Leukemia, Myelodysplasia, Transplantation

Image by Joshua Stokes

A newly identified pathway plays a “fundamental” role in acute myeloid leukemia (AML), according to researchers.

The team discovered that AML cells have a secretory pathway that leads to the production and release of the immune receptor Tim-3 and its ligand galectin-9, both of which prevent natural killer (NK) and other cytotoxic cells from killing the AML cells.

Vadim Sumbayev, PhD, of the University of Kent in the UK, and his colleagues recounted these findings in EBioMedicine.

The researchers found that AML cells—but not healthy blood cells—express a receptor called latrophilin 1 (LPHN1). LPHN1 induces activation of PKCα, which triggers the translation and secretion of Tim-3 and galectin-9.

Soluble Tim-3 prevents the secretion of interleukin 2, which is required for the activation of NK cells and cytotoxic T cells. Galectin-9 impairs the AML-cell-killing ability of NK cells and other cytotoxic lymphocytes.

The researchers said their work revealed both biomarkers for AML diagnostics and potential targets for AML treatment.

“Targeting this pathway will crucially enhance patients’ own immune defenses, helping them to eliminate leukemia cells,” Dr Sumbayev said.

He added that his group’s discovery might be applied to the treatment of other cancers as well.

Image by Joshua Stokes

A newly identified pathway plays a “fundamental” role in acute myeloid leukemia (AML), according to researchers.

The team discovered that AML cells have a secretory pathway that leads to the production and release of the immune receptor Tim-3 and its ligand galectin-9, both of which prevent natural killer (NK) and other cytotoxic cells from killing the AML cells.

Vadim Sumbayev, PhD, of the University of Kent in the UK, and his colleagues recounted these findings in EBioMedicine.

The researchers found that AML cells—but not healthy blood cells—express a receptor called latrophilin 1 (LPHN1). LPHN1 induces activation of PKCα, which triggers the translation and secretion of Tim-3 and galectin-9.

Soluble Tim-3 prevents the secretion of interleukin 2, which is required for the activation of NK cells and cytotoxic T cells. Galectin-9 impairs the AML-cell-killing ability of NK cells and other cytotoxic lymphocytes.

The researchers said their work revealed both biomarkers for AML diagnostics and potential targets for AML treatment.

“Targeting this pathway will crucially enhance patients’ own immune defenses, helping them to eliminate leukemia cells,” Dr Sumbayev said.

He added that his group’s discovery might be applied to the treatment of other cancers as well.

Image by Joshua Stokes

A newly identified pathway plays a “fundamental” role in acute myeloid leukemia (AML), according to researchers.

The team discovered that AML cells have a secretory pathway that leads to the production and release of the immune receptor Tim-3 and its ligand galectin-9, both of which prevent natural killer (NK) and other cytotoxic cells from killing the AML cells.

Vadim Sumbayev, PhD, of the University of Kent in the UK, and his colleagues recounted these findings in EBioMedicine.

The researchers found that AML cells—but not healthy blood cells—express a receptor called latrophilin 1 (LPHN1). LPHN1 induces activation of PKCα, which triggers the translation and secretion of Tim-3 and galectin-9.

Soluble Tim-3 prevents the secretion of interleukin 2, which is required for the activation of NK cells and cytotoxic T cells. Galectin-9 impairs the AML-cell-killing ability of NK cells and other cytotoxic lymphocytes.

The researchers said their work revealed both biomarkers for AML diagnostics and potential targets for AML treatment.

“Targeting this pathway will crucially enhance patients’ own immune defenses, helping them to eliminate leukemia cells,” Dr Sumbayev said.

He added that his group’s discovery might be applied to the treatment of other cancers as well.

New York – Venetoclax monotherapy is associated with high and durable objective response rates in patients with del(17p) chronic lymphocytic leukemia (CLL), according to efficacy findings from the open-label M13-982 trial.

Additionally, a safety expansion of the pivotal phase 2 study showed that treatment was well tolerated, and assessment of minimal residual disease (MRD) status in the peripheral blood and bone marrow of study participants correlated with the 24-month progression-free survival estimate of 100% for patients with complete remission/complete remission with incomplete blood count recovery (CR/CRi), Stephan Stilgenbauer, MD, of the University of Ulm, Germany, and his colleagues reported in a poster at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.

Frontline Medical News

[email protected]

New York – Venetoclax monotherapy is associated with high and durable objective response rates in patients with del(17p) chronic lymphocytic leukemia (CLL), according to efficacy findings from the open-label M13-982 trial.

Additionally, a safety expansion of the pivotal phase 2 study showed that treatment was well tolerated, and assessment of minimal residual disease (MRD) status in the peripheral blood and bone marrow of study participants correlated with the 24-month progression-free survival estimate of 100% for patients with complete remission/complete remission with incomplete blood count recovery (CR/CRi), Stephan Stilgenbauer, MD, of the University of Ulm, Germany, and his colleagues reported in a poster at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.

Frontline Medical News

[email protected]

New York – Venetoclax monotherapy is associated with high and durable objective response rates in patients with del(17p) chronic lymphocytic leukemia (CLL), according to efficacy findings from the open-label M13-982 trial.

Additionally, a safety expansion of the pivotal phase 2 study showed that treatment was well tolerated, and assessment of minimal residual disease (MRD) status in the peripheral blood and bone marrow of study participants correlated with the 24-month progression-free survival estimate of 100% for patients with complete remission/complete remission with incomplete blood count recovery (CR/CRi), Stephan Stilgenbauer, MD, of the University of Ulm, Germany, and his colleagues reported in a poster at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.

Frontline Medical News

[email protected]

AML cells

Researchers say they have determined which patients will respond to treatment with SY-1425, a retinoic acid receptor alpha (RARα) agonist.

The team discovered a subset of patients with acute myeloid leukemia (AML) who had a super-enhancer associated with the RARA gene, which is predictive of response to SY-1425.

The researchers also identified a subset of patients with myelodysplastic syndromes (MDS) who had high expression of the RARA gene.

And experiments showed that RARA-high MDS had a similar response to SY-1425 as that seen in AML driven by the RARA super-enhancer.

Ravindra Majeti MD, PhD, of Stanford University School of Medicine in California, and colleagues reported these findings in Cancer Discovery. Employees of Syros Pharmaceuticals, the company developing SY-1425, were also involved in this research.

In collaboration with the Majeti lab, Syros used its gene control platform to analyze 66 AML patients’ tumor samples. In this way, the researchers identified 6 distinct patient subsets based on super-enhancer profiles, including 1 enriched for a super-enhancer associated with the RARA gene.

The team found that super-enhancer profiles were strongly associated with survival outcomes, often independent of known genetic mutations in AML.

The RARA super-enhancer was associated with high expression of the RARA gene, which codes for a transcription factor targeted by SY-1425.

The RARA super-enhancer was predictive of response to SY-1425. In AML cells with high RARA expression, SY-1425 reduced proliferation and promoted differentiation.

Moreover, SY-1425 decreased tumor burden and prolonged survival in patient-derived xenograft models of AML with high RARA expression. However, there was no effect on AML cells or models with low RARA expression.

The researchers said SY-1425 induced profound transcriptional changes promoting cell differentiation in AML cells with high RARA expression, but the drug produced little to no transcriptional changes in AML cells with low RARA expression.

DHRS3 was the most strongly and rapidly induced gene in response to treatment with SY-1425. This led to the identification of DHRS3 induction as an early indicator of whether SY-1425 is affecting the targeted biology in defined subsets of AML and MDS patients. It is therefore used as a pharmacodynamic marker in the ongoing phase 2 trial of SY-1425.

In this trial, researchers are assessing the safety and efficacy of SY-1425 as a single agent in 4 AML and MDS patient populations, as well as testing SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.

AML cells

Researchers say they have determined which patients will respond to treatment with SY-1425, a retinoic acid receptor alpha (RARα) agonist.

The team discovered a subset of patients with acute myeloid leukemia (AML) who had a super-enhancer associated with the RARA gene, which is predictive of response to SY-1425.

The researchers also identified a subset of patients with myelodysplastic syndromes (MDS) who had high expression of the RARA gene.

And experiments showed that RARA-high MDS had a similar response to SY-1425 as that seen in AML driven by the RARA super-enhancer.

Ravindra Majeti MD, PhD, of Stanford University School of Medicine in California, and colleagues reported these findings in Cancer Discovery. Employees of Syros Pharmaceuticals, the company developing SY-1425, were also involved in this research.

In collaboration with the Majeti lab, Syros used its gene control platform to analyze 66 AML patients’ tumor samples. In this way, the researchers identified 6 distinct patient subsets based on super-enhancer profiles, including 1 enriched for a super-enhancer associated with the RARA gene.

The team found that super-enhancer profiles were strongly associated with survival outcomes, often independent of known genetic mutations in AML.

The RARA super-enhancer was associated with high expression of the RARA gene, which codes for a transcription factor targeted by SY-1425.

The RARA super-enhancer was predictive of response to SY-1425. In AML cells with high RARA expression, SY-1425 reduced proliferation and promoted differentiation.

Moreover, SY-1425 decreased tumor burden and prolonged survival in patient-derived xenograft models of AML with high RARA expression. However, there was no effect on AML cells or models with low RARA expression.

The researchers said SY-1425 induced profound transcriptional changes promoting cell differentiation in AML cells with high RARA expression, but the drug produced little to no transcriptional changes in AML cells with low RARA expression.

DHRS3 was the most strongly and rapidly induced gene in response to treatment with SY-1425. This led to the identification of DHRS3 induction as an early indicator of whether SY-1425 is affecting the targeted biology in defined subsets of AML and MDS patients. It is therefore used as a pharmacodynamic marker in the ongoing phase 2 trial of SY-1425.

In this trial, researchers are assessing the safety and efficacy of SY-1425 as a single agent in 4 AML and MDS patient populations, as well as testing SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.

AML cells

Researchers say they have determined which patients will respond to treatment with SY-1425, a retinoic acid receptor alpha (RARα) agonist.

The team discovered a subset of patients with acute myeloid leukemia (AML) who had a super-enhancer associated with the RARA gene, which is predictive of response to SY-1425.

The researchers also identified a subset of patients with myelodysplastic syndromes (MDS) who had high expression of the RARA gene.

And experiments showed that RARA-high MDS had a similar response to SY-1425 as that seen in AML driven by the RARA super-enhancer.

Ravindra Majeti MD, PhD, of Stanford University School of Medicine in California, and colleagues reported these findings in Cancer Discovery. Employees of Syros Pharmaceuticals, the company developing SY-1425, were also involved in this research.

In collaboration with the Majeti lab, Syros used its gene control platform to analyze 66 AML patients’ tumor samples. In this way, the researchers identified 6 distinct patient subsets based on super-enhancer profiles, including 1 enriched for a super-enhancer associated with the RARA gene.

The team found that super-enhancer profiles were strongly associated with survival outcomes, often independent of known genetic mutations in AML.

The RARA super-enhancer was associated with high expression of the RARA gene, which codes for a transcription factor targeted by SY-1425.

The RARA super-enhancer was predictive of response to SY-1425. In AML cells with high RARA expression, SY-1425 reduced proliferation and promoted differentiation.

Moreover, SY-1425 decreased tumor burden and prolonged survival in patient-derived xenograft models of AML with high RARA expression. However, there was no effect on AML cells or models with low RARA expression.

The researchers said SY-1425 induced profound transcriptional changes promoting cell differentiation in AML cells with high RARA expression, but the drug produced little to no transcriptional changes in AML cells with low RARA expression.

DHRS3 was the most strongly and rapidly induced gene in response to treatment with SY-1425. This led to the identification of DHRS3 induction as an early indicator of whether SY-1425 is affecting the targeted biology in defined subsets of AML and MDS patients. It is therefore used as a pharmacodynamic marker in the ongoing phase 2 trial of SY-1425.

In this trial, researchers are assessing the safety and efficacy of SY-1425 as a single agent in 4 AML and MDS patient populations, as well as testing SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.

Micrograph showing CLL

LUGANO, SWITZERLAND—A sequential treatment regimen can produce a high overall response rate (ORR) in patients with treatment-naïve (TN) or relapsed/refractory (RR) chronic lymphocytic leukemia (CLL), results of the CLL2-BAG study suggest.

Patients who received bendamustine followed by obinutuzumab and venetoclax achieved an ORR of 95%, and 87% of them were negative for minimal residual disease (MRD) in the peripheral blood.

In addition, this regimen did not lead to cumulative or unexpected toxicity, according to study investigator Paula Cramer, MD, of University Hospital of Cologne in Germany.

Dr Cramer presented results from CLL2-BAG at the 14th International Conference on Malignant Lymphoma (ICML). The trial was sponsored by the German CLL Study Group.

CLL2-BAG included 63 patients—34 with TN and 29 with RR CLL. The median age was 58 (range, 43-76) and 61 (range, 28-77), respectively.

Thirty-five percent of TN patients had bulky disease (>5 cm), as did 45% of RR patients. Twelve percent and 10%, respectively, had massive splenomegaly (>20 cm)

Twenty-one percent of TN patients and 35% of RR patients were Binet stage A. Thirty-two percent and 21%, respectively, were stage B, and 47% and 45%, respectively, were stage C.

Treatment

Patients first underwent debulking with bendamustine, given at 70 mg/m² on days 1 and 2 for two 28-day cycles. They then received induction with obinutuzumab and venetoclax for six 28-day cycles.

In cycle 1, patients received obinutuzumab at 100 mg or 900 mg on day 1 or 2 and 1000 mg on days 8 and 15. For cycles 2-6, patients received 1000 mg of obinutuzumab on day 1.

In cycle 2, patients received venetoclax at 20 mg on days 1-7, 50 mg on days 8-14, 100 mg on days 15-21, and 200 mg on days 22-28. For cycles 3-6, they received venetoclax at 400 mg on days 1-28.

Patients also received maintenance with obinutuzumab and venetoclax for 2 to 8 cycles with a duration of 84 days. Obinutuzumab was given at 1000 mg on day 1 of each cycle, and venetoclax was given at 400 mg on days 1-84.

Maintenance was continued until patients completed 24 months of maintenance therapy, until 3 months after patients achieved a complete response (CR) or CR with incomplete count recovery (CRi) and MRD negativity, until progression of CLL or start of new CLL treatment, or until unacceptable toxicity.

ORR, MRD, and survival

At the end of induction, the ORR was 95% in the entire population—100% among TN patients and 90% among RR patients.

The rate of CR was 8%, 9%, and 7%, respectively. The rate of unconfirmed/clinical CR/CRi was 32%, 41%, and 21%, respectively.

Five percent of patients progressed, all of them in the RR group.

Eighty-seven percent of evaluable patients were MRD negative (<10^-4) in the peripheral blood, including 91% of TN patients and 83% of RR patients. Two patients (3%) were missing data on MRD status in peripheral blood.

Thirteen percent of all evaluable patients were MRD negative in the bone marrow, including 12% of TN patients and 14% of RR patients. The remaining patients (87%, 88%, and 86%, respectively) were missing data on MRD status in the bone marrow.

The progression-free survival at 15 months was 100% in the TN patients and 83% in the RR patients.

Adverse events

After debulking, 28.1% of TN patients and 46.7% of RR patients had experienced adverse events (AEs).

These included (in TN and RR patients, respectively) neutropenia (9.4% and 13.3%), anemia (6.3% and 20.0%), thrombocytopenia (6.3% and 6.7%), infections (6.3% and 6.7%), coronary artery disorders (1 TN patient, 3.1%), rash (1 TN patient, 3.1%), tumor lysis syndrome (1 TN patient, 3.1%), vomiting (1 TN patient, 3.1%), and pyrexia (1 RR patient, 6.7%).

After induction, 54.3% of TN patients and 80.6% of RR patients had experienced AEs.

These included (in TN and RR patients, respectively) neutropenia (34.3% and 54.8%), infections (8.6% and 29.0%), thrombocytopenia (2.9% and 22.6%), infusion-related reactions (5 RR patients, 16.1%), neoplasms (2.9% and 9.7%), hypertension (2.9% and 6.5%), coronary artery disorders (2.9% and 6.5%), anemia (3 RR patients, 9.7%), and tumor lysis syndrome (2 RR patients, 6.5%).

Micrograph showing CLL

LUGANO, SWITZERLAND—A sequential treatment regimen can produce a high overall response rate (ORR) in patients with treatment-naïve (TN) or relapsed/refractory (RR) chronic lymphocytic leukemia (CLL), results of the CLL2-BAG study suggest.

Patients who received bendamustine followed by obinutuzumab and venetoclax achieved an ORR of 95%, and 87% of them were negative for minimal residual disease (MRD) in the peripheral blood.

In addition, this regimen did not lead to cumulative or unexpected toxicity, according to study investigator Paula Cramer, MD, of University Hospital of Cologne in Germany.

Dr Cramer presented results from CLL2-BAG at the 14th International Conference on Malignant Lymphoma (ICML). The trial was sponsored by the German CLL Study Group.

CLL2-BAG included 63 patients—34 with TN and 29 with RR CLL. The median age was 58 (range, 43-76) and 61 (range, 28-77), respectively.

Thirty-five percent of TN patients had bulky disease (>5 cm), as did 45% of RR patients. Twelve percent and 10%, respectively, had massive splenomegaly (>20 cm)

Twenty-one percent of TN patients and 35% of RR patients were Binet stage A. Thirty-two percent and 21%, respectively, were stage B, and 47% and 45%, respectively, were stage C.

Treatment

Patients first underwent debulking with bendamustine, given at 70 mg/m² on days 1 and 2 for two 28-day cycles. They then received induction with obinutuzumab and venetoclax for six 28-day cycles.

In cycle 1, patients received obinutuzumab at 100 mg or 900 mg on day 1 or 2 and 1000 mg on days 8 and 15. For cycles 2-6, patients received 1000 mg of obinutuzumab on day 1.

In cycle 2, patients received venetoclax at 20 mg on days 1-7, 50 mg on days 8-14, 100 mg on days 15-21, and 200 mg on days 22-28. For cycles 3-6, they received venetoclax at 400 mg on days 1-28.

Patients also received maintenance with obinutuzumab and venetoclax for 2 to 8 cycles with a duration of 84 days. Obinutuzumab was given at 1000 mg on day 1 of each cycle, and venetoclax was given at 400 mg on days 1-84.

Maintenance was continued until patients completed 24 months of maintenance therapy, until 3 months after patients achieved a complete response (CR) or CR with incomplete count recovery (CRi) and MRD negativity, until progression of CLL or start of new CLL treatment, or until unacceptable toxicity.

ORR, MRD, and survival

At the end of induction, the ORR was 95% in the entire population—100% among TN patients and 90% among RR patients.

The rate of CR was 8%, 9%, and 7%, respectively. The rate of unconfirmed/clinical CR/CRi was 32%, 41%, and 21%, respectively.

Five percent of patients progressed, all of them in the RR group.

Eighty-seven percent of evaluable patients were MRD negative (<10^-4) in the peripheral blood, including 91% of TN patients and 83% of RR patients. Two patients (3%) were missing data on MRD status in peripheral blood.

Thirteen percent of all evaluable patients were MRD negative in the bone marrow, including 12% of TN patients and 14% of RR patients. The remaining patients (87%, 88%, and 86%, respectively) were missing data on MRD status in the bone marrow.

The progression-free survival at 15 months was 100% in the TN patients and 83% in the RR patients.

Adverse events

After debulking, 28.1% of TN patients and 46.7% of RR patients had experienced adverse events (AEs).

These included (in TN and RR patients, respectively) neutropenia (9.4% and 13.3%), anemia (6.3% and 20.0%), thrombocytopenia (6.3% and 6.7%), infections (6.3% and 6.7%), coronary artery disorders (1 TN patient, 3.1%), rash (1 TN patient, 3.1%), tumor lysis syndrome (1 TN patient, 3.1%), vomiting (1 TN patient, 3.1%), and pyrexia (1 RR patient, 6.7%).

After induction, 54.3% of TN patients and 80.6% of RR patients had experienced AEs.

These included (in TN and RR patients, respectively) neutropenia (34.3% and 54.8%), infections (8.6% and 29.0%), thrombocytopenia (2.9% and 22.6%), infusion-related reactions (5 RR patients, 16.1%), neoplasms (2.9% and 9.7%), hypertension (2.9% and 6.5%), coronary artery disorders (2.9% and 6.5%), anemia (3 RR patients, 9.7%), and tumor lysis syndrome (2 RR patients, 6.5%).

Micrograph showing CLL

LUGANO, SWITZERLAND—A sequential treatment regimen can produce a high overall response rate (ORR) in patients with treatment-naïve (TN) or relapsed/refractory (RR) chronic lymphocytic leukemia (CLL), results of the CLL2-BAG study suggest.

Patients who received bendamustine followed by obinutuzumab and venetoclax achieved an ORR of 95%, and 87% of them were negative for minimal residual disease (MRD) in the peripheral blood.

In addition, this regimen did not lead to cumulative or unexpected toxicity, according to study investigator Paula Cramer, MD, of University Hospital of Cologne in Germany.

Dr Cramer presented results from CLL2-BAG at the 14th International Conference on Malignant Lymphoma (ICML). The trial was sponsored by the German CLL Study Group.

CLL2-BAG included 63 patients—34 with TN and 29 with RR CLL. The median age was 58 (range, 43-76) and 61 (range, 28-77), respectively.

Thirty-five percent of TN patients had bulky disease (>5 cm), as did 45% of RR patients. Twelve percent and 10%, respectively, had massive splenomegaly (>20 cm)

Twenty-one percent of TN patients and 35% of RR patients were Binet stage A. Thirty-two percent and 21%, respectively, were stage B, and 47% and 45%, respectively, were stage C.

Treatment

Patients first underwent debulking with bendamustine, given at 70 mg/m² on days 1 and 2 for two 28-day cycles. They then received induction with obinutuzumab and venetoclax for six 28-day cycles.

In cycle 1, patients received obinutuzumab at 100 mg or 900 mg on day 1 or 2 and 1000 mg on days 8 and 15. For cycles 2-6, patients received 1000 mg of obinutuzumab on day 1.

In cycle 2, patients received venetoclax at 20 mg on days 1-7, 50 mg on days 8-14, 100 mg on days 15-21, and 200 mg on days 22-28. For cycles 3-6, they received venetoclax at 400 mg on days 1-28.

Patients also received maintenance with obinutuzumab and venetoclax for 2 to 8 cycles with a duration of 84 days. Obinutuzumab was given at 1000 mg on day 1 of each cycle, and venetoclax was given at 400 mg on days 1-84.

Maintenance was continued until patients completed 24 months of maintenance therapy, until 3 months after patients achieved a complete response (CR) or CR with incomplete count recovery (CRi) and MRD negativity, until progression of CLL or start of new CLL treatment, or until unacceptable toxicity.

ORR, MRD, and survival

At the end of induction, the ORR was 95% in the entire population—100% among TN patients and 90% among RR patients.

The rate of CR was 8%, 9%, and 7%, respectively. The rate of unconfirmed/clinical CR/CRi was 32%, 41%, and 21%, respectively.

Five percent of patients progressed, all of them in the RR group.

Eighty-seven percent of evaluable patients were MRD negative (<10^-4) in the peripheral blood, including 91% of TN patients and 83% of RR patients. Two patients (3%) were missing data on MRD status in peripheral blood.

Thirteen percent of all evaluable patients were MRD negative in the bone marrow, including 12% of TN patients and 14% of RR patients. The remaining patients (87%, 88%, and 86%, respectively) were missing data on MRD status in the bone marrow.

The progression-free survival at 15 months was 100% in the TN patients and 83% in the RR patients.

Adverse events

After debulking, 28.1% of TN patients and 46.7% of RR patients had experienced adverse events (AEs).

These included (in TN and RR patients, respectively) neutropenia (9.4% and 13.3%), anemia (6.3% and 20.0%), thrombocytopenia (6.3% and 6.7%), infections (6.3% and 6.7%), coronary artery disorders (1 TN patient, 3.1%), rash (1 TN patient, 3.1%), tumor lysis syndrome (1 TN patient, 3.1%), vomiting (1 TN patient, 3.1%), and pyrexia (1 RR patient, 6.7%).

After induction, 54.3% of TN patients and 80.6% of RR patients had experienced AEs.

These included (in TN and RR patients, respectively) neutropenia (34.3% and 54.8%), infections (8.6% and 29.0%), thrombocytopenia (2.9% and 22.6%), infusion-related reactions (5 RR patients, 16.1%), neoplasms (2.9% and 9.7%), hypertension (2.9% and 6.5%), coronary artery disorders (2.9% and 6.5%), anemia (3 RR patients, 9.7%), and tumor lysis syndrome (2 RR patients, 6.5%).

Photo courtesy of Novartis

The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) is recommending approval for midostaurin (Rydapt®) as a treatment for acute myeloid leukemia (AML) and systemic mastocytosis (SM).

If approved by the European Commission, midostaurin would be used in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation—followed by midostaurin maintenance for patients in complete response—in adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3-mutation-positive.

Midostaurin would also be approved to treat adults with aggressive SM, SM with associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL).

If approved, midostaurin would be the first targeted treatment available in the European Union for newly diagnosed FLT3+ AML patients and advanced SM patients.

The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 2 to 3 months’ of the CHMP’s recommendation. The decision will be applicable to all member states of the European Union, plus Iceland, Liechtenstein, and Norway.

Midostaurin in AML

The CHMP’s recommendation for midostaurin in AML is based on results from the phase 3 RATIFY trial, which were recently published in NEJM.

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

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

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

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

The most frequent grade 3/4 AEs (occurring in at least 10% of patients) were febrile neutropenia, device-related infection, and mucositis. Nine percent of patients in the midostaurin arm stopped treatment due to AEs, as did 6% in the placebo arm.

Midostaurin in advanced SM

The CHMP’s recommendation for midostaurin in advanced SM was based on results from a pair of phase 2, single-arm studies, hereafter referred to as Study 2 and Study 3.

Data from Study 2 were published in NEJM in June 2016, and data from Study 3 were presented at the 2010 ASH Annual Meeting.

Study 2 included 116 patients, 115 of whom were evaluable for response.

The overall response rate (ORR) was 17% in the entire cohort, 31% among patients with ASM, 11% among patients with SM-AHN, and 19% among patients with MCL. The complete response rates were 2%, 6%, 0%, and 5%, respectively.

Study 3 included 26 patients with advanced SM. In 3 of the patients, the subtype of SM was unconfirmed.

Among the 17 patients with SM-AHN, there were 10 responses (ORR=59%), including 1 partial response and 9 major responses. In the 6 patients with MCL, there were 2 responses (ORR=33%), which included 1 partial response and 1 major response.

In both studies combined, there were 142 adults with ASM, SM-AHN, or MCL.

The most frequent AEs (excluding laboratory abnormalities) that occurred in at least 20% of these patients were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea.

The most frequent grade 3 or higher AEs (excluding laboratory abnormalities) that occurred in at least 5% of patients were fatigue, sepsis, gastrointestinal hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema, dyspnea, nausea, vomiting, abdominal pain, and renal insufficiency.

Serious AEs occurred in 68% of patients, most commonly infections and gastrointestinal disorders. Twenty-one percent of patients discontinued treatment due to AEs, the most frequent of which were infection, nausea or vomiting, QT prolongation, and gastrointestinal hemorrhage.

Photo courtesy of Novartis

The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) is recommending approval for midostaurin (Rydapt®) as a treatment for acute myeloid leukemia (AML) and systemic mastocytosis (SM).

If approved by the European Commission, midostaurin would be used in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation—followed by midostaurin maintenance for patients in complete response—in adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3-mutation-positive.

Midostaurin would also be approved to treat adults with aggressive SM, SM with associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL).

If approved, midostaurin would be the first targeted treatment available in the European Union for newly diagnosed FLT3+ AML patients and advanced SM patients.

The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 2 to 3 months’ of the CHMP’s recommendation. The decision will be applicable to all member states of the European Union, plus Iceland, Liechtenstein, and Norway.

Midostaurin in AML

The CHMP’s recommendation for midostaurin in AML is based on results from the phase 3 RATIFY trial, which were recently published in NEJM.

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

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

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

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

The most frequent grade 3/4 AEs (occurring in at least 10% of patients) were febrile neutropenia, device-related infection, and mucositis. Nine percent of patients in the midostaurin arm stopped treatment due to AEs, as did 6% in the placebo arm.

Midostaurin in advanced SM

The CHMP’s recommendation for midostaurin in advanced SM was based on results from a pair of phase 2, single-arm studies, hereafter referred to as Study 2 and Study 3.

Data from Study 2 were published in NEJM in June 2016, and data from Study 3 were presented at the 2010 ASH Annual Meeting.

Study 2 included 116 patients, 115 of whom were evaluable for response.

The overall response rate (ORR) was 17% in the entire cohort, 31% among patients with ASM, 11% among patients with SM-AHN, and 19% among patients with MCL. The complete response rates were 2%, 6%, 0%, and 5%, respectively.

Study 3 included 26 patients with advanced SM. In 3 of the patients, the subtype of SM was unconfirmed.

Among the 17 patients with SM-AHN, there were 10 responses (ORR=59%), including 1 partial response and 9 major responses. In the 6 patients with MCL, there were 2 responses (ORR=33%), which included 1 partial response and 1 major response.

In both studies combined, there were 142 adults with ASM, SM-AHN, or MCL.

The most frequent AEs (excluding laboratory abnormalities) that occurred in at least 20% of these patients were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea.

The most frequent grade 3 or higher AEs (excluding laboratory abnormalities) that occurred in at least 5% of patients were fatigue, sepsis, gastrointestinal hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema, dyspnea, nausea, vomiting, abdominal pain, and renal insufficiency.

Serious AEs occurred in 68% of patients, most commonly infections and gastrointestinal disorders. Twenty-one percent of patients discontinued treatment due to AEs, the most frequent of which were infection, nausea or vomiting, QT prolongation, and gastrointestinal hemorrhage.

Photo courtesy of Novartis

The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) is recommending approval for midostaurin (Rydapt®) as a treatment for acute myeloid leukemia (AML) and systemic mastocytosis (SM).

If approved by the European Commission, midostaurin would be used in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation—followed by midostaurin maintenance for patients in complete response—in adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3-mutation-positive.

Midostaurin would also be approved to treat adults with aggressive SM, SM with associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL).

If approved, midostaurin would be the first targeted treatment available in the European Union for newly diagnosed FLT3+ AML patients and advanced SM patients.

The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 2 to 3 months’ of the CHMP’s recommendation. The decision will be applicable to all member states of the European Union, plus Iceland, Liechtenstein, and Norway.

Midostaurin in AML

The CHMP’s recommendation for midostaurin in AML is based on results from the phase 3 RATIFY trial, which were recently published in NEJM.

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

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

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

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

The most frequent grade 3/4 AEs (occurring in at least 10% of patients) were febrile neutropenia, device-related infection, and mucositis. Nine percent of patients in the midostaurin arm stopped treatment due to AEs, as did 6% in the placebo arm.

Midostaurin in advanced SM

The CHMP’s recommendation for midostaurin in advanced SM was based on results from a pair of phase 2, single-arm studies, hereafter referred to as Study 2 and Study 3.

Data from Study 2 were published in NEJM in June 2016, and data from Study 3 were presented at the 2010 ASH Annual Meeting.

Study 2 included 116 patients, 115 of whom were evaluable for response.

The overall response rate (ORR) was 17% in the entire cohort, 31% among patients with ASM, 11% among patients with SM-AHN, and 19% among patients with MCL. The complete response rates were 2%, 6%, 0%, and 5%, respectively.

Study 3 included 26 patients with advanced SM. In 3 of the patients, the subtype of SM was unconfirmed.

Among the 17 patients with SM-AHN, there were 10 responses (ORR=59%), including 1 partial response and 9 major responses. In the 6 patients with MCL, there were 2 responses (ORR=33%), which included 1 partial response and 1 major response.

In both studies combined, there were 142 adults with ASM, SM-AHN, or MCL.

The most frequent AEs (excluding laboratory abnormalities) that occurred in at least 20% of these patients were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea.

The most frequent grade 3 or higher AEs (excluding laboratory abnormalities) that occurred in at least 5% of patients were fatigue, sepsis, gastrointestinal hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema, dyspnea, nausea, vomiting, abdominal pain, and renal insufficiency.

Serious AEs occurred in 68% of patients, most commonly infections and gastrointestinal disorders. Twenty-one percent of patients discontinued treatment due to AEs, the most frequent of which were infection, nausea or vomiting, QT prolongation, and gastrointestinal hemorrhage.

Image by Joshua Stokes

Natural killer (NK) cells derived from cord blood (CB) can be modified to fight chronic lymphocytic leukemia (CLL) and Burkitt lymphoma (BL), according to research published in Leukemia.

Using a viral vector, researchers transduced CB-derived NK cells with a chimeric antigen receptor (CAR), interleukin-15 (IL-15), and an inducible caspase-9-based suicide gene.

The CAR directed the NK cells to kill CD19-expressing cells, IL-15 prolonged the NK cells’ survival and enhanced their antitumor activity, and the suicide gene allowed researchers to kill off the NK cells in the event of a severe inflammatory response.

“Natural killer cells are the immune system’s most potent killers, but they are short-lived, and cancers manage to evade a patient’s own NK cells to progress,” said study author Katy Rezvani, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“Our cord-blood derived NK cells, genetically equipped with a receptor that focuses them on B-cell malignancies and with interleukin-15 to help them persist longer—potentially for months instead of 2 or 3 weeks—are designed to address these challenges.”

Dr Rezvani and her colleagues tested their CB-derived CAR NK cells in primary CLL cells and a mouse model of BL. Compared to unmodified NK cells, the CAR NK cells killed malignant cells more efficiently and extended the survival of mice.

Another experiment showed the CB-derived CAR NK cells killed CLL cells more efficiently than NK cells that were taken from CLL patients and modified in the same way. The researchers said this highlights the need to transplant CAR-engineered NK cells derived from healthy CB rather than using a patient’s own cells.

Additional experiments in the mouse model of BL showed that a single infusion of low-dose CAR NK cells resulted in prolonged survival.

When CAR NK cells were given at a higher dose, none of the mice died of BL. Half of them survived 100 days and beyond. However, all mice treated with other types of NK cells died by day 41.

Some mice treated with the higher dose of CAR NK cells died of cytokine release syndrome (CRS).

To counteract this toxicity, the researchers activated the suicide gene (iC9) via treatment with a small-molecule dimerizer, AP1903.

The team found that adding as little as 10 nM of AP1903 to cell cultures induced apoptosis/necrosis of the CAR NK cells within 4 hours but had no effect on non-CAR CB-derived NK cells. Similar results were observed in the mouse model.

Next steps

A phase 1/2 trial of these CB-derived CAR NK cells opened at MD Anderson in June for patients with relapsed or refractory CLL, acute lymphocytic leukemia, or non-Hodgkin lymphoma.

Dr Rezvani, the principal investigator of the trial, said the protocol calls for vigilance for signs of CRS, treatment with steroids and tocilizumab for low-grade CRS, and AP1903 added to activate the suicide gene for grade 3 or 4 CRS.

She and her colleagues noted that CB-derived NK cells do not cause graft-vs-host disease. Therefore, they can be an off-the-shelf product, prepared in advance with the necessary receptor and given to patients promptly.

The researchers are developing CB-derived CAR NK cells for other targets in hematologic and solid tumor malignancies.

MD Anderson and the researchers have intellectual property related to the engineered NK cells, which is being managed in accordance with the institution’s conflict-of-interest rules.

Funding for this research was provided by MD Anderson’s Moon Shots Program, the National Cancer Institute of the National Institutes of Health Cancer Center Support Grant (CA016672) to MD Anderson, and grants from the Leukemia and Lymphoma Society and the American Cancer Society.

Image by Joshua Stokes

Natural killer (NK) cells derived from cord blood (CB) can be modified to fight chronic lymphocytic leukemia (CLL) and Burkitt lymphoma (BL), according to research published in Leukemia.

Using a viral vector, researchers transduced CB-derived NK cells with a chimeric antigen receptor (CAR), interleukin-15 (IL-15), and an inducible caspase-9-based suicide gene.

The CAR directed the NK cells to kill CD19-expressing cells, IL-15 prolonged the NK cells’ survival and enhanced their antitumor activity, and the suicide gene allowed researchers to kill off the NK cells in the event of a severe inflammatory response.

“Natural killer cells are the immune system’s most potent killers, but they are short-lived, and cancers manage to evade a patient’s own NK cells to progress,” said study author Katy Rezvani, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“Our cord-blood derived NK cells, genetically equipped with a receptor that focuses them on B-cell malignancies and with interleukin-15 to help them persist longer—potentially for months instead of 2 or 3 weeks—are designed to address these challenges.”

Dr Rezvani and her colleagues tested their CB-derived CAR NK cells in primary CLL cells and a mouse model of BL. Compared to unmodified NK cells, the CAR NK cells killed malignant cells more efficiently and extended the survival of mice.

Another experiment showed the CB-derived CAR NK cells killed CLL cells more efficiently than NK cells that were taken from CLL patients and modified in the same way. The researchers said this highlights the need to transplant CAR-engineered NK cells derived from healthy CB rather than using a patient’s own cells.

Additional experiments in the mouse model of BL showed that a single infusion of low-dose CAR NK cells resulted in prolonged survival.

When CAR NK cells were given at a higher dose, none of the mice died of BL. Half of them survived 100 days and beyond. However, all mice treated with other types of NK cells died by day 41.

Some mice treated with the higher dose of CAR NK cells died of cytokine release syndrome (CRS).

To counteract this toxicity, the researchers activated the suicide gene (iC9) via treatment with a small-molecule dimerizer, AP1903.

The team found that adding as little as 10 nM of AP1903 to cell cultures induced apoptosis/necrosis of the CAR NK cells within 4 hours but had no effect on non-CAR CB-derived NK cells. Similar results were observed in the mouse model.

Next steps

A phase 1/2 trial of these CB-derived CAR NK cells opened at MD Anderson in June for patients with relapsed or refractory CLL, acute lymphocytic leukemia, or non-Hodgkin lymphoma.

Dr Rezvani, the principal investigator of the trial, said the protocol calls for vigilance for signs of CRS, treatment with steroids and tocilizumab for low-grade CRS, and AP1903 added to activate the suicide gene for grade 3 or 4 CRS.

She and her colleagues noted that CB-derived NK cells do not cause graft-vs-host disease. Therefore, they can be an off-the-shelf product, prepared in advance with the necessary receptor and given to patients promptly.

The researchers are developing CB-derived CAR NK cells for other targets in hematologic and solid tumor malignancies.

MD Anderson and the researchers have intellectual property related to the engineered NK cells, which is being managed in accordance with the institution’s conflict-of-interest rules.

Funding for this research was provided by MD Anderson’s Moon Shots Program, the National Cancer Institute of the National Institutes of Health Cancer Center Support Grant (CA016672) to MD Anderson, and grants from the Leukemia and Lymphoma Society and the American Cancer Society.

Image by Joshua Stokes

Natural killer (NK) cells derived from cord blood (CB) can be modified to fight chronic lymphocytic leukemia (CLL) and Burkitt lymphoma (BL), according to research published in Leukemia.

Using a viral vector, researchers transduced CB-derived NK cells with a chimeric antigen receptor (CAR), interleukin-15 (IL-15), and an inducible caspase-9-based suicide gene.

The CAR directed the NK cells to kill CD19-expressing cells, IL-15 prolonged the NK cells’ survival and enhanced their antitumor activity, and the suicide gene allowed researchers to kill off the NK cells in the event of a severe inflammatory response.

“Natural killer cells are the immune system’s most potent killers, but they are short-lived, and cancers manage to evade a patient’s own NK cells to progress,” said study author Katy Rezvani, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“Our cord-blood derived NK cells, genetically equipped with a receptor that focuses them on B-cell malignancies and with interleukin-15 to help them persist longer—potentially for months instead of 2 or 3 weeks—are designed to address these challenges.”

Dr Rezvani and her colleagues tested their CB-derived CAR NK cells in primary CLL cells and a mouse model of BL. Compared to unmodified NK cells, the CAR NK cells killed malignant cells more efficiently and extended the survival of mice.

Another experiment showed the CB-derived CAR NK cells killed CLL cells more efficiently than NK cells that were taken from CLL patients and modified in the same way. The researchers said this highlights the need to transplant CAR-engineered NK cells derived from healthy CB rather than using a patient’s own cells.

Additional experiments in the mouse model of BL showed that a single infusion of low-dose CAR NK cells resulted in prolonged survival.

When CAR NK cells were given at a higher dose, none of the mice died of BL. Half of them survived 100 days and beyond. However, all mice treated with other types of NK cells died by day 41.

Some mice treated with the higher dose of CAR NK cells died of cytokine release syndrome (CRS).

To counteract this toxicity, the researchers activated the suicide gene (iC9) via treatment with a small-molecule dimerizer, AP1903.

The team found that adding as little as 10 nM of AP1903 to cell cultures induced apoptosis/necrosis of the CAR NK cells within 4 hours but had no effect on non-CAR CB-derived NK cells. Similar results were observed in the mouse model.

Next steps

A phase 1/2 trial of these CB-derived CAR NK cells opened at MD Anderson in June for patients with relapsed or refractory CLL, acute lymphocytic leukemia, or non-Hodgkin lymphoma.

Dr Rezvani, the principal investigator of the trial, said the protocol calls for vigilance for signs of CRS, treatment with steroids and tocilizumab for low-grade CRS, and AP1903 added to activate the suicide gene for grade 3 or 4 CRS.

She and her colleagues noted that CB-derived NK cells do not cause graft-vs-host disease. Therefore, they can be an off-the-shelf product, prepared in advance with the necessary receptor and given to patients promptly.

The researchers are developing CB-derived CAR NK cells for other targets in hematologic and solid tumor malignancies.

MD Anderson and the researchers have intellectual property related to the engineered NK cells, which is being managed in accordance with the institution’s conflict-of-interest rules.

Funding for this research was provided by MD Anderson’s Moon Shots Program, the National Cancer Institute of the National Institutes of Health Cancer Center Support Grant (CA016672) to MD Anderson, and grants from the Leukemia and Lymphoma Society and the American Cancer Society.

Photo by Rhoda Baer

New research suggests young cancer survivors struggle to get their social lives “back to normal” within the first 2 years of their diagnosis.

The study showed that adolescents and young adults (AYAs) with cancer had significantly worse social functioning than the general population around the time of cancer diagnosis as well as 1 year and 2 years later.

These findings were published in Cancer.

“The research is important to help these young survivors better reintegrate into society,” said study author Brad Zebrack, PhD, of the University of Michigan in Ann Arbor.

He and his colleagues collected data from 141 AYA cancer patients (ages 14 to 39) who visited 1 of 5 US medical facilities between March 2008 and April 2010.

The patients completed a self-report measure of social functioning within the first 4 months of diagnosis, then again at 12 months and 24 months.

Compared to the general population, the AYA cancer patients had significantly worse social functioning scores at all time points:

• Around the time of diagnosis—52.0 vs 85.1 (P<0.001)
• At 12 months—73.1 vs 85.1 (P<0.001)
• At 24 months—69.2 vs 85.1 (P<0.001).

Overall, the patients did experience improvements in social functioning from baseline to the 12-month time point, but their scores remained stable after that.

The researchers noted that 9% of patients had consistently high/normal social functioning, 47% had improvements in social functioning over time, 13% had worsening social functioning over time, and 32% had consistently low social functioning.

“This finding highlights the need to screen, identify, and respond to the needs of high-risk young adult-adolescent patients at the time of diagnosis and then monitor them over time,” Dr Zebrack said.

“They are likely the ones most in need of help in managing work, school, and potentially problematic relationships with family members and friends.”

Photo by Rhoda Baer

New research suggests young cancer survivors struggle to get their social lives “back to normal” within the first 2 years of their diagnosis.

The study showed that adolescents and young adults (AYAs) with cancer had significantly worse social functioning than the general population around the time of cancer diagnosis as well as 1 year and 2 years later.

These findings were published in Cancer.

“The research is important to help these young survivors better reintegrate into society,” said study author Brad Zebrack, PhD, of the University of Michigan in Ann Arbor.

He and his colleagues collected data from 141 AYA cancer patients (ages 14 to 39) who visited 1 of 5 US medical facilities between March 2008 and April 2010.

The patients completed a self-report measure of social functioning within the first 4 months of diagnosis, then again at 12 months and 24 months.

Compared to the general population, the AYA cancer patients had significantly worse social functioning scores at all time points:

• Around the time of diagnosis—52.0 vs 85.1 (P<0.001)
• At 12 months—73.1 vs 85.1 (P<0.001)
• At 24 months—69.2 vs 85.1 (P<0.001).

Overall, the patients did experience improvements in social functioning from baseline to the 12-month time point, but their scores remained stable after that.

The researchers noted that 9% of patients had consistently high/normal social functioning, 47% had improvements in social functioning over time, 13% had worsening social functioning over time, and 32% had consistently low social functioning.

“This finding highlights the need to screen, identify, and respond to the needs of high-risk young adult-adolescent patients at the time of diagnosis and then monitor them over time,” Dr Zebrack said.

“They are likely the ones most in need of help in managing work, school, and potentially problematic relationships with family members and friends.”

Photo by Rhoda Baer

New research suggests young cancer survivors struggle to get their social lives “back to normal” within the first 2 years of their diagnosis.

The study showed that adolescents and young adults (AYAs) with cancer had significantly worse social functioning than the general population around the time of cancer diagnosis as well as 1 year and 2 years later.

These findings were published in Cancer.

“The research is important to help these young survivors better reintegrate into society,” said study author Brad Zebrack, PhD, of the University of Michigan in Ann Arbor.

He and his colleagues collected data from 141 AYA cancer patients (ages 14 to 39) who visited 1 of 5 US medical facilities between March 2008 and April 2010.

The patients completed a self-report measure of social functioning within the first 4 months of diagnosis, then again at 12 months and 24 months.

Compared to the general population, the AYA cancer patients had significantly worse social functioning scores at all time points:

• Around the time of diagnosis—52.0 vs 85.1 (P<0.001)
• At 12 months—73.1 vs 85.1 (P<0.001)
• At 24 months—69.2 vs 85.1 (P<0.001).

Overall, the patients did experience improvements in social functioning from baseline to the 12-month time point, but their scores remained stable after that.

The researchers noted that 9% of patients had consistently high/normal social functioning, 47% had improvements in social functioning over time, 13% had worsening social functioning over time, and 32% had consistently low social functioning.

“This finding highlights the need to screen, identify, and respond to the needs of high-risk young adult-adolescent patients at the time of diagnosis and then monitor them over time,” Dr Zebrack said.

“They are likely the ones most in need of help in managing work, school, and potentially problematic relationships with family members and friends.”

Image by Lance Liotta

The US Food and Drug Administration (FDA) has granted orphan drug designation to gilteritinib for the treatment of patients with acute myeloid leukemia (AML).

Gilteritinib, an inhibitor of FLT3 and AXL, has demonstrated activity against FLT3 internal tandem duplication (ITD) as well as tyrosine kinase domain, 2 mutations that are seen in up to a third of patients with AML.

Astellas Pharma Inc. is currently investigating gilteritinib in phase 3 trials of AML patients.

Results from a phase 1/2 study of gilteritinib in AML were presented at the 2017 ASCO Annual Meeting.

The goal of the study was to determine the tolerability and antileukemic activity of once-daily gilteritinib in a FLT3-ITD-enriched, relapsed/refractory AML population.

The drug exhibited “potent” FLT3 inhibition at doses greater than 80 mg/day. In patients who received such doses, the greatest overall response rate was 52%, and the longest median overall survival was 31 weeks.

The maximum tolerated dose of gilteritinib was 300 mg/day. Dose-limiting toxicities included diarrhea and liver function abnormalities.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Image by Lance Liotta

The US Food and Drug Administration (FDA) has granted orphan drug designation to gilteritinib for the treatment of patients with acute myeloid leukemia (AML).

Gilteritinib, an inhibitor of FLT3 and AXL, has demonstrated activity against FLT3 internal tandem duplication (ITD) as well as tyrosine kinase domain, 2 mutations that are seen in up to a third of patients with AML.

Astellas Pharma Inc. is currently investigating gilteritinib in phase 3 trials of AML patients.

Results from a phase 1/2 study of gilteritinib in AML were presented at the 2017 ASCO Annual Meeting.

The goal of the study was to determine the tolerability and antileukemic activity of once-daily gilteritinib in a FLT3-ITD-enriched, relapsed/refractory AML population.

The drug exhibited “potent” FLT3 inhibition at doses greater than 80 mg/day. In patients who received such doses, the greatest overall response rate was 52%, and the longest median overall survival was 31 weeks.

The maximum tolerated dose of gilteritinib was 300 mg/day. Dose-limiting toxicities included diarrhea and liver function abnormalities.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Image by Lance Liotta

The US Food and Drug Administration (FDA) has granted orphan drug designation to gilteritinib for the treatment of patients with acute myeloid leukemia (AML).

Gilteritinib, an inhibitor of FLT3 and AXL, has demonstrated activity against FLT3 internal tandem duplication (ITD) as well as tyrosine kinase domain, 2 mutations that are seen in up to a third of patients with AML.

Astellas Pharma Inc. is currently investigating gilteritinib in phase 3 trials of AML patients.

Results from a phase 1/2 study of gilteritinib in AML were presented at the 2017 ASCO Annual Meeting.

The goal of the study was to determine the tolerability and antileukemic activity of once-daily gilteritinib in a FLT3-ITD-enriched, relapsed/refractory AML population.

The drug exhibited “potent” FLT3 inhibition at doses greater than 80 mg/day. In patients who received such doses, the greatest overall response rate was 52%, and the longest median overall survival was 31 weeks.

The maximum tolerated dose of gilteritinib was 300 mg/day. Dose-limiting toxicities included diarrhea and liver function abnormalities.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Tyrosine kinase inhibitor de-escalation is generally safe and may lead to symptom improvement in patients with chronic myeloid leukemia who respond well to the therapy, according to an interim analysis of the nonrandomized phase 2 DESTINY trial.

The findings imply that some patients are unnecessarily overtreated, as responses were sometimes maintained with lower tyrosine kinase inhibitor (TKI) doses, according to Richard E. Clark, MD, of the University of Liverpool, England, and his colleagues (Lancet Haematol. 2017 May 26;4:e310-16).

Of 174 patients with chronic myeloid leukemia (CML) in first chronic phase who had received TKIs for at least 3 years and who were either in stable molecular response 4 logs below the standard arbitrary baseline (MR4, 125 patients) or stable major molecular response (MMR) but not MR4 (49 patients) for at least 12 months at the time of enrollment, 12 (7%) had molecular recurrence during 12 months of half-dose TKI therapy, and all patients who experienced molecular recurrence regained MMR within 4 months of being back on full-dose TKIs, the researchers noted.

The median time to recovery was 77 days.

The recurrence rate was significantly lower in the MR4 cohort than in the MMR cohort (2% vs. 19%; hazard ratio, 0.12), and time to relapse was significantly longer in the MR4 cohort (median, 8.7 vs. 4.4 months), the investigators said.

Recurrence was not associated with age, sex, weight, performance status, BCR-ABL1 transcript type, or duration of TKI therapy, which was a median of 6.9 years overall, they noted.

During the first 3 months of de-escalation, adverse events associated with treatment, including lethargy, diarrhea, rash, and nausea, all improved.

Adverse events during de-escalation occurred in 16 patients, and included one fatality due to worsening of peripheral arterial occlusive disease, but all were deemed unrelated to the TKI or underlying chronic CML, the investigators noted.

Study subjects were adults with positive BCR-ABL1 transcripts, with either e13a2, e14a2, or e19a2 fusion transcript. They were enrolled between December 2013 and April 2015 from 20 hospitals in the United Kingdom; 148 were receiving imatinib, 16 were receiving nilotinib, and 10 were receiving dasatinib. They received half of their standard dose of imatinib (200 mg daily), dasatinib (50 mg daily), or nilotinib (200 mg twice daily) for 12 months. Recurrence during de-escalation was defined as BCR-ABL1:ABL1 ratio greater than 0.1% on two consecutive measurements.

“Although several studies of TKI cessation have been reported, little is known about the feasibility of treatment de-escalation in patients with stable molecular responses,” the investigators wrote, adding that the current study shows that de-escalation is “clearly safe for patients in stable MR4 or deeper remission” and could be a “reasonable option.”

This “practice-changing view” is reinforced by the finding of general improvement of adverse events in both cohorts, they said.

Also of note, de-escalation in this study was associated with savings of almost half the expected TKI costs, they added.

The findings imply that many patients with stable responses might be able to maintain responses on lower TKI doses, they concluded, adding that studies of more ambitious de-escalation are warranted.

Newcastle University and Bloodwise funded the study. Dr. Clark received other grants from Bloodwise during the study, as well as grants and personal fees from Novartis, Bristol-Myers Squibb, and Pfizer, and personal fees from Ariad/Incyte.

[email protected]

Tyrosine kinase inhibitor de-escalation is generally safe and may lead to symptom improvement in patients with chronic myeloid leukemia who respond well to the therapy, according to an interim analysis of the nonrandomized phase 2 DESTINY trial.

The findings imply that some patients are unnecessarily overtreated, as responses were sometimes maintained with lower tyrosine kinase inhibitor (TKI) doses, according to Richard E. Clark, MD, of the University of Liverpool, England, and his colleagues (Lancet Haematol. 2017 May 26;4:e310-16).

Of 174 patients with chronic myeloid leukemia (CML) in first chronic phase who had received TKIs for at least 3 years and who were either in stable molecular response 4 logs below the standard arbitrary baseline (MR4, 125 patients) or stable major molecular response (MMR) but not MR4 (49 patients) for at least 12 months at the time of enrollment, 12 (7%) had molecular recurrence during 12 months of half-dose TKI therapy, and all patients who experienced molecular recurrence regained MMR within 4 months of being back on full-dose TKIs, the researchers noted.

The median time to recovery was 77 days.

The recurrence rate was significantly lower in the MR4 cohort than in the MMR cohort (2% vs. 19%; hazard ratio, 0.12), and time to relapse was significantly longer in the MR4 cohort (median, 8.7 vs. 4.4 months), the investigators said.

Recurrence was not associated with age, sex, weight, performance status, BCR-ABL1 transcript type, or duration of TKI therapy, which was a median of 6.9 years overall, they noted.

During the first 3 months of de-escalation, adverse events associated with treatment, including lethargy, diarrhea, rash, and nausea, all improved.

Adverse events during de-escalation occurred in 16 patients, and included one fatality due to worsening of peripheral arterial occlusive disease, but all were deemed unrelated to the TKI or underlying chronic CML, the investigators noted.

Study subjects were adults with positive BCR-ABL1 transcripts, with either e13a2, e14a2, or e19a2 fusion transcript. They were enrolled between December 2013 and April 2015 from 20 hospitals in the United Kingdom; 148 were receiving imatinib, 16 were receiving nilotinib, and 10 were receiving dasatinib. They received half of their standard dose of imatinib (200 mg daily), dasatinib (50 mg daily), or nilotinib (200 mg twice daily) for 12 months. Recurrence during de-escalation was defined as BCR-ABL1:ABL1 ratio greater than 0.1% on two consecutive measurements.

“Although several studies of TKI cessation have been reported, little is known about the feasibility of treatment de-escalation in patients with stable molecular responses,” the investigators wrote, adding that the current study shows that de-escalation is “clearly safe for patients in stable MR4 or deeper remission” and could be a “reasonable option.”

This “practice-changing view” is reinforced by the finding of general improvement of adverse events in both cohorts, they said.

Also of note, de-escalation in this study was associated with savings of almost half the expected TKI costs, they added.

The findings imply that many patients with stable responses might be able to maintain responses on lower TKI doses, they concluded, adding that studies of more ambitious de-escalation are warranted.

Newcastle University and Bloodwise funded the study. Dr. Clark received other grants from Bloodwise during the study, as well as grants and personal fees from Novartis, Bristol-Myers Squibb, and Pfizer, and personal fees from Ariad/Incyte.

[email protected]

Tyrosine kinase inhibitor de-escalation is generally safe and may lead to symptom improvement in patients with chronic myeloid leukemia who respond well to the therapy, according to an interim analysis of the nonrandomized phase 2 DESTINY trial.

The findings imply that some patients are unnecessarily overtreated, as responses were sometimes maintained with lower tyrosine kinase inhibitor (TKI) doses, according to Richard E. Clark, MD, of the University of Liverpool, England, and his colleagues (Lancet Haematol. 2017 May 26;4:e310-16).

Of 174 patients with chronic myeloid leukemia (CML) in first chronic phase who had received TKIs for at least 3 years and who were either in stable molecular response 4 logs below the standard arbitrary baseline (MR4, 125 patients) or stable major molecular response (MMR) but not MR4 (49 patients) for at least 12 months at the time of enrollment, 12 (7%) had molecular recurrence during 12 months of half-dose TKI therapy, and all patients who experienced molecular recurrence regained MMR within 4 months of being back on full-dose TKIs, the researchers noted.

The median time to recovery was 77 days.

The recurrence rate was significantly lower in the MR4 cohort than in the MMR cohort (2% vs. 19%; hazard ratio, 0.12), and time to relapse was significantly longer in the MR4 cohort (median, 8.7 vs. 4.4 months), the investigators said.

Recurrence was not associated with age, sex, weight, performance status, BCR-ABL1 transcript type, or duration of TKI therapy, which was a median of 6.9 years overall, they noted.

During the first 3 months of de-escalation, adverse events associated with treatment, including lethargy, diarrhea, rash, and nausea, all improved.

Adverse events during de-escalation occurred in 16 patients, and included one fatality due to worsening of peripheral arterial occlusive disease, but all were deemed unrelated to the TKI or underlying chronic CML, the investigators noted.

Study subjects were adults with positive BCR-ABL1 transcripts, with either e13a2, e14a2, or e19a2 fusion transcript. They were enrolled between December 2013 and April 2015 from 20 hospitals in the United Kingdom; 148 were receiving imatinib, 16 were receiving nilotinib, and 10 were receiving dasatinib. They received half of their standard dose of imatinib (200 mg daily), dasatinib (50 mg daily), or nilotinib (200 mg twice daily) for 12 months. Recurrence during de-escalation was defined as BCR-ABL1:ABL1 ratio greater than 0.1% on two consecutive measurements.

“Although several studies of TKI cessation have been reported, little is known about the feasibility of treatment de-escalation in patients with stable molecular responses,” the investigators wrote, adding that the current study shows that de-escalation is “clearly safe for patients in stable MR4 or deeper remission” and could be a “reasonable option.”

This “practice-changing view” is reinforced by the finding of general improvement of adverse events in both cohorts, they said.

Also of note, de-escalation in this study was associated with savings of almost half the expected TKI costs, they added.

The findings imply that many patients with stable responses might be able to maintain responses on lower TKI doses, they concluded, adding that studies of more ambitious de-escalation are warranted.

Newcastle University and Bloodwise funded the study. Dr. Clark received other grants from Bloodwise during the study, as well as grants and personal fees from Novartis, Bristol-Myers Squibb, and Pfizer, and personal fees from Ariad/Incyte.

[email protected]

Research Center

A chimeric antigen receptor (CAR) T-cell therapy is “highly effective” in high-risk patients with chronic lymphocytic leukemia (CLL), according to researchers.

The CD19 CAR T-cell therapy, JCAR014, produced an overall response rate of 71% and a complete response (CR) rate of 17% in a phase 1/2 trial of patients with relapsed/refractory CLL.

Eighty-three percent of patients experienced cytokine release syndrome (CRS), and 33% developed neurotoxicity. One patient died of CRS/neurotoxicity.

Researchers reported these results in The Journal of Clinical Oncology.

The study was supported by Juno Therapeutics, Life Science Discovery Fund, the Bezos Family, the University of British Columbia Clinical Investigator Program, and grants from the National Cancer Institute and National Institute of Diabetes and Digestive and Kidney Diseases.

The trial included 24 patients with relapsed or refractory CLL. The patients’ median age was 61 (range, 40-73), and they had received a median of 5 prior therapies (range, 3-9). Nineteen patients had progressed while on ibrutinib, and 3 could not tolerate the drug.

“It was not known whether CAR T cells could be used to treat these high-risk CLL patients,” said study author Cameron Turtle, MBBS, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington.

“Our study shows that CD19 CAR T cells are a highly promising treatment for CLL patients who have failed ibrutinib.”

Treatment and safety

All 24 patients received lymphodepletion prior to JCAR014. Lymphodepleting regimens consisted of cyclophosphamide, fludarabine, or both.

Patients received JCAR014 at 1 of 3 dose levels—2 x 10⁵, 2 x 10⁶, or 2 x 10⁷ CAR T cells/kg.

Twenty patients (83%) developed CRS—18 with grade 1/2, 1 with grade 4, and 1 with grade 5 CRS.

Eight patients (33%) developed neurotoxicity, all of whom also had CRS. Five patients had grade 3 neurotoxicity, and 1 had grade 5 (same patient with grade 5 CRS).

Initial response

The overall response rate, according to IWCLL criteria, was 71%. Seventeen patients responded, 4 with CRs and 13 with partial responses (PRs).

One of the patients who achieved a CR had received a second dose of JCAR014, without lymphodepletion, 14 days after the first dose.

One of the patients with a PR initially had stable disease (SD) at the 4-week assessment but was in PR 8 weeks later.

Twenty-one patients had a bone marrow evaluation 4 weeks after treatment with JCAR014. Seventeen of these patients (81%) had no residual disease according to high-resolution flow cytometry.

The researchers also performed IGH sequencing of bone marrow in 12 patients with no residual disease by flow cytometry. Seven of these patients (58%) had no detectable malignant IGH sequences 4 weeks after receiving JCAR014.

Second dose

Six patients who had persistent disease or who relapsed after receiving JCAR014 received a second cycle of lymphodepletion and JCAR014 at the same dose (n=1) or a 10-fold higher dose (n=5).

Four of these patients developed CRS (2 grade 3 or higher), and 1 developed reversible neurotoxicity (grade 3).

Two patients achieved a CR and had no residual disease by flow cytometry or IGH sequencing.

Survival

Responders had significantly superior progression-free survival (PFS) and overall survival (OS) compared to non-responders.

The median PFS was 9.8 months in patients who achieved a CR, was not reached in those with a PR, and was 1.1 months in patients with progressive disease (PD) or SD (P=0.0068 for CR/PR vs SD/PD).

The median OS was not reached in patients who achieved a CR or a PR, but it was 11.2 months in patients with SD or PD (P=0.0011 for CR/PR vs SD/PD).

The researchers also found that IGH sequencing revealed patients with durable PFS.

The median PFS was not reached in patients with no malignant IGH sequences, but it was 8.5 months in IGH-positive patients (P=0.253). The median OS was not reached in either group (P=0.25).

Research Center

A chimeric antigen receptor (CAR) T-cell therapy is “highly effective” in high-risk patients with chronic lymphocytic leukemia (CLL), according to researchers.

The CD19 CAR T-cell therapy, JCAR014, produced an overall response rate of 71% and a complete response (CR) rate of 17% in a phase 1/2 trial of patients with relapsed/refractory CLL.

Eighty-three percent of patients experienced cytokine release syndrome (CRS), and 33% developed neurotoxicity. One patient died of CRS/neurotoxicity.

Researchers reported these results in The Journal of Clinical Oncology.

The study was supported by Juno Therapeutics, Life Science Discovery Fund, the Bezos Family, the University of British Columbia Clinical Investigator Program, and grants from the National Cancer Institute and National Institute of Diabetes and Digestive and Kidney Diseases.

The trial included 24 patients with relapsed or refractory CLL. The patients’ median age was 61 (range, 40-73), and they had received a median of 5 prior therapies (range, 3-9). Nineteen patients had progressed while on ibrutinib, and 3 could not tolerate the drug.

“It was not known whether CAR T cells could be used to treat these high-risk CLL patients,” said study author Cameron Turtle, MBBS, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington.

“Our study shows that CD19 CAR T cells are a highly promising treatment for CLL patients who have failed ibrutinib.”

Treatment and safety

All 24 patients received lymphodepletion prior to JCAR014. Lymphodepleting regimens consisted of cyclophosphamide, fludarabine, or both.

Patients received JCAR014 at 1 of 3 dose levels—2 x 10⁵, 2 x 10⁶, or 2 x 10⁷ CAR T cells/kg.

Twenty patients (83%) developed CRS—18 with grade 1/2, 1 with grade 4, and 1 with grade 5 CRS.

Eight patients (33%) developed neurotoxicity, all of whom also had CRS. Five patients had grade 3 neurotoxicity, and 1 had grade 5 (same patient with grade 5 CRS).

Initial response

The overall response rate, according to IWCLL criteria, was 71%. Seventeen patients responded, 4 with CRs and 13 with partial responses (PRs).

One of the patients who achieved a CR had received a second dose of JCAR014, without lymphodepletion, 14 days after the first dose.

One of the patients with a PR initially had stable disease (SD) at the 4-week assessment but was in PR 8 weeks later.

Twenty-one patients had a bone marrow evaluation 4 weeks after treatment with JCAR014. Seventeen of these patients (81%) had no residual disease according to high-resolution flow cytometry.

The researchers also performed IGH sequencing of bone marrow in 12 patients with no residual disease by flow cytometry. Seven of these patients (58%) had no detectable malignant IGH sequences 4 weeks after receiving JCAR014.

Second dose

Six patients who had persistent disease or who relapsed after receiving JCAR014 received a second cycle of lymphodepletion and JCAR014 at the same dose (n=1) or a 10-fold higher dose (n=5).

Four of these patients developed CRS (2 grade 3 or higher), and 1 developed reversible neurotoxicity (grade 3).

Two patients achieved a CR and had no residual disease by flow cytometry or IGH sequencing.

Survival

Responders had significantly superior progression-free survival (PFS) and overall survival (OS) compared to non-responders.

The median PFS was 9.8 months in patients who achieved a CR, was not reached in those with a PR, and was 1.1 months in patients with progressive disease (PD) or SD (P=0.0068 for CR/PR vs SD/PD).

The median OS was not reached in patients who achieved a CR or a PR, but it was 11.2 months in patients with SD or PD (P=0.0011 for CR/PR vs SD/PD).

The researchers also found that IGH sequencing revealed patients with durable PFS.

The median PFS was not reached in patients with no malignant IGH sequences, but it was 8.5 months in IGH-positive patients (P=0.253). The median OS was not reached in either group (P=0.25).

Research Center

A chimeric antigen receptor (CAR) T-cell therapy is “highly effective” in high-risk patients with chronic lymphocytic leukemia (CLL), according to researchers.

The CD19 CAR T-cell therapy, JCAR014, produced an overall response rate of 71% and a complete response (CR) rate of 17% in a phase 1/2 trial of patients with relapsed/refractory CLL.

Eighty-three percent of patients experienced cytokine release syndrome (CRS), and 33% developed neurotoxicity. One patient died of CRS/neurotoxicity.

Researchers reported these results in The Journal of Clinical Oncology.

The study was supported by Juno Therapeutics, Life Science Discovery Fund, the Bezos Family, the University of British Columbia Clinical Investigator Program, and grants from the National Cancer Institute and National Institute of Diabetes and Digestive and Kidney Diseases.

The trial included 24 patients with relapsed or refractory CLL. The patients’ median age was 61 (range, 40-73), and they had received a median of 5 prior therapies (range, 3-9). Nineteen patients had progressed while on ibrutinib, and 3 could not tolerate the drug.

“It was not known whether CAR T cells could be used to treat these high-risk CLL patients,” said study author Cameron Turtle, MBBS, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington.

“Our study shows that CD19 CAR T cells are a highly promising treatment for CLL patients who have failed ibrutinib.”

Treatment and safety

All 24 patients received lymphodepletion prior to JCAR014. Lymphodepleting regimens consisted of cyclophosphamide, fludarabine, or both.

Patients received JCAR014 at 1 of 3 dose levels—2 x 10⁵, 2 x 10⁶, or 2 x 10⁷ CAR T cells/kg.

Twenty patients (83%) developed CRS—18 with grade 1/2, 1 with grade 4, and 1 with grade 5 CRS.

Eight patients (33%) developed neurotoxicity, all of whom also had CRS. Five patients had grade 3 neurotoxicity, and 1 had grade 5 (same patient with grade 5 CRS).

Initial response

The overall response rate, according to IWCLL criteria, was 71%. Seventeen patients responded, 4 with CRs and 13 with partial responses (PRs).

One of the patients who achieved a CR had received a second dose of JCAR014, without lymphodepletion, 14 days after the first dose.

One of the patients with a PR initially had stable disease (SD) at the 4-week assessment but was in PR 8 weeks later.

Twenty-one patients had a bone marrow evaluation 4 weeks after treatment with JCAR014. Seventeen of these patients (81%) had no residual disease according to high-resolution flow cytometry.

The researchers also performed IGH sequencing of bone marrow in 12 patients with no residual disease by flow cytometry. Seven of these patients (58%) had no detectable malignant IGH sequences 4 weeks after receiving JCAR014.

Second dose

Six patients who had persistent disease or who relapsed after receiving JCAR014 received a second cycle of lymphodepletion and JCAR014 at the same dose (n=1) or a 10-fold higher dose (n=5).

Four of these patients developed CRS (2 grade 3 or higher), and 1 developed reversible neurotoxicity (grade 3).

Two patients achieved a CR and had no residual disease by flow cytometry or IGH sequencing.

Survival

Responders had significantly superior progression-free survival (PFS) and overall survival (OS) compared to non-responders.

The median PFS was 9.8 months in patients who achieved a CR, was not reached in those with a PR, and was 1.1 months in patients with progressive disease (PD) or SD (P=0.0068 for CR/PR vs SD/PD).

The median OS was not reached in patients who achieved a CR or a PR, but it was 11.2 months in patients with SD or PD (P=0.0011 for CR/PR vs SD/PD).

The researchers also found that IGH sequencing revealed patients with durable PFS.

The median PFS was not reached in patients with no malignant IGH sequences, but it was 8.5 months in IGH-positive patients (P=0.253). The median OS was not reached in either group (P=0.25).