Leukemia, Myelodysplasia, Transplantation

At least 2% of people over the age of 40 and 5% over age 70 have mutations linked to leukemia and lymphoma, according to research published in Nature Medicine.

The findings, based on blood samples from nearly 3000 patients, don’t necessarily mean that people with these mutations will develop leukemia or lymphoma.

They may have a higher-than-normal risk of developing these malignancies, but more research is needed to determine the risk.

“We would not want anyone to think they should be screened for these mutations to understand their risk of leukemia or lymphoma,” said Timothy Ley, MD, of the Washington University School of Medicine in St Louis, Missouri.

“The ability to understand how mutations in these genes increase a person’s risk of blood cancers is a long way off, and genetic testing would be of no benefit at this time.”

Dr Ley and his colleagues analyzed blood samples from people enrolled in The Cancer Genome Atlas project. The patients had been diagnosed with cancer but were not known to have leukemia, lymphoma, or a blood disease.

They ranged in age from 10 to 90 at the time of diagnosis and had donated blood and tumor samples before starting cancer treatment. Therefore, any mutations the researchers identified would not have been associated with chemotherapy or radiation.

The team looked closely at 556 known cancer genes. In 341 patients ages 40 to 49, fewer than 1% had mutations in 19 leukemia- or lymphoma-related genes.

But among 475 people ages 70 to 79, more than 5% did. And more than 6% of the 132 people ages 80 to 89 had mutations in these genes.

The researchers noted that 9 of the 19 genes were mutated repeatedly, an indicator that the changes drive or initiate the expansion of blood cells.

This expansion of cells is clearly not leukemia or lymphoma, the researchers said. It may be a precursor to hematologic malignancies in a small subset of patients, but the study was not designed to predict the future risk of developing these diseases.

The researchers also said this study likely underestimates the percentage of people with mutations in leukemia and lymphoma genes because the team was only able to identify small mutations, not large structural variations or the insertions and deletions of chunks of genetic material.

At least 2% of people over the age of 40 and 5% over age 70 have mutations linked to leukemia and lymphoma, according to research published in Nature Medicine.

The findings, based on blood samples from nearly 3000 patients, don’t necessarily mean that people with these mutations will develop leukemia or lymphoma.

They may have a higher-than-normal risk of developing these malignancies, but more research is needed to determine the risk.

“We would not want anyone to think they should be screened for these mutations to understand their risk of leukemia or lymphoma,” said Timothy Ley, MD, of the Washington University School of Medicine in St Louis, Missouri.

“The ability to understand how mutations in these genes increase a person’s risk of blood cancers is a long way off, and genetic testing would be of no benefit at this time.”

Dr Ley and his colleagues analyzed blood samples from people enrolled in The Cancer Genome Atlas project. The patients had been diagnosed with cancer but were not known to have leukemia, lymphoma, or a blood disease.

They ranged in age from 10 to 90 at the time of diagnosis and had donated blood and tumor samples before starting cancer treatment. Therefore, any mutations the researchers identified would not have been associated with chemotherapy or radiation.

The team looked closely at 556 known cancer genes. In 341 patients ages 40 to 49, fewer than 1% had mutations in 19 leukemia- or lymphoma-related genes.

But among 475 people ages 70 to 79, more than 5% did. And more than 6% of the 132 people ages 80 to 89 had mutations in these genes.

The researchers noted that 9 of the 19 genes were mutated repeatedly, an indicator that the changes drive or initiate the expansion of blood cells.

This expansion of cells is clearly not leukemia or lymphoma, the researchers said. It may be a precursor to hematologic malignancies in a small subset of patients, but the study was not designed to predict the future risk of developing these diseases.

The researchers also said this study likely underestimates the percentage of people with mutations in leukemia and lymphoma genes because the team was only able to identify small mutations, not large structural variations or the insertions and deletions of chunks of genetic material.

At least 2% of people over the age of 40 and 5% over age 70 have mutations linked to leukemia and lymphoma, according to research published in Nature Medicine.

The findings, based on blood samples from nearly 3000 patients, don’t necessarily mean that people with these mutations will develop leukemia or lymphoma.

They may have a higher-than-normal risk of developing these malignancies, but more research is needed to determine the risk.

“We would not want anyone to think they should be screened for these mutations to understand their risk of leukemia or lymphoma,” said Timothy Ley, MD, of the Washington University School of Medicine in St Louis, Missouri.

“The ability to understand how mutations in these genes increase a person’s risk of blood cancers is a long way off, and genetic testing would be of no benefit at this time.”

Dr Ley and his colleagues analyzed blood samples from people enrolled in The Cancer Genome Atlas project. The patients had been diagnosed with cancer but were not known to have leukemia, lymphoma, or a blood disease.

They ranged in age from 10 to 90 at the time of diagnosis and had donated blood and tumor samples before starting cancer treatment. Therefore, any mutations the researchers identified would not have been associated with chemotherapy or radiation.

The team looked closely at 556 known cancer genes. In 341 patients ages 40 to 49, fewer than 1% had mutations in 19 leukemia- or lymphoma-related genes.

But among 475 people ages 70 to 79, more than 5% did. And more than 6% of the 132 people ages 80 to 89 had mutations in these genes.

The researchers noted that 9 of the 19 genes were mutated repeatedly, an indicator that the changes drive or initiate the expansion of blood cells.

This expansion of cells is clearly not leukemia or lymphoma, the researchers said. It may be a precursor to hematologic malignancies in a small subset of patients, but the study was not designed to predict the future risk of developing these diseases.

The researchers also said this study likely underestimates the percentage of people with mutations in leukemia and lymphoma genes because the team was only able to identify small mutations, not large structural variations or the insertions and deletions of chunks of genetic material.

Prescription medications

Credit: Steven Harbour

The European Commission has granted marketing approval for the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) in the European Union (EU).

The drug is now approved to treat adult patients with relapsed or refractory mantle cell lymphoma (MCL), adults with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, and first-line CLL patients who have 17p deletion or TP53 mutation and are unsuitable for chemotherapy.

In the EU and all other countries except the US, ibrutinib is marketed by Janssen Pharmaceutical Companies. In the US, the drug is being jointly developed and commercialized by Pharmacyclics and Janssen Biotech, Inc.

The EU approval of ibrutinib was based on data from a phase 2 study (PCYC-1104) in patients with MCL, the phase 3 RESONATE trial (PCYC-1112-CA) in CLL and small lymphocytic lymphoma (SLL), and a phase 1b/2 study (PCYC-1102) in CLL/SLL.

PCYC-1104: Ibrutinib in MCL

Results of this trial were presented at ASH 2012 and published in NEJM in 2013. The NEJM data included 111 patients who received ibrutinib at 560 mg daily in continuous, 28-day cycles until disease progression.

The overall response rate was 68%, with a complete response rate of 21% and a partial response rate of 47%. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months.

The estimated progression-free survival was 13.9 months, and the overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.

Common nonhematologic adverse events included diarrhea (50%), fatigue (41%), nausea (31%), peripheral edema (28%), dyspnea (27%), constipation (25%), upper respiratory tract infection (23%), vomiting (23%), and decreased appetite (21%). The most common grade 3, 4, or 5 infection was pneumonia (6%).

Grade 3 and 4 hematologic adverse events included neutropenia (16%), thrombocytopenia (11%), and anemia (10%). Grade 3 bleeding events occurred in 5 patients.

RESONATE: Ibrutinib in CLL/SLL

Results of the RESONATE trial were reported at EHA 2014 and published in NEJM in July. This trial was stopped early after an interim analysis showed that ibrutinib-treated patients experienced a 78% reduction in the risk of disease progression or death.

The trial included 391 patients with relapsed or refractory CLL or SLL who were randomized to receive ibrutinib (n=195) or ofatumumab (n=196). Patients in the ofatumumab arm were allowed to cross over to ibrutinib if they progressed (n=57). The median time on study was 9.4 months.

The best overall response rate was higher in the ibrutinib arm than the ofatumumab arm, at 78% and 11%, respectively. And ibrutinib significantly prolonged progression-free survival. The median was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001).

Ibrutinib significantly prolonged overall survival as well. The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).

Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39% of patients, respectively.

Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.

PCYC-1102: Ibrutinib in CLL/SLL

Results of this phase 1b/2 trial were published in The Lancet Oncology in January. The trial enrolled 29 patients with previously untreated CLL and 2 with SLL.

They received 28-day cycles of once-daily ibrutinib at 420 mg or 840 mg. The 840 mg dose was discontinued after enrollment had begun because the doses showed comparable activity.

After a median follow-up of 22.1 months, 71% of patients achieved an objective response. Four patients (13%) had a complete response. The median time to response was 1.9 months.

Study investigators did not establish whether ibrutinib confers improvements in survival or disease-related symptoms.

Common adverse events included diarrhea (68%), nausea (48%), fatigue (32%), peripheral edema (29%), hypertension (29%), dizziness (26%), dyspepsia (26%), upper respiratory tract infection (26%), arthralgia (23%), constipation (23%), urinary tract infection (23%), and vomiting (23%).

Grade 3 adverse events included diarrhea (13%), fatigue (3%), hypertension (6%), dizziness (3%), urinary tract infection (3%), headache (3%), back pain (3%), and neutropenia (3%). One patient (3%) had grade 4 thrombocytopenia.

Prescription medications

Credit: Steven Harbour

The European Commission has granted marketing approval for the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) in the European Union (EU).

The drug is now approved to treat adult patients with relapsed or refractory mantle cell lymphoma (MCL), adults with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, and first-line CLL patients who have 17p deletion or TP53 mutation and are unsuitable for chemotherapy.

In the EU and all other countries except the US, ibrutinib is marketed by Janssen Pharmaceutical Companies. In the US, the drug is being jointly developed and commercialized by Pharmacyclics and Janssen Biotech, Inc.

The EU approval of ibrutinib was based on data from a phase 2 study (PCYC-1104) in patients with MCL, the phase 3 RESONATE trial (PCYC-1112-CA) in CLL and small lymphocytic lymphoma (SLL), and a phase 1b/2 study (PCYC-1102) in CLL/SLL.

PCYC-1104: Ibrutinib in MCL

Results of this trial were presented at ASH 2012 and published in NEJM in 2013. The NEJM data included 111 patients who received ibrutinib at 560 mg daily in continuous, 28-day cycles until disease progression.

The overall response rate was 68%, with a complete response rate of 21% and a partial response rate of 47%. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months.

The estimated progression-free survival was 13.9 months, and the overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.

Common nonhematologic adverse events included diarrhea (50%), fatigue (41%), nausea (31%), peripheral edema (28%), dyspnea (27%), constipation (25%), upper respiratory tract infection (23%), vomiting (23%), and decreased appetite (21%). The most common grade 3, 4, or 5 infection was pneumonia (6%).

Grade 3 and 4 hematologic adverse events included neutropenia (16%), thrombocytopenia (11%), and anemia (10%). Grade 3 bleeding events occurred in 5 patients.

RESONATE: Ibrutinib in CLL/SLL

Results of the RESONATE trial were reported at EHA 2014 and published in NEJM in July. This trial was stopped early after an interim analysis showed that ibrutinib-treated patients experienced a 78% reduction in the risk of disease progression or death.

The trial included 391 patients with relapsed or refractory CLL or SLL who were randomized to receive ibrutinib (n=195) or ofatumumab (n=196). Patients in the ofatumumab arm were allowed to cross over to ibrutinib if they progressed (n=57). The median time on study was 9.4 months.

The best overall response rate was higher in the ibrutinib arm than the ofatumumab arm, at 78% and 11%, respectively. And ibrutinib significantly prolonged progression-free survival. The median was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001).

Ibrutinib significantly prolonged overall survival as well. The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).

Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39% of patients, respectively.

Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.

PCYC-1102: Ibrutinib in CLL/SLL

Results of this phase 1b/2 trial were published in The Lancet Oncology in January. The trial enrolled 29 patients with previously untreated CLL and 2 with SLL.

They received 28-day cycles of once-daily ibrutinib at 420 mg or 840 mg. The 840 mg dose was discontinued after enrollment had begun because the doses showed comparable activity.

After a median follow-up of 22.1 months, 71% of patients achieved an objective response. Four patients (13%) had a complete response. The median time to response was 1.9 months.

Study investigators did not establish whether ibrutinib confers improvements in survival or disease-related symptoms.

Common adverse events included diarrhea (68%), nausea (48%), fatigue (32%), peripheral edema (29%), hypertension (29%), dizziness (26%), dyspepsia (26%), upper respiratory tract infection (26%), arthralgia (23%), constipation (23%), urinary tract infection (23%), and vomiting (23%).

Grade 3 adverse events included diarrhea (13%), fatigue (3%), hypertension (6%), dizziness (3%), urinary tract infection (3%), headache (3%), back pain (3%), and neutropenia (3%). One patient (3%) had grade 4 thrombocytopenia.

Prescription medications

Credit: Steven Harbour

The European Commission has granted marketing approval for the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) in the European Union (EU).

The drug is now approved to treat adult patients with relapsed or refractory mantle cell lymphoma (MCL), adults with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, and first-line CLL patients who have 17p deletion or TP53 mutation and are unsuitable for chemotherapy.

In the EU and all other countries except the US, ibrutinib is marketed by Janssen Pharmaceutical Companies. In the US, the drug is being jointly developed and commercialized by Pharmacyclics and Janssen Biotech, Inc.

The EU approval of ibrutinib was based on data from a phase 2 study (PCYC-1104) in patients with MCL, the phase 3 RESONATE trial (PCYC-1112-CA) in CLL and small lymphocytic lymphoma (SLL), and a phase 1b/2 study (PCYC-1102) in CLL/SLL.

PCYC-1104: Ibrutinib in MCL

Results of this trial were presented at ASH 2012 and published in NEJM in 2013. The NEJM data included 111 patients who received ibrutinib at 560 mg daily in continuous, 28-day cycles until disease progression.

The overall response rate was 68%, with a complete response rate of 21% and a partial response rate of 47%. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months.

The estimated progression-free survival was 13.9 months, and the overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.

Common nonhematologic adverse events included diarrhea (50%), fatigue (41%), nausea (31%), peripheral edema (28%), dyspnea (27%), constipation (25%), upper respiratory tract infection (23%), vomiting (23%), and decreased appetite (21%). The most common grade 3, 4, or 5 infection was pneumonia (6%).

Grade 3 and 4 hematologic adverse events included neutropenia (16%), thrombocytopenia (11%), and anemia (10%). Grade 3 bleeding events occurred in 5 patients.

RESONATE: Ibrutinib in CLL/SLL

Results of the RESONATE trial were reported at EHA 2014 and published in NEJM in July. This trial was stopped early after an interim analysis showed that ibrutinib-treated patients experienced a 78% reduction in the risk of disease progression or death.

The trial included 391 patients with relapsed or refractory CLL or SLL who were randomized to receive ibrutinib (n=195) or ofatumumab (n=196). Patients in the ofatumumab arm were allowed to cross over to ibrutinib if they progressed (n=57). The median time on study was 9.4 months.

The best overall response rate was higher in the ibrutinib arm than the ofatumumab arm, at 78% and 11%, respectively. And ibrutinib significantly prolonged progression-free survival. The median was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001).

Ibrutinib significantly prolonged overall survival as well. The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).

Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39% of patients, respectively.

Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.

PCYC-1102: Ibrutinib in CLL/SLL

Results of this phase 1b/2 trial were published in The Lancet Oncology in January. The trial enrolled 29 patients with previously untreated CLL and 2 with SLL.

They received 28-day cycles of once-daily ibrutinib at 420 mg or 840 mg. The 840 mg dose was discontinued after enrollment had begun because the doses showed comparable activity.

After a median follow-up of 22.1 months, 71% of patients achieved an objective response. Four patients (13%) had a complete response. The median time to response was 1.9 months.

Study investigators did not establish whether ibrutinib confers improvements in survival or disease-related symptoms.

Common adverse events included diarrhea (68%), nausea (48%), fatigue (32%), peripheral edema (29%), hypertension (29%), dizziness (26%), dyspepsia (26%), upper respiratory tract infection (26%), arthralgia (23%), constipation (23%), urinary tract infection (23%), and vomiting (23%).

Grade 3 adverse events included diarrhea (13%), fatigue (3%), hypertension (6%), dizziness (3%), urinary tract infection (3%), headache (3%), back pain (3%), and neutropenia (3%). One patient (3%) had grade 4 thrombocytopenia.

An NK cell in action

Credit: Bjorn Onfelt/Dan Davis

Inhibiting STAT3 in natural killer (NK) cells can kill leukemia in two ways, according to research published in Blood.

In mouse models lacking STAT3, NK cells were still able to develop normally, and the loss of STAT3 prompted an increase in antileukemic activity.

Mice whose NK cells lacked STAT3 showed a reduction in tumor growth and an increase in survival compared to controls.

Similar results were observed in mouse models of melanoma.

“We were expecting the loss of STAT3 to make the NK cells less efficient,” said study author Dagmar Gotthardt, of the University of Veterinary Medicine, Vienna (Vetmeduni Vienna).

“Instead, it makes them even more potent killers. Inhibiting STAT3 could thus help cancer patients in two ways: both stopping the cancer cells from dividing and helping the patients’ NK cells to fight them more efficiently.”

Researchers are already attempting to develop STAT3 inhibitors for cancer therapy, but their effect on NK cells was not known.

So Gotthardt and her colleagues assessed the function of STAT3 in NK cells using Stat3^Δ/ΔNcr1-iCreTg mice, whose NK cells lack STAT3.

The team discovered that NK cells lacking STAT3 still develop and mature normally, but they do have alterations in the kinetics of interferon-γ production. In addition, there is a consistent increase in levels of perforin, granzyme B, and DNAM-1 in the absence of STAT3.

The investigators also found the loss of STAT3 in NK cells improved tumor surveillance against leukemia.

They injected v-abl1 leukemic cell lines into Stat3^fl/fl and Stat3^Δ/ΔNcr1-iCreTg mice. After 12 days, the Stat3^fl/fl mice had large tumors, but there was “a pronounced reduction of tumor mass” in the Stat3^Δ/ΔNcr1-iCreTg mice.

The researchers then injected 2 individually derived leukemic cell lines into Stat3^fl/fl and Stat3^Δ/ΔNcr1-iCreTg mice. And the results were similar to those of the previous experiment. Stat3^Δ/ΔNcr1-iCreTg mice survived significantly longer than Stat3^fl/fl mice (P=0.0002).

Next, the investigators injected newborn mice with a replication-incompetent ecotropic retrovirus encoding for v-abl, as this model more closely mimics the development of human disease.

Again, there was a significant difference in survival between Stat3^fl/fl mice and Stat3^Δ/ΔNcr1-iCreTg mice (P=0.007). All Stat3^fl/fl mice died, but 20% of Stat3^Δ/ΔNcr1-iCreTg mice were still alive at 150 days post-injection, and their disease latency was significantly delayed.

The researchers also found that loss of STAT3 in NK cells led to an increase in killing activity against melanoma cells. They said the decrease in metastasis caused by melanoma cells was especially dramatic and confirmed that NK cells lacking STAT3 are extremely efficient killers of tumor cells.

An NK cell in action

Credit: Bjorn Onfelt/Dan Davis

Inhibiting STAT3 in natural killer (NK) cells can kill leukemia in two ways, according to research published in Blood.

In mouse models lacking STAT3, NK cells were still able to develop normally, and the loss of STAT3 prompted an increase in antileukemic activity.

Mice whose NK cells lacked STAT3 showed a reduction in tumor growth and an increase in survival compared to controls.

Similar results were observed in mouse models of melanoma.

“We were expecting the loss of STAT3 to make the NK cells less efficient,” said study author Dagmar Gotthardt, of the University of Veterinary Medicine, Vienna (Vetmeduni Vienna).

“Instead, it makes them even more potent killers. Inhibiting STAT3 could thus help cancer patients in two ways: both stopping the cancer cells from dividing and helping the patients’ NK cells to fight them more efficiently.”

Researchers are already attempting to develop STAT3 inhibitors for cancer therapy, but their effect on NK cells was not known.

So Gotthardt and her colleagues assessed the function of STAT3 in NK cells using Stat3^Δ/ΔNcr1-iCreTg mice, whose NK cells lack STAT3.

The team discovered that NK cells lacking STAT3 still develop and mature normally, but they do have alterations in the kinetics of interferon-γ production. In addition, there is a consistent increase in levels of perforin, granzyme B, and DNAM-1 in the absence of STAT3.

The investigators also found the loss of STAT3 in NK cells improved tumor surveillance against leukemia.

They injected v-abl1 leukemic cell lines into Stat3^fl/fl and Stat3^Δ/ΔNcr1-iCreTg mice. After 12 days, the Stat3^fl/fl mice had large tumors, but there was “a pronounced reduction of tumor mass” in the Stat3^Δ/ΔNcr1-iCreTg mice.

The researchers then injected 2 individually derived leukemic cell lines into Stat3^fl/fl and Stat3^Δ/ΔNcr1-iCreTg mice. And the results were similar to those of the previous experiment. Stat3^Δ/ΔNcr1-iCreTg mice survived significantly longer than Stat3^fl/fl mice (P=0.0002).

Next, the investigators injected newborn mice with a replication-incompetent ecotropic retrovirus encoding for v-abl, as this model more closely mimics the development of human disease.

Again, there was a significant difference in survival between Stat3^fl/fl mice and Stat3^Δ/ΔNcr1-iCreTg mice (P=0.007). All Stat3^fl/fl mice died, but 20% of Stat3^Δ/ΔNcr1-iCreTg mice were still alive at 150 days post-injection, and their disease latency was significantly delayed.

The researchers also found that loss of STAT3 in NK cells led to an increase in killing activity against melanoma cells. They said the decrease in metastasis caused by melanoma cells was especially dramatic and confirmed that NK cells lacking STAT3 are extremely efficient killers of tumor cells.

An NK cell in action

Credit: Bjorn Onfelt/Dan Davis

Inhibiting STAT3 in natural killer (NK) cells can kill leukemia in two ways, according to research published in Blood.

In mouse models lacking STAT3, NK cells were still able to develop normally, and the loss of STAT3 prompted an increase in antileukemic activity.

Mice whose NK cells lacked STAT3 showed a reduction in tumor growth and an increase in survival compared to controls.

Similar results were observed in mouse models of melanoma.

“We were expecting the loss of STAT3 to make the NK cells less efficient,” said study author Dagmar Gotthardt, of the University of Veterinary Medicine, Vienna (Vetmeduni Vienna).

“Instead, it makes them even more potent killers. Inhibiting STAT3 could thus help cancer patients in two ways: both stopping the cancer cells from dividing and helping the patients’ NK cells to fight them more efficiently.”

Researchers are already attempting to develop STAT3 inhibitors for cancer therapy, but their effect on NK cells was not known.

So Gotthardt and her colleagues assessed the function of STAT3 in NK cells using Stat3^Δ/ΔNcr1-iCreTg mice, whose NK cells lack STAT3.

The team discovered that NK cells lacking STAT3 still develop and mature normally, but they do have alterations in the kinetics of interferon-γ production. In addition, there is a consistent increase in levels of perforin, granzyme B, and DNAM-1 in the absence of STAT3.

The investigators also found the loss of STAT3 in NK cells improved tumor surveillance against leukemia.

They injected v-abl1 leukemic cell lines into Stat3^fl/fl and Stat3^Δ/ΔNcr1-iCreTg mice. After 12 days, the Stat3^fl/fl mice had large tumors, but there was “a pronounced reduction of tumor mass” in the Stat3^Δ/ΔNcr1-iCreTg mice.

The researchers then injected 2 individually derived leukemic cell lines into Stat3^fl/fl and Stat3^Δ/ΔNcr1-iCreTg mice. And the results were similar to those of the previous experiment. Stat3^Δ/ΔNcr1-iCreTg mice survived significantly longer than Stat3^fl/fl mice (P=0.0002).

Next, the investigators injected newborn mice with a replication-incompetent ecotropic retrovirus encoding for v-abl, as this model more closely mimics the development of human disease.

Again, there was a significant difference in survival between Stat3^fl/fl mice and Stat3^Δ/ΔNcr1-iCreTg mice (P=0.007). All Stat3^fl/fl mice died, but 20% of Stat3^Δ/ΔNcr1-iCreTg mice were still alive at 150 days post-injection, and their disease latency was significantly delayed.

The researchers also found that loss of STAT3 in NK cells led to an increase in killing activity against melanoma cells. They said the decrease in metastasis caused by melanoma cells was especially dramatic and confirmed that NK cells lacking STAT3 are extremely efficient killers of tumor cells.

CTL019 preparation

Credit: Penn Medicine

In a small study, 90% of children and adults with relapsed or refractory acute lymphoblastic leukemia (ALL) achieved remission after receiving CTL019, a chimeric antigen receptor (CAR) T-cell therapy.

Seven of these 27 patients ultimately relapsed, and 5 went on to receive additional therapy, including stem cell transplant.

Still, 15 of these heavily pretreated patients remained in remission at a median of 7 months of follow-up and did not require further treatment.

“[Patients] had relapsed as many as 4 times, including 60% whose cancers came back even after stem cell transplants,” said Stephan Grupp, MD, PhD, of the Children’s Hospital of Philadelphia in Pennsylvania.

“Their cancers were so aggressive they had no treatment options left. The durable responses we have observed with CTL019 therapy are unprecedented.”

Dr Grupp and his colleagues reported these results in NEJM. The new data build on preliminary findings presented at the 2013 ASH Annual Meeting and the 2012 ASH Annual Meeting.

CTL019 cells are a patient’s own T cells genetically engineered to express an anti-CD19 scFv coupled to CD3ζ signaling and 4-1BB co-stimulatory domains. The cells are activated and expanded ex vivo with anti-CD3 and anti-CD28 beads, then infused into patients.

In all, 30 patients received CTL019, including 25 children and young adults (ages 5 to 22) and 5 adults (ages 26 to 60). Three patients had primary refractory disease, 5 had relapsed once, and 22 patients had relapsed 2 or more times. Eighteen patients had received an allogeneic stem cell transplant.

Twenty-seven patients achieved a complete remission after an infusion of CTL019. Nineteen patients remain in remission, 15 of whom received CTL019 alone. Follow-up ranged from 1.4 months to 24 months.

Tests in patients who experienced complete remissions showed that their normal B cells had been eliminated along with their tumors. The researchers noted that persistent absence of normal B cells following CTL019 treatment indicates continued activity of the CAR T cells.

“Our results support that CTL019 can produce long-lasting remissions for certain heavily pretreated ALL patients without further therapy,” said Noelle Frey, MD, of the University of Pennsylvania in Philadelphia.

However, 5 patients did seek additional therapy, 3 of whom proceeded to allogeneic stem cell transplants while in remission.

Seven patients relapsed, between 6 weeks and 8.5 months after their infusions, including 3 whose cancers returned as CD19-negative leukemia that would not have been targeted by CTL019.

At 6 months, the overall survival rate was 78%, and the event-free survival rate was 67%.

All of the patients experienced cytokine release syndrome (CRS) within a few days of receiving CTL019, but they all fully recovered.

Twenty-two patients experienced mild to moderate CRS, which included varying degrees of flu-like symptoms, with high fevers, nausea, and muscle pain. Eight patients developed severe CRS, which required treatment for low blood pressure and breathing difficulties.

Nine patients were treated with tocilizumab, an immunosuppressant that inhibits the effects of the inflammatory cytokine IL-6, which have been found to spike during the most robust phase of the CAR T cells’ expansion in the body. Six patients also received short courses of steroids to combat CRS symptoms.

CTL019 was invented at The University of Pennsylvania but has been licensed to Novartis. In July, the US Food and Drug Administration granted CTL019 breakthrough therapy designation for the treatment of relapsed and refractory adult and pediatric ALL.

The first multicenter trial of CTL019 recently opened in the US, and additional multisite trials are expected to begin by the end of the year.

CTL019 preparation

Credit: Penn Medicine

In a small study, 90% of children and adults with relapsed or refractory acute lymphoblastic leukemia (ALL) achieved remission after receiving CTL019, a chimeric antigen receptor (CAR) T-cell therapy.

Seven of these 27 patients ultimately relapsed, and 5 went on to receive additional therapy, including stem cell transplant.

Still, 15 of these heavily pretreated patients remained in remission at a median of 7 months of follow-up and did not require further treatment.

“[Patients] had relapsed as many as 4 times, including 60% whose cancers came back even after stem cell transplants,” said Stephan Grupp, MD, PhD, of the Children’s Hospital of Philadelphia in Pennsylvania.

“Their cancers were so aggressive they had no treatment options left. The durable responses we have observed with CTL019 therapy are unprecedented.”

Dr Grupp and his colleagues reported these results in NEJM. The new data build on preliminary findings presented at the 2013 ASH Annual Meeting and the 2012 ASH Annual Meeting.

CTL019 cells are a patient’s own T cells genetically engineered to express an anti-CD19 scFv coupled to CD3ζ signaling and 4-1BB co-stimulatory domains. The cells are activated and expanded ex vivo with anti-CD3 and anti-CD28 beads, then infused into patients.

In all, 30 patients received CTL019, including 25 children and young adults (ages 5 to 22) and 5 adults (ages 26 to 60). Three patients had primary refractory disease, 5 had relapsed once, and 22 patients had relapsed 2 or more times. Eighteen patients had received an allogeneic stem cell transplant.

Twenty-seven patients achieved a complete remission after an infusion of CTL019. Nineteen patients remain in remission, 15 of whom received CTL019 alone. Follow-up ranged from 1.4 months to 24 months.

Tests in patients who experienced complete remissions showed that their normal B cells had been eliminated along with their tumors. The researchers noted that persistent absence of normal B cells following CTL019 treatment indicates continued activity of the CAR T cells.

“Our results support that CTL019 can produce long-lasting remissions for certain heavily pretreated ALL patients without further therapy,” said Noelle Frey, MD, of the University of Pennsylvania in Philadelphia.

However, 5 patients did seek additional therapy, 3 of whom proceeded to allogeneic stem cell transplants while in remission.

Seven patients relapsed, between 6 weeks and 8.5 months after their infusions, including 3 whose cancers returned as CD19-negative leukemia that would not have been targeted by CTL019.

At 6 months, the overall survival rate was 78%, and the event-free survival rate was 67%.

All of the patients experienced cytokine release syndrome (CRS) within a few days of receiving CTL019, but they all fully recovered.

Twenty-two patients experienced mild to moderate CRS, which included varying degrees of flu-like symptoms, with high fevers, nausea, and muscle pain. Eight patients developed severe CRS, which required treatment for low blood pressure and breathing difficulties.

Nine patients were treated with tocilizumab, an immunosuppressant that inhibits the effects of the inflammatory cytokine IL-6, which have been found to spike during the most robust phase of the CAR T cells’ expansion in the body. Six patients also received short courses of steroids to combat CRS symptoms.

CTL019 was invented at The University of Pennsylvania but has been licensed to Novartis. In July, the US Food and Drug Administration granted CTL019 breakthrough therapy designation for the treatment of relapsed and refractory adult and pediatric ALL.

The first multicenter trial of CTL019 recently opened in the US, and additional multisite trials are expected to begin by the end of the year.

CTL019 preparation

Credit: Penn Medicine

In a small study, 90% of children and adults with relapsed or refractory acute lymphoblastic leukemia (ALL) achieved remission after receiving CTL019, a chimeric antigen receptor (CAR) T-cell therapy.

Seven of these 27 patients ultimately relapsed, and 5 went on to receive additional therapy, including stem cell transplant.

Still, 15 of these heavily pretreated patients remained in remission at a median of 7 months of follow-up and did not require further treatment.

“[Patients] had relapsed as many as 4 times, including 60% whose cancers came back even after stem cell transplants,” said Stephan Grupp, MD, PhD, of the Children’s Hospital of Philadelphia in Pennsylvania.

“Their cancers were so aggressive they had no treatment options left. The durable responses we have observed with CTL019 therapy are unprecedented.”

Dr Grupp and his colleagues reported these results in NEJM. The new data build on preliminary findings presented at the 2013 ASH Annual Meeting and the 2012 ASH Annual Meeting.

CTL019 cells are a patient’s own T cells genetically engineered to express an anti-CD19 scFv coupled to CD3ζ signaling and 4-1BB co-stimulatory domains. The cells are activated and expanded ex vivo with anti-CD3 and anti-CD28 beads, then infused into patients.

In all, 30 patients received CTL019, including 25 children and young adults (ages 5 to 22) and 5 adults (ages 26 to 60). Three patients had primary refractory disease, 5 had relapsed once, and 22 patients had relapsed 2 or more times. Eighteen patients had received an allogeneic stem cell transplant.

Twenty-seven patients achieved a complete remission after an infusion of CTL019. Nineteen patients remain in remission, 15 of whom received CTL019 alone. Follow-up ranged from 1.4 months to 24 months.

Tests in patients who experienced complete remissions showed that their normal B cells had been eliminated along with their tumors. The researchers noted that persistent absence of normal B cells following CTL019 treatment indicates continued activity of the CAR T cells.

“Our results support that CTL019 can produce long-lasting remissions for certain heavily pretreated ALL patients without further therapy,” said Noelle Frey, MD, of the University of Pennsylvania in Philadelphia.

However, 5 patients did seek additional therapy, 3 of whom proceeded to allogeneic stem cell transplants while in remission.

Seven patients relapsed, between 6 weeks and 8.5 months after their infusions, including 3 whose cancers returned as CD19-negative leukemia that would not have been targeted by CTL019.

At 6 months, the overall survival rate was 78%, and the event-free survival rate was 67%.

All of the patients experienced cytokine release syndrome (CRS) within a few days of receiving CTL019, but they all fully recovered.

Twenty-two patients experienced mild to moderate CRS, which included varying degrees of flu-like symptoms, with high fevers, nausea, and muscle pain. Eight patients developed severe CRS, which required treatment for low blood pressure and breathing difficulties.

Nine patients were treated with tocilizumab, an immunosuppressant that inhibits the effects of the inflammatory cytokine IL-6, which have been found to spike during the most robust phase of the CAR T cells’ expansion in the body. Six patients also received short courses of steroids to combat CRS symptoms.

CTL019 was invented at The University of Pennsylvania but has been licensed to Novartis. In July, the US Food and Drug Administration granted CTL019 breakthrough therapy designation for the treatment of relapsed and refractory adult and pediatric ALL.

The first multicenter trial of CTL019 recently opened in the US, and additional multisite trials are expected to begin by the end of the year.

Dictyostelium discoideum

Experiments in a soil-dwelling amoeba have provided insight that could help us treat cancers characterized by PTEN mutations, researchers have reported in PLOS ONE.

The team discovered that this amoeba has two genes that function like the human tumor suppressor PTEN.

And increasing expression of one of these genes compensated for a mutation in the other gene.

If the same method works in humans with mutated PTEN, this finding could have implications for a range of cancers.

PTEN mutations are thought to be involved in nearly half of all leukemia cases, 40% of breast cancer cases, and up to 70% of prostate cancer cases.

“If you look at tumors across the board . . . , you find that PTEN is the most generally mutated gene, and, when you mutate PTEN in mice, you cause tumors,” said study author David Soll, PhD, of the University of Iowa in Iowa City.

He and his colleagues found that the amoeba Dictyostelium discoideum has the gene ptenA, which mutates similarly to the human PTEN gene and causes behavioral defects in the cell.

They also found a close relative of ptenA in the amoeba, called lpten, that performs the same functions of ptenA but to a lesser degree.

The researchers hypothesized that ramping up the presence of lpten could compensate for the mutated ptenA.

They tested this theory by placing lpten in a plasmid behind a powerful promoter designed to overexpress the gene. They then introduced the super-charged lpten into a cell with the mutated ptenA gene.

The team found that the overexpressed lpten gene fully compensated for all of the defects in the ptenA mutant.

If this method works in human cells, it could lead to a new way to treat cancers, the researchers said. They are now aiming to identify a drug that would activate the promoter for one of PTEN’s close relatives.

Once a patient is diagnosed with cancer caused by a PTEN mutation, the patient could take the drug, overexpress the PTEN replacement gene, and potentially stop cancer in its tracks, Dr Soll said.

This research has also led Dr Soll and his colleagues to study other human genes that may be able to step in for the mutated PTEN gene and perform the same tumor-suppressing role. The team is currently studying 2 close relatives of PTEN.

“And nature might have put them there just for that; that’s the curious thing,” Dr Soll said. “Somewhere, there may be a backup system, what we call ‘redundancy,’ that might be the basis for better identifying tumors and possibly creating cancer-fighting drugs. You have another gene which might be able to step in for the broken gene to keep things normal, and that’s what we’re playing with here. It’s very sophisticated.”

Dictyostelium discoideum

Experiments in a soil-dwelling amoeba have provided insight that could help us treat cancers characterized by PTEN mutations, researchers have reported in PLOS ONE.

The team discovered that this amoeba has two genes that function like the human tumor suppressor PTEN.

And increasing expression of one of these genes compensated for a mutation in the other gene.

If the same method works in humans with mutated PTEN, this finding could have implications for a range of cancers.

PTEN mutations are thought to be involved in nearly half of all leukemia cases, 40% of breast cancer cases, and up to 70% of prostate cancer cases.

“If you look at tumors across the board . . . , you find that PTEN is the most generally mutated gene, and, when you mutate PTEN in mice, you cause tumors,” said study author David Soll, PhD, of the University of Iowa in Iowa City.

He and his colleagues found that the amoeba Dictyostelium discoideum has the gene ptenA, which mutates similarly to the human PTEN gene and causes behavioral defects in the cell.

They also found a close relative of ptenA in the amoeba, called lpten, that performs the same functions of ptenA but to a lesser degree.

The researchers hypothesized that ramping up the presence of lpten could compensate for the mutated ptenA.

They tested this theory by placing lpten in a plasmid behind a powerful promoter designed to overexpress the gene. They then introduced the super-charged lpten into a cell with the mutated ptenA gene.

The team found that the overexpressed lpten gene fully compensated for all of the defects in the ptenA mutant.

If this method works in human cells, it could lead to a new way to treat cancers, the researchers said. They are now aiming to identify a drug that would activate the promoter for one of PTEN’s close relatives.

Once a patient is diagnosed with cancer caused by a PTEN mutation, the patient could take the drug, overexpress the PTEN replacement gene, and potentially stop cancer in its tracks, Dr Soll said.

This research has also led Dr Soll and his colleagues to study other human genes that may be able to step in for the mutated PTEN gene and perform the same tumor-suppressing role. The team is currently studying 2 close relatives of PTEN.

“And nature might have put them there just for that; that’s the curious thing,” Dr Soll said. “Somewhere, there may be a backup system, what we call ‘redundancy,’ that might be the basis for better identifying tumors and possibly creating cancer-fighting drugs. You have another gene which might be able to step in for the broken gene to keep things normal, and that’s what we’re playing with here. It’s very sophisticated.”

Dictyostelium discoideum

Experiments in a soil-dwelling amoeba have provided insight that could help us treat cancers characterized by PTEN mutations, researchers have reported in PLOS ONE.

The team discovered that this amoeba has two genes that function like the human tumor suppressor PTEN.

And increasing expression of one of these genes compensated for a mutation in the other gene.

If the same method works in humans with mutated PTEN, this finding could have implications for a range of cancers.

PTEN mutations are thought to be involved in nearly half of all leukemia cases, 40% of breast cancer cases, and up to 70% of prostate cancer cases.

“If you look at tumors across the board . . . , you find that PTEN is the most generally mutated gene, and, when you mutate PTEN in mice, you cause tumors,” said study author David Soll, PhD, of the University of Iowa in Iowa City.

He and his colleagues found that the amoeba Dictyostelium discoideum has the gene ptenA, which mutates similarly to the human PTEN gene and causes behavioral defects in the cell.

They also found a close relative of ptenA in the amoeba, called lpten, that performs the same functions of ptenA but to a lesser degree.

The researchers hypothesized that ramping up the presence of lpten could compensate for the mutated ptenA.

They tested this theory by placing lpten in a plasmid behind a powerful promoter designed to overexpress the gene. They then introduced the super-charged lpten into a cell with the mutated ptenA gene.

The team found that the overexpressed lpten gene fully compensated for all of the defects in the ptenA mutant.

If this method works in human cells, it could lead to a new way to treat cancers, the researchers said. They are now aiming to identify a drug that would activate the promoter for one of PTEN’s close relatives.

Once a patient is diagnosed with cancer caused by a PTEN mutation, the patient could take the drug, overexpress the PTEN replacement gene, and potentially stop cancer in its tracks, Dr Soll said.

This research has also led Dr Soll and his colleagues to study other human genes that may be able to step in for the mutated PTEN gene and perform the same tumor-suppressing role. The team is currently studying 2 close relatives of PTEN.

“And nature might have put them there just for that; that’s the curious thing,” Dr Soll said. “Somewhere, there may be a backup system, what we call ‘redundancy,’ that might be the basis for better identifying tumors and possibly creating cancer-fighting drugs. You have another gene which might be able to step in for the broken gene to keep things normal, and that’s what we’re playing with here. It’s very sophisticated.”

Lab mouse

The protein kinases Cdk4 and Cdk6 may determine the incidence and aggressiveness of leukemia, according to preclinical research.

The study showed that Cdk4 and Cdk6 cooperate to promote hematopoietic tumor development in mice.

And inhibiting Cdk4 and Cdk6 simultaneously proved a more effective method of fighting leukemia than inhibiting either protein alone.

The researchers recounted these findings in Blood.

“Cdk4/6 inhibitors used in cancer treatment don’t differentiate between the two molecules,” said study author Marcos Malumbres, PhD, of the Spanish National Cancer Research Centre (CNIO).

“The effectiveness of blocking both proteins at once has not been demonstrated to date.”

To get a wider perspective on this issue, Dr Malumbres and his colleagues designed genetically modified mice carrying active Cdk4, active Cdk6, or both versions of the active proteins.

The researchers found that simultaneous activation of both proteins promoted tumor growth in the mice, leading to more aggressive tumors and an increased risk of developing leukemia.

The team also found an explanation for why the simultaneous activation of Cdk4 and Cdk6 leads to such aggressive tumors.

Under normal conditions, Cdk4 and Cdk6 are inhibited by p16INK4A proteins. But when both Cdk4 and Cdk6 are present at high levels, p16INK4A proteins are unable to act as a retaining wall, leading to uncontrolled tumor growth.

“The assumption to date has been that these molecules act independently of each other,” Dr Malumbres said. “However, our recent findings now suggest that the combined inhibitors could be a more effective cancer treatment.”

“The clinical success of these compounds depends on the appropriate selection of patients. Our findings could help us to understand the molecular basis underpinning the success of these inhibitors, thereby contributing to the development of novel and more effective drugs.”

Lab mouse

The protein kinases Cdk4 and Cdk6 may determine the incidence and aggressiveness of leukemia, according to preclinical research.

The study showed that Cdk4 and Cdk6 cooperate to promote hematopoietic tumor development in mice.

And inhibiting Cdk4 and Cdk6 simultaneously proved a more effective method of fighting leukemia than inhibiting either protein alone.

The researchers recounted these findings in Blood.

“Cdk4/6 inhibitors used in cancer treatment don’t differentiate between the two molecules,” said study author Marcos Malumbres, PhD, of the Spanish National Cancer Research Centre (CNIO).

“The effectiveness of blocking both proteins at once has not been demonstrated to date.”

To get a wider perspective on this issue, Dr Malumbres and his colleagues designed genetically modified mice carrying active Cdk4, active Cdk6, or both versions of the active proteins.

The researchers found that simultaneous activation of both proteins promoted tumor growth in the mice, leading to more aggressive tumors and an increased risk of developing leukemia.

The team also found an explanation for why the simultaneous activation of Cdk4 and Cdk6 leads to such aggressive tumors.

Under normal conditions, Cdk4 and Cdk6 are inhibited by p16INK4A proteins. But when both Cdk4 and Cdk6 are present at high levels, p16INK4A proteins are unable to act as a retaining wall, leading to uncontrolled tumor growth.

“The assumption to date has been that these molecules act independently of each other,” Dr Malumbres said. “However, our recent findings now suggest that the combined inhibitors could be a more effective cancer treatment.”

“The clinical success of these compounds depends on the appropriate selection of patients. Our findings could help us to understand the molecular basis underpinning the success of these inhibitors, thereby contributing to the development of novel and more effective drugs.”

Lab mouse

The protein kinases Cdk4 and Cdk6 may determine the incidence and aggressiveness of leukemia, according to preclinical research.

The study showed that Cdk4 and Cdk6 cooperate to promote hematopoietic tumor development in mice.

And inhibiting Cdk4 and Cdk6 simultaneously proved a more effective method of fighting leukemia than inhibiting either protein alone.

The researchers recounted these findings in Blood.

“Cdk4/6 inhibitors used in cancer treatment don’t differentiate between the two molecules,” said study author Marcos Malumbres, PhD, of the Spanish National Cancer Research Centre (CNIO).

“The effectiveness of blocking both proteins at once has not been demonstrated to date.”

To get a wider perspective on this issue, Dr Malumbres and his colleagues designed genetically modified mice carrying active Cdk4, active Cdk6, or both versions of the active proteins.

The researchers found that simultaneous activation of both proteins promoted tumor growth in the mice, leading to more aggressive tumors and an increased risk of developing leukemia.

The team also found an explanation for why the simultaneous activation of Cdk4 and Cdk6 leads to such aggressive tumors.

Under normal conditions, Cdk4 and Cdk6 are inhibited by p16INK4A proteins. But when both Cdk4 and Cdk6 are present at high levels, p16INK4A proteins are unable to act as a retaining wall, leading to uncontrolled tumor growth.

“The assumption to date has been that these molecules act independently of each other,” Dr Malumbres said. “However, our recent findings now suggest that the combined inhibitors could be a more effective cancer treatment.”

“The clinical success of these compounds depends on the appropriate selection of patients. Our findings could help us to understand the molecular basis underpinning the success of these inhibitors, thereby contributing to the development of novel and more effective drugs.”

Blood collection

Credit: Charles Haymond

An anti-CD19 chimeric antigen receptor (CAR) T-cell therapy can elicit complete responses (CRs) in heavily pretreated patients with acute lymphoblastic leukemia (ALL), results of a phase 1 trial suggest.

More than half of the 21 patients enrolled achieved a CR, and most of those patients went on to hematopoietic stem cell transplant (HSCT).

All 10 patients who underwent HSCT remain leukemia-free at a median follow-up of 10 months.

The CAR T cells did prompt some serious adverse effects, but all effects were fully reversible.

Crystal L. Mackall, MD, of the National Cancer Institute in Bethesda, Maryland, and her colleagues reported these results in The Lancet.

The phase 1 study enrolled patients ages 1 to 30 years who had relapsed or refractory ALL or non-Hodgkin lymphoma. Twenty patients had B-cell ALL, and 1 had diffuse large B-cell lymphoma (DLBCL). All of the patients had been heavily pretreated, and 8 had received a prior HSCT.

Patients received a conditioning regimen of cyclophosphamide and fludarabine, followed by a single infusion of CAR T cells: either 1×10⁶ CAR-transduced T cells per kg or 3×10⁶ CAR-transduced T cells per kg.

The CAR T cells were produced from each patient’s own peripheral blood mononuclear cells, modified using a gammaretroviral vector encoding the CAR, as well as a CD28 costimulatory moiety. After the dose-escalation phase, an expansion cohort was treated at the maximum-tolerated dose.

Twenty-one patients were enrolled and infused, but 2 of them did not receive the prescribed dose of CAR T cells, as the assigned dose could not be generated. The maximum-tolerated dose was 1×10⁶ CAR T cells per kg.

All toxicities were fully reversible. The most common non-hematologic grade 3 adverse events were fever (n=9), hypokalemia (n=9), fever and neutropenia (n=8), and cytokine release syndrome (n=3). Grade 4 cytokine release syndrome occurred in 3 patients.

At day 28, 12 patients had achieved a minimal residual disease (MRD)-negative CR. One patient had an MRD-positive CR, 1 had an MRD-positive CR with incomplete count recovery, and 3 patients had stable disease. Four patients, including the one with DLBCL, progressed.

Ten of the patients with an MRD-negative CR subsequently underwent HSCT, and all 10 remained disease-free with a median follow-up of 10 months.

“The results show that this treatment is feasible in many patients with ALL and can eradicate chemoresistant disease with an acceptable toxicity profile,” said Gary Schiller, MD, of the University of California, Los Angeles, who was not involved in this study.

“Further, the findings demonstrate substantially higher response rates than seen in the literature for the most recently approved agent for refractory ALL. CD19-CAR therapy represents a potentially important new tool to address the urgent need for new treatment modalities in these patients.”

Researchers previously reported positive results with this therapy in patients with chemotherapy-refractory DLBCL.

Blood collection

Credit: Charles Haymond

An anti-CD19 chimeric antigen receptor (CAR) T-cell therapy can elicit complete responses (CRs) in heavily pretreated patients with acute lymphoblastic leukemia (ALL), results of a phase 1 trial suggest.

More than half of the 21 patients enrolled achieved a CR, and most of those patients went on to hematopoietic stem cell transplant (HSCT).

All 10 patients who underwent HSCT remain leukemia-free at a median follow-up of 10 months.

The CAR T cells did prompt some serious adverse effects, but all effects were fully reversible.

Crystal L. Mackall, MD, of the National Cancer Institute in Bethesda, Maryland, and her colleagues reported these results in The Lancet.

The phase 1 study enrolled patients ages 1 to 30 years who had relapsed or refractory ALL or non-Hodgkin lymphoma. Twenty patients had B-cell ALL, and 1 had diffuse large B-cell lymphoma (DLBCL). All of the patients had been heavily pretreated, and 8 had received a prior HSCT.

Patients received a conditioning regimen of cyclophosphamide and fludarabine, followed by a single infusion of CAR T cells: either 1×10⁶ CAR-transduced T cells per kg or 3×10⁶ CAR-transduced T cells per kg.

The CAR T cells were produced from each patient’s own peripheral blood mononuclear cells, modified using a gammaretroviral vector encoding the CAR, as well as a CD28 costimulatory moiety. After the dose-escalation phase, an expansion cohort was treated at the maximum-tolerated dose.

Twenty-one patients were enrolled and infused, but 2 of them did not receive the prescribed dose of CAR T cells, as the assigned dose could not be generated. The maximum-tolerated dose was 1×10⁶ CAR T cells per kg.

All toxicities were fully reversible. The most common non-hematologic grade 3 adverse events were fever (n=9), hypokalemia (n=9), fever and neutropenia (n=8), and cytokine release syndrome (n=3). Grade 4 cytokine release syndrome occurred in 3 patients.

At day 28, 12 patients had achieved a minimal residual disease (MRD)-negative CR. One patient had an MRD-positive CR, 1 had an MRD-positive CR with incomplete count recovery, and 3 patients had stable disease. Four patients, including the one with DLBCL, progressed.

Ten of the patients with an MRD-negative CR subsequently underwent HSCT, and all 10 remained disease-free with a median follow-up of 10 months.

“The results show that this treatment is feasible in many patients with ALL and can eradicate chemoresistant disease with an acceptable toxicity profile,” said Gary Schiller, MD, of the University of California, Los Angeles, who was not involved in this study.

“Further, the findings demonstrate substantially higher response rates than seen in the literature for the most recently approved agent for refractory ALL. CD19-CAR therapy represents a potentially important new tool to address the urgent need for new treatment modalities in these patients.”

Researchers previously reported positive results with this therapy in patients with chemotherapy-refractory DLBCL.

Blood collection

Credit: Charles Haymond

An anti-CD19 chimeric antigen receptor (CAR) T-cell therapy can elicit complete responses (CRs) in heavily pretreated patients with acute lymphoblastic leukemia (ALL), results of a phase 1 trial suggest.

More than half of the 21 patients enrolled achieved a CR, and most of those patients went on to hematopoietic stem cell transplant (HSCT).

All 10 patients who underwent HSCT remain leukemia-free at a median follow-up of 10 months.

The CAR T cells did prompt some serious adverse effects, but all effects were fully reversible.

Crystal L. Mackall, MD, of the National Cancer Institute in Bethesda, Maryland, and her colleagues reported these results in The Lancet.

The phase 1 study enrolled patients ages 1 to 30 years who had relapsed or refractory ALL or non-Hodgkin lymphoma. Twenty patients had B-cell ALL, and 1 had diffuse large B-cell lymphoma (DLBCL). All of the patients had been heavily pretreated, and 8 had received a prior HSCT.

Patients received a conditioning regimen of cyclophosphamide and fludarabine, followed by a single infusion of CAR T cells: either 1×10⁶ CAR-transduced T cells per kg or 3×10⁶ CAR-transduced T cells per kg.

The CAR T cells were produced from each patient’s own peripheral blood mononuclear cells, modified using a gammaretroviral vector encoding the CAR, as well as a CD28 costimulatory moiety. After the dose-escalation phase, an expansion cohort was treated at the maximum-tolerated dose.

Twenty-one patients were enrolled and infused, but 2 of them did not receive the prescribed dose of CAR T cells, as the assigned dose could not be generated. The maximum-tolerated dose was 1×10⁶ CAR T cells per kg.

All toxicities were fully reversible. The most common non-hematologic grade 3 adverse events were fever (n=9), hypokalemia (n=9), fever and neutropenia (n=8), and cytokine release syndrome (n=3). Grade 4 cytokine release syndrome occurred in 3 patients.

At day 28, 12 patients had achieved a minimal residual disease (MRD)-negative CR. One patient had an MRD-positive CR, 1 had an MRD-positive CR with incomplete count recovery, and 3 patients had stable disease. Four patients, including the one with DLBCL, progressed.

Ten of the patients with an MRD-negative CR subsequently underwent HSCT, and all 10 remained disease-free with a median follow-up of 10 months.

“The results show that this treatment is feasible in many patients with ALL and can eradicate chemoresistant disease with an acceptable toxicity profile,” said Gary Schiller, MD, of the University of California, Los Angeles, who was not involved in this study.

“Further, the findings demonstrate substantially higher response rates than seen in the literature for the most recently approved agent for refractory ALL. CD19-CAR therapy represents a potentially important new tool to address the urgent need for new treatment modalities in these patients.”

Researchers previously reported positive results with this therapy in patients with chemotherapy-refractory DLBCL.

Ching-Hon Pui, MD

Credit: St Jude Biomedical

Communications

Risk-directed therapy can level the playing field for patients with BCR-ABL1-like acute lymphoblastic leukemia (ALL), new research suggests.

Using minimal residual disease (MRD) and other risk factors to guide treatment intensity allowed patients withBCR-ABL1-like ALL to have survival rates comparable to those of other B-ALL patients.

The research also revealed that not all BCR-ABL1-like ALL patients have high-risk disease.

Ching-Hon Pui, MD, of St Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these results in the Journal of Clinical Oncology.

Patients with BCR-ABL1-like ALL tend to have poor outcomes, so Dr Pui and his colleagues evaluated the utility of risk-directed therapy in these and other B-ALL patients.

The team assessed patients enrolled in the Total Therapy XV study between 2000 and 2007. They were 1 to 18 years of age at diagnosis. There were 344 subjects with adequate samples for gene expression profiling.

Forty patients (11.6%) had BCR-ABL1-like ALL. They were significantly more likely than other study participants to be male, have Down syndrome, and have higher MRD levels on day 19 and at the end of induction.

The researchers monitored patients and adjusted their treatment intensity based on MRD at days 19 and 42. The treatment regimen was described in JAMA in 2009.

The MRD monitoring combined with conventional risk factors, such as patient age and white blood count at diagnosis, demonstrated that BCR-ABL1-like ALL is not a uniformly high-risk disease.

Forty percent of BCR-ABL1-like ALL patients were actually classified as having low-risk disease because they had other favorable clinical or biological features and no MRD at the end of remission induction.

The other 60% were classified as having standard-risk or high-risk disease. The group included 6 patients who underwent transplant.

There were no significant differences in event-free or overall survival in patients with BCR-ABL1-like ALL and the other ALL patients. At 5 years, event-free survival was 90.0% ± 4.7% and 88.4% ± 1.9%, respectively. And 5-year overall survival was 92.5% ± 4.2% and 95.1% ± 1.3%, respectively.

When available, more sophisticated genetic testing should be used to identify which of the B-ALL patients with high levels of MRD have the BCR-ABL1-like ALL subtype, Dr Pui said. Many of these patients have genetic alterations that make them responsive to tyrosine kinase inhibitors (TKIs) and possibly other targeted therapies.

For example, in this study, the researchers evaluated genetic abnormalities in 25 BCR-ABL1-like ALL patients. Eleven had a genomic rearrangement of CRLF2, 6 had fusion transcripts responsive to ABL TKIs or JAK inhibitors, and 7 had mutations involving the Ras signaling pathway.

“In the future, genetic testing will likely be used at diagnosis to identify [BCR-ABL1-like ALL] and direct patients to the best targeted therapy,” Dr Pui said, “possibly including some drugs that are currently experimental.”

Ching-Hon Pui, MD

Credit: St Jude Biomedical

Communications

Risk-directed therapy can level the playing field for patients with BCR-ABL1-like acute lymphoblastic leukemia (ALL), new research suggests.

Using minimal residual disease (MRD) and other risk factors to guide treatment intensity allowed patients withBCR-ABL1-like ALL to have survival rates comparable to those of other B-ALL patients.

The research also revealed that not all BCR-ABL1-like ALL patients have high-risk disease.

Ching-Hon Pui, MD, of St Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these results in the Journal of Clinical Oncology.

Patients with BCR-ABL1-like ALL tend to have poor outcomes, so Dr Pui and his colleagues evaluated the utility of risk-directed therapy in these and other B-ALL patients.

The team assessed patients enrolled in the Total Therapy XV study between 2000 and 2007. They were 1 to 18 years of age at diagnosis. There were 344 subjects with adequate samples for gene expression profiling.

Forty patients (11.6%) had BCR-ABL1-like ALL. They were significantly more likely than other study participants to be male, have Down syndrome, and have higher MRD levels on day 19 and at the end of induction.

The researchers monitored patients and adjusted their treatment intensity based on MRD at days 19 and 42. The treatment regimen was described in JAMA in 2009.

The MRD monitoring combined with conventional risk factors, such as patient age and white blood count at diagnosis, demonstrated that BCR-ABL1-like ALL is not a uniformly high-risk disease.

Forty percent of BCR-ABL1-like ALL patients were actually classified as having low-risk disease because they had other favorable clinical or biological features and no MRD at the end of remission induction.

The other 60% were classified as having standard-risk or high-risk disease. The group included 6 patients who underwent transplant.

There were no significant differences in event-free or overall survival in patients with BCR-ABL1-like ALL and the other ALL patients. At 5 years, event-free survival was 90.0% ± 4.7% and 88.4% ± 1.9%, respectively. And 5-year overall survival was 92.5% ± 4.2% and 95.1% ± 1.3%, respectively.

When available, more sophisticated genetic testing should be used to identify which of the B-ALL patients with high levels of MRD have the BCR-ABL1-like ALL subtype, Dr Pui said. Many of these patients have genetic alterations that make them responsive to tyrosine kinase inhibitors (TKIs) and possibly other targeted therapies.

For example, in this study, the researchers evaluated genetic abnormalities in 25 BCR-ABL1-like ALL patients. Eleven had a genomic rearrangement of CRLF2, 6 had fusion transcripts responsive to ABL TKIs or JAK inhibitors, and 7 had mutations involving the Ras signaling pathway.

“In the future, genetic testing will likely be used at diagnosis to identify [BCR-ABL1-like ALL] and direct patients to the best targeted therapy,” Dr Pui said, “possibly including some drugs that are currently experimental.”

Ching-Hon Pui, MD

Credit: St Jude Biomedical

Communications

Risk-directed therapy can level the playing field for patients with BCR-ABL1-like acute lymphoblastic leukemia (ALL), new research suggests.

Using minimal residual disease (MRD) and other risk factors to guide treatment intensity allowed patients withBCR-ABL1-like ALL to have survival rates comparable to those of other B-ALL patients.

The research also revealed that not all BCR-ABL1-like ALL patients have high-risk disease.

Ching-Hon Pui, MD, of St Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these results in the Journal of Clinical Oncology.

Patients with BCR-ABL1-like ALL tend to have poor outcomes, so Dr Pui and his colleagues evaluated the utility of risk-directed therapy in these and other B-ALL patients.

The team assessed patients enrolled in the Total Therapy XV study between 2000 and 2007. They were 1 to 18 years of age at diagnosis. There were 344 subjects with adequate samples for gene expression profiling.

Forty patients (11.6%) had BCR-ABL1-like ALL. They were significantly more likely than other study participants to be male, have Down syndrome, and have higher MRD levels on day 19 and at the end of induction.

The researchers monitored patients and adjusted their treatment intensity based on MRD at days 19 and 42. The treatment regimen was described in JAMA in 2009.

The MRD monitoring combined with conventional risk factors, such as patient age and white blood count at diagnosis, demonstrated that BCR-ABL1-like ALL is not a uniformly high-risk disease.

Forty percent of BCR-ABL1-like ALL patients were actually classified as having low-risk disease because they had other favorable clinical or biological features and no MRD at the end of remission induction.

The other 60% were classified as having standard-risk or high-risk disease. The group included 6 patients who underwent transplant.

There were no significant differences in event-free or overall survival in patients with BCR-ABL1-like ALL and the other ALL patients. At 5 years, event-free survival was 90.0% ± 4.7% and 88.4% ± 1.9%, respectively. And 5-year overall survival was 92.5% ± 4.2% and 95.1% ± 1.3%, respectively.

When available, more sophisticated genetic testing should be used to identify which of the B-ALL patients with high levels of MRD have the BCR-ABL1-like ALL subtype, Dr Pui said. Many of these patients have genetic alterations that make them responsive to tyrosine kinase inhibitors (TKIs) and possibly other targeted therapies.

For example, in this study, the researchers evaluated genetic abnormalities in 25 BCR-ABL1-like ALL patients. Eleven had a genomic rearrangement of CRLF2, 6 had fusion transcripts responsive to ABL TKIs or JAK inhibitors, and 7 had mutations involving the Ras signaling pathway.

“In the future, genetic testing will likely be used at diagnosis to identify [BCR-ABL1-like ALL] and direct patients to the best targeted therapy,” Dr Pui said, “possibly including some drugs that are currently experimental.”

The sea mollusk Aplysia

californica

releasing ink

after being disturbed

Results of preclinical research appear to explain how the anticancer agent doxorubicin can cause chemo brain.

Neuroscientists conducted experiments in cells from rats and Aplysia californica, a marine mollusk that has many of the same memory mechanisms as humans.

This revealed memory mechanisms that are inhibited by doxorubicin, as well as a method of unblocking these mechanisms—administering a drug known as SB203580.

“Our research has implications in the care of people given to cognitive deficits following drug treatment for cancer,” said John H. Byrne, PhD, of the University of Texas Health Medical School.

He added that understanding how drugs like doxorubicin impact the brain is an important first step in alleviating chemo brain, which is characterized by forgetfulness, trouble concentrating, and difficulty multitasking.

Dr Byrne and his colleagues explained this first step in The Journal of Neuroscience.

The researchers knew that, in non-neuronal cells, doxorubicin inhibits the expression of MAPK phosphatases, thereby inhibiting the dephosphorylation of ERK and p38 MAPK, 2 MAPK isoforms that are important for long-term memory.

To evaluate doxorubicin’s effects on levels of phosphorylated ERK and p38 MAPK, the team used cultures of cortical neurons from rats and sensory neurons from Aplysia californica.

Experiments showed that doxorubicin elevated levels of phosphorylated ERK and phosphorylated p38 MAPK in sensory neurons and cortical neurons. In addition, the drug increased phosphorylation of the downstream transcriptional repressor CREB2 in sensory neurons.

The researchers also assessed doxorubicin’s effects on long-term enhanced excitability, long-term synaptic facilitation, and long-term

synaptic depression.

They found that doxorubicin enhanced long-term synaptic depression induced by the neuropeptide Phe-Met-Arg-Phe-NH2. And the drug inhibited long-term synaptic facilitation induced by serotonin.

However, the researchers were able to restore long-term synaptic facilitation with SB203580, an inhibitor of p38 MAPK.

Unfortunately, SB203580 would not be appropriate for human use, Dr Byrne noted, adding that his team would like to identify other drugs that might have the same effect as SB203580.

The researchers also hope to determine if doxorubicin works the same way in humans as it did in these experiments.

The sea mollusk Aplysia

californica

releasing ink

after being disturbed

Results of preclinical research appear to explain how the anticancer agent doxorubicin can cause chemo brain.

Neuroscientists conducted experiments in cells from rats and Aplysia californica, a marine mollusk that has many of the same memory mechanisms as humans.

This revealed memory mechanisms that are inhibited by doxorubicin, as well as a method of unblocking these mechanisms—administering a drug known as SB203580.

“Our research has implications in the care of people given to cognitive deficits following drug treatment for cancer,” said John H. Byrne, PhD, of the University of Texas Health Medical School.

He added that understanding how drugs like doxorubicin impact the brain is an important first step in alleviating chemo brain, which is characterized by forgetfulness, trouble concentrating, and difficulty multitasking.

Dr Byrne and his colleagues explained this first step in The Journal of Neuroscience.

The researchers knew that, in non-neuronal cells, doxorubicin inhibits the expression of MAPK phosphatases, thereby inhibiting the dephosphorylation of ERK and p38 MAPK, 2 MAPK isoforms that are important for long-term memory.

To evaluate doxorubicin’s effects on levels of phosphorylated ERK and p38 MAPK, the team used cultures of cortical neurons from rats and sensory neurons from Aplysia californica.

Experiments showed that doxorubicin elevated levels of phosphorylated ERK and phosphorylated p38 MAPK in sensory neurons and cortical neurons. In addition, the drug increased phosphorylation of the downstream transcriptional repressor CREB2 in sensory neurons.

The researchers also assessed doxorubicin’s effects on long-term enhanced excitability, long-term synaptic facilitation, and long-term

synaptic depression.

They found that doxorubicin enhanced long-term synaptic depression induced by the neuropeptide Phe-Met-Arg-Phe-NH2. And the drug inhibited long-term synaptic facilitation induced by serotonin.

However, the researchers were able to restore long-term synaptic facilitation with SB203580, an inhibitor of p38 MAPK.

Unfortunately, SB203580 would not be appropriate for human use, Dr Byrne noted, adding that his team would like to identify other drugs that might have the same effect as SB203580.

The researchers also hope to determine if doxorubicin works the same way in humans as it did in these experiments.

The sea mollusk Aplysia

californica

releasing ink

after being disturbed

Results of preclinical research appear to explain how the anticancer agent doxorubicin can cause chemo brain.

Neuroscientists conducted experiments in cells from rats and Aplysia californica, a marine mollusk that has many of the same memory mechanisms as humans.

This revealed memory mechanisms that are inhibited by doxorubicin, as well as a method of unblocking these mechanisms—administering a drug known as SB203580.

“Our research has implications in the care of people given to cognitive deficits following drug treatment for cancer,” said John H. Byrne, PhD, of the University of Texas Health Medical School.

He added that understanding how drugs like doxorubicin impact the brain is an important first step in alleviating chemo brain, which is characterized by forgetfulness, trouble concentrating, and difficulty multitasking.

Dr Byrne and his colleagues explained this first step in The Journal of Neuroscience.

The researchers knew that, in non-neuronal cells, doxorubicin inhibits the expression of MAPK phosphatases, thereby inhibiting the dephosphorylation of ERK and p38 MAPK, 2 MAPK isoforms that are important for long-term memory.

To evaluate doxorubicin’s effects on levels of phosphorylated ERK and p38 MAPK, the team used cultures of cortical neurons from rats and sensory neurons from Aplysia californica.

Experiments showed that doxorubicin elevated levels of phosphorylated ERK and phosphorylated p38 MAPK in sensory neurons and cortical neurons. In addition, the drug increased phosphorylation of the downstream transcriptional repressor CREB2 in sensory neurons.

The researchers also assessed doxorubicin’s effects on long-term enhanced excitability, long-term synaptic facilitation, and long-term

synaptic depression.

They found that doxorubicin enhanced long-term synaptic depression induced by the neuropeptide Phe-Met-Arg-Phe-NH2. And the drug inhibited long-term synaptic facilitation induced by serotonin.

However, the researchers were able to restore long-term synaptic facilitation with SB203580, an inhibitor of p38 MAPK.

Unfortunately, SB203580 would not be appropriate for human use, Dr Byrne noted, adding that his team would like to identify other drugs that might have the same effect as SB203580.

The researchers also hope to determine if doxorubicin works the same way in humans as it did in these experiments.