As more people are surviving breast cancer, more will be given bisphosphonate (BP) for bone metastases—and may be at risk for treatment adverse effects, such as atypical femoral fracture (AFF). Clinicians from Royal Victoria Hospital, Belfast, United Kingdom, describe what they learned in the first reported case of AFF caused by daily ibandronate.

The patient, a 55-year-old woman, had been diagnosed and treated for breast cancer. Twelve years later, she began having hip and lower back pain and was diagnosed with bony metastatic spread. She was started on hormone-suppressing therapy as well as daily ibandronic acid. Four years later, she began having new lower limb and groin pain. Radiography, bone scans and other tests indicated further metastatic spread to her left femur.

While she was waiting for scheduled radiotherapy, she fell, fracturing her left femur. Radiographs revealed AFF, presumed secondary to her BP therapy rather than metastasis. She underwent intramedullary nail fixation.

Evidence suggests that AFFs are stress fractures, the clinicians say. Repetitive loading on bone can lead to micro cracks, which are even more vulnerable to stress when BPs suppress the normal bone repair process.

Atypical femoral fracture is rare. Most cases have been patients receiving intravenous BP; to the clinicians’ knowledge this is the first report of AFF with an oral BP prescribed for bone metastatic breast cancer. But incidence of AFF grows with prolonged treatment, and the risk is raised with oral dosing, which is much higher in cancer cases, the clinicians note, compared with osteoporosis.

Because patients often have prodromal pain before an overt break, the clinicians suggest asking all oncology patients on BP about pain in thigh, hip, or groin. Bone scans and magnetic resonance imaging may reveal an imminent fracture. The clinicians caution that AFFs can be bilateral, so the opposite side also should be imaged.

Source:

Espey R, Grimes S, Heyburn G, Kealey WD. BMJ Case Rep. 2017;2017. pii: bcr-2016-217489.
doi: 10.1136/bcr-2016-217489.

As more people are surviving breast cancer, more will be given bisphosphonate (BP) for bone metastases—and may be at risk for treatment adverse effects, such as atypical femoral fracture (AFF). Clinicians from Royal Victoria Hospital, Belfast, United Kingdom, describe what they learned in the first reported case of AFF caused by daily ibandronate.

The patient, a 55-year-old woman, had been diagnosed and treated for breast cancer. Twelve years later, she began having hip and lower back pain and was diagnosed with bony metastatic spread. She was started on hormone-suppressing therapy as well as daily ibandronic acid. Four years later, she began having new lower limb and groin pain. Radiography, bone scans and other tests indicated further metastatic spread to her left femur.

While she was waiting for scheduled radiotherapy, she fell, fracturing her left femur. Radiographs revealed AFF, presumed secondary to her BP therapy rather than metastasis. She underwent intramedullary nail fixation.

Evidence suggests that AFFs are stress fractures, the clinicians say. Repetitive loading on bone can lead to micro cracks, which are even more vulnerable to stress when BPs suppress the normal bone repair process.

Atypical femoral fracture is rare. Most cases have been patients receiving intravenous BP; to the clinicians’ knowledge this is the first report of AFF with an oral BP prescribed for bone metastatic breast cancer. But incidence of AFF grows with prolonged treatment, and the risk is raised with oral dosing, which is much higher in cancer cases, the clinicians note, compared with osteoporosis.

Because patients often have prodromal pain before an overt break, the clinicians suggest asking all oncology patients on BP about pain in thigh, hip, or groin. Bone scans and magnetic resonance imaging may reveal an imminent fracture. The clinicians caution that AFFs can be bilateral, so the opposite side also should be imaged.

Source:

Espey R, Grimes S, Heyburn G, Kealey WD. BMJ Case Rep. 2017;2017. pii: bcr-2016-217489.
doi: 10.1136/bcr-2016-217489.

As more people are surviving breast cancer, more will be given bisphosphonate (BP) for bone metastases—and may be at risk for treatment adverse effects, such as atypical femoral fracture (AFF). Clinicians from Royal Victoria Hospital, Belfast, United Kingdom, describe what they learned in the first reported case of AFF caused by daily ibandronate.

The patient, a 55-year-old woman, had been diagnosed and treated for breast cancer. Twelve years later, she began having hip and lower back pain and was diagnosed with bony metastatic spread. She was started on hormone-suppressing therapy as well as daily ibandronic acid. Four years later, she began having new lower limb and groin pain. Radiography, bone scans and other tests indicated further metastatic spread to her left femur.

While she was waiting for scheduled radiotherapy, she fell, fracturing her left femur. Radiographs revealed AFF, presumed secondary to her BP therapy rather than metastasis. She underwent intramedullary nail fixation.

Evidence suggests that AFFs are stress fractures, the clinicians say. Repetitive loading on bone can lead to micro cracks, which are even more vulnerable to stress when BPs suppress the normal bone repair process.

Atypical femoral fracture is rare. Most cases have been patients receiving intravenous BP; to the clinicians’ knowledge this is the first report of AFF with an oral BP prescribed for bone metastatic breast cancer. But incidence of AFF grows with prolonged treatment, and the risk is raised with oral dosing, which is much higher in cancer cases, the clinicians note, compared with osteoporosis.

Because patients often have prodromal pain before an overt break, the clinicians suggest asking all oncology patients on BP about pain in thigh, hip, or groin. Bone scans and magnetic resonance imaging may reveal an imminent fracture. The clinicians caution that AFFs can be bilateral, so the opposite side also should be imaged.

Source:

Espey R, Grimes S, Heyburn G, Kealey WD. BMJ Case Rep. 2017;2017. pii: bcr-2016-217489.
doi: 10.1136/bcr-2016-217489.

In an “important first,” the FDA has fast-tracked a cancer treatment based on a biomarker rather than on the location of the tumor.

Pembrolizumab (Keytruda) has already been approved for certain patients with metastatic melanoma, metastatic non-small cell lung cancer, and other cancers. With the new approval, pembrolizumab is now indicated for adult and pediatric patients with unresectable or metastatic solid tumors that have a biomarker known as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). Microsatellite instability-high and dMMR tumors have abnormalities that affect the proper repair of DNA inside the cell. Pembrolizumab blocks a cellular pathway (PD-1/PD-L1—proteins found in immune cells and some cancer cells), which may help the immune system fight the cancer cells.

Tumors with the biomarkers are most commonly found in colorectal, endometrial, and gastrointestinal cancers. About 5% of patients with metastatic colorectal cancer have MSI-H or dMMR tumors. Less commonly, they are found in cancers in the breast, prostate, bladder, thyroid gland, and other locations.

In 5 clinical trials, of 149 patients treated with pembrolizumab for 15 cancer types, 40% had a complete or partial response. For most of those patients, the response lasted ≥ 6 months.

In an “important first,” the FDA has fast-tracked a cancer treatment based on a biomarker rather than on the location of the tumor.

Pembrolizumab (Keytruda) has already been approved for certain patients with metastatic melanoma, metastatic non-small cell lung cancer, and other cancers. With the new approval, pembrolizumab is now indicated for adult and pediatric patients with unresectable or metastatic solid tumors that have a biomarker known as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). Microsatellite instability-high and dMMR tumors have abnormalities that affect the proper repair of DNA inside the cell. Pembrolizumab blocks a cellular pathway (PD-1/PD-L1—proteins found in immune cells and some cancer cells), which may help the immune system fight the cancer cells.

Tumors with the biomarkers are most commonly found in colorectal, endometrial, and gastrointestinal cancers. About 5% of patients with metastatic colorectal cancer have MSI-H or dMMR tumors. Less commonly, they are found in cancers in the breast, prostate, bladder, thyroid gland, and other locations.

In 5 clinical trials, of 149 patients treated with pembrolizumab for 15 cancer types, 40% had a complete or partial response. For most of those patients, the response lasted ≥ 6 months.

In an “important first,” the FDA has fast-tracked a cancer treatment based on a biomarker rather than on the location of the tumor.

Pembrolizumab (Keytruda) has already been approved for certain patients with metastatic melanoma, metastatic non-small cell lung cancer, and other cancers. With the new approval, pembrolizumab is now indicated for adult and pediatric patients with unresectable or metastatic solid tumors that have a biomarker known as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). Microsatellite instability-high and dMMR tumors have abnormalities that affect the proper repair of DNA inside the cell. Pembrolizumab blocks a cellular pathway (PD-1/PD-L1—proteins found in immune cells and some cancer cells), which may help the immune system fight the cancer cells.

Tumors with the biomarkers are most commonly found in colorectal, endometrial, and gastrointestinal cancers. About 5% of patients with metastatic colorectal cancer have MSI-H or dMMR tumors. Less commonly, they are found in cancers in the breast, prostate, bladder, thyroid gland, and other locations.

In 5 clinical trials, of 149 patients treated with pembrolizumab for 15 cancer types, 40% had a complete or partial response. For most of those patients, the response lasted ≥ 6 months.

Congress of EHA

An all-oral treatment regimen can produce deep and durable responses in patients with newly diagnosed multiple myeloma (MM), according to a speaker at the 22nd Congress of the European Hematology Association (EHA).

In a phase 1/2 study, patients with newly diagnosed MM received treatment with ixazomib, lenalidomide, and dexamethasone for up to 12 cycles, followed by maintenance with ixazomib alone.

The overall response rate was 88% for the entire cohort and 80% among patients who did not proceed to transplant.

The median progression-free survival was 35.4 months in the entire cohort and 29.4 months in patients who did not proceed to transplant.

Most patients did not complete all 12 cycles of induction, but 38% proceeded to maintenance, and 12% remain on study treatment at a median follow-up of 56 months.

Shaji Kumar, MD, of the Mayo Clinic in Rochester, Minnesota, presented these results at the EHA Congress as abstract S408. The research was sponsored by Millennium Pharmaceuticals, Inc., a subsidiary of Takeda Pharmaceutical Company Limited.

Patients

The trial included 65 patients. Their median age was 66 (range, 34-86), and 55% were male. Eight percent of patients had high-risk cytogenetics.

ECOG performance status was 0 for 43% of patients, 1 for 52%, and 2 for 5%. ISS stage was 1 for 43% of patients, 2 for 43%, and 3 for 14%.

Treatment

Patients received ixazomib (1.68 - 3.95 mg/m² in phase 1 and 4.0 mg in phase 2 on days 1, 8, and 15) plus lenalidomide (25 mg on days 1-21), and dexamethasone (40 mg on days 1, 8, 15, and 22) for up to twelve, 28-day cycles. Patients could then receive ixazomib maintenance until disease progression or unacceptable toxicity.

Twenty-three patients (35%) discontinued induction to undergo hematopoietic stem cell transplant (HSCT).

Thirty-seven patients discontinued study treatment for other reasons—17 of them during induction. Twenty-one patients discontinued due to progressive disease, 9 due to adverse events (AEs), 5 due to patient withdrawal, 1 due to unsatisfactory response, and 1 due to other reasons.

Twenty-five patients completed induction and went on to receive ixazomib maintenance. Five patients remain on study treatment.

Safety

Seventy-eight percent of patients had a grade 3 or higher AE, 46% had a serious AE, 57% had an AE leading to dose reduction, and 15% had an AE leading to discontinuation of any of the study drugs. There were 2 on-study deaths.

The most common grade 3 or higher AEs were neutropenia, thrombocytopenia, diarrhea, back pain, vomiting, nausea, peripheral neuropathy, and rashes/eruptions/exanthems.

Efficacy

The overall response rate was 88% for the entire cohort and 80% among patients who did not go on to receive HSCT.

The complete response (CR) rates were 23% and 32%, respectively. Thirty four percent and 32%, respectively, had a very good partial response (VGPR). And 30% and 17%, respectively, had a partial response (PR).

Thirty-two percent of patients who received maintenance (n=8) had an improvement in their response during the maintenance phase.  Two patients went from a VGPR to a stringent CR, 3 went from a VGPR to a CR, 2 went from a VGPR to a near CR, and 1 went from a PR to a VGPR.

Sixteen patients were evaluated for minimal residual disease (MRD). Of the patients with a stringent CR/CR, 89% (8/9) were MRD-negative.

The median progression-free survival was 35.4 months in the entire cohort and 29.4 months in patients who did not proceed to HSCT. The 4-year overall survival rate was 84% and 82%, respectively.

“Long-term follow-up, a median follow-up of 56 months, with the combination of ixazomib, lenalidomide, and dexamethasone demonstrates that this is an efficacious regimen for newly diagnosed myeloma patients, with excellent tolerability, and something that can be maintained for a long period of time,” Dr Kumar said. “These results form the basis for an ongoing phase 3 program.”

Congress of EHA

An all-oral treatment regimen can produce deep and durable responses in patients with newly diagnosed multiple myeloma (MM), according to a speaker at the 22nd Congress of the European Hematology Association (EHA).

In a phase 1/2 study, patients with newly diagnosed MM received treatment with ixazomib, lenalidomide, and dexamethasone for up to 12 cycles, followed by maintenance with ixazomib alone.

The overall response rate was 88% for the entire cohort and 80% among patients who did not proceed to transplant.

The median progression-free survival was 35.4 months in the entire cohort and 29.4 months in patients who did not proceed to transplant.

Most patients did not complete all 12 cycles of induction, but 38% proceeded to maintenance, and 12% remain on study treatment at a median follow-up of 56 months.

Shaji Kumar, MD, of the Mayo Clinic in Rochester, Minnesota, presented these results at the EHA Congress as abstract S408. The research was sponsored by Millennium Pharmaceuticals, Inc., a subsidiary of Takeda Pharmaceutical Company Limited.

Patients

The trial included 65 patients. Their median age was 66 (range, 34-86), and 55% were male. Eight percent of patients had high-risk cytogenetics.

ECOG performance status was 0 for 43% of patients, 1 for 52%, and 2 for 5%. ISS stage was 1 for 43% of patients, 2 for 43%, and 3 for 14%.

Treatment

Patients received ixazomib (1.68 - 3.95 mg/m² in phase 1 and 4.0 mg in phase 2 on days 1, 8, and 15) plus lenalidomide (25 mg on days 1-21), and dexamethasone (40 mg on days 1, 8, 15, and 22) for up to twelve, 28-day cycles. Patients could then receive ixazomib maintenance until disease progression or unacceptable toxicity.

Twenty-three patients (35%) discontinued induction to undergo hematopoietic stem cell transplant (HSCT).

Thirty-seven patients discontinued study treatment for other reasons—17 of them during induction. Twenty-one patients discontinued due to progressive disease, 9 due to adverse events (AEs), 5 due to patient withdrawal, 1 due to unsatisfactory response, and 1 due to other reasons.

Twenty-five patients completed induction and went on to receive ixazomib maintenance. Five patients remain on study treatment.

Safety

Seventy-eight percent of patients had a grade 3 or higher AE, 46% had a serious AE, 57% had an AE leading to dose reduction, and 15% had an AE leading to discontinuation of any of the study drugs. There were 2 on-study deaths.

The most common grade 3 or higher AEs were neutropenia, thrombocytopenia, diarrhea, back pain, vomiting, nausea, peripheral neuropathy, and rashes/eruptions/exanthems.

Efficacy

The overall response rate was 88% for the entire cohort and 80% among patients who did not go on to receive HSCT.

The complete response (CR) rates were 23% and 32%, respectively. Thirty four percent and 32%, respectively, had a very good partial response (VGPR). And 30% and 17%, respectively, had a partial response (PR).

Thirty-two percent of patients who received maintenance (n=8) had an improvement in their response during the maintenance phase.  Two patients went from a VGPR to a stringent CR, 3 went from a VGPR to a CR, 2 went from a VGPR to a near CR, and 1 went from a PR to a VGPR.

Sixteen patients were evaluated for minimal residual disease (MRD). Of the patients with a stringent CR/CR, 89% (8/9) were MRD-negative.

The median progression-free survival was 35.4 months in the entire cohort and 29.4 months in patients who did not proceed to HSCT. The 4-year overall survival rate was 84% and 82%, respectively.

“Long-term follow-up, a median follow-up of 56 months, with the combination of ixazomib, lenalidomide, and dexamethasone demonstrates that this is an efficacious regimen for newly diagnosed myeloma patients, with excellent tolerability, and something that can be maintained for a long period of time,” Dr Kumar said. “These results form the basis for an ongoing phase 3 program.”

Congress of EHA

An all-oral treatment regimen can produce deep and durable responses in patients with newly diagnosed multiple myeloma (MM), according to a speaker at the 22nd Congress of the European Hematology Association (EHA).

In a phase 1/2 study, patients with newly diagnosed MM received treatment with ixazomib, lenalidomide, and dexamethasone for up to 12 cycles, followed by maintenance with ixazomib alone.

The overall response rate was 88% for the entire cohort and 80% among patients who did not proceed to transplant.

The median progression-free survival was 35.4 months in the entire cohort and 29.4 months in patients who did not proceed to transplant.

Most patients did not complete all 12 cycles of induction, but 38% proceeded to maintenance, and 12% remain on study treatment at a median follow-up of 56 months.

Shaji Kumar, MD, of the Mayo Clinic in Rochester, Minnesota, presented these results at the EHA Congress as abstract S408. The research was sponsored by Millennium Pharmaceuticals, Inc., a subsidiary of Takeda Pharmaceutical Company Limited.

Patients

The trial included 65 patients. Their median age was 66 (range, 34-86), and 55% were male. Eight percent of patients had high-risk cytogenetics.

ECOG performance status was 0 for 43% of patients, 1 for 52%, and 2 for 5%. ISS stage was 1 for 43% of patients, 2 for 43%, and 3 for 14%.

Treatment

Patients received ixazomib (1.68 - 3.95 mg/m² in phase 1 and 4.0 mg in phase 2 on days 1, 8, and 15) plus lenalidomide (25 mg on days 1-21), and dexamethasone (40 mg on days 1, 8, 15, and 22) for up to twelve, 28-day cycles. Patients could then receive ixazomib maintenance until disease progression or unacceptable toxicity.

Twenty-three patients (35%) discontinued induction to undergo hematopoietic stem cell transplant (HSCT).

Thirty-seven patients discontinued study treatment for other reasons—17 of them during induction. Twenty-one patients discontinued due to progressive disease, 9 due to adverse events (AEs), 5 due to patient withdrawal, 1 due to unsatisfactory response, and 1 due to other reasons.

Twenty-five patients completed induction and went on to receive ixazomib maintenance. Five patients remain on study treatment.

Safety

Seventy-eight percent of patients had a grade 3 or higher AE, 46% had a serious AE, 57% had an AE leading to dose reduction, and 15% had an AE leading to discontinuation of any of the study drugs. There were 2 on-study deaths.

The most common grade 3 or higher AEs were neutropenia, thrombocytopenia, diarrhea, back pain, vomiting, nausea, peripheral neuropathy, and rashes/eruptions/exanthems.

Efficacy

The overall response rate was 88% for the entire cohort and 80% among patients who did not go on to receive HSCT.

The complete response (CR) rates were 23% and 32%, respectively. Thirty four percent and 32%, respectively, had a very good partial response (VGPR). And 30% and 17%, respectively, had a partial response (PR).

Thirty-two percent of patients who received maintenance (n=8) had an improvement in their response during the maintenance phase.  Two patients went from a VGPR to a stringent CR, 3 went from a VGPR to a CR, 2 went from a VGPR to a near CR, and 1 went from a PR to a VGPR.

Sixteen patients were evaluated for minimal residual disease (MRD). Of the patients with a stringent CR/CR, 89% (8/9) were MRD-negative.

The median progression-free survival was 35.4 months in the entire cohort and 29.4 months in patients who did not proceed to HSCT. The 4-year overall survival rate was 84% and 82%, respectively.

“Long-term follow-up, a median follow-up of 56 months, with the combination of ixazomib, lenalidomide, and dexamethasone demonstrates that this is an efficacious regimen for newly diagnosed myeloma patients, with excellent tolerability, and something that can be maintained for a long period of time,” Dr Kumar said. “These results form the basis for an ongoing phase 3 program.”

Children’s Research Hospital

Researchers say they have uncovered new details of the genomic landscape of T-lineage acute lymphoblastic leukemia (T-ALL).

The team believes their findings will aid the development of drugs to target newly discovered mutations and enable researchers to engineer better mouse models to probe the leukemia’s aberrant biological machinery.

Charles Mullighan, MD, MBBS, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and reported their findings in Nature Genetics.

“This first comprehensive and systematic analysis in a large group of patients revealed many new mutations that are biologically significant as well as new drug targets that could be clinically important,” Dr Mullighan said.

“Leukemias typically arise from multiple genetic changes that work together. Most previous studies have not had the breadth of genomic data in enough patients to identify the constellations of mutations and recognize their associations.”

Dr Mullighan and his colleagues sequenced the genomes of 264 children and young adults with T-ALL. This revealed 106 driver genes, half of which had not been identified in childhood T-ALL.

“We went into this study knowing that we didn’t know the full genomic landscape of T-ALL,” said Stephen Hunger, MD, of the Children’s Hospital of Philadelphia in Pennsylvania.

“But we were surprised that over half of the new targets and mutations were previously unrecognized. It was particularly unexpected and very striking that some mutations were exclusively found in some subtypes of T-ALL but not others.”

The researchers’ analysis confirmed that T-ALL was driven by mutations in known signaling pathways, including JAK-STAT, Ras, and PTEN-PI3K. However, the study also revealed new mutations in those known pathways.

In addition, the researchers identified cases in which the same T-ALL subtype had mutations in different pathways triggered by the same founding mutation.

“We believe this finding suggests we can target such subtypes with an inhibitor drug for one of the pathways, and it’s likely to be effective,” Dr Mullighan said.

He and his colleagues also believe the mutations uncovered in this study will enable researchers to create mouse models that more accurately reflect human T-ALL.

“We now have a launching pad, if you will, to design mouse models that include multiple genetic mutations to more faithfully reflect the leukemias we see in humans,” Dr Mullighan said.

Data from this study are available to researchers through the St. Jude PeCan data portal and the TARGET Data Matrix.

Children’s Research Hospital

Researchers say they have uncovered new details of the genomic landscape of T-lineage acute lymphoblastic leukemia (T-ALL).

The team believes their findings will aid the development of drugs to target newly discovered mutations and enable researchers to engineer better mouse models to probe the leukemia’s aberrant biological machinery.

Charles Mullighan, MD, MBBS, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and reported their findings in Nature Genetics.

“This first comprehensive and systematic analysis in a large group of patients revealed many new mutations that are biologically significant as well as new drug targets that could be clinically important,” Dr Mullighan said.

“Leukemias typically arise from multiple genetic changes that work together. Most previous studies have not had the breadth of genomic data in enough patients to identify the constellations of mutations and recognize their associations.”

Dr Mullighan and his colleagues sequenced the genomes of 264 children and young adults with T-ALL. This revealed 106 driver genes, half of which had not been identified in childhood T-ALL.

“We went into this study knowing that we didn’t know the full genomic landscape of T-ALL,” said Stephen Hunger, MD, of the Children’s Hospital of Philadelphia in Pennsylvania.

“But we were surprised that over half of the new targets and mutations were previously unrecognized. It was particularly unexpected and very striking that some mutations were exclusively found in some subtypes of T-ALL but not others.”

The researchers’ analysis confirmed that T-ALL was driven by mutations in known signaling pathways, including JAK-STAT, Ras, and PTEN-PI3K. However, the study also revealed new mutations in those known pathways.

In addition, the researchers identified cases in which the same T-ALL subtype had mutations in different pathways triggered by the same founding mutation.

“We believe this finding suggests we can target such subtypes with an inhibitor drug for one of the pathways, and it’s likely to be effective,” Dr Mullighan said.

He and his colleagues also believe the mutations uncovered in this study will enable researchers to create mouse models that more accurately reflect human T-ALL.

“We now have a launching pad, if you will, to design mouse models that include multiple genetic mutations to more faithfully reflect the leukemias we see in humans,” Dr Mullighan said.

Data from this study are available to researchers through the St. Jude PeCan data portal and the TARGET Data Matrix.

Children’s Research Hospital

Researchers say they have uncovered new details of the genomic landscape of T-lineage acute lymphoblastic leukemia (T-ALL).

The team believes their findings will aid the development of drugs to target newly discovered mutations and enable researchers to engineer better mouse models to probe the leukemia’s aberrant biological machinery.

Charles Mullighan, MD, MBBS, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and reported their findings in Nature Genetics.

“This first comprehensive and systematic analysis in a large group of patients revealed many new mutations that are biologically significant as well as new drug targets that could be clinically important,” Dr Mullighan said.

“Leukemias typically arise from multiple genetic changes that work together. Most previous studies have not had the breadth of genomic data in enough patients to identify the constellations of mutations and recognize their associations.”

Dr Mullighan and his colleagues sequenced the genomes of 264 children and young adults with T-ALL. This revealed 106 driver genes, half of which had not been identified in childhood T-ALL.

“We went into this study knowing that we didn’t know the full genomic landscape of T-ALL,” said Stephen Hunger, MD, of the Children’s Hospital of Philadelphia in Pennsylvania.

“But we were surprised that over half of the new targets and mutations were previously unrecognized. It was particularly unexpected and very striking that some mutations were exclusively found in some subtypes of T-ALL but not others.”

The researchers’ analysis confirmed that T-ALL was driven by mutations in known signaling pathways, including JAK-STAT, Ras, and PTEN-PI3K. However, the study also revealed new mutations in those known pathways.

In addition, the researchers identified cases in which the same T-ALL subtype had mutations in different pathways triggered by the same founding mutation.

“We believe this finding suggests we can target such subtypes with an inhibitor drug for one of the pathways, and it’s likely to be effective,” Dr Mullighan said.

He and his colleagues also believe the mutations uncovered in this study will enable researchers to create mouse models that more accurately reflect human T-ALL.

“We now have a launching pad, if you will, to design mouse models that include multiple genetic mutations to more faithfully reflect the leukemias we see in humans,” Dr Mullighan said.

Data from this study are available to researchers through the St. Jude PeCan data portal and the TARGET Data Matrix.

Photo courtesy of Merck

The US Food and Drug Administration (FDA) has placed clinical holds on 3 trials testing combination therapy with pembrolizumab (Keytruda) in patients with multiple myeloma (MM)—KEYNOTE-183, KEYNOTE-185, and KEYNOTE-023.

In 2 of these trials—KEYNOTE-183 and -185—there were more deaths among patients receiving pembrolizumab than among patients receiving comparator treatments.

KEYNOTE-183 is a phase 3 study of pomalidomide and low-dose dexamethasone with or without pembrolizumab in refractory or relapsed and refractory MM.

KEYNOTE-185 is a phase 3 study of lenalidomide and low-dose dexamethasone with or without pembrolizumab in newly diagnosed and treatment-naïve MM.

The excess deaths in the pembrolizumab arms of KEYNOTE-183 and -185 led to a pause in enrollment for both trials, which was announced last month.

Now, the FDA says available data suggest the risks of pembrolizumab plus pomalidomide or lenalidomide outweigh any potential benefit for MM patients.

Therefore, all patients enrolled in KEYNOTE-183 and -185 will discontinue investigational treatment with pembrolizumab.

The same applies to patients in the pembrolizumab/lenalidomide/dexamethasone cohort of KEYNOTE-023.

KEYNOTE-023 is a phase 1 trial of pembrolizumab in combination with backbone treatments. Cohort 1 of this trial was designed to evaluate pembrolizumab in combination with lenalidomide and dexamethasone in MM patients who received prior treatment with an immunomodulatory agent (lenalidomide, pomalidomide, or thalidomide).

Pembrolizumab is a humanized monoclonal antibody that blocks interaction between the programmed cell death protein 1 (PD-1) and its receptor ligands, PD-L1 and PD-L2.

Pembrolizumab is FDA-approved to treat classical Hodgkin lymphoma, melanoma, non-small cell lung cancer, head and neck cancer, urothelial carcinoma, and microsatellite instability-high solid tumors.

Photo courtesy of Merck

The US Food and Drug Administration (FDA) has placed clinical holds on 3 trials testing combination therapy with pembrolizumab (Keytruda) in patients with multiple myeloma (MM)—KEYNOTE-183, KEYNOTE-185, and KEYNOTE-023.

In 2 of these trials—KEYNOTE-183 and -185—there were more deaths among patients receiving pembrolizumab than among patients receiving comparator treatments.

KEYNOTE-183 is a phase 3 study of pomalidomide and low-dose dexamethasone with or without pembrolizumab in refractory or relapsed and refractory MM.

KEYNOTE-185 is a phase 3 study of lenalidomide and low-dose dexamethasone with or without pembrolizumab in newly diagnosed and treatment-naïve MM.

The excess deaths in the pembrolizumab arms of KEYNOTE-183 and -185 led to a pause in enrollment for both trials, which was announced last month.

Now, the FDA says available data suggest the risks of pembrolizumab plus pomalidomide or lenalidomide outweigh any potential benefit for MM patients.

Therefore, all patients enrolled in KEYNOTE-183 and -185 will discontinue investigational treatment with pembrolizumab.

The same applies to patients in the pembrolizumab/lenalidomide/dexamethasone cohort of KEYNOTE-023.

KEYNOTE-023 is a phase 1 trial of pembrolizumab in combination with backbone treatments. Cohort 1 of this trial was designed to evaluate pembrolizumab in combination with lenalidomide and dexamethasone in MM patients who received prior treatment with an immunomodulatory agent (lenalidomide, pomalidomide, or thalidomide).

Pembrolizumab is a humanized monoclonal antibody that blocks interaction between the programmed cell death protein 1 (PD-1) and its receptor ligands, PD-L1 and PD-L2.

Pembrolizumab is FDA-approved to treat classical Hodgkin lymphoma, melanoma, non-small cell lung cancer, head and neck cancer, urothelial carcinoma, and microsatellite instability-high solid tumors.

Photo courtesy of Merck

The US Food and Drug Administration (FDA) has placed clinical holds on 3 trials testing combination therapy with pembrolizumab (Keytruda) in patients with multiple myeloma (MM)—KEYNOTE-183, KEYNOTE-185, and KEYNOTE-023.

In 2 of these trials—KEYNOTE-183 and -185—there were more deaths among patients receiving pembrolizumab than among patients receiving comparator treatments.

KEYNOTE-183 is a phase 3 study of pomalidomide and low-dose dexamethasone with or without pembrolizumab in refractory or relapsed and refractory MM.

KEYNOTE-185 is a phase 3 study of lenalidomide and low-dose dexamethasone with or without pembrolizumab in newly diagnosed and treatment-naïve MM.

The excess deaths in the pembrolizumab arms of KEYNOTE-183 and -185 led to a pause in enrollment for both trials, which was announced last month.

Now, the FDA says available data suggest the risks of pembrolizumab plus pomalidomide or lenalidomide outweigh any potential benefit for MM patients.

Therefore, all patients enrolled in KEYNOTE-183 and -185 will discontinue investigational treatment with pembrolizumab.

The same applies to patients in the pembrolizumab/lenalidomide/dexamethasone cohort of KEYNOTE-023.

KEYNOTE-023 is a phase 1 trial of pembrolizumab in combination with backbone treatments. Cohort 1 of this trial was designed to evaluate pembrolizumab in combination with lenalidomide and dexamethasone in MM patients who received prior treatment with an immunomodulatory agent (lenalidomide, pomalidomide, or thalidomide).

Pembrolizumab is a humanized monoclonal antibody that blocks interaction between the programmed cell death protein 1 (PD-1) and its receptor ligands, PD-L1 and PD-L2.

Pembrolizumab is FDA-approved to treat classical Hodgkin lymphoma, melanoma, non-small cell lung cancer, head and neck cancer, urothelial carcinoma, and microsatellite instability-high solid tumors.

ANSWER

The correct answer is eczema/atopic dermatitis (choice “c”).

Patients with eczema have a low threshold for itching, so they scratch, often making the condition appear far worse than it really is. In such cases, it’s typical for the problem to be mistaken for impetigo (choice “a”) or yeast infection (choice “d”). The latter, much like psoriasis (choice “b”), is quite rare in the perioral area. Furthermore, the patient had no indicative signs of psoriasis.

DISCUSSION

Eczema is one of several manifestations of atopic dermatitis, a syndrome that affects more than 20% of newborns in this country. These children have extraordinarily dry, thin skin that overreacts to wetting and drying, as well as scratching. Certain areas are especially prone to these changes and consequently develop scaling and itching.

The perioral area is one, in large part because it is kept moist by food, drink, nasal secretions, and saliva (due to habitual lip licking). The scaly rash becomes inflamed; on people with skin of color, this frequently manifests with hyperpigmentation.

When picked enough, this type of rash can become impetiginized—that is, superficially infected with staph or strep. But in this patient’s case, antibiotics were of no practical use.

A topical steroid ointment (hydrocortisone 2.5%) was used, and the patient was urged to stop picking (or licking!) and to use moisturizers (eg, petroleum jelly). The family was educated about the problem and its origins, and the parents were reassured of the self-limiting nature of postinflammatory hyperpigmentation (a major source of concern).

In this case, the key to making the correct diagnosis was the significance of the personal and family history of atopy—and an appreciation for how common atopic dermatitis and associated eczema are.

ANSWER

The correct answer is eczema/atopic dermatitis (choice “c”).

Patients with eczema have a low threshold for itching, so they scratch, often making the condition appear far worse than it really is. In such cases, it’s typical for the problem to be mistaken for impetigo (choice “a”) or yeast infection (choice “d”). The latter, much like psoriasis (choice “b”), is quite rare in the perioral area. Furthermore, the patient had no indicative signs of psoriasis.

DISCUSSION

Eczema is one of several manifestations of atopic dermatitis, a syndrome that affects more than 20% of newborns in this country. These children have extraordinarily dry, thin skin that overreacts to wetting and drying, as well as scratching. Certain areas are especially prone to these changes and consequently develop scaling and itching.

The perioral area is one, in large part because it is kept moist by food, drink, nasal secretions, and saliva (due to habitual lip licking). The scaly rash becomes inflamed; on people with skin of color, this frequently manifests with hyperpigmentation.

When picked enough, this type of rash can become impetiginized—that is, superficially infected with staph or strep. But in this patient’s case, antibiotics were of no practical use.

A topical steroid ointment (hydrocortisone 2.5%) was used, and the patient was urged to stop picking (or licking!) and to use moisturizers (eg, petroleum jelly). The family was educated about the problem and its origins, and the parents were reassured of the self-limiting nature of postinflammatory hyperpigmentation (a major source of concern).

In this case, the key to making the correct diagnosis was the significance of the personal and family history of atopy—and an appreciation for how common atopic dermatitis and associated eczema are.

ANSWER

The correct answer is eczema/atopic dermatitis (choice “c”).

Patients with eczema have a low threshold for itching, so they scratch, often making the condition appear far worse than it really is. In such cases, it’s typical for the problem to be mistaken for impetigo (choice “a”) or yeast infection (choice “d”). The latter, much like psoriasis (choice “b”), is quite rare in the perioral area. Furthermore, the patient had no indicative signs of psoriasis.

DISCUSSION

Eczema is one of several manifestations of atopic dermatitis, a syndrome that affects more than 20% of newborns in this country. These children have extraordinarily dry, thin skin that overreacts to wetting and drying, as well as scratching. Certain areas are especially prone to these changes and consequently develop scaling and itching.

The perioral area is one, in large part because it is kept moist by food, drink, nasal secretions, and saliva (due to habitual lip licking). The scaly rash becomes inflamed; on people with skin of color, this frequently manifests with hyperpigmentation.

When picked enough, this type of rash can become impetiginized—that is, superficially infected with staph or strep. But in this patient’s case, antibiotics were of no practical use.

A topical steroid ointment (hydrocortisone 2.5%) was used, and the patient was urged to stop picking (or licking!) and to use moisturizers (eg, petroleum jelly). The family was educated about the problem and its origins, and the parents were reassured of the self-limiting nature of postinflammatory hyperpigmentation (a major source of concern).

In this case, the key to making the correct diagnosis was the significance of the personal and family history of atopy—and an appreciation for how common atopic dermatitis and associated eczema are.

SEATTLE – Diverting loop ileostomies save patients with inflammatory bowel disease (IBD) with severe colitis from rushed total abdominal colectomies, buying time for patient optimization before surgery, and perhaps even saving colons, according to a report from the University of California, Los Angeles.

Urgent colectomy is the standard of care, but it’s a big operation when patients aren’t doing well. Immunosuppression, malnutrition, and other problems lead to high rates of complications.

In 2013, UCLA physicians decided to try rescue diverting loop ileostomies (DLIs), a relatively quick, minimally invasive option to temporarily divert the fecal stream, instead. The idea is to give the colon a chance to heal and the patient another shot at medical management and recovery before definitive surgery. There’s even a chance of colon salvage.

The approach has been working well at UCLA. Investigators previously reported good results for their first eight patients. They presented updated results for the series – now up to 34 patients – at the annual meeting of the American Society of Colon and Rectal Surgeons.

So far, DLI allowed 91% of patients (31/34) to avoid urgent total colectomies. It’s “a safe alternative. Patients undergoing DLI have acceptably low complication rates and most are afforded time for medical and nutritional optimization prior to proceeding with their definitive surgical care,” said presenter Tara Russell, MD, a UCLA surgery resident.

“Currently, [almost every] patient presenting with acute colitis who we aren’t able to get to the point of discharge with medical optimization” is now offered rescue DLI at the university, and patients have been eager for a chance at avoiding total colectomy. The only patients who are not offered DLI are those with, for instance, fulminant toxic megacolon, Dr. Russell said.

The DLI approach failed in just 2 of the 18 ulcerative colitis patients and 1 of the 16 Crohn’s patients in the series. All three went on to emergent total colectomies 11-53 days after the procedure.

The majority of DLI patients tolerated oral intake by postop day 1, and the median time to resuming a regular diet was 2 days. Most people were discharged within a day or 2 of diversion, and a few took longer to achieve medical rescue. Almost 90% had an improvement in nutritional status, and over 80% went on to elective laparoscopic definitive procedures or colon salvage.

Two patients had postop wound infections, “but there were no other complications” with DLI, Dr. Russell said.

All DLIs were performed with a single-incision laparoscopic approach and took an average of about a half hour. Most of the diversions were in the right lower abdominal quadrant.

The mean age of the patients was 36 years, with a range of 16-81 years. Just over half were men. Of 21 patients who met systemic inflammatory response syndrome criteria at the time of operation, 13 (62%) resolved within 24 hours of DLI.
 

[email protected]

SEATTLE – Diverting loop ileostomies save patients with inflammatory bowel disease (IBD) with severe colitis from rushed total abdominal colectomies, buying time for patient optimization before surgery, and perhaps even saving colons, according to a report from the University of California, Los Angeles.

Urgent colectomy is the standard of care, but it’s a big operation when patients aren’t doing well. Immunosuppression, malnutrition, and other problems lead to high rates of complications.

In 2013, UCLA physicians decided to try rescue diverting loop ileostomies (DLIs), a relatively quick, minimally invasive option to temporarily divert the fecal stream, instead. The idea is to give the colon a chance to heal and the patient another shot at medical management and recovery before definitive surgery. There’s even a chance of colon salvage.

The approach has been working well at UCLA. Investigators previously reported good results for their first eight patients. They presented updated results for the series – now up to 34 patients – at the annual meeting of the American Society of Colon and Rectal Surgeons.

So far, DLI allowed 91% of patients (31/34) to avoid urgent total colectomies. It’s “a safe alternative. Patients undergoing DLI have acceptably low complication rates and most are afforded time for medical and nutritional optimization prior to proceeding with their definitive surgical care,” said presenter Tara Russell, MD, a UCLA surgery resident.

“Currently, [almost every] patient presenting with acute colitis who we aren’t able to get to the point of discharge with medical optimization” is now offered rescue DLI at the university, and patients have been eager for a chance at avoiding total colectomy. The only patients who are not offered DLI are those with, for instance, fulminant toxic megacolon, Dr. Russell said.

The DLI approach failed in just 2 of the 18 ulcerative colitis patients and 1 of the 16 Crohn’s patients in the series. All three went on to emergent total colectomies 11-53 days after the procedure.

The majority of DLI patients tolerated oral intake by postop day 1, and the median time to resuming a regular diet was 2 days. Most people were discharged within a day or 2 of diversion, and a few took longer to achieve medical rescue. Almost 90% had an improvement in nutritional status, and over 80% went on to elective laparoscopic definitive procedures or colon salvage.

Two patients had postop wound infections, “but there were no other complications” with DLI, Dr. Russell said.

All DLIs were performed with a single-incision laparoscopic approach and took an average of about a half hour. Most of the diversions were in the right lower abdominal quadrant.

The mean age of the patients was 36 years, with a range of 16-81 years. Just over half were men. Of 21 patients who met systemic inflammatory response syndrome criteria at the time of operation, 13 (62%) resolved within 24 hours of DLI.
 

[email protected]

SEATTLE – Diverting loop ileostomies save patients with inflammatory bowel disease (IBD) with severe colitis from rushed total abdominal colectomies, buying time for patient optimization before surgery, and perhaps even saving colons, according to a report from the University of California, Los Angeles.

Urgent colectomy is the standard of care, but it’s a big operation when patients aren’t doing well. Immunosuppression, malnutrition, and other problems lead to high rates of complications.

In 2013, UCLA physicians decided to try rescue diverting loop ileostomies (DLIs), a relatively quick, minimally invasive option to temporarily divert the fecal stream, instead. The idea is to give the colon a chance to heal and the patient another shot at medical management and recovery before definitive surgery. There’s even a chance of colon salvage.

The approach has been working well at UCLA. Investigators previously reported good results for their first eight patients. They presented updated results for the series – now up to 34 patients – at the annual meeting of the American Society of Colon and Rectal Surgeons.

So far, DLI allowed 91% of patients (31/34) to avoid urgent total colectomies. It’s “a safe alternative. Patients undergoing DLI have acceptably low complication rates and most are afforded time for medical and nutritional optimization prior to proceeding with their definitive surgical care,” said presenter Tara Russell, MD, a UCLA surgery resident.

“Currently, [almost every] patient presenting with acute colitis who we aren’t able to get to the point of discharge with medical optimization” is now offered rescue DLI at the university, and patients have been eager for a chance at avoiding total colectomy. The only patients who are not offered DLI are those with, for instance, fulminant toxic megacolon, Dr. Russell said.

The DLI approach failed in just 2 of the 18 ulcerative colitis patients and 1 of the 16 Crohn’s patients in the series. All three went on to emergent total colectomies 11-53 days after the procedure.

The majority of DLI patients tolerated oral intake by postop day 1, and the median time to resuming a regular diet was 2 days. Most people were discharged within a day or 2 of diversion, and a few took longer to achieve medical rescue. Almost 90% had an improvement in nutritional status, and over 80% went on to elective laparoscopic definitive procedures or colon salvage.

Two patients had postop wound infections, “but there were no other complications” with DLI, Dr. Russell said.

All DLIs were performed with a single-incision laparoscopic approach and took an average of about a half hour. Most of the diversions were in the right lower abdominal quadrant.

The mean age of the patients was 36 years, with a range of 16-81 years. Just over half were men. Of 21 patients who met systemic inflammatory response syndrome criteria at the time of operation, 13 (62%) resolved within 24 hours of DLI.
 

[email protected]

In a recent column entitled “To the limit,” I tried to make the case that the negative consequences of permissive parenting are numerous enough to warrant the attention of primary care pediatricians and family physicians. The evidence linking atypical sensory adaptation, behavior difficulties, sleep deprivation, and obesity to a permissive parenting style is just beginning to appear in the literature, but the numbers are in sync with the anecdotal observations of many experienced pediatricians like me. In that previous column, I offered to provide a more nuanced discussion of when and how clinicians might address the issue of permissive parenting with families in their practices.

First, let me make it clear that I don’t consider parenting style to be a topic that needs to occur on the checklist of every patient at every health maintenance visit. You already are overburdened with the demands of experts who have lobbied to have their favorite hot button issues included in your 15 minutes of face-to-face time with your young patients.

ChamilleWhite/Thinkstock

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

In a recent column entitled “To the limit,” I tried to make the case that the negative consequences of permissive parenting are numerous enough to warrant the attention of primary care pediatricians and family physicians. The evidence linking atypical sensory adaptation, behavior difficulties, sleep deprivation, and obesity to a permissive parenting style is just beginning to appear in the literature, but the numbers are in sync with the anecdotal observations of many experienced pediatricians like me. In that previous column, I offered to provide a more nuanced discussion of when and how clinicians might address the issue of permissive parenting with families in their practices.

First, let me make it clear that I don’t consider parenting style to be a topic that needs to occur on the checklist of every patient at every health maintenance visit. You already are overburdened with the demands of experts who have lobbied to have their favorite hot button issues included in your 15 minutes of face-to-face time with your young patients.

ChamilleWhite/Thinkstock

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

In a recent column entitled “To the limit,” I tried to make the case that the negative consequences of permissive parenting are numerous enough to warrant the attention of primary care pediatricians and family physicians. The evidence linking atypical sensory adaptation, behavior difficulties, sleep deprivation, and obesity to a permissive parenting style is just beginning to appear in the literature, but the numbers are in sync with the anecdotal observations of many experienced pediatricians like me. In that previous column, I offered to provide a more nuanced discussion of when and how clinicians might address the issue of permissive parenting with families in their practices.

First, let me make it clear that I don’t consider parenting style to be a topic that needs to occur on the checklist of every patient at every health maintenance visit. You already are overburdened with the demands of experts who have lobbied to have their favorite hot button issues included in your 15 minutes of face-to-face time with your young patients.

ChamilleWhite/Thinkstock

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

Do you believe that children whose parents can make and enforce rules are more likely to thrive than those children whose parents are hesitant to set limits? If you don’t see limit setting as a critical function of parenting, you and I are not only marching to different drummers, we aren’t even in the same parade.

You may be tempted to write me off as just another old school ranter because I believe that limit setting is one of the cornerstones of parenting. But, let’s look at some of the evidence. There are several studies demonstrating that children whose parents set bedtimes get more sleep. One recent survey also found that teenagers who got more sleep as a result of enforced bedtimes functioned better in school (Sleep. 2011 Jun 1;34[6]:797-800).

©iStockphoto

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.”

Do you believe that children whose parents can make and enforce rules are more likely to thrive than those children whose parents are hesitant to set limits? If you don’t see limit setting as a critical function of parenting, you and I are not only marching to different drummers, we aren’t even in the same parade.

You may be tempted to write me off as just another old school ranter because I believe that limit setting is one of the cornerstones of parenting. But, let’s look at some of the evidence. There are several studies demonstrating that children whose parents set bedtimes get more sleep. One recent survey also found that teenagers who got more sleep as a result of enforced bedtimes functioned better in school (Sleep. 2011 Jun 1;34[6]:797-800).

©iStockphoto

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.”

Do you believe that children whose parents can make and enforce rules are more likely to thrive than those children whose parents are hesitant to set limits? If you don’t see limit setting as a critical function of parenting, you and I are not only marching to different drummers, we aren’t even in the same parade.

You may be tempted to write me off as just another old school ranter because I believe that limit setting is one of the cornerstones of parenting. But, let’s look at some of the evidence. There are several studies demonstrating that children whose parents set bedtimes get more sleep. One recent survey also found that teenagers who got more sleep as a result of enforced bedtimes functioned better in school (Sleep. 2011 Jun 1;34[6]:797-800).

©iStockphoto

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.”

NEW YORK – The novel NF-kB inhibitor IT-901 appears active against Richter syndrome, according to in vitro analyses of primary leukemic cells and in vivo analyses in patient-derived xenograft models.

The findings suggest that NF-kB inhibition should be considered as a therapeutic strategy for Richter syndrome patients, Tiziana Vaisitti, PhD, said at the annual International Workshop on Chronic Lymphocytic Leukemia.

Several factors have been shown to be associated with the development of Richter syndrome (RS), including somatic and germline genetic characteristics, biologic and clinical features, and certain CLL therapies. Recent studies have identified a critical role of mutations in specific genes, such as CKN2A, TP53, and NOTCH1 in the transformation of CLL to RS, which ultimately results in the aberrant activation of selected pathways – including NF-kB, Dr. Vaisitti of the University of Turin and the Italian Institute for Genomic Medicine, Turin, Italy explained.

In an ongoing study on the effects of IT-901 in CLL, she and her colleagues showed that “this compound was able to interfere with NF-kB transcriptional activity.”

That effect is followed by rapid and marked reduction in “the oxidative phosphorylation capacity of CLL cells, determined also by the transcriptional regulation of genes that control this process.”

“Moreover, this compound induces a significant increase and release of mitochondrial reactive oxygen species,” she said, adding: “The final result of this cascade of events is that IT-901 is able to rapidly induce apoptosis selectively in primary CLL cells, independently of the clinical subgroup of patients we are considering, and with very little toxicity on normal lymphocytes.”

The experimental data indicated that IT-901 is effective not only on the leukemic side, but it also acts on the stromal bystander component of the disease, mainly on nurse-like cells, by modulating the expression of molecules critical for CLL survival, she said.

Those findings were reported at the 2016 American Society of Hematology annual meeting (Blood. 2016;128:304).

For the current analyses, she and her colleagues tested the effects of IT-901 in RS, which affects up to 10% of patients with CLL, and for which there is an unmet therapeutic need. They looked at the mechanisms of action of the compound in leukemic cells both in vitro and in vivo.

In line with previous data, NF-kB was “constitutively highly active in RS cells freshly isolated from patients,” she reported.

Exposure to IT-901 at a 5 microM dose for 6 hours significantly decreased binding of p50 and p65 to DNA, and western blotting analyses on nuclear extracts indicated impaired translocation of those subunits in the nucleus, and compromised expression of the whole NF-kB complex, she said.

IT-901 also induced apoptosis in primary RS cells in a dose- and time-dependent manner; significant efficacy was seen after 24 hours of treatment, with more than half of the cells dead.

These results were then confirmed in an RS cell line established in the lab from a patient-derived xenograft (PDX) model, and even in the presence of a protective stromal layer IT-901 was able to induce apoptosis, she said.

The effects of IT-901 treatment were then analyzed in vivo using 3 different PDX models established from primary cells of RS patients and characterized by different molecular and genetic features. RS cells obtained from the PDX-tumor mass, were subcutaneously injected in severely immune-compromised mice and left to engraft until a palpable mass was present. IT-901 was then administered at a dose of 15 mg/kg, every day for 2 weeks, with a 2 day break after 5 days of administration.

Tumor size was significantly reduced, and as was demonstrated in vitro, immune-histochemical analyses of the tumor mass showed diminished expression and localization of the p65 subunit into the nucleus of tumor cells and increased cleavage of Caspase-3 in the treated mice as compared with vehicle-treated mice.

The findings provide proof-of-principle that IT-901 is effective in RS cells, diminishing NF-kB transcriptional activity and expression, and finally inducing apoptosis, Dr. Vaisitti said.

Dr. Vaisitti has received research funding from Immune Target.

[email protected]

NEW YORK – The novel NF-kB inhibitor IT-901 appears active against Richter syndrome, according to in vitro analyses of primary leukemic cells and in vivo analyses in patient-derived xenograft models.

The findings suggest that NF-kB inhibition should be considered as a therapeutic strategy for Richter syndrome patients, Tiziana Vaisitti, PhD, said at the annual International Workshop on Chronic Lymphocytic Leukemia.

Several factors have been shown to be associated with the development of Richter syndrome (RS), including somatic and germline genetic characteristics, biologic and clinical features, and certain CLL therapies. Recent studies have identified a critical role of mutations in specific genes, such as CKN2A, TP53, and NOTCH1 in the transformation of CLL to RS, which ultimately results in the aberrant activation of selected pathways – including NF-kB, Dr. Vaisitti of the University of Turin and the Italian Institute for Genomic Medicine, Turin, Italy explained.

In an ongoing study on the effects of IT-901 in CLL, she and her colleagues showed that “this compound was able to interfere with NF-kB transcriptional activity.”

That effect is followed by rapid and marked reduction in “the oxidative phosphorylation capacity of CLL cells, determined also by the transcriptional regulation of genes that control this process.”

“Moreover, this compound induces a significant increase and release of mitochondrial reactive oxygen species,” she said, adding: “The final result of this cascade of events is that IT-901 is able to rapidly induce apoptosis selectively in primary CLL cells, independently of the clinical subgroup of patients we are considering, and with very little toxicity on normal lymphocytes.”

The experimental data indicated that IT-901 is effective not only on the leukemic side, but it also acts on the stromal bystander component of the disease, mainly on nurse-like cells, by modulating the expression of molecules critical for CLL survival, she said.

Those findings were reported at the 2016 American Society of Hematology annual meeting (Blood. 2016;128:304).

For the current analyses, she and her colleagues tested the effects of IT-901 in RS, which affects up to 10% of patients with CLL, and for which there is an unmet therapeutic need. They looked at the mechanisms of action of the compound in leukemic cells both in vitro and in vivo.

In line with previous data, NF-kB was “constitutively highly active in RS cells freshly isolated from patients,” she reported.

Exposure to IT-901 at a 5 microM dose for 6 hours significantly decreased binding of p50 and p65 to DNA, and western blotting analyses on nuclear extracts indicated impaired translocation of those subunits in the nucleus, and compromised expression of the whole NF-kB complex, she said.

IT-901 also induced apoptosis in primary RS cells in a dose- and time-dependent manner; significant efficacy was seen after 24 hours of treatment, with more than half of the cells dead.

These results were then confirmed in an RS cell line established in the lab from a patient-derived xenograft (PDX) model, and even in the presence of a protective stromal layer IT-901 was able to induce apoptosis, she said.

The effects of IT-901 treatment were then analyzed in vivo using 3 different PDX models established from primary cells of RS patients and characterized by different molecular and genetic features. RS cells obtained from the PDX-tumor mass, were subcutaneously injected in severely immune-compromised mice and left to engraft until a palpable mass was present. IT-901 was then administered at a dose of 15 mg/kg, every day for 2 weeks, with a 2 day break after 5 days of administration.

Tumor size was significantly reduced, and as was demonstrated in vitro, immune-histochemical analyses of the tumor mass showed diminished expression and localization of the p65 subunit into the nucleus of tumor cells and increased cleavage of Caspase-3 in the treated mice as compared with vehicle-treated mice.

The findings provide proof-of-principle that IT-901 is effective in RS cells, diminishing NF-kB transcriptional activity and expression, and finally inducing apoptosis, Dr. Vaisitti said.

Dr. Vaisitti has received research funding from Immune Target.

[email protected]

NEW YORK – The novel NF-kB inhibitor IT-901 appears active against Richter syndrome, according to in vitro analyses of primary leukemic cells and in vivo analyses in patient-derived xenograft models.

The findings suggest that NF-kB inhibition should be considered as a therapeutic strategy for Richter syndrome patients, Tiziana Vaisitti, PhD, said at the annual International Workshop on Chronic Lymphocytic Leukemia.

Several factors have been shown to be associated with the development of Richter syndrome (RS), including somatic and germline genetic characteristics, biologic and clinical features, and certain CLL therapies. Recent studies have identified a critical role of mutations in specific genes, such as CKN2A, TP53, and NOTCH1 in the transformation of CLL to RS, which ultimately results in the aberrant activation of selected pathways – including NF-kB, Dr. Vaisitti of the University of Turin and the Italian Institute for Genomic Medicine, Turin, Italy explained.

In an ongoing study on the effects of IT-901 in CLL, she and her colleagues showed that “this compound was able to interfere with NF-kB transcriptional activity.”

That effect is followed by rapid and marked reduction in “the oxidative phosphorylation capacity of CLL cells, determined also by the transcriptional regulation of genes that control this process.”

“Moreover, this compound induces a significant increase and release of mitochondrial reactive oxygen species,” she said, adding: “The final result of this cascade of events is that IT-901 is able to rapidly induce apoptosis selectively in primary CLL cells, independently of the clinical subgroup of patients we are considering, and with very little toxicity on normal lymphocytes.”

The experimental data indicated that IT-901 is effective not only on the leukemic side, but it also acts on the stromal bystander component of the disease, mainly on nurse-like cells, by modulating the expression of molecules critical for CLL survival, she said.

Those findings were reported at the 2016 American Society of Hematology annual meeting (Blood. 2016;128:304).

For the current analyses, she and her colleagues tested the effects of IT-901 in RS, which affects up to 10% of patients with CLL, and for which there is an unmet therapeutic need. They looked at the mechanisms of action of the compound in leukemic cells both in vitro and in vivo.

In line with previous data, NF-kB was “constitutively highly active in RS cells freshly isolated from patients,” she reported.

Exposure to IT-901 at a 5 microM dose for 6 hours significantly decreased binding of p50 and p65 to DNA, and western blotting analyses on nuclear extracts indicated impaired translocation of those subunits in the nucleus, and compromised expression of the whole NF-kB complex, she said.

IT-901 also induced apoptosis in primary RS cells in a dose- and time-dependent manner; significant efficacy was seen after 24 hours of treatment, with more than half of the cells dead.

These results were then confirmed in an RS cell line established in the lab from a patient-derived xenograft (PDX) model, and even in the presence of a protective stromal layer IT-901 was able to induce apoptosis, she said.

The effects of IT-901 treatment were then analyzed in vivo using 3 different PDX models established from primary cells of RS patients and characterized by different molecular and genetic features. RS cells obtained from the PDX-tumor mass, were subcutaneously injected in severely immune-compromised mice and left to engraft until a palpable mass was present. IT-901 was then administered at a dose of 15 mg/kg, every day for 2 weeks, with a 2 day break after 5 days of administration.

Tumor size was significantly reduced, and as was demonstrated in vitro, immune-histochemical analyses of the tumor mass showed diminished expression and localization of the p65 subunit into the nucleus of tumor cells and increased cleavage of Caspase-3 in the treated mice as compared with vehicle-treated mice.

The findings provide proof-of-principle that IT-901 is effective in RS cells, diminishing NF-kB transcriptional activity and expression, and finally inducing apoptosis, Dr. Vaisitti said.

Dr. Vaisitti has received research funding from Immune Target.

[email protected]