Leukemia, Myelodysplasia, Transplantation

SAN DIEGO – More than 90% of the first patients with previously untreated chronic lymphocytic leukemia who received ibrutinib in an early study are alive and without disease progression 5 years later, investigators reported.

Among 31 treatment-naive patients with chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) who were started on the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) in the phase Ib/II PCYC-1102/1103 study, the 5-year progression-free survival (PFS) rate was 92%, with the median PFS not reached. Estimated 5-year overall survival (OS) among these patients was also 92%, with the median not reached, Susan O’Brien, MD, of the University of California, Irvine, reported at the annual meeting of the American Society of Hematology.

The 5-year PFS rate for patients with relapsed/refractory disease who had received a median of four prior lines of therapy before starting on single-agent ibrutinib was 43%, with a median PFS of 52 months. In this group, the overall survival (OS) rate was 57%, with the median not reached.

“At 5 years of follow-up, there are very durable responses in treatment-naive and relapsed refractory patients. You saw that, in the treatment-naive group, there is, in fact, only one patient who has progressed so far,” Dr. O’Brien said.

In a separate study, investigators from the phase III RESONATE-2 trial reported updated safety and efficacy data showing that in first-line therapy for patients aged 65 years and older with CLL/SLL with active disease, ibrutinib was associated with significantly better PFS at 24 months, compared with chlorambucil.

In this study by Dr. O’Brien and colleagues, 31 patients with previously untreated CLL/SLL and 101 patients with relapsed/refractory disease (progression or no objective response within 24 months of starting on chemoimmunotherapy) were treated with oral ibrutinib once daily at doses of 420 mg or 840 mg until disease progression or unacceptable toxicity.

After 5 years of follow-up, 20 of the 31 treatment-naive patients (65%) and 30 of the 101 relapsed/refractory patients (30%) remained on ibrutinib therapy. The primary reasons for discontinuation among relapsed/refractory patients included progressive disease in 33%, adverse events in 21%, and investigator decision in 11%.

Best response rates in treatment-naive patients were 87% (29% complete response, 55% partial response, 3% partial response-L) and 89% in relapsed/refractory patients (10%, 76%, and 3%, respectively).

An analysis of survival by IGHV (immunoglobulin heavy chain variable) mutational status in patients with relapsed/refractory disease showed a 53% 5-year PFS rate among patients with mutated IGHV and a median PFS of 63 months, compared with 38% and 43 months for patients with unmutated IGHV. Respective 5-year overall survival rates were 66% (median OS, 63 months) and 55% (median not reached).

In an analysis of survival outcomes by chromosomal abnormalities detected by FISH (fluorescent in situ hybridization) among patients with relapsed/refractory disease, median PFS and OS rates were highest among patients with the 13q deletion, at 91% for both PFS and OS, compared with 80% for each in patients with trisomy 12, 33% and 61% for patients with deletion 11q, and 19% and 32% for patients with deletion 17p. In patients with no chromosomal abnormalities, the 5-year PFS rate was 66% (median not reached), and the 5-year OS rate was 83% (median not reached).

Among patients with complex karyotype, 90% of whom had relapsed refractory disease, the 5-year PFS rate was 36% (median 33 months), and the OS rate was 46% (median 57 months). In contrast, respective PFS and OS rates for patients without complex karyotype were 69% and 84%, with the median not reached in either survival category.

In multivariate analysis, only deletion 17p was identified as a significant predictor of PFS and OS.

Grade 3 or greater treatment-emergent adverse events occurred mostly frequently in the first year of therapy and declined thereafter. The most common grade 3 or greater events were hypertension, (26% of all patients), pneumonia (22%), neutropenia (17%), and atrial fibrillation (9%).

Paul M. Barr, MD, of the University of Rochester presented updated data from RESONATE-2, comparing ibrutinib with chlorambucil in patients 65 and older with newly diagnosed, active CLL/SLL.

At a median follow-up of 29 months, the rates of 2-year PFS were 89% for patients treated with ibrutinib (median PFS not reached) vs. 34% for chlorambucil (median PFS 15 months). This translated into a hazard ratio for ibrutinib of 0.121 (P less than .0001). The benefit of ibrutinib occurred without regard to IGHV status, and ibrutinib continues to demonstrate an OS benefit over chlorambucil with longer follow-up and crossover. Overall survival at 24 months was 95% for patients treated with ibrutinib (included 55 patients who were crossed over from chlorambucil) vs. 84% for patients treated with chlorambucil only.

“The depth of the responses has improved over time, now with 18% of patients achieving a CR with ibrutinib, and lastly, ibrutinib remains tolerable in this elderly population, with 79% of patients that are continuing on therapy,” Dr. Barr said.

Both studies were funded by Pharmacyclics. Dr. Barr and Dr. O’Brien disclosed serving as consultants to the company, and Dr. O’Brien further disclosed honoraria and research funding from Pharmacyclics.

SAN DIEGO – More than 90% of the first patients with previously untreated chronic lymphocytic leukemia who received ibrutinib in an early study are alive and without disease progression 5 years later, investigators reported.

Among 31 treatment-naive patients with chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) who were started on the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) in the phase Ib/II PCYC-1102/1103 study, the 5-year progression-free survival (PFS) rate was 92%, with the median PFS not reached. Estimated 5-year overall survival (OS) among these patients was also 92%, with the median not reached, Susan O’Brien, MD, of the University of California, Irvine, reported at the annual meeting of the American Society of Hematology.

The 5-year PFS rate for patients with relapsed/refractory disease who had received a median of four prior lines of therapy before starting on single-agent ibrutinib was 43%, with a median PFS of 52 months. In this group, the overall survival (OS) rate was 57%, with the median not reached.

“At 5 years of follow-up, there are very durable responses in treatment-naive and relapsed refractory patients. You saw that, in the treatment-naive group, there is, in fact, only one patient who has progressed so far,” Dr. O’Brien said.

In a separate study, investigators from the phase III RESONATE-2 trial reported updated safety and efficacy data showing that in first-line therapy for patients aged 65 years and older with CLL/SLL with active disease, ibrutinib was associated with significantly better PFS at 24 months, compared with chlorambucil.

In this study by Dr. O’Brien and colleagues, 31 patients with previously untreated CLL/SLL and 101 patients with relapsed/refractory disease (progression or no objective response within 24 months of starting on chemoimmunotherapy) were treated with oral ibrutinib once daily at doses of 420 mg or 840 mg until disease progression or unacceptable toxicity.

After 5 years of follow-up, 20 of the 31 treatment-naive patients (65%) and 30 of the 101 relapsed/refractory patients (30%) remained on ibrutinib therapy. The primary reasons for discontinuation among relapsed/refractory patients included progressive disease in 33%, adverse events in 21%, and investigator decision in 11%.

Best response rates in treatment-naive patients were 87% (29% complete response, 55% partial response, 3% partial response-L) and 89% in relapsed/refractory patients (10%, 76%, and 3%, respectively).

An analysis of survival by IGHV (immunoglobulin heavy chain variable) mutational status in patients with relapsed/refractory disease showed a 53% 5-year PFS rate among patients with mutated IGHV and a median PFS of 63 months, compared with 38% and 43 months for patients with unmutated IGHV. Respective 5-year overall survival rates were 66% (median OS, 63 months) and 55% (median not reached).

In an analysis of survival outcomes by chromosomal abnormalities detected by FISH (fluorescent in situ hybridization) among patients with relapsed/refractory disease, median PFS and OS rates were highest among patients with the 13q deletion, at 91% for both PFS and OS, compared with 80% for each in patients with trisomy 12, 33% and 61% for patients with deletion 11q, and 19% and 32% for patients with deletion 17p. In patients with no chromosomal abnormalities, the 5-year PFS rate was 66% (median not reached), and the 5-year OS rate was 83% (median not reached).

Among patients with complex karyotype, 90% of whom had relapsed refractory disease, the 5-year PFS rate was 36% (median 33 months), and the OS rate was 46% (median 57 months). In contrast, respective PFS and OS rates for patients without complex karyotype were 69% and 84%, with the median not reached in either survival category.

In multivariate analysis, only deletion 17p was identified as a significant predictor of PFS and OS.

Grade 3 or greater treatment-emergent adverse events occurred mostly frequently in the first year of therapy and declined thereafter. The most common grade 3 or greater events were hypertension, (26% of all patients), pneumonia (22%), neutropenia (17%), and atrial fibrillation (9%).

Paul M. Barr, MD, of the University of Rochester presented updated data from RESONATE-2, comparing ibrutinib with chlorambucil in patients 65 and older with newly diagnosed, active CLL/SLL.

At a median follow-up of 29 months, the rates of 2-year PFS were 89% for patients treated with ibrutinib (median PFS not reached) vs. 34% for chlorambucil (median PFS 15 months). This translated into a hazard ratio for ibrutinib of 0.121 (P less than .0001). The benefit of ibrutinib occurred without regard to IGHV status, and ibrutinib continues to demonstrate an OS benefit over chlorambucil with longer follow-up and crossover. Overall survival at 24 months was 95% for patients treated with ibrutinib (included 55 patients who were crossed over from chlorambucil) vs. 84% for patients treated with chlorambucil only.

“The depth of the responses has improved over time, now with 18% of patients achieving a CR with ibrutinib, and lastly, ibrutinib remains tolerable in this elderly population, with 79% of patients that are continuing on therapy,” Dr. Barr said.

Both studies were funded by Pharmacyclics. Dr. Barr and Dr. O’Brien disclosed serving as consultants to the company, and Dr. O’Brien further disclosed honoraria and research funding from Pharmacyclics.

SAN DIEGO – More than 90% of the first patients with previously untreated chronic lymphocytic leukemia who received ibrutinib in an early study are alive and without disease progression 5 years later, investigators reported.

Among 31 treatment-naive patients with chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) who were started on the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) in the phase Ib/II PCYC-1102/1103 study, the 5-year progression-free survival (PFS) rate was 92%, with the median PFS not reached. Estimated 5-year overall survival (OS) among these patients was also 92%, with the median not reached, Susan O’Brien, MD, of the University of California, Irvine, reported at the annual meeting of the American Society of Hematology.

The 5-year PFS rate for patients with relapsed/refractory disease who had received a median of four prior lines of therapy before starting on single-agent ibrutinib was 43%, with a median PFS of 52 months. In this group, the overall survival (OS) rate was 57%, with the median not reached.

“At 5 years of follow-up, there are very durable responses in treatment-naive and relapsed refractory patients. You saw that, in the treatment-naive group, there is, in fact, only one patient who has progressed so far,” Dr. O’Brien said.

In a separate study, investigators from the phase III RESONATE-2 trial reported updated safety and efficacy data showing that in first-line therapy for patients aged 65 years and older with CLL/SLL with active disease, ibrutinib was associated with significantly better PFS at 24 months, compared with chlorambucil.

In this study by Dr. O’Brien and colleagues, 31 patients with previously untreated CLL/SLL and 101 patients with relapsed/refractory disease (progression or no objective response within 24 months of starting on chemoimmunotherapy) were treated with oral ibrutinib once daily at doses of 420 mg or 840 mg until disease progression or unacceptable toxicity.

After 5 years of follow-up, 20 of the 31 treatment-naive patients (65%) and 30 of the 101 relapsed/refractory patients (30%) remained on ibrutinib therapy. The primary reasons for discontinuation among relapsed/refractory patients included progressive disease in 33%, adverse events in 21%, and investigator decision in 11%.

Best response rates in treatment-naive patients were 87% (29% complete response, 55% partial response, 3% partial response-L) and 89% in relapsed/refractory patients (10%, 76%, and 3%, respectively).

An analysis of survival by IGHV (immunoglobulin heavy chain variable) mutational status in patients with relapsed/refractory disease showed a 53% 5-year PFS rate among patients with mutated IGHV and a median PFS of 63 months, compared with 38% and 43 months for patients with unmutated IGHV. Respective 5-year overall survival rates were 66% (median OS, 63 months) and 55% (median not reached).

In an analysis of survival outcomes by chromosomal abnormalities detected by FISH (fluorescent in situ hybridization) among patients with relapsed/refractory disease, median PFS and OS rates were highest among patients with the 13q deletion, at 91% for both PFS and OS, compared with 80% for each in patients with trisomy 12, 33% and 61% for patients with deletion 11q, and 19% and 32% for patients with deletion 17p. In patients with no chromosomal abnormalities, the 5-year PFS rate was 66% (median not reached), and the 5-year OS rate was 83% (median not reached).

Among patients with complex karyotype, 90% of whom had relapsed refractory disease, the 5-year PFS rate was 36% (median 33 months), and the OS rate was 46% (median 57 months). In contrast, respective PFS and OS rates for patients without complex karyotype were 69% and 84%, with the median not reached in either survival category.

In multivariate analysis, only deletion 17p was identified as a significant predictor of PFS and OS.

Grade 3 or greater treatment-emergent adverse events occurred mostly frequently in the first year of therapy and declined thereafter. The most common grade 3 or greater events were hypertension, (26% of all patients), pneumonia (22%), neutropenia (17%), and atrial fibrillation (9%).

Paul M. Barr, MD, of the University of Rochester presented updated data from RESONATE-2, comparing ibrutinib with chlorambucil in patients 65 and older with newly diagnosed, active CLL/SLL.

At a median follow-up of 29 months, the rates of 2-year PFS were 89% for patients treated with ibrutinib (median PFS not reached) vs. 34% for chlorambucil (median PFS 15 months). This translated into a hazard ratio for ibrutinib of 0.121 (P less than .0001). The benefit of ibrutinib occurred without regard to IGHV status, and ibrutinib continues to demonstrate an OS benefit over chlorambucil with longer follow-up and crossover. Overall survival at 24 months was 95% for patients treated with ibrutinib (included 55 patients who were crossed over from chlorambucil) vs. 84% for patients treated with chlorambucil only.

“The depth of the responses has improved over time, now with 18% of patients achieving a CR with ibrutinib, and lastly, ibrutinib remains tolerable in this elderly population, with 79% of patients that are continuing on therapy,” Dr. Barr said.

Both studies were funded by Pharmacyclics. Dr. Barr and Dr. O’Brien disclosed serving as consultants to the company, and Dr. O’Brien further disclosed honoraria and research funding from Pharmacyclics.

Lab mouse

Investigators may have discovered a new way to treat mixed-lineage leukemia (MLL)-rearranged leukemia, according to research published in Cell.

The team found they could disrupt the balance between wild-type MLL proteins and MLL chimeras.
 
This impeded MLL leukemia cell proliferation in vitro, delayed disease progression in a mouse model of MLL-AF9 leukemia, and prolonged survival in the mice.

The investigators are now attempting to translate these findings to the clinic.

“We’ve spent the last 20 years in my laboratory trying to molecularly understand how MLL translocations cause this rare and devastating form of leukemia in children so that we can use this information to develop an effective therapy for this cancer,” said lead investigator Ali Shilatifard, PhD, of Northwestern University Feinberg School of Medicine in Chicago, Illinois.

“Now, we’ve made a fundamentally important breakthrough.”

The investigators found that wild-type MLL protein is less stable than the MLL chimeras in MLL leukemia cells. They therefore theorized that stabilizing the wild-type copy of the protein would displace the mutated version that drives MLL-rearranged leukemia.

The team set out to identify factors regulating MLL protein degradation and found the ubiquitin-conjugating enzyme E2O (UBE2O).

The investigators said UBE2O regulates the stability of wild-type MLL in response to interleukin-1 signaling. And inhibiting interleukin-1 receptor-associated kinases (IRAKs) increases the stability and chromatin occupancy of wild-type MLL.

The team also found that IRAK inhibition displaces the MLL chimera and subunits of the super elongation complex at a subset of target genes (LGALS1, LMO2, and GNA15).

To determine the implications of these findings for treatment, the investigators tested an IRAK4 inhibitor in patient-derived cell lines, including MLL leukemia and non-MLL leukemia/lymphoma cells. The inhibitor preferentially impeded the growth of MLL-rearranged leukemia cells.

The team also tested IRAK inhibitors in a murine MLL-AF9 leukemia transplantation model. They injected the animals with IRAK inhibitors on day 19 after transplant, which is just before the mice succumb to leukemia.

The mice received injections with an IRAK1/4 inhibitor (8 mg/kg), an IRAK4 inhibitor (75 mg/kg), or vehicle control every other day for 10 days.

The investigators said both IRAK inhibitors significantly extended survival beyond the 27-day mark, when all of the vehicle-treated mice had succumbed to the disease. Two mice treated with an IRAK inhibitor (1 mouse for each drug) were still alive at day 55.

The team also treated mice with the IRAK inhibitors or vehicle control at 10 days after transplant.

Eight of the 10 mice that received the IRAK1/4 inhibitor had not developed MLL-AF9 leukemia as of day 55. And the same was true for 4 of the 9 mice that received the IRAK4 inhibitor.

However, all of the vehicle-treated mice had succumbed to the disease by the 31-day mark.

The investigators said they are now synthesizing better compounds and hope to eventually launch a phase 1 trial to test these compounds in Chicago.

Lab mouse

Investigators may have discovered a new way to treat mixed-lineage leukemia (MLL)-rearranged leukemia, according to research published in Cell.

The team found they could disrupt the balance between wild-type MLL proteins and MLL chimeras.
 
This impeded MLL leukemia cell proliferation in vitro, delayed disease progression in a mouse model of MLL-AF9 leukemia, and prolonged survival in the mice.

The investigators are now attempting to translate these findings to the clinic.

“We’ve spent the last 20 years in my laboratory trying to molecularly understand how MLL translocations cause this rare and devastating form of leukemia in children so that we can use this information to develop an effective therapy for this cancer,” said lead investigator Ali Shilatifard, PhD, of Northwestern University Feinberg School of Medicine in Chicago, Illinois.

“Now, we’ve made a fundamentally important breakthrough.”

The investigators found that wild-type MLL protein is less stable than the MLL chimeras in MLL leukemia cells. They therefore theorized that stabilizing the wild-type copy of the protein would displace the mutated version that drives MLL-rearranged leukemia.

The team set out to identify factors regulating MLL protein degradation and found the ubiquitin-conjugating enzyme E2O (UBE2O).

The investigators said UBE2O regulates the stability of wild-type MLL in response to interleukin-1 signaling. And inhibiting interleukin-1 receptor-associated kinases (IRAKs) increases the stability and chromatin occupancy of wild-type MLL.

The team also found that IRAK inhibition displaces the MLL chimera and subunits of the super elongation complex at a subset of target genes (LGALS1, LMO2, and GNA15).

To determine the implications of these findings for treatment, the investigators tested an IRAK4 inhibitor in patient-derived cell lines, including MLL leukemia and non-MLL leukemia/lymphoma cells. The inhibitor preferentially impeded the growth of MLL-rearranged leukemia cells.

The team also tested IRAK inhibitors in a murine MLL-AF9 leukemia transplantation model. They injected the animals with IRAK inhibitors on day 19 after transplant, which is just before the mice succumb to leukemia.

The mice received injections with an IRAK1/4 inhibitor (8 mg/kg), an IRAK4 inhibitor (75 mg/kg), or vehicle control every other day for 10 days.

The investigators said both IRAK inhibitors significantly extended survival beyond the 27-day mark, when all of the vehicle-treated mice had succumbed to the disease. Two mice treated with an IRAK inhibitor (1 mouse for each drug) were still alive at day 55.

The team also treated mice with the IRAK inhibitors or vehicle control at 10 days after transplant.

Eight of the 10 mice that received the IRAK1/4 inhibitor had not developed MLL-AF9 leukemia as of day 55. And the same was true for 4 of the 9 mice that received the IRAK4 inhibitor.

However, all of the vehicle-treated mice had succumbed to the disease by the 31-day mark.

The investigators said they are now synthesizing better compounds and hope to eventually launch a phase 1 trial to test these compounds in Chicago.

Lab mouse

Investigators may have discovered a new way to treat mixed-lineage leukemia (MLL)-rearranged leukemia, according to research published in Cell.

The team found they could disrupt the balance between wild-type MLL proteins and MLL chimeras.
 
This impeded MLL leukemia cell proliferation in vitro, delayed disease progression in a mouse model of MLL-AF9 leukemia, and prolonged survival in the mice.

The investigators are now attempting to translate these findings to the clinic.

“We’ve spent the last 20 years in my laboratory trying to molecularly understand how MLL translocations cause this rare and devastating form of leukemia in children so that we can use this information to develop an effective therapy for this cancer,” said lead investigator Ali Shilatifard, PhD, of Northwestern University Feinberg School of Medicine in Chicago, Illinois.

“Now, we’ve made a fundamentally important breakthrough.”

The investigators found that wild-type MLL protein is less stable than the MLL chimeras in MLL leukemia cells. They therefore theorized that stabilizing the wild-type copy of the protein would displace the mutated version that drives MLL-rearranged leukemia.

The team set out to identify factors regulating MLL protein degradation and found the ubiquitin-conjugating enzyme E2O (UBE2O).

The investigators said UBE2O regulates the stability of wild-type MLL in response to interleukin-1 signaling. And inhibiting interleukin-1 receptor-associated kinases (IRAKs) increases the stability and chromatin occupancy of wild-type MLL.

The team also found that IRAK inhibition displaces the MLL chimera and subunits of the super elongation complex at a subset of target genes (LGALS1, LMO2, and GNA15).

To determine the implications of these findings for treatment, the investigators tested an IRAK4 inhibitor in patient-derived cell lines, including MLL leukemia and non-MLL leukemia/lymphoma cells. The inhibitor preferentially impeded the growth of MLL-rearranged leukemia cells.

The team also tested IRAK inhibitors in a murine MLL-AF9 leukemia transplantation model. They injected the animals with IRAK inhibitors on day 19 after transplant, which is just before the mice succumb to leukemia.

The mice received injections with an IRAK1/4 inhibitor (8 mg/kg), an IRAK4 inhibitor (75 mg/kg), or vehicle control every other day for 10 days.

The investigators said both IRAK inhibitors significantly extended survival beyond the 27-day mark, when all of the vehicle-treated mice had succumbed to the disease. Two mice treated with an IRAK inhibitor (1 mouse for each drug) were still alive at day 55.

The team also treated mice with the IRAK inhibitors or vehicle control at 10 days after transplant.

Eight of the 10 mice that received the IRAK1/4 inhibitor had not developed MLL-AF9 leukemia as of day 55. And the same was true for 4 of the 9 mice that received the IRAK4 inhibitor.

However, all of the vehicle-treated mice had succumbed to the disease by the 31-day mark.

The investigators said they are now synthesizing better compounds and hope to eventually launch a phase 1 trial to test these compounds in Chicago.

Micrograph showing CLL

The US Food and Drug Administration (FDA) has granted orphan drug designation for the combination of TG-1101 (ublituximab) and TGR-1202 for the treatment of patients with chronic lymphocytic leukemia (CLL).

Ublituximab is a glycoengineered anti-CD20 monoclonal antibody, and TGR-1202 is a next-generation PI3K delta inhibitor. Both drugs are being developed by TG Therapeutics, Inc.

Researchers have evaluated ublituximab and TGR-1202 in combination in a phase 1 trial of patients with relapsed or refractory CLL/small lymphocytic lymphoma (SLL) and non-Hodgkin lymphomas (NHLs).

Results were presented at the 2015 ASH Annual Meeting.

There was a 3+3 dose-escalation portion of the study and a dose-expansion phase. The patients received  TGR-1202 at doses ranging from 400 mg to 1200 mg and 2 different doses of ublituximab—900 mg for patients with NHL and 600 mg or 900 mg for patients with CLL/SLL.

As of ASH, there were 58 patients evaluable for efficacy and 71 evaluable for safety.

There were 10 CLL/SLL patients exposed to higher doses of TGR-1202. Among these patients, the overall response rate was 80%. Seven patients achieved a partial response, 1 achieved a complete response, and the remaining 2 patients had stable disease.

For the entire safety population, the most common adverse events were nausea (46%), diarrhea (44%), fatigue (41%), neutropenia (30%), and infusion-related reactions (25%).

Grade 3/4 adverse events included neutropenia (25%), diarrhea (3%), fatigue (3%), dyspnea (3%), pyrexia (3%), nausea (1%), infusion-related reactions (1%), sinusitis (1%), anemia (1%), hypophosphatemia (1%), and peripheral edema (1%). 

Now, the combination of ublituximab and TGR-1202 is being evaluated in the UNITY-CLL phase 3 trial for patients with previously treated or untreated CLL.

“[W]ith enrollment into our UNITY-CLL phase 3 trial currently exceeding our expectations, we expect to be able to commence a regulatory filing for the combination in 2018, and having orphan drug designation will provide certain cost-saving advantages for us during the regulatory approval process,” said Michael S. Weiss, executive chairman and chief executive officer of TG Therapeutics. 

The FDA grants orphan designation to drugs and biologics 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 CLL

The US Food and Drug Administration (FDA) has granted orphan drug designation for the combination of TG-1101 (ublituximab) and TGR-1202 for the treatment of patients with chronic lymphocytic leukemia (CLL).

Ublituximab is a glycoengineered anti-CD20 monoclonal antibody, and TGR-1202 is a next-generation PI3K delta inhibitor. Both drugs are being developed by TG Therapeutics, Inc.

Researchers have evaluated ublituximab and TGR-1202 in combination in a phase 1 trial of patients with relapsed or refractory CLL/small lymphocytic lymphoma (SLL) and non-Hodgkin lymphomas (NHLs).

Results were presented at the 2015 ASH Annual Meeting.

There was a 3+3 dose-escalation portion of the study and a dose-expansion phase. The patients received  TGR-1202 at doses ranging from 400 mg to 1200 mg and 2 different doses of ublituximab—900 mg for patients with NHL and 600 mg or 900 mg for patients with CLL/SLL.

As of ASH, there were 58 patients evaluable for efficacy and 71 evaluable for safety.

There were 10 CLL/SLL patients exposed to higher doses of TGR-1202. Among these patients, the overall response rate was 80%. Seven patients achieved a partial response, 1 achieved a complete response, and the remaining 2 patients had stable disease.

For the entire safety population, the most common adverse events were nausea (46%), diarrhea (44%), fatigue (41%), neutropenia (30%), and infusion-related reactions (25%).

Grade 3/4 adverse events included neutropenia (25%), diarrhea (3%), fatigue (3%), dyspnea (3%), pyrexia (3%), nausea (1%), infusion-related reactions (1%), sinusitis (1%), anemia (1%), hypophosphatemia (1%), and peripheral edema (1%). 

Now, the combination of ublituximab and TGR-1202 is being evaluated in the UNITY-CLL phase 3 trial for patients with previously treated or untreated CLL.

“[W]ith enrollment into our UNITY-CLL phase 3 trial currently exceeding our expectations, we expect to be able to commence a regulatory filing for the combination in 2018, and having orphan drug designation will provide certain cost-saving advantages for us during the regulatory approval process,” said Michael S. Weiss, executive chairman and chief executive officer of TG Therapeutics. 

The FDA grants orphan designation to drugs and biologics 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 CLL

The US Food and Drug Administration (FDA) has granted orphan drug designation for the combination of TG-1101 (ublituximab) and TGR-1202 for the treatment of patients with chronic lymphocytic leukemia (CLL).

Ublituximab is a glycoengineered anti-CD20 monoclonal antibody, and TGR-1202 is a next-generation PI3K delta inhibitor. Both drugs are being developed by TG Therapeutics, Inc.

Researchers have evaluated ublituximab and TGR-1202 in combination in a phase 1 trial of patients with relapsed or refractory CLL/small lymphocytic lymphoma (SLL) and non-Hodgkin lymphomas (NHLs).

Results were presented at the 2015 ASH Annual Meeting.

There was a 3+3 dose-escalation portion of the study and a dose-expansion phase. The patients received  TGR-1202 at doses ranging from 400 mg to 1200 mg and 2 different doses of ublituximab—900 mg for patients with NHL and 600 mg or 900 mg for patients with CLL/SLL.

As of ASH, there were 58 patients evaluable for efficacy and 71 evaluable for safety.

There were 10 CLL/SLL patients exposed to higher doses of TGR-1202. Among these patients, the overall response rate was 80%. Seven patients achieved a partial response, 1 achieved a complete response, and the remaining 2 patients had stable disease.

For the entire safety population, the most common adverse events were nausea (46%), diarrhea (44%), fatigue (41%), neutropenia (30%), and infusion-related reactions (25%).

Grade 3/4 adverse events included neutropenia (25%), diarrhea (3%), fatigue (3%), dyspnea (3%), pyrexia (3%), nausea (1%), infusion-related reactions (1%), sinusitis (1%), anemia (1%), hypophosphatemia (1%), and peripheral edema (1%). 

Now, the combination of ublituximab and TGR-1202 is being evaluated in the UNITY-CLL phase 3 trial for patients with previously treated or untreated CLL.

“[W]ith enrollment into our UNITY-CLL phase 3 trial currently exceeding our expectations, we expect to be able to commence a regulatory filing for the combination in 2018, and having orphan drug designation will provide certain cost-saving advantages for us during the regulatory approval process,” said Michael S. Weiss, executive chairman and chief executive officer of TG Therapeutics. 

The FDA grants orphan designation to drugs and biologics 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.

Child with cancer
Photo by Bill Branson

A yoga program for children with cancer can be carried out during cancer treatment and has quality of life (QOL) benefits for the children as well as their caregivers, according to research published in Rehabilitation Oncology.

However, the program was not feasible for all patients. More than half of those initially enrolled could not complete the study due to treatment toxicity or scheduling conflicts.

Andrea Orsey, MD, of Connecticut Children’s Medical Center in Hartford, and her colleagues conducted this research to evaluate the feasibility and effectiveness of a yoga intervention for children with cancer and their families.

The team began by conducting a survey of 20 children and adolescents with cancer and their parents/guardians.

Survey respondents expressed interest in a yoga program. But they also perceived several barriers to such a program, including concerns about side effects, pain/discomfort, and physical limitations.

With these barriers in mind, Dr Orsey and her colleagues developed a yoga intervention for pediatric cancer patients, delivered by certified yoga instructors.

The program was designed to be performed in a variety of settings and tailored to the children’s physical condition or mobility issues.

A pilot evaluation included 10 children with cancer and their caregivers. Twenty-two patient/caregiver pairs were actually enrolled, but 6 pairs withdrew because of treatment toxicity, and 6 had the study window lapse due to scheduling conflicts.

Although limited by its small size, the study suggested that yoga improved health-related QOL for both caregivers and children.

The children had significant improvements in both social and emotional QOL. They had an overall improvement in fatigue, but this was not statistically significant.

Caregivers had a significant improvement in mental health but not physical health or caregiver burden.

Both caregivers and children said they were satisfied with the yoga program and would recommend it to others.

Dr Orsey and her colleagues hope this pilot study will help guide future efforts to provide yoga to children with cancer and their families.

The researchers noted that a key issue will be coordinating yoga sessions with the medical demands of chemotherapy.

Child with cancer
Photo by Bill Branson

A yoga program for children with cancer can be carried out during cancer treatment and has quality of life (QOL) benefits for the children as well as their caregivers, according to research published in Rehabilitation Oncology.

However, the program was not feasible for all patients. More than half of those initially enrolled could not complete the study due to treatment toxicity or scheduling conflicts.

Andrea Orsey, MD, of Connecticut Children’s Medical Center in Hartford, and her colleagues conducted this research to evaluate the feasibility and effectiveness of a yoga intervention for children with cancer and their families.

The team began by conducting a survey of 20 children and adolescents with cancer and their parents/guardians.

Survey respondents expressed interest in a yoga program. But they also perceived several barriers to such a program, including concerns about side effects, pain/discomfort, and physical limitations.

With these barriers in mind, Dr Orsey and her colleagues developed a yoga intervention for pediatric cancer patients, delivered by certified yoga instructors.

The program was designed to be performed in a variety of settings and tailored to the children’s physical condition or mobility issues.

A pilot evaluation included 10 children with cancer and their caregivers. Twenty-two patient/caregiver pairs were actually enrolled, but 6 pairs withdrew because of treatment toxicity, and 6 had the study window lapse due to scheduling conflicts.

Although limited by its small size, the study suggested that yoga improved health-related QOL for both caregivers and children.

The children had significant improvements in both social and emotional QOL. They had an overall improvement in fatigue, but this was not statistically significant.

Caregivers had a significant improvement in mental health but not physical health or caregiver burden.

Both caregivers and children said they were satisfied with the yoga program and would recommend it to others.

Dr Orsey and her colleagues hope this pilot study will help guide future efforts to provide yoga to children with cancer and their families.

The researchers noted that a key issue will be coordinating yoga sessions with the medical demands of chemotherapy.

Child with cancer
Photo by Bill Branson

A yoga program for children with cancer can be carried out during cancer treatment and has quality of life (QOL) benefits for the children as well as their caregivers, according to research published in Rehabilitation Oncology.

However, the program was not feasible for all patients. More than half of those initially enrolled could not complete the study due to treatment toxicity or scheduling conflicts.

Andrea Orsey, MD, of Connecticut Children’s Medical Center in Hartford, and her colleagues conducted this research to evaluate the feasibility and effectiveness of a yoga intervention for children with cancer and their families.

The team began by conducting a survey of 20 children and adolescents with cancer and their parents/guardians.

Survey respondents expressed interest in a yoga program. But they also perceived several barriers to such a program, including concerns about side effects, pain/discomfort, and physical limitations.

With these barriers in mind, Dr Orsey and her colleagues developed a yoga intervention for pediatric cancer patients, delivered by certified yoga instructors.

The program was designed to be performed in a variety of settings and tailored to the children’s physical condition or mobility issues.

A pilot evaluation included 10 children with cancer and their caregivers. Twenty-two patient/caregiver pairs were actually enrolled, but 6 pairs withdrew because of treatment toxicity, and 6 had the study window lapse due to scheduling conflicts.

Although limited by its small size, the study suggested that yoga improved health-related QOL for both caregivers and children.

The children had significant improvements in both social and emotional QOL. They had an overall improvement in fatigue, but this was not statistically significant.

Caregivers had a significant improvement in mental health but not physical health or caregiver burden.

Both caregivers and children said they were satisfied with the yoga program and would recommend it to others.

Dr Orsey and her colleagues hope this pilot study will help guide future efforts to provide yoga to children with cancer and their families.

The researchers noted that a key issue will be coordinating yoga sessions with the medical demands of chemotherapy.

Doctor consults with cancer
patient and her father
Photo by Rhoda Baer

The US may see nearly 1.7 million new cancer cases in 2017 and more than 600,000 cancer-related deaths, according to a report from the American Cancer Society (ACS).

In addition to estimates for 2017, the report, “Cancer Statistics 2017,” includes the most recent data on cancer incidence, mortality, and survival in the US.

The report was published in CA: A Cancer Journal for Clinicians.

The report projects there will be 1,688,780 new cancer cases and 600,920 cancer deaths in the US this year.

This includes:

• 80,500 new cases of lymphoma and 21,210 lymphoma deaths
• 62,130 new cases of leukemia and 24,500 leukemia deaths
• 30,280 new cases of myeloma and 12,590 myeloma deaths.

The report also shows that, from 2004 to 2013, the overall cancer incidence rate was stable in women and declined by about 2% per year in men. From 2005 to 2014, the cancer death rate declined by about 1.5% annually in both men and women.

Overall, the cancer death rate dropped 25% from its peak of 215.1 (per 100,000 population) in 1991 to 161.2 (per 100,000 population) in 2014, the latest year for which data was available. This translates to about 2,143,200 fewer cancer deaths.

“The continuing drops in the cancer death rate are a powerful sign of the potential we have to reduce cancer’s deadly toll,” said Otis W. Brawley, MD, chief medical officer of the ACS.

He said the decrease in cancer death rates is the result of steady reductions in smoking and advances in early detection and treatment. The decrease is driven by decreasing death rates for the 4 major cancer sites—lung, breast, colorectal, and prostate.

The report also shows that racial disparities in cancer death rates continue to decline. The excess risk of cancer death in black men has dropped from 47% in 1990 to 21% in 2014. The black/white disparity declined similarly in women, from a peak of 20% in 1998 to 13% in 2014.

On the other hand, significant gender disparities persist for both cancer incidence and death in the US. For all cancer sites combined, the incidence rate is 20% higher in men than in women, and the cancer death rate is 40% higher in men.

Dr Brawley said the gender gap in cancer mortality largely reflects variation in the distribution of cancers that occur in men and women, much of which is due to differences in the prevalence of cancer risk factors.

The yearly “Cancer Statistics” reports have been published by ACS researchers since 1967 to inform and guide clinicians, investigators, and others in public health in prioritizing efforts to reduce the burden of cancer.

Cancer incidence data for the current report were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data were collected by the National Center for Health Statistics.

Doctor consults with cancer
patient and her father
Photo by Rhoda Baer

The US may see nearly 1.7 million new cancer cases in 2017 and more than 600,000 cancer-related deaths, according to a report from the American Cancer Society (ACS).

In addition to estimates for 2017, the report, “Cancer Statistics 2017,” includes the most recent data on cancer incidence, mortality, and survival in the US.

The report was published in CA: A Cancer Journal for Clinicians.

The report projects there will be 1,688,780 new cancer cases and 600,920 cancer deaths in the US this year.

This includes:

• 80,500 new cases of lymphoma and 21,210 lymphoma deaths
• 62,130 new cases of leukemia and 24,500 leukemia deaths
• 30,280 new cases of myeloma and 12,590 myeloma deaths.

The report also shows that, from 2004 to 2013, the overall cancer incidence rate was stable in women and declined by about 2% per year in men. From 2005 to 2014, the cancer death rate declined by about 1.5% annually in both men and women.

Overall, the cancer death rate dropped 25% from its peak of 215.1 (per 100,000 population) in 1991 to 161.2 (per 100,000 population) in 2014, the latest year for which data was available. This translates to about 2,143,200 fewer cancer deaths.

“The continuing drops in the cancer death rate are a powerful sign of the potential we have to reduce cancer’s deadly toll,” said Otis W. Brawley, MD, chief medical officer of the ACS.

He said the decrease in cancer death rates is the result of steady reductions in smoking and advances in early detection and treatment. The decrease is driven by decreasing death rates for the 4 major cancer sites—lung, breast, colorectal, and prostate.

The report also shows that racial disparities in cancer death rates continue to decline. The excess risk of cancer death in black men has dropped from 47% in 1990 to 21% in 2014. The black/white disparity declined similarly in women, from a peak of 20% in 1998 to 13% in 2014.

On the other hand, significant gender disparities persist for both cancer incidence and death in the US. For all cancer sites combined, the incidence rate is 20% higher in men than in women, and the cancer death rate is 40% higher in men.

Dr Brawley said the gender gap in cancer mortality largely reflects variation in the distribution of cancers that occur in men and women, much of which is due to differences in the prevalence of cancer risk factors.

The yearly “Cancer Statistics” reports have been published by ACS researchers since 1967 to inform and guide clinicians, investigators, and others in public health in prioritizing efforts to reduce the burden of cancer.

Cancer incidence data for the current report were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data were collected by the National Center for Health Statistics.

Doctor consults with cancer
patient and her father
Photo by Rhoda Baer

The US may see nearly 1.7 million new cancer cases in 2017 and more than 600,000 cancer-related deaths, according to a report from the American Cancer Society (ACS).

In addition to estimates for 2017, the report, “Cancer Statistics 2017,” includes the most recent data on cancer incidence, mortality, and survival in the US.

The report was published in CA: A Cancer Journal for Clinicians.

The report projects there will be 1,688,780 new cancer cases and 600,920 cancer deaths in the US this year.

This includes:

• 80,500 new cases of lymphoma and 21,210 lymphoma deaths
• 62,130 new cases of leukemia and 24,500 leukemia deaths
• 30,280 new cases of myeloma and 12,590 myeloma deaths.

The report also shows that, from 2004 to 2013, the overall cancer incidence rate was stable in women and declined by about 2% per year in men. From 2005 to 2014, the cancer death rate declined by about 1.5% annually in both men and women.

Overall, the cancer death rate dropped 25% from its peak of 215.1 (per 100,000 population) in 1991 to 161.2 (per 100,000 population) in 2014, the latest year for which data was available. This translates to about 2,143,200 fewer cancer deaths.

“The continuing drops in the cancer death rate are a powerful sign of the potential we have to reduce cancer’s deadly toll,” said Otis W. Brawley, MD, chief medical officer of the ACS.

He said the decrease in cancer death rates is the result of steady reductions in smoking and advances in early detection and treatment. The decrease is driven by decreasing death rates for the 4 major cancer sites—lung, breast, colorectal, and prostate.

The report also shows that racial disparities in cancer death rates continue to decline. The excess risk of cancer death in black men has dropped from 47% in 1990 to 21% in 2014. The black/white disparity declined similarly in women, from a peak of 20% in 1998 to 13% in 2014.

On the other hand, significant gender disparities persist for both cancer incidence and death in the US. For all cancer sites combined, the incidence rate is 20% higher in men than in women, and the cancer death rate is 40% higher in men.

Dr Brawley said the gender gap in cancer mortality largely reflects variation in the distribution of cancers that occur in men and women, much of which is due to differences in the prevalence of cancer risk factors.

The yearly “Cancer Statistics” reports have been published by ACS researchers since 1967 to inform and guide clinicians, investigators, and others in public health in prioritizing efforts to reduce the burden of cancer.

Cancer incidence data for the current report were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data were collected by the National Center for Health Statistics.

Genome testing
Photo courtesy of the
National Institute of
General Medical Sciences

The American Association for Cancer Research (AACR) has announced the first public release of cancer genomic data aggregated through the AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE).

The data set includes nearly 19,000 de-identified genomic records collected from patients who were treated at 8 international institutions, making it one of the largest public cancer genomic data sets released to date.

The release includes data for 59 major cancer types, including leukemias, lymphomas, and multiple myeloma.

The genomic data and a limited amount of linked clinical data for each patient can be accessed via the AACR Project GENIE cBioPortal or from Sage Bionetworks. (Users must create an account for either site to access the data.)

“We are excited to make publicly available this very large set of clinical-grade, next-generation sequencing data obtained during routine patient care,” said Charles L. Sawyers, MD, AACR Project GENIE Steering Committee chairperson.

“These data were generated as part of routine patient care and, without AACR Project GENIE, they would likely never have been shared with the global cancer research community.”

AACR Project GENIE is a multi-phase, international data-sharing project aimed at catalyzing precision oncology through the development of a registry that aggregates and links clinical-grade cancer genomic data with clinical outcomes from tens of thousands of cancer patients treated at multiple institutions.

The newly released data are fully de-identified in compliance with the Health Insurance Portability and Accountability Act (HIPAA).

The data are derived from patients whose tumors were genetically sequenced as part of their care at any of the 8 institutions that participated in the first phase of AACR Project GENIE.

The goal of releasing these data to the cancer research community is to aid new research that will accelerate the pace of progress against cancer.

According to AACR, the data can be used to validate gene signatures of drug response or prognosis, identify new patient populations for drugs that are currently available, and uncover new drug targets and biomarkers.

“I am extremely proud that the American Association for Cancer Research, as the coordinating center for AACR Project GENIE, is delivering on its promise to make these important data publicly available just over a year after unveiling the initiative,” said Margaret Foti, PhD, MD, chief executive officer of the AACR.

To expand the AACR Project GENIE registry, the consortium is accepting applications for new participating centers. Any nonprofit institution that meets certain criteria can submit an application to become a project participant.

For more information on AACR Project GENIE, visit the project website or send an email to [email protected].

Genome testing
Photo courtesy of the
National Institute of
General Medical Sciences

The American Association for Cancer Research (AACR) has announced the first public release of cancer genomic data aggregated through the AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE).

The data set includes nearly 19,000 de-identified genomic records collected from patients who were treated at 8 international institutions, making it one of the largest public cancer genomic data sets released to date.

The release includes data for 59 major cancer types, including leukemias, lymphomas, and multiple myeloma.

The genomic data and a limited amount of linked clinical data for each patient can be accessed via the AACR Project GENIE cBioPortal or from Sage Bionetworks. (Users must create an account for either site to access the data.)

“We are excited to make publicly available this very large set of clinical-grade, next-generation sequencing data obtained during routine patient care,” said Charles L. Sawyers, MD, AACR Project GENIE Steering Committee chairperson.

“These data were generated as part of routine patient care and, without AACR Project GENIE, they would likely never have been shared with the global cancer research community.”

AACR Project GENIE is a multi-phase, international data-sharing project aimed at catalyzing precision oncology through the development of a registry that aggregates and links clinical-grade cancer genomic data with clinical outcomes from tens of thousands of cancer patients treated at multiple institutions.

The newly released data are fully de-identified in compliance with the Health Insurance Portability and Accountability Act (HIPAA).

The data are derived from patients whose tumors were genetically sequenced as part of their care at any of the 8 institutions that participated in the first phase of AACR Project GENIE.

The goal of releasing these data to the cancer research community is to aid new research that will accelerate the pace of progress against cancer.

According to AACR, the data can be used to validate gene signatures of drug response or prognosis, identify new patient populations for drugs that are currently available, and uncover new drug targets and biomarkers.

“I am extremely proud that the American Association for Cancer Research, as the coordinating center for AACR Project GENIE, is delivering on its promise to make these important data publicly available just over a year after unveiling the initiative,” said Margaret Foti, PhD, MD, chief executive officer of the AACR.

To expand the AACR Project GENIE registry, the consortium is accepting applications for new participating centers. Any nonprofit institution that meets certain criteria can submit an application to become a project participant.

For more information on AACR Project GENIE, visit the project website or send an email to [email protected].

Genome testing
Photo courtesy of the
National Institute of
General Medical Sciences

The American Association for Cancer Research (AACR) has announced the first public release of cancer genomic data aggregated through the AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE).

The data set includes nearly 19,000 de-identified genomic records collected from patients who were treated at 8 international institutions, making it one of the largest public cancer genomic data sets released to date.

The release includes data for 59 major cancer types, including leukemias, lymphomas, and multiple myeloma.

The genomic data and a limited amount of linked clinical data for each patient can be accessed via the AACR Project GENIE cBioPortal or from Sage Bionetworks. (Users must create an account for either site to access the data.)

“We are excited to make publicly available this very large set of clinical-grade, next-generation sequencing data obtained during routine patient care,” said Charles L. Sawyers, MD, AACR Project GENIE Steering Committee chairperson.

“These data were generated as part of routine patient care and, without AACR Project GENIE, they would likely never have been shared with the global cancer research community.”

AACR Project GENIE is a multi-phase, international data-sharing project aimed at catalyzing precision oncology through the development of a registry that aggregates and links clinical-grade cancer genomic data with clinical outcomes from tens of thousands of cancer patients treated at multiple institutions.

The newly released data are fully de-identified in compliance with the Health Insurance Portability and Accountability Act (HIPAA).

The data are derived from patients whose tumors were genetically sequenced as part of their care at any of the 8 institutions that participated in the first phase of AACR Project GENIE.

The goal of releasing these data to the cancer research community is to aid new research that will accelerate the pace of progress against cancer.

According to AACR, the data can be used to validate gene signatures of drug response or prognosis, identify new patient populations for drugs that are currently available, and uncover new drug targets and biomarkers.

“I am extremely proud that the American Association for Cancer Research, as the coordinating center for AACR Project GENIE, is delivering on its promise to make these important data publicly available just over a year after unveiling the initiative,” said Margaret Foti, PhD, MD, chief executive officer of the AACR.

To expand the AACR Project GENIE registry, the consortium is accepting applications for new participating centers. Any nonprofit institution that meets certain criteria can submit an application to become a project participant.

For more information on AACR Project GENIE, visit the project website or send an email to [email protected].

SAN DIEGO – Dual therapy with lenalidomide and epoetin alfa was safe and led to freedom from transfusion significantly more often than lenalidomide alone in patients with erythropoietin-refractory, lower-risk, non-del(5q) myelodysplastic syndromes, according to a randomized phase III head-to-head trial.

After 16 weeks of treatment, 33% of patients who received both lenalidomide and epoetin alfa met International Working Group 2000 criteria for major erythroid response, compared with only 14% of patients receiving lenalidomide monotherapy (P = .03), Alan F. List, MD, reported at the annual meeting of the American Society of Hematology.

H. Lee Moffitt Cancer Center

SAN DIEGO – Dual therapy with lenalidomide and epoetin alfa was safe and led to freedom from transfusion significantly more often than lenalidomide alone in patients with erythropoietin-refractory, lower-risk, non-del(5q) myelodysplastic syndromes, according to a randomized phase III head-to-head trial.

After 16 weeks of treatment, 33% of patients who received both lenalidomide and epoetin alfa met International Working Group 2000 criteria for major erythroid response, compared with only 14% of patients receiving lenalidomide monotherapy (P = .03), Alan F. List, MD, reported at the annual meeting of the American Society of Hematology.

H. Lee Moffitt Cancer Center

SAN DIEGO – Dual therapy with lenalidomide and epoetin alfa was safe and led to freedom from transfusion significantly more often than lenalidomide alone in patients with erythropoietin-refractory, lower-risk, non-del(5q) myelodysplastic syndromes, according to a randomized phase III head-to-head trial.

After 16 weeks of treatment, 33% of patients who received both lenalidomide and epoetin alfa met International Working Group 2000 criteria for major erythroid response, compared with only 14% of patients receiving lenalidomide monotherapy (P = .03), Alan F. List, MD, reported at the annual meeting of the American Society of Hematology.

H. Lee Moffitt Cancer Center

Jianjun Chen, PhD
Photo courtesy of
University of Cincinnati

Preclinical research indicates that a protein associated with obesity is also involved in the development of acute myeloid leukemia (AML) and may affect AML patients’ response to treatment.

Researchers found evidence to suggest that the fat mass- and obesity-associated protein (FTO) regulates the expression of a set of genes through a mechanism involving RNA modification, thereby increasing the reproduction of leukemia cells and prohibiting drug response. 

Jianjun Chen, PhD, of the University of Cincinnati in Ohio, and his colleagues conducted this research and reported the findings in Cancer Cell.

The team noted that N6-methyladenosine (m6A) RNA methylation is the most prevalent internal modification in messenger RNAs (mRNAs) in genes. And they found that FTO, an m6A demethylase, plays a critical oncogenic role in AML.

The researchers made this discovery by analyzing 2 microarray datasets of samples from AML as well as samples from control subjects.

The team found that FTO was highly expressed in AMLs with t(11q23)/MLL rearrangements, t(15;17)/PML-RARA, FLT3-ITD, and/or NPM1 mutations.

The high level of FTO expression contributed to leukemia cells multiplying and surviving and also promoted the development of AML in animal models and the non-response of AML cells to therapeutic agents.

Additionally, the researchers found that genes like ASB2 and RARA, which were reported to inhibit leukemia cell growth and/or mediate the response of leukemia cells to therapeutic agents, were suppressed in the AML samples with higher FTO expression.

The suppression of these genes was attributed to FTO-controlled decreased stability of their mRNA and was connected to FTO’s m6A demethylase activity.

“Our study shows, for the first time, the functional importance of the m6A modification machinery in leukemia,” Dr Chen said. “In addition, given the functional importance of FTO in the formation of leukemia and drug response, targeting FTO signaling may present a new therapeutic strategy to treat leukemia.”

“As FTO may also play a cancer-promoting role in various types of solid tumors, besides leukemia, our discoveries may have a broad impact in cancer biology and cancer therapy. Further studies are needed to advance our understanding of the critical role of FTO in various types of cancers and to develop more effective novel therapeutic strategies based on such understanding to treat cancers.”

Jianjun Chen, PhD
Photo courtesy of
University of Cincinnati

Preclinical research indicates that a protein associated with obesity is also involved in the development of acute myeloid leukemia (AML) and may affect AML patients’ response to treatment.

Researchers found evidence to suggest that the fat mass- and obesity-associated protein (FTO) regulates the expression of a set of genes through a mechanism involving RNA modification, thereby increasing the reproduction of leukemia cells and prohibiting drug response. 

Jianjun Chen, PhD, of the University of Cincinnati in Ohio, and his colleagues conducted this research and reported the findings in Cancer Cell.

The team noted that N6-methyladenosine (m6A) RNA methylation is the most prevalent internal modification in messenger RNAs (mRNAs) in genes. And they found that FTO, an m6A demethylase, plays a critical oncogenic role in AML.

The researchers made this discovery by analyzing 2 microarray datasets of samples from AML as well as samples from control subjects.

The team found that FTO was highly expressed in AMLs with t(11q23)/MLL rearrangements, t(15;17)/PML-RARA, FLT3-ITD, and/or NPM1 mutations.

The high level of FTO expression contributed to leukemia cells multiplying and surviving and also promoted the development of AML in animal models and the non-response of AML cells to therapeutic agents.

Additionally, the researchers found that genes like ASB2 and RARA, which were reported to inhibit leukemia cell growth and/or mediate the response of leukemia cells to therapeutic agents, were suppressed in the AML samples with higher FTO expression.

The suppression of these genes was attributed to FTO-controlled decreased stability of their mRNA and was connected to FTO’s m6A demethylase activity.

“Our study shows, for the first time, the functional importance of the m6A modification machinery in leukemia,” Dr Chen said. “In addition, given the functional importance of FTO in the formation of leukemia and drug response, targeting FTO signaling may present a new therapeutic strategy to treat leukemia.”

“As FTO may also play a cancer-promoting role in various types of solid tumors, besides leukemia, our discoveries may have a broad impact in cancer biology and cancer therapy. Further studies are needed to advance our understanding of the critical role of FTO in various types of cancers and to develop more effective novel therapeutic strategies based on such understanding to treat cancers.”

Jianjun Chen, PhD
Photo courtesy of
University of Cincinnati

Preclinical research indicates that a protein associated with obesity is also involved in the development of acute myeloid leukemia (AML) and may affect AML patients’ response to treatment.

Researchers found evidence to suggest that the fat mass- and obesity-associated protein (FTO) regulates the expression of a set of genes through a mechanism involving RNA modification, thereby increasing the reproduction of leukemia cells and prohibiting drug response. 

Jianjun Chen, PhD, of the University of Cincinnati in Ohio, and his colleagues conducted this research and reported the findings in Cancer Cell.

The team noted that N6-methyladenosine (m6A) RNA methylation is the most prevalent internal modification in messenger RNAs (mRNAs) in genes. And they found that FTO, an m6A demethylase, plays a critical oncogenic role in AML.

The researchers made this discovery by analyzing 2 microarray datasets of samples from AML as well as samples from control subjects.

The team found that FTO was highly expressed in AMLs with t(11q23)/MLL rearrangements, t(15;17)/PML-RARA, FLT3-ITD, and/or NPM1 mutations.

The high level of FTO expression contributed to leukemia cells multiplying and surviving and also promoted the development of AML in animal models and the non-response of AML cells to therapeutic agents.

Additionally, the researchers found that genes like ASB2 and RARA, which were reported to inhibit leukemia cell growth and/or mediate the response of leukemia cells to therapeutic agents, were suppressed in the AML samples with higher FTO expression.

The suppression of these genes was attributed to FTO-controlled decreased stability of their mRNA and was connected to FTO’s m6A demethylase activity.

“Our study shows, for the first time, the functional importance of the m6A modification machinery in leukemia,” Dr Chen said. “In addition, given the functional importance of FTO in the formation of leukemia and drug response, targeting FTO signaling may present a new therapeutic strategy to treat leukemia.”

“As FTO may also play a cancer-promoting role in various types of solid tumors, besides leukemia, our discoveries may have a broad impact in cancer biology and cancer therapy. Further studies are needed to advance our understanding of the critical role of FTO in various types of cancers and to develop more effective novel therapeutic strategies based on such understanding to treat cancers.”

Cancer patient receiving
chemotherapy
Photo by Rhoda Baer

Results of a small study suggest a single dose of the hallucinogenic drug psilocybin, when combined with counseling, can significantly lessen psychological distress in cancer patients for months at a time.

The study showed that psychological counseling and a single dose of psilocybin brought relief from distress that lasted for more than 6 months in a majority of the subjects monitored.

This was based on clinical evaluation scores for anxiety and depression.

“Our results represent the strongest evidence to date of a clinical benefit from psilocybin therapy, with the potential to transform care for patients with cancer-related psychological distress,” said study author Stephen Ross, MD, of New York University School of Medicine in New York, New York.

“If larger clinical trials prove successful, then we could ultimately have available a safe, effective, and inexpensive medication—dispensed under strict control—to alleviate the distress that increases suicide rates among cancer patients.”

Dr Ross and his colleagues reported the results of their study in the Journal of Psychopharmacology alongside a related study and 11 accompanying editorials.

Dr Ross’s study included 29 patients with cancer-related anxiety and depression. Their mean age was 56, and 62% were female. Ninety percent were Caucasian, and 10% were classified as “other” race.

Patients had breast cancer (31%), reproductive cancers (28%), digestive cancers (17%), leukemia/lymphoma (14%), and other cancers (10%).

All patients had been diagnosed as suffering from serious psychological distress related to their disease.

Treatment

Half of the patients were randomly assigned to receive a 0.3 mg/kg dose of psilocybin, and half received a vitamin placebo (250 mg of niacin) known to produce a “rush” that mimics a hallucinogenic drug experience.

Approximately half way through the study’s monitoring period (after 7 weeks), all patients switched treatments. Those who initially received psilocybin took a single dose of niacin, and vice-versa. Neither patients nor researchers knew who had first received psilocybin or placebo.

All patients were provided with tailored counseling from a psychiatrist, psychologist, nurse, or social worker. And the patients were monitored for side effects and improvements in their mental state.

Safety

The researchers said there were no serious adverse events (AEs), either medical or psychiatric, that were attributed to psilocybin.

The most common medical AEs that were attributable to psilocybin were non-clinically significant elevations in blood pressure and heart rate (76%), headaches/migraines (28%), and nausea (14%).

The most common psychiatric AEs attributable to psilocybin were transient anxiety (17%) and transient psychotic-like symptoms (7%; 1 case of transient paranoid ideation and 1 case of transient thought disorder).
 
Efficacy

The researchers said that, prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression.

Specifically, patients who received psilocybin first had significant improvements in responses on the Hospital Anxiety and Depression Scale and the Beck Depression Inventory, when compared to patients who received niacin first.

The differences were significant 1 day after the patients’ first session and 7 weeks after the first session (P≤0.01 for all).

At the 6.5-month follow-up, 60% to 80% of participants continued with clinically significant reductions in depression or anxiety.

The researchers said a key finding of this study was that improvements in clinical evaluation scores for anxiety and depression lasted for the study’s extended monitoring period, which was 8 months for those who took psilocybin first.

Patients also reported post-psilocybin improvements in their quality of life, such as going out more, greater energy, getting along better with family members, and doing well at work. Some reported variations of spirituality, unusual peacefulness, and increased feelings of altruism.

“Our study showed that psilocybin facilitated experiences that drove reductions in psychological distress,” said study author Anthony Bossis, PhD, of New York University School of Medicine. “And if it’s true for cancer care, then it could apply to other stressful medical conditions.”

He cautioned that patients should not consume psilocybin on their own or without supervision from a physician and a trained counselor.

“Psilocybin therapy may not work for everyone,” he noted. “And some groups, such as people with schizophrenia, as well as adolescents, should not be treated with it.”

Cancer patient receiving
chemotherapy
Photo by Rhoda Baer

Results of a small study suggest a single dose of the hallucinogenic drug psilocybin, when combined with counseling, can significantly lessen psychological distress in cancer patients for months at a time.

The study showed that psychological counseling and a single dose of psilocybin brought relief from distress that lasted for more than 6 months in a majority of the subjects monitored.

This was based on clinical evaluation scores for anxiety and depression.

“Our results represent the strongest evidence to date of a clinical benefit from psilocybin therapy, with the potential to transform care for patients with cancer-related psychological distress,” said study author Stephen Ross, MD, of New York University School of Medicine in New York, New York.

“If larger clinical trials prove successful, then we could ultimately have available a safe, effective, and inexpensive medication—dispensed under strict control—to alleviate the distress that increases suicide rates among cancer patients.”

Dr Ross and his colleagues reported the results of their study in the Journal of Psychopharmacology alongside a related study and 11 accompanying editorials.

Dr Ross’s study included 29 patients with cancer-related anxiety and depression. Their mean age was 56, and 62% were female. Ninety percent were Caucasian, and 10% were classified as “other” race.

Patients had breast cancer (31%), reproductive cancers (28%), digestive cancers (17%), leukemia/lymphoma (14%), and other cancers (10%).

All patients had been diagnosed as suffering from serious psychological distress related to their disease.

Treatment

Half of the patients were randomly assigned to receive a 0.3 mg/kg dose of psilocybin, and half received a vitamin placebo (250 mg of niacin) known to produce a “rush” that mimics a hallucinogenic drug experience.

Approximately half way through the study’s monitoring period (after 7 weeks), all patients switched treatments. Those who initially received psilocybin took a single dose of niacin, and vice-versa. Neither patients nor researchers knew who had first received psilocybin or placebo.

All patients were provided with tailored counseling from a psychiatrist, psychologist, nurse, or social worker. And the patients were monitored for side effects and improvements in their mental state.

Safety

The researchers said there were no serious adverse events (AEs), either medical or psychiatric, that were attributed to psilocybin.

The most common medical AEs that were attributable to psilocybin were non-clinically significant elevations in blood pressure and heart rate (76%), headaches/migraines (28%), and nausea (14%).

The most common psychiatric AEs attributable to psilocybin were transient anxiety (17%) and transient psychotic-like symptoms (7%; 1 case of transient paranoid ideation and 1 case of transient thought disorder).
 
Efficacy

The researchers said that, prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression.

Specifically, patients who received psilocybin first had significant improvements in responses on the Hospital Anxiety and Depression Scale and the Beck Depression Inventory, when compared to patients who received niacin first.

The differences were significant 1 day after the patients’ first session and 7 weeks after the first session (P≤0.01 for all).

At the 6.5-month follow-up, 60% to 80% of participants continued with clinically significant reductions in depression or anxiety.

The researchers said a key finding of this study was that improvements in clinical evaluation scores for anxiety and depression lasted for the study’s extended monitoring period, which was 8 months for those who took psilocybin first.

Patients also reported post-psilocybin improvements in their quality of life, such as going out more, greater energy, getting along better with family members, and doing well at work. Some reported variations of spirituality, unusual peacefulness, and increased feelings of altruism.

“Our study showed that psilocybin facilitated experiences that drove reductions in psychological distress,” said study author Anthony Bossis, PhD, of New York University School of Medicine. “And if it’s true for cancer care, then it could apply to other stressful medical conditions.”

He cautioned that patients should not consume psilocybin on their own or without supervision from a physician and a trained counselor.

“Psilocybin therapy may not work for everyone,” he noted. “And some groups, such as people with schizophrenia, as well as adolescents, should not be treated with it.”

Cancer patient receiving
chemotherapy
Photo by Rhoda Baer

Results of a small study suggest a single dose of the hallucinogenic drug psilocybin, when combined with counseling, can significantly lessen psychological distress in cancer patients for months at a time.

The study showed that psychological counseling and a single dose of psilocybin brought relief from distress that lasted for more than 6 months in a majority of the subjects monitored.

This was based on clinical evaluation scores for anxiety and depression.

“Our results represent the strongest evidence to date of a clinical benefit from psilocybin therapy, with the potential to transform care for patients with cancer-related psychological distress,” said study author Stephen Ross, MD, of New York University School of Medicine in New York, New York.

“If larger clinical trials prove successful, then we could ultimately have available a safe, effective, and inexpensive medication—dispensed under strict control—to alleviate the distress that increases suicide rates among cancer patients.”

Dr Ross and his colleagues reported the results of their study in the Journal of Psychopharmacology alongside a related study and 11 accompanying editorials.

Dr Ross’s study included 29 patients with cancer-related anxiety and depression. Their mean age was 56, and 62% were female. Ninety percent were Caucasian, and 10% were classified as “other” race.

Patients had breast cancer (31%), reproductive cancers (28%), digestive cancers (17%), leukemia/lymphoma (14%), and other cancers (10%).

All patients had been diagnosed as suffering from serious psychological distress related to their disease.

Treatment

Half of the patients were randomly assigned to receive a 0.3 mg/kg dose of psilocybin, and half received a vitamin placebo (250 mg of niacin) known to produce a “rush” that mimics a hallucinogenic drug experience.

Approximately half way through the study’s monitoring period (after 7 weeks), all patients switched treatments. Those who initially received psilocybin took a single dose of niacin, and vice-versa. Neither patients nor researchers knew who had first received psilocybin or placebo.

All patients were provided with tailored counseling from a psychiatrist, psychologist, nurse, or social worker. And the patients were monitored for side effects and improvements in their mental state.

Safety

The researchers said there were no serious adverse events (AEs), either medical or psychiatric, that were attributed to psilocybin.

The most common medical AEs that were attributable to psilocybin were non-clinically significant elevations in blood pressure and heart rate (76%), headaches/migraines (28%), and nausea (14%).

The most common psychiatric AEs attributable to psilocybin were transient anxiety (17%) and transient psychotic-like symptoms (7%; 1 case of transient paranoid ideation and 1 case of transient thought disorder).
 
Efficacy

The researchers said that, prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression.

Specifically, patients who received psilocybin first had significant improvements in responses on the Hospital Anxiety and Depression Scale and the Beck Depression Inventory, when compared to patients who received niacin first.

The differences were significant 1 day after the patients’ first session and 7 weeks after the first session (P≤0.01 for all).

At the 6.5-month follow-up, 60% to 80% of participants continued with clinically significant reductions in depression or anxiety.

The researchers said a key finding of this study was that improvements in clinical evaluation scores for anxiety and depression lasted for the study’s extended monitoring period, which was 8 months for those who took psilocybin first.

Patients also reported post-psilocybin improvements in their quality of life, such as going out more, greater energy, getting along better with family members, and doing well at work. Some reported variations of spirituality, unusual peacefulness, and increased feelings of altruism.

“Our study showed that psilocybin facilitated experiences that drove reductions in psychological distress,” said study author Anthony Bossis, PhD, of New York University School of Medicine. “And if it’s true for cancer care, then it could apply to other stressful medical conditions.”

He cautioned that patients should not consume psilocybin on their own or without supervision from a physician and a trained counselor.

“Psilocybin therapy may not work for everyone,” he noted. “And some groups, such as people with schizophrenia, as well as adolescents, should not be treated with it.”

Enterococcus bacteria
Photo courtesy of
Janice Carr/CDC

The quest to understand a prolonged infection in an infant with acute myeloid leukemia (AML) has led to the discovery of a mutation that allows bacteria to tolerate antibiotic therapy.

Researchers described this discovery in the journal mBio.

“These findings detail a ‘perfect storm’ for development of antibiotic tolerance by bacteria that already pose a clinical challenge,” said study author Jason Rosch, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“The same conditions may be present in other patients with immune systems that have been compromised by chemotherapy or disease,” added co-author Joshua Wolf, MBBS, also of St. Jude.

The “perfect storm” involved a patient who was 6 weeks old when she was diagnosed with AML. The treatment wiped out her white blood cells, and, despite infection-control measures, she developed a bloodstream infection with vancomycin-resistant Enterococcus faecium (VRE).

The infection persisted for 26 days and only resolved after her immune system recovered. She then successfully completed AML treatment.

In-depth DNA sequencing of 22 VRE samples collected during the patient’s infection helped researchers link the prolonged infection to a point mutation in the relA gene of VRE.

The mutation inappropriately activated the stringent response pathway, which bacteria use to survive under stress and to tolerate antibiotics.

The mutation resulted in elevated levels of the signaling molecule alarmone, and this likely primed the bacteria to survive exposure to multiple antibiotics, the researchers said.

The team also noted that relA-mutant VRE was susceptible to the antibiotics linezolid and daptomycin in minimum inhibitory concentration testing and during planktonic growth.

However, when growing in biofilm, relA-mutant VRE could tolerate high doses of both antibiotics.

“This mutation has particular clinical significance because the antibiotics involved, linezolid and daptomycin, are the last line of defense against VRE infection,” Dr Wolf said.

Among the compounds in development for the treatment of bacterial biofilms is the experimental antibiotic ADEP-4. In this study, ADEP-4 killed relA-mutant and non-mutant VRE growing in biofilm in the lab.

“In the future, compounds like ADEP-4 may provide a new approach to resolving persistent infections,” Dr Wolf said.

Dr Rosch noted that evidence gleaned from tracking the evolution of VRE throughout the infection suggested the patient’s immune-compromised state was essential to survival of the mutant VRE.

Gene transcription was altered significantly in relA-mutant VRE and produced biofilms that were less robust and possibly unlikely to otherwise survive.

“The case expands our understanding of the role of the stringent response in susceptibility and tolerance to a wide range of antibiotics, especially in biofilms,” Dr Rosch said. “It also demonstrates that these mutations can develop and gain a foothold during a human infection.”

Enterococcus bacteria
Photo courtesy of
Janice Carr/CDC

The quest to understand a prolonged infection in an infant with acute myeloid leukemia (AML) has led to the discovery of a mutation that allows bacteria to tolerate antibiotic therapy.

Researchers described this discovery in the journal mBio.

“These findings detail a ‘perfect storm’ for development of antibiotic tolerance by bacteria that already pose a clinical challenge,” said study author Jason Rosch, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“The same conditions may be present in other patients with immune systems that have been compromised by chemotherapy or disease,” added co-author Joshua Wolf, MBBS, also of St. Jude.

The “perfect storm” involved a patient who was 6 weeks old when she was diagnosed with AML. The treatment wiped out her white blood cells, and, despite infection-control measures, she developed a bloodstream infection with vancomycin-resistant Enterococcus faecium (VRE).

The infection persisted for 26 days and only resolved after her immune system recovered. She then successfully completed AML treatment.

In-depth DNA sequencing of 22 VRE samples collected during the patient’s infection helped researchers link the prolonged infection to a point mutation in the relA gene of VRE.

The mutation inappropriately activated the stringent response pathway, which bacteria use to survive under stress and to tolerate antibiotics.

The mutation resulted in elevated levels of the signaling molecule alarmone, and this likely primed the bacteria to survive exposure to multiple antibiotics, the researchers said.

The team also noted that relA-mutant VRE was susceptible to the antibiotics linezolid and daptomycin in minimum inhibitory concentration testing and during planktonic growth.

However, when growing in biofilm, relA-mutant VRE could tolerate high doses of both antibiotics.

“This mutation has particular clinical significance because the antibiotics involved, linezolid and daptomycin, are the last line of defense against VRE infection,” Dr Wolf said.

Among the compounds in development for the treatment of bacterial biofilms is the experimental antibiotic ADEP-4. In this study, ADEP-4 killed relA-mutant and non-mutant VRE growing in biofilm in the lab.

“In the future, compounds like ADEP-4 may provide a new approach to resolving persistent infections,” Dr Wolf said.

Dr Rosch noted that evidence gleaned from tracking the evolution of VRE throughout the infection suggested the patient’s immune-compromised state was essential to survival of the mutant VRE.

Gene transcription was altered significantly in relA-mutant VRE and produced biofilms that were less robust and possibly unlikely to otherwise survive.

“The case expands our understanding of the role of the stringent response in susceptibility and tolerance to a wide range of antibiotics, especially in biofilms,” Dr Rosch said. “It also demonstrates that these mutations can develop and gain a foothold during a human infection.”

Enterococcus bacteria
Photo courtesy of
Janice Carr/CDC

The quest to understand a prolonged infection in an infant with acute myeloid leukemia (AML) has led to the discovery of a mutation that allows bacteria to tolerate antibiotic therapy.

Researchers described this discovery in the journal mBio.

“These findings detail a ‘perfect storm’ for development of antibiotic tolerance by bacteria that already pose a clinical challenge,” said study author Jason Rosch, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“The same conditions may be present in other patients with immune systems that have been compromised by chemotherapy or disease,” added co-author Joshua Wolf, MBBS, also of St. Jude.

The “perfect storm” involved a patient who was 6 weeks old when she was diagnosed with AML. The treatment wiped out her white blood cells, and, despite infection-control measures, she developed a bloodstream infection with vancomycin-resistant Enterococcus faecium (VRE).

The infection persisted for 26 days and only resolved after her immune system recovered. She then successfully completed AML treatment.

In-depth DNA sequencing of 22 VRE samples collected during the patient’s infection helped researchers link the prolonged infection to a point mutation in the relA gene of VRE.

The mutation inappropriately activated the stringent response pathway, which bacteria use to survive under stress and to tolerate antibiotics.

The mutation resulted in elevated levels of the signaling molecule alarmone, and this likely primed the bacteria to survive exposure to multiple antibiotics, the researchers said.

The team also noted that relA-mutant VRE was susceptible to the antibiotics linezolid and daptomycin in minimum inhibitory concentration testing and during planktonic growth.

However, when growing in biofilm, relA-mutant VRE could tolerate high doses of both antibiotics.

“This mutation has particular clinical significance because the antibiotics involved, linezolid and daptomycin, are the last line of defense against VRE infection,” Dr Wolf said.

Among the compounds in development for the treatment of bacterial biofilms is the experimental antibiotic ADEP-4. In this study, ADEP-4 killed relA-mutant and non-mutant VRE growing in biofilm in the lab.

“In the future, compounds like ADEP-4 may provide a new approach to resolving persistent infections,” Dr Wolf said.

Dr Rosch noted that evidence gleaned from tracking the evolution of VRE throughout the infection suggested the patient’s immune-compromised state was essential to survival of the mutant VRE.

Gene transcription was altered significantly in relA-mutant VRE and produced biofilms that were less robust and possibly unlikely to otherwise survive.

“The case expands our understanding of the role of the stringent response in susceptibility and tolerance to a wide range of antibiotics, especially in biofilms,” Dr Rosch said. “It also demonstrates that these mutations can develop and gain a foothold during a human infection.”