultures because fluoroquinolone susceptibilities were infrequently reported.

“This study provides evidence of a strong association between prophylaxis with oral levofloxacin and the rate of febrile neutropenia, but further study is required to evaluate the impact of fluoroquinolone use on antibiotic resistance and [Clostridium difficile–associated diarrhea] rates in this patient setting,” the investigators wrote.

The study was limited by the small sample size, which precluded accurate ascertainment of some outcomes, including safety outcomes, they noted. Additionally, adherence to oral therapy was unknown, and some data, such as fluoroquinolone resistance, were missing for patients admitted for febrile neutropenia to outside hospitals.

Dr. Lee reported having no relevant conflicts of interest.

In patients with acute myeloid leukemia (AML), giving levofloxacin for febrile neutropenia prophylaxis reduced hospital admissions due to this complication by about one-quarter, according to results of a retrospective cohort study.

“Multiple studies have demonstrated the use of an oral fluoroquinolone antibiotic to prevent febrile neutropenia readmission to hospital after receiving consolidation chemotherapy,” Samantha S. F. Lee, PharmD, a clinical pharmacist at St. Michael’s Hospital in Toronto, and her colleagues wrote. “However, this is the first study to demonstrate a positive outcome specific to the AML population.”

The results support recommendations made by the Infectious Diseases Society of America and the National Comprehensive Cancer Network related to treatment of AML after receiving consolidation chemotherapy.

For the study, the investigators retrospectively reviewed the charts of consecutive patients with AML treated at London Health Sciences Centre, a tertiary academic medical center, between 2006 and 2013. They compared outcomes between 50 patients who were prescribed prophylactic levofloxacin (Levaquin) after consolidation therapy and 50 patients who were not prescribed any antibiotics.

Overall, patients given levofloxacin had a lower rate of hospital readmission due to febrile neutropenia whether given the antibiotic after the first chemotherapy consolidation cycle (42% vs. 72%, P = .002) or after all cycles (51.4% vs. 67%, P = .023).

None of the patients in the levofloxacin group developed Clostridium difficile–associated diarrhea within 30 days from discharge after receiving the first cycle of consolidation chemotherapy, compared with one patient in the group not given the antibiotic (Support Care Cancer. 2017 Nov 23. doi: 10.1007/s00520-017-3976-1).

The use of levofloxacin did not significantly impact secondary outcomes, including total days of antibiotic treatment provided to febrile neutropenic patients, days to readmission for febrile neutropenia, or the rate of positive bacterial cultures returned in febrile neutropenic patients.

It was not possible to assess differences in the rate of fluoroquinolone resistance in positive bacterial cultures because fluoroquinolone susceptibilities were infrequently reported.

“This study provides evidence of a strong association between prophylaxis with oral levofloxacin and the rate of febrile neutropenia, but further study is required to evaluate the impact of fluoroquinolone use on antibiotic resistance and [Clostridium difficile–associated diarrhea] rates in this patient setting,” the investigators wrote.

The study was limited by the small sample size, which precluded accurate ascertainment of some outcomes, including safety outcomes, they noted. Additionally, adherence to oral therapy was unknown, and some data, such as fluoroquinolone resistance, were missing for patients admitted for febrile neutropenia to outside hospitals.

Dr. Lee reported having no relevant conflicts of interest.

Image by Lance Liotta

New research has revealed a potential therapeutic target for acute myeloid leukemia (AML)—the methyl transferase enzyme METTL3.

Researchers found that inhibiting METTL3 destroys human and mouse AML cells without harming non-leukemic blood cells.

The team also discovered why METTL3 is required for AML cell survival by deciphering the mechanism it uses to regulate several other leukemia genes.

The researchers described this work in Nature.

“New treatments for AML are desperately needed, and we have been looking for genes that would be good drug targets,” said study author Tony Kouzarides, PhD, of University of Cambridge in the UK.

“We identified the methyl transferase enzyme METTL3 as a highly viable target against AML. Our study will inspire pharmaceutical efforts to find drugs that specifically inhibit METTL3 to treat AML.”

In their attempt to find therapeutic targets for AML, Dr Kouzarides and his colleagues used CRISPR-Cas9 to screen AML cells for vulnerable points.

The researchers created mouse leukemia cells with mutations in genes that may be targeted in human AML cells and systematically tested each gene, finding which were essential for AML survival.

The team ended up with 46 likely candidate genes, many of which produce proteins that could modify RNA. Among these, METTL3 was one of the genes with the strongest effect.

Experiments revealed that METTL3 was essential for the survival of AML cells, but it was not required for healthy blood cells.

Having found a potential target in METTL3, the researchers investigated how it worked.

They discovered that the protein produced by METTL3 bound to the beginning of 126 different genes, including several required for AML cell survival.

As RNAs were produced, the METTL3 protein added methyl groups to their middle section, something which had not been previously observed. These middle methyl groups increased the ability of the RNAs to be translated into proteins.

The researchers then found that when METTL3 was inhibited, no methyl groups were added to the RNA. This prevented the production of their essential proteins, so the AML cells started dying.

“This study uncovered an entirely new mechanism of gene regulation in AML that operates through modifications of RNA,” said study author Konstantinos Tzelepis, PhD, of Wellcome Trust Sanger Institute in Cambridge, UK.

“We discovered that inhibiting the methyl transferase activity of METTL3 would stop the translation of a whole set of proteins that the leukemia needs. This mechanism shows that a drug to inhibit methylation could be effective against AML without affecting normal cells.”

Image by Lance Liotta

New research has revealed a potential therapeutic target for acute myeloid leukemia (AML)—the methyl transferase enzyme METTL3.

Researchers found that inhibiting METTL3 destroys human and mouse AML cells without harming non-leukemic blood cells.

The team also discovered why METTL3 is required for AML cell survival by deciphering the mechanism it uses to regulate several other leukemia genes.

The researchers described this work in Nature.

“New treatments for AML are desperately needed, and we have been looking for genes that would be good drug targets,” said study author Tony Kouzarides, PhD, of University of Cambridge in the UK.

“We identified the methyl transferase enzyme METTL3 as a highly viable target against AML. Our study will inspire pharmaceutical efforts to find drugs that specifically inhibit METTL3 to treat AML.”

In their attempt to find therapeutic targets for AML, Dr Kouzarides and his colleagues used CRISPR-Cas9 to screen AML cells for vulnerable points.

The researchers created mouse leukemia cells with mutations in genes that may be targeted in human AML cells and systematically tested each gene, finding which were essential for AML survival.

The team ended up with 46 likely candidate genes, many of which produce proteins that could modify RNA. Among these, METTL3 was one of the genes with the strongest effect.

Experiments revealed that METTL3 was essential for the survival of AML cells, but it was not required for healthy blood cells.

Having found a potential target in METTL3, the researchers investigated how it worked.

They discovered that the protein produced by METTL3 bound to the beginning of 126 different genes, including several required for AML cell survival.

As RNAs were produced, the METTL3 protein added methyl groups to their middle section, something which had not been previously observed. These middle methyl groups increased the ability of the RNAs to be translated into proteins.

The researchers then found that when METTL3 was inhibited, no methyl groups were added to the RNA. This prevented the production of their essential proteins, so the AML cells started dying.

“This study uncovered an entirely new mechanism of gene regulation in AML that operates through modifications of RNA,” said study author Konstantinos Tzelepis, PhD, of Wellcome Trust Sanger Institute in Cambridge, UK.

“We discovered that inhibiting the methyl transferase activity of METTL3 would stop the translation of a whole set of proteins that the leukemia needs. This mechanism shows that a drug to inhibit methylation could be effective against AML without affecting normal cells.”

Image by Lance Liotta

New research has revealed a potential therapeutic target for acute myeloid leukemia (AML)—the methyl transferase enzyme METTL3.

Researchers found that inhibiting METTL3 destroys human and mouse AML cells without harming non-leukemic blood cells.

The team also discovered why METTL3 is required for AML cell survival by deciphering the mechanism it uses to regulate several other leukemia genes.

The researchers described this work in Nature.

“New treatments for AML are desperately needed, and we have been looking for genes that would be good drug targets,” said study author Tony Kouzarides, PhD, of University of Cambridge in the UK.

“We identified the methyl transferase enzyme METTL3 as a highly viable target against AML. Our study will inspire pharmaceutical efforts to find drugs that specifically inhibit METTL3 to treat AML.”

In their attempt to find therapeutic targets for AML, Dr Kouzarides and his colleagues used CRISPR-Cas9 to screen AML cells for vulnerable points.

The researchers created mouse leukemia cells with mutations in genes that may be targeted in human AML cells and systematically tested each gene, finding which were essential for AML survival.

The team ended up with 46 likely candidate genes, many of which produce proteins that could modify RNA. Among these, METTL3 was one of the genes with the strongest effect.

Experiments revealed that METTL3 was essential for the survival of AML cells, but it was not required for healthy blood cells.

Having found a potential target in METTL3, the researchers investigated how it worked.

They discovered that the protein produced by METTL3 bound to the beginning of 126 different genes, including several required for AML cell survival.

As RNAs were produced, the METTL3 protein added methyl groups to their middle section, something which had not been previously observed. These middle methyl groups increased the ability of the RNAs to be translated into proteins.

The researchers then found that when METTL3 was inhibited, no methyl groups were added to the RNA. This prevented the production of their essential proteins, so the AML cells started dying.

“This study uncovered an entirely new mechanism of gene regulation in AML that operates through modifications of RNA,” said study author Konstantinos Tzelepis, PhD, of Wellcome Trust Sanger Institute in Cambridge, UK.

“We discovered that inhibiting the methyl transferase activity of METTL3 would stop the translation of a whole set of proteins that the leukemia needs. This mechanism shows that a drug to inhibit methylation could be effective against AML without affecting normal cells.”

Micrograph showing MDS

The US Food and Drug Administration (FDA) has granted orphan drug designation to AMV564, a CD33/CD3 bispecific antibody, for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

AMV564 is a T-cell engager, derived from human protein sequences, that binds both CD33 and CD3 to mediate T-cell directed lysis of CD33-positive cancer cells.

Amphivena Therapeutics Inc., is currently conducting a phase 1 trial of AMV564 in relapsed or refractory AML. The company plans to launch a phase 1 trial in patients with MDS in early 2018.

According to Amphivena, AMV564 has demonstrated “potent activity” in AML patient samples, and that activity was independent of CD33 expression level, disease stage, and cytogenetic risk.

AMV564 also eliminated nearly all blasts from the bone marrow and spleen in a stringent AML patient-derived xenograft murine model.

In addition, Amphivena established a therapeutic window for AMV564 in cynomolgus monkeys, with rapid and sustained elimination of CD33-expressing cells during AMV564 dosing and rapid hematopoietic recovery following dosing.

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.

Micrograph showing MDS

The US Food and Drug Administration (FDA) has granted orphan drug designation to AMV564, a CD33/CD3 bispecific antibody, for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

AMV564 is a T-cell engager, derived from human protein sequences, that binds both CD33 and CD3 to mediate T-cell directed lysis of CD33-positive cancer cells.

Amphivena Therapeutics Inc., is currently conducting a phase 1 trial of AMV564 in relapsed or refractory AML. The company plans to launch a phase 1 trial in patients with MDS in early 2018.

According to Amphivena, AMV564 has demonstrated “potent activity” in AML patient samples, and that activity was independent of CD33 expression level, disease stage, and cytogenetic risk.

AMV564 also eliminated nearly all blasts from the bone marrow and spleen in a stringent AML patient-derived xenograft murine model.

In addition, Amphivena established a therapeutic window for AMV564 in cynomolgus monkeys, with rapid and sustained elimination of CD33-expressing cells during AMV564 dosing and rapid hematopoietic recovery following dosing.

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.

Micrograph showing MDS

The US Food and Drug Administration (FDA) has granted orphan drug designation to AMV564, a CD33/CD3 bispecific antibody, for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

AMV564 is a T-cell engager, derived from human protein sequences, that binds both CD33 and CD3 to mediate T-cell directed lysis of CD33-positive cancer cells.

Amphivena Therapeutics Inc., is currently conducting a phase 1 trial of AMV564 in relapsed or refractory AML. The company plans to launch a phase 1 trial in patients with MDS in early 2018.

According to Amphivena, AMV564 has demonstrated “potent activity” in AML patient samples, and that activity was independent of CD33 expression level, disease stage, and cytogenetic risk.

AMV564 also eliminated nearly all blasts from the bone marrow and spleen in a stringent AML patient-derived xenograft murine model.

In addition, Amphivena established a therapeutic window for AMV564 in cynomolgus monkeys, with rapid and sustained elimination of CD33-expressing cells during AMV564 dosing and rapid hematopoietic recovery following dosing.

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.

Researchers in the United States and the United Kingdom believe they have found a new gene target that could aid in the development of more effective treatments for acute myeloid leukemia (AML).

Inhibition of the METTL3 gene allowed for the destruction of AML in human and mouse cells without damaging healthy blood cells, the researchers reported in a research letter published Nov. 27 in the journal Nature.

National Institutes of Health/Wikimedia Commons/Public Domain

[email protected]

On Twitter @maryellenny

Researchers in the United States and the United Kingdom believe they have found a new gene target that could aid in the development of more effective treatments for acute myeloid leukemia (AML).

Inhibition of the METTL3 gene allowed for the destruction of AML in human and mouse cells without damaging healthy blood cells, the researchers reported in a research letter published Nov. 27 in the journal Nature.

National Institutes of Health/Wikimedia Commons/Public Domain

[email protected]

On Twitter @maryellenny

Researchers in the United States and the United Kingdom believe they have found a new gene target that could aid in the development of more effective treatments for acute myeloid leukemia (AML).

Inhibition of the METTL3 gene allowed for the destruction of AML in human and mouse cells without damaging healthy blood cells, the researchers reported in a research letter published Nov. 27 in the journal Nature.

National Institutes of Health/Wikimedia Commons/Public Domain

[email protected]

On Twitter @maryellenny

Augusta University

New research has shown an increased risk of early death in patients with acute myeloid leukemia (AML) who have high levels of indoleamine 2,3 dioxygenase-1 (IDO-1), an enzyme known to suppress the immune system.

Researchers quantified IDO-1 expression in diagnostic samples from patients with AML and discovered that high levels of IDO-1 were significantly associated with induction failure and poor overall survival (OS).

Ravindra Kolhe, MD, PhD, of the Medical College of Georgia at Augusta University, and his colleagues recounted these findings in Scientific Reports.

The researchers reviewed data from 40 AML patients. They had a median age at diagnosis of 60 (range, 27–89), 60% were female, and 55% were self-reported as Caucasian.

Most patients (72.5%) received standard anthracycline and cytarabine as induction, 10% received hypomethylating agents, and 17.5% were untreated or had unknown treatment status.

Fifteen percent of patients underwent allogeneic hematopoietic stem cell transplant (allo-HSCT) at the time of first complete remission.

Half of all patients achieved remission, and half of those patients (n=10, 25%) had a subsequent relapse. The median OS was 283 days (range, 32–1941). Twenty percent of patients (n=8) were still alive at the time of data analysis.

IDO-1 analysis

“We wanted to look at what makes this leukemia so aggressive that initial induction chemotherapy is not working,” Dr Kolhe said. “Early relapse tends to predict early mortality in these patients, and one of the things we looked at was IDO.”

The researchers extracted IDO-1 mRNA from diagnostic bone marrow samples from 29 of the patients but assessed IDO-1 protein expression in all 40 patients via immunohistochemistry.

The team quantified IDO-1 expression using a “composite IDO-1 score.” They used a cut-off point of 0.45 and divided patients’ samples into 2 groups: high (≥0.45) and low (<0.45) IDO-1 score.

The researchers compared IDO-1 results across 4 survival groups, which included patients surviving:

• Less than 6 months
• More than 6 months to 1 year
• More than 1 year to less than 5 years
• Beyond 5 years.

The team found a direct correlation between poor OS and higher composite IDO-1 score (P=0.0005).

“The patients who died at 6 months had a high expression of IDO, while the blasts produced relatively little IDO in the patients who lived 5 years or more,” Dr Kolhe said.

Independent predictor

The researchers conducted a univariate analysis and identified several factors that were significantly associated with poor OS, including:

• Higher IDO-1 mRNA (P=0.005)
• Higher composite IDO-1 score (P<0.0001)
• Higher age (P=0.0018)
• Male gender (P=0.019)
• High-risk cytogenetics (P=0.002)
• Not undergoing allo-HSCT (P=0.0005).

In a multivariate analysis including the above variables, the researchers found that a higher composite IDO-1 score (P=0.007) and not undergoing allo-HSCT (P=0.007) were significantly associated with poor OS.

The team also found that patients who failed induction had a higher composite IDO-1 score (P=0.01).

“Most of the time, we don’t know why patients are not responding to chemotherapy,” Dr Kolhe noted. “But when the researchers adjusted for other risk factors for AML, like increased age and severe anemia, IDO levels were a standout. Right now, we know it’s high in patients who die at 6 months, and we show that it’s an independent indicator if you adjust for other known variables.”

Dr Kolhe said these results suggest IDO-1 expression should be measured when the diagnostic bone marrow biopsy is performed. This may help identify AML patients who could benefit from receiving an IDO inhibitor along with standard therapy.

Researchers are currently conducting a phase 1/2 trial of the IDO inhibitor indoximod in combination with idarubicin and cytarabine in patients with newly diagnosed AML (NCT02835729).

Augusta University

New research has shown an increased risk of early death in patients with acute myeloid leukemia (AML) who have high levels of indoleamine 2,3 dioxygenase-1 (IDO-1), an enzyme known to suppress the immune system.

Researchers quantified IDO-1 expression in diagnostic samples from patients with AML and discovered that high levels of IDO-1 were significantly associated with induction failure and poor overall survival (OS).

Ravindra Kolhe, MD, PhD, of the Medical College of Georgia at Augusta University, and his colleagues recounted these findings in Scientific Reports.

The researchers reviewed data from 40 AML patients. They had a median age at diagnosis of 60 (range, 27–89), 60% were female, and 55% were self-reported as Caucasian.

Most patients (72.5%) received standard anthracycline and cytarabine as induction, 10% received hypomethylating agents, and 17.5% were untreated or had unknown treatment status.

Fifteen percent of patients underwent allogeneic hematopoietic stem cell transplant (allo-HSCT) at the time of first complete remission.

Half of all patients achieved remission, and half of those patients (n=10, 25%) had a subsequent relapse. The median OS was 283 days (range, 32–1941). Twenty percent of patients (n=8) were still alive at the time of data analysis.

IDO-1 analysis

“We wanted to look at what makes this leukemia so aggressive that initial induction chemotherapy is not working,” Dr Kolhe said. “Early relapse tends to predict early mortality in these patients, and one of the things we looked at was IDO.”

The researchers extracted IDO-1 mRNA from diagnostic bone marrow samples from 29 of the patients but assessed IDO-1 protein expression in all 40 patients via immunohistochemistry.

The team quantified IDO-1 expression using a “composite IDO-1 score.” They used a cut-off point of 0.45 and divided patients’ samples into 2 groups: high (≥0.45) and low (<0.45) IDO-1 score.

The researchers compared IDO-1 results across 4 survival groups, which included patients surviving:

• Less than 6 months
• More than 6 months to 1 year
• More than 1 year to less than 5 years
• Beyond 5 years.

The team found a direct correlation between poor OS and higher composite IDO-1 score (P=0.0005).

“The patients who died at 6 months had a high expression of IDO, while the blasts produced relatively little IDO in the patients who lived 5 years or more,” Dr Kolhe said.

Independent predictor

The researchers conducted a univariate analysis and identified several factors that were significantly associated with poor OS, including:

• Higher IDO-1 mRNA (P=0.005)
• Higher composite IDO-1 score (P<0.0001)
• Higher age (P=0.0018)
• Male gender (P=0.019)
• High-risk cytogenetics (P=0.002)
• Not undergoing allo-HSCT (P=0.0005).

In a multivariate analysis including the above variables, the researchers found that a higher composite IDO-1 score (P=0.007) and not undergoing allo-HSCT (P=0.007) were significantly associated with poor OS.

The team also found that patients who failed induction had a higher composite IDO-1 score (P=0.01).

“Most of the time, we don’t know why patients are not responding to chemotherapy,” Dr Kolhe noted. “But when the researchers adjusted for other risk factors for AML, like increased age and severe anemia, IDO levels were a standout. Right now, we know it’s high in patients who die at 6 months, and we show that it’s an independent indicator if you adjust for other known variables.”

Dr Kolhe said these results suggest IDO-1 expression should be measured when the diagnostic bone marrow biopsy is performed. This may help identify AML patients who could benefit from receiving an IDO inhibitor along with standard therapy.

Researchers are currently conducting a phase 1/2 trial of the IDO inhibitor indoximod in combination with idarubicin and cytarabine in patients with newly diagnosed AML (NCT02835729).

Augusta University

New research has shown an increased risk of early death in patients with acute myeloid leukemia (AML) who have high levels of indoleamine 2,3 dioxygenase-1 (IDO-1), an enzyme known to suppress the immune system.

Researchers quantified IDO-1 expression in diagnostic samples from patients with AML and discovered that high levels of IDO-1 were significantly associated with induction failure and poor overall survival (OS).

Ravindra Kolhe, MD, PhD, of the Medical College of Georgia at Augusta University, and his colleagues recounted these findings in Scientific Reports.

The researchers reviewed data from 40 AML patients. They had a median age at diagnosis of 60 (range, 27–89), 60% were female, and 55% were self-reported as Caucasian.

Most patients (72.5%) received standard anthracycline and cytarabine as induction, 10% received hypomethylating agents, and 17.5% were untreated or had unknown treatment status.

Fifteen percent of patients underwent allogeneic hematopoietic stem cell transplant (allo-HSCT) at the time of first complete remission.

Half of all patients achieved remission, and half of those patients (n=10, 25%) had a subsequent relapse. The median OS was 283 days (range, 32–1941). Twenty percent of patients (n=8) were still alive at the time of data analysis.

IDO-1 analysis

“We wanted to look at what makes this leukemia so aggressive that initial induction chemotherapy is not working,” Dr Kolhe said. “Early relapse tends to predict early mortality in these patients, and one of the things we looked at was IDO.”

The researchers extracted IDO-1 mRNA from diagnostic bone marrow samples from 29 of the patients but assessed IDO-1 protein expression in all 40 patients via immunohistochemistry.

The team quantified IDO-1 expression using a “composite IDO-1 score.” They used a cut-off point of 0.45 and divided patients’ samples into 2 groups: high (≥0.45) and low (<0.45) IDO-1 score.

The researchers compared IDO-1 results across 4 survival groups, which included patients surviving:

• Less than 6 months
• More than 6 months to 1 year
• More than 1 year to less than 5 years
• Beyond 5 years.

The team found a direct correlation between poor OS and higher composite IDO-1 score (P=0.0005).

“The patients who died at 6 months had a high expression of IDO, while the blasts produced relatively little IDO in the patients who lived 5 years or more,” Dr Kolhe said.

Independent predictor

The researchers conducted a univariate analysis and identified several factors that were significantly associated with poor OS, including:

• Higher IDO-1 mRNA (P=0.005)
• Higher composite IDO-1 score (P<0.0001)
• Higher age (P=0.0018)
• Male gender (P=0.019)
• High-risk cytogenetics (P=0.002)
• Not undergoing allo-HSCT (P=0.0005).

In a multivariate analysis including the above variables, the researchers found that a higher composite IDO-1 score (P=0.007) and not undergoing allo-HSCT (P=0.007) were significantly associated with poor OS.

The team also found that patients who failed induction had a higher composite IDO-1 score (P=0.01).

“Most of the time, we don’t know why patients are not responding to chemotherapy,” Dr Kolhe noted. “But when the researchers adjusted for other risk factors for AML, like increased age and severe anemia, IDO levels were a standout. Right now, we know it’s high in patients who die at 6 months, and we show that it’s an independent indicator if you adjust for other known variables.”

Dr Kolhe said these results suggest IDO-1 expression should be measured when the diagnostic bone marrow biopsy is performed. This may help identify AML patients who could benefit from receiving an IDO inhibitor along with standard therapy.

Researchers are currently conducting a phase 1/2 trial of the IDO inhibitor indoximod in combination with idarubicin and cytarabine in patients with newly diagnosed AML (NCT02835729).

Wolfgang Däuble

An ex vivo drug screening method can reveal optimal therapies for patients with hematologic malignancies, according to research published in The Lancet Haematology.

Researchers used a method called pharmacoscopy to measure single-cell responses to possible treatments in samples from patients with leukemias and lymphomas.

The team then used these results to guide treatment decisions and found that pharmacoscopy-guided treatment greatly improved response rates and progression-free survival (PFS).

“Having a robust, fast, and reliable predictive test at our disposal during the patient treatment process, especially at the time of relapse where a new intervention must be selected quickly, will change how medical doctors prioritize drugs to use for late-stage patients,” said study author Philipp Staber, MD, of Medical University of Vienna in Austria.

With pharmacoscopy, hundreds of drug options can be pre-tested ex vivo in small liquid biopsy samples collected from individual patients. The effects of each drug on the individual cells are quantified using high-throughput and high-content automated confocal microscopy.

In combination with specially developed analysis methods, machine learning, and other algorithms, pharmacoscopy allows quantification of never-before visualized phenotypes. The method was first described last April in Nature Chemical Biology.

Now, Dr Staber and his colleagues have reported, in The Lancet Haematology, an interim analysis of the first clinical trial testing pharmacoscopy-guided treatment.

There were 17 evaluable patients, all of whom had aggressive hematologic malignancies. This included diffuse large B-cell lymphoma (n=6), acute myeloid leukemia (n=3), B-cell acute lymphoblastic leukemia (n=2), precursor B-cell lymphoblastic lymphoma (n=1), peripheral T-cell lymphoma (n=1), primary mediastinal B-cell lymphoma (n=1), T-cell lymphoblastic lymphoma (n=1), follicular lymphoma (n=1), and T-cell prolymphocytic leukemia (n=1).

The researchers compared outcomes with pharmacoscopy-guided treatment to outcomes with the most recent regimen on which the patient had progressed.

The overall response rate was 88% with pharmacoscopy-guided treatment and 24% with the patients’ most recent previous treatment regimen (odds ratio=24.38; 95%, CI 3.99–125.4; P=0.0013).

None of the patients had progressive disease as their best overall response when they received pharmacoscopy-guided treatment. However, 7 patients had progressive disease in response to their most recent prior regimen.

At the time of analysis, 8 patients (47%) still had ongoing responses after pharmacoscopy-guided treatment.

In addition, pharmacoscopy-guided treatment significantly improved PFS. The median PFS was 22.6 weeks with pharmacoscopy-guided treatment and 5.7 weeks with the most recent prior regimen (hazard ratio=3.14; 95%, CI 1.37–7.22; P=0.0075).

“Evidence that the pharmacoscopy approach is helpful for clinical evaluation of therapy is wonderful,” said study author Giulio Superti-Furga, PhD, of CeMM Research Center for Molecular Medicine in Vienna, Austria.

“Single-cell functional analysis of primary material gives unprecedented resolution and precision that we are sure to further develop in the future to address yet more diseases.”

Wolfgang Däuble

An ex vivo drug screening method can reveal optimal therapies for patients with hematologic malignancies, according to research published in The Lancet Haematology.

Researchers used a method called pharmacoscopy to measure single-cell responses to possible treatments in samples from patients with leukemias and lymphomas.

The team then used these results to guide treatment decisions and found that pharmacoscopy-guided treatment greatly improved response rates and progression-free survival (PFS).

“Having a robust, fast, and reliable predictive test at our disposal during the patient treatment process, especially at the time of relapse where a new intervention must be selected quickly, will change how medical doctors prioritize drugs to use for late-stage patients,” said study author Philipp Staber, MD, of Medical University of Vienna in Austria.

With pharmacoscopy, hundreds of drug options can be pre-tested ex vivo in small liquid biopsy samples collected from individual patients. The effects of each drug on the individual cells are quantified using high-throughput and high-content automated confocal microscopy.

In combination with specially developed analysis methods, machine learning, and other algorithms, pharmacoscopy allows quantification of never-before visualized phenotypes. The method was first described last April in Nature Chemical Biology.

Now, Dr Staber and his colleagues have reported, in The Lancet Haematology, an interim analysis of the first clinical trial testing pharmacoscopy-guided treatment.

There were 17 evaluable patients, all of whom had aggressive hematologic malignancies. This included diffuse large B-cell lymphoma (n=6), acute myeloid leukemia (n=3), B-cell acute lymphoblastic leukemia (n=2), precursor B-cell lymphoblastic lymphoma (n=1), peripheral T-cell lymphoma (n=1), primary mediastinal B-cell lymphoma (n=1), T-cell lymphoblastic lymphoma (n=1), follicular lymphoma (n=1), and T-cell prolymphocytic leukemia (n=1).

The researchers compared outcomes with pharmacoscopy-guided treatment to outcomes with the most recent regimen on which the patient had progressed.

The overall response rate was 88% with pharmacoscopy-guided treatment and 24% with the patients’ most recent previous treatment regimen (odds ratio=24.38; 95%, CI 3.99–125.4; P=0.0013).

None of the patients had progressive disease as their best overall response when they received pharmacoscopy-guided treatment. However, 7 patients had progressive disease in response to their most recent prior regimen.

At the time of analysis, 8 patients (47%) still had ongoing responses after pharmacoscopy-guided treatment.

In addition, pharmacoscopy-guided treatment significantly improved PFS. The median PFS was 22.6 weeks with pharmacoscopy-guided treatment and 5.7 weeks with the most recent prior regimen (hazard ratio=3.14; 95%, CI 1.37–7.22; P=0.0075).

“Evidence that the pharmacoscopy approach is helpful for clinical evaluation of therapy is wonderful,” said study author Giulio Superti-Furga, PhD, of CeMM Research Center for Molecular Medicine in Vienna, Austria.

“Single-cell functional analysis of primary material gives unprecedented resolution and precision that we are sure to further develop in the future to address yet more diseases.”

Wolfgang Däuble

An ex vivo drug screening method can reveal optimal therapies for patients with hematologic malignancies, according to research published in The Lancet Haematology.

Researchers used a method called pharmacoscopy to measure single-cell responses to possible treatments in samples from patients with leukemias and lymphomas.

The team then used these results to guide treatment decisions and found that pharmacoscopy-guided treatment greatly improved response rates and progression-free survival (PFS).

“Having a robust, fast, and reliable predictive test at our disposal during the patient treatment process, especially at the time of relapse where a new intervention must be selected quickly, will change how medical doctors prioritize drugs to use for late-stage patients,” said study author Philipp Staber, MD, of Medical University of Vienna in Austria.

With pharmacoscopy, hundreds of drug options can be pre-tested ex vivo in small liquid biopsy samples collected from individual patients. The effects of each drug on the individual cells are quantified using high-throughput and high-content automated confocal microscopy.

In combination with specially developed analysis methods, machine learning, and other algorithms, pharmacoscopy allows quantification of never-before visualized phenotypes. The method was first described last April in Nature Chemical Biology.

Now, Dr Staber and his colleagues have reported, in The Lancet Haematology, an interim analysis of the first clinical trial testing pharmacoscopy-guided treatment.

There were 17 evaluable patients, all of whom had aggressive hematologic malignancies. This included diffuse large B-cell lymphoma (n=6), acute myeloid leukemia (n=3), B-cell acute lymphoblastic leukemia (n=2), precursor B-cell lymphoblastic lymphoma (n=1), peripheral T-cell lymphoma (n=1), primary mediastinal B-cell lymphoma (n=1), T-cell lymphoblastic lymphoma (n=1), follicular lymphoma (n=1), and T-cell prolymphocytic leukemia (n=1).

The researchers compared outcomes with pharmacoscopy-guided treatment to outcomes with the most recent regimen on which the patient had progressed.

The overall response rate was 88% with pharmacoscopy-guided treatment and 24% with the patients’ most recent previous treatment regimen (odds ratio=24.38; 95%, CI 3.99–125.4; P=0.0013).

None of the patients had progressive disease as their best overall response when they received pharmacoscopy-guided treatment. However, 7 patients had progressive disease in response to their most recent prior regimen.

At the time of analysis, 8 patients (47%) still had ongoing responses after pharmacoscopy-guided treatment.

In addition, pharmacoscopy-guided treatment significantly improved PFS. The median PFS was 22.6 weeks with pharmacoscopy-guided treatment and 5.7 weeks with the most recent prior regimen (hazard ratio=3.14; 95%, CI 1.37–7.22; P=0.0075).

“Evidence that the pharmacoscopy approach is helpful for clinical evaluation of therapy is wonderful,” said study author Giulio Superti-Furga, PhD, of CeMM Research Center for Molecular Medicine in Vienna, Austria.

“Single-cell functional analysis of primary material gives unprecedented resolution and precision that we are sure to further develop in the future to address yet more diseases.”