ALL

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

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

luiscar/Thinkstock

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

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

luiscar/Thinkstock

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

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

luiscar/Thinkstock

Children’s Cancer Institute

Researchers say they have developed a more accurate risk scoring system for children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) who are typically thought to have standard- or medium-risk disease.

The scoring system includes 3 factors associated with higher-risk BCP-ALL—the presence of high-risk ALL gene microdeletions, having minimal residual disease (MRD) greater than 5 x 10^-5 at day 33, and being high-risk according to National Cancer Institute (NCI) classification.

The researchers found that children with 2 or more of these characteristics were most likely to relapse or die within 7 years of treatment initiation.

On the other hand, children without any of the 3 characteristics had high rates of relapse-free survival (RFS) and overall survival (OS).

Rosemary Sutton, PhD, of Children’s Cancer Institute in Sydney, New South Wales, Australia, and her colleagues devised this risk scoring system and described it in the British Journal of Haematology.

The researchers created their system with the help of data from 475 patients (ages 1 to 18) who had BCP-ALL and were considered non-high-risk. The patients were enrolled on the ANZCHOG ALL8 trial.

Dr Sutton and her colleagues noted that children with standard- or medium-risk BCP-ALL typically receive less intensive treatment than children with high-risk BCP-ALL. However, some of the standard- and medium-risk patients do relapse.

“For the standard- to medium-risk group, we needed more information to get a better handle on the biology of the child’s cancer to better determine their risk,” Dr Sutton said. “So we supplemented MRD results with 2 other pieces of patient information—the presence or absence of specific gene microdeletions and a score called the NCI risk, based on age and white blood cell count.”

“We tested for microdeletions in 9 genes involved in leukemia and found that 2 of the genes—IKZF1 and P2RY8-CRLF2—were important predictors of relapse.”

The researchers combined patients with IKZF1 intragenic deletions, P2RY8-CRLF2 gene fusion, or both into a “high-risk deletion group.”

And the team based the scoring system on 3 factors—the high-risk deletion group, MRD >5 x 10^-5 at day 33, and high risk according to NCI risk classification. Patients received 1 point for each of these factors.

The RFS rate was 93% for patients with a score of 0, 78% for those with a score of 1, and 49% for patients with a score of 2 or 3. The OS rate was 99%, 91%, and 71%, respectively.

The researchers said their scoring system provided greater discrimination than MRD-based risk stratification into a standard-risk group—which had an RFS of 89% and an OS of 96%—and a medium-risk group—which had an RFS of 79% and an OS of 91%.

Study author Toby Trahair, MBBS, PhD, of Sydney Children’s Hospital in Randwick, New South Wales, said this scoring system could make a big difference to the success of BCP-ALL treatment.

“We are always trying to improve how we diagnose and treat children with this most common childhood cancer,” Dr Trahair said. “This risk score will mean doctors can fine tune a child’s risk category and so fine tune their treatment. It will mean more kids can conquer this horrible disease, which, only 50 years ago, had survival rates of close to 0.”

Children’s Cancer Institute

Researchers say they have developed a more accurate risk scoring system for children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) who are typically thought to have standard- or medium-risk disease.

The scoring system includes 3 factors associated with higher-risk BCP-ALL—the presence of high-risk ALL gene microdeletions, having minimal residual disease (MRD) greater than 5 x 10^-5 at day 33, and being high-risk according to National Cancer Institute (NCI) classification.

The researchers found that children with 2 or more of these characteristics were most likely to relapse or die within 7 years of treatment initiation.

On the other hand, children without any of the 3 characteristics had high rates of relapse-free survival (RFS) and overall survival (OS).

Rosemary Sutton, PhD, of Children’s Cancer Institute in Sydney, New South Wales, Australia, and her colleagues devised this risk scoring system and described it in the British Journal of Haematology.

The researchers created their system with the help of data from 475 patients (ages 1 to 18) who had BCP-ALL and were considered non-high-risk. The patients were enrolled on the ANZCHOG ALL8 trial.

Dr Sutton and her colleagues noted that children with standard- or medium-risk BCP-ALL typically receive less intensive treatment than children with high-risk BCP-ALL. However, some of the standard- and medium-risk patients do relapse.

“For the standard- to medium-risk group, we needed more information to get a better handle on the biology of the child’s cancer to better determine their risk,” Dr Sutton said. “So we supplemented MRD results with 2 other pieces of patient information—the presence or absence of specific gene microdeletions and a score called the NCI risk, based on age and white blood cell count.”

“We tested for microdeletions in 9 genes involved in leukemia and found that 2 of the genes—IKZF1 and P2RY8-CRLF2—were important predictors of relapse.”

The researchers combined patients with IKZF1 intragenic deletions, P2RY8-CRLF2 gene fusion, or both into a “high-risk deletion group.”

And the team based the scoring system on 3 factors—the high-risk deletion group, MRD >5 x 10^-5 at day 33, and high risk according to NCI risk classification. Patients received 1 point for each of these factors.

The RFS rate was 93% for patients with a score of 0, 78% for those with a score of 1, and 49% for patients with a score of 2 or 3. The OS rate was 99%, 91%, and 71%, respectively.

The researchers said their scoring system provided greater discrimination than MRD-based risk stratification into a standard-risk group—which had an RFS of 89% and an OS of 96%—and a medium-risk group—which had an RFS of 79% and an OS of 91%.

Study author Toby Trahair, MBBS, PhD, of Sydney Children’s Hospital in Randwick, New South Wales, said this scoring system could make a big difference to the success of BCP-ALL treatment.

“We are always trying to improve how we diagnose and treat children with this most common childhood cancer,” Dr Trahair said. “This risk score will mean doctors can fine tune a child’s risk category and so fine tune their treatment. It will mean more kids can conquer this horrible disease, which, only 50 years ago, had survival rates of close to 0.”

Children’s Cancer Institute

Researchers say they have developed a more accurate risk scoring system for children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) who are typically thought to have standard- or medium-risk disease.

The scoring system includes 3 factors associated with higher-risk BCP-ALL—the presence of high-risk ALL gene microdeletions, having minimal residual disease (MRD) greater than 5 x 10^-5 at day 33, and being high-risk according to National Cancer Institute (NCI) classification.

The researchers found that children with 2 or more of these characteristics were most likely to relapse or die within 7 years of treatment initiation.

On the other hand, children without any of the 3 characteristics had high rates of relapse-free survival (RFS) and overall survival (OS).

Rosemary Sutton, PhD, of Children’s Cancer Institute in Sydney, New South Wales, Australia, and her colleagues devised this risk scoring system and described it in the British Journal of Haematology.

The researchers created their system with the help of data from 475 patients (ages 1 to 18) who had BCP-ALL and were considered non-high-risk. The patients were enrolled on the ANZCHOG ALL8 trial.

Dr Sutton and her colleagues noted that children with standard- or medium-risk BCP-ALL typically receive less intensive treatment than children with high-risk BCP-ALL. However, some of the standard- and medium-risk patients do relapse.

“For the standard- to medium-risk group, we needed more information to get a better handle on the biology of the child’s cancer to better determine their risk,” Dr Sutton said. “So we supplemented MRD results with 2 other pieces of patient information—the presence or absence of specific gene microdeletions and a score called the NCI risk, based on age and white blood cell count.”

“We tested for microdeletions in 9 genes involved in leukemia and found that 2 of the genes—IKZF1 and P2RY8-CRLF2—were important predictors of relapse.”

The researchers combined patients with IKZF1 intragenic deletions, P2RY8-CRLF2 gene fusion, or both into a “high-risk deletion group.”

And the team based the scoring system on 3 factors—the high-risk deletion group, MRD >5 x 10^-5 at day 33, and high risk according to NCI risk classification. Patients received 1 point for each of these factors.

The RFS rate was 93% for patients with a score of 0, 78% for those with a score of 1, and 49% for patients with a score of 2 or 3. The OS rate was 99%, 91%, and 71%, respectively.

The researchers said their scoring system provided greater discrimination than MRD-based risk stratification into a standard-risk group—which had an RFS of 89% and an OS of 96%—and a medium-risk group—which had an RFS of 79% and an OS of 91%.

Study author Toby Trahair, MBBS, PhD, of Sydney Children’s Hospital in Randwick, New South Wales, said this scoring system could make a big difference to the success of BCP-ALL treatment.

“We are always trying to improve how we diagnose and treat children with this most common childhood cancer,” Dr Trahair said. “This risk score will mean doctors can fine tune a child’s risk category and so fine tune their treatment. It will mean more kids can conquer this horrible disease, which, only 50 years ago, had survival rates of close to 0.”

Research Hospital

An antimalarial drug and a BH3 mimetic have demonstrated promise for treating BCR-ABL-positive acute lymphoblastic leukemia (ALL), according to work published in Clinical Cancer Research.

Investigators found the widely used antimalarial dihydroartemisinin (DHA) sensitized BCR-ABL+ ALL to the BH3 mimetic navitoclax (formerly ABT-263).

The combination therapy had a synergistic effect on mouse and human BCR-ABL+ leukemic cell death and extended the lives of mice with BCR-ABL+ ALL.

“Survival rates for children and adults with this leukemia still lag, highlighting the urgent need for new therapies,” said study author Joseph Opferman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“Our findings suggest that combining DHA with ABT-263 can significantly improve treatment response.”

As opposed to mice that received navitoclax alone, there was no evidence of navitoclax resistance in mice treated with navitoclax and DHA.

The investigators determined that DHA worked by repressing production of MCL-1, a protein that is elevated in many cancers and helps malignant cells resist BH3 mimetics.

“MCL-1 is widely recognized as an important survival molecule in many normal cell types as well as cancer,” Dr Opferman said. “MCL-1 inhibitors are in development, but none are currently available for treating patients.”

“And because MCL-1 is essential for proper functioning of many normal cell types, there is concern about potential toxicity. We sought to identify drugs that are available now to augment treatment of BCR-ABL+ ALL.”

The search for a drug to sensitize BCR-ABL+ ALL to navitoclax and related compounds led Dr Opferman and his colleagues to DHA. A drug screen showed that DHA killed BCR-ABL+ ALL cells from mice.

The investigators showed how DHA induced expression of the protein CHOP, which is a key regulator of the endoplasmic reticulum stress pathway in cells. CHOP expression triggered the stress pathway in BCR-ABL+ ALL cells from mice and led to the suppression of MCL-1.

“MCL-1 has a short half-life, so the cell’s MCL-1 stores are rapidly depleted if the protein’s translation is repressed,” said study author Amit Budhraja, PhD, a postdoctoral fellow in Dr Opferman’s lab.

Now, the investigators are studying the mechanism in human BCR-ABL+ leukemic cells as well as in other cancers.

“Identifying the mechanism will allow us to study the pathway in detail for other points to target for anticancer drug development,” Dr Opferman said.

Research Hospital

An antimalarial drug and a BH3 mimetic have demonstrated promise for treating BCR-ABL-positive acute lymphoblastic leukemia (ALL), according to work published in Clinical Cancer Research.

Investigators found the widely used antimalarial dihydroartemisinin (DHA) sensitized BCR-ABL+ ALL to the BH3 mimetic navitoclax (formerly ABT-263).

The combination therapy had a synergistic effect on mouse and human BCR-ABL+ leukemic cell death and extended the lives of mice with BCR-ABL+ ALL.

“Survival rates for children and adults with this leukemia still lag, highlighting the urgent need for new therapies,” said study author Joseph Opferman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“Our findings suggest that combining DHA with ABT-263 can significantly improve treatment response.”

As opposed to mice that received navitoclax alone, there was no evidence of navitoclax resistance in mice treated with navitoclax and DHA.

The investigators determined that DHA worked by repressing production of MCL-1, a protein that is elevated in many cancers and helps malignant cells resist BH3 mimetics.

“MCL-1 is widely recognized as an important survival molecule in many normal cell types as well as cancer,” Dr Opferman said. “MCL-1 inhibitors are in development, but none are currently available for treating patients.”

“And because MCL-1 is essential for proper functioning of many normal cell types, there is concern about potential toxicity. We sought to identify drugs that are available now to augment treatment of BCR-ABL+ ALL.”

The search for a drug to sensitize BCR-ABL+ ALL to navitoclax and related compounds led Dr Opferman and his colleagues to DHA. A drug screen showed that DHA killed BCR-ABL+ ALL cells from mice.

The investigators showed how DHA induced expression of the protein CHOP, which is a key regulator of the endoplasmic reticulum stress pathway in cells. CHOP expression triggered the stress pathway in BCR-ABL+ ALL cells from mice and led to the suppression of MCL-1.

“MCL-1 has a short half-life, so the cell’s MCL-1 stores are rapidly depleted if the protein’s translation is repressed,” said study author Amit Budhraja, PhD, a postdoctoral fellow in Dr Opferman’s lab.

Now, the investigators are studying the mechanism in human BCR-ABL+ leukemic cells as well as in other cancers.

“Identifying the mechanism will allow us to study the pathway in detail for other points to target for anticancer drug development,” Dr Opferman said.

Research Hospital

An antimalarial drug and a BH3 mimetic have demonstrated promise for treating BCR-ABL-positive acute lymphoblastic leukemia (ALL), according to work published in Clinical Cancer Research.

Investigators found the widely used antimalarial dihydroartemisinin (DHA) sensitized BCR-ABL+ ALL to the BH3 mimetic navitoclax (formerly ABT-263).

The combination therapy had a synergistic effect on mouse and human BCR-ABL+ leukemic cell death and extended the lives of mice with BCR-ABL+ ALL.

“Survival rates for children and adults with this leukemia still lag, highlighting the urgent need for new therapies,” said study author Joseph Opferman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“Our findings suggest that combining DHA with ABT-263 can significantly improve treatment response.”

As opposed to mice that received navitoclax alone, there was no evidence of navitoclax resistance in mice treated with navitoclax and DHA.

The investigators determined that DHA worked by repressing production of MCL-1, a protein that is elevated in many cancers and helps malignant cells resist BH3 mimetics.

“MCL-1 is widely recognized as an important survival molecule in many normal cell types as well as cancer,” Dr Opferman said. “MCL-1 inhibitors are in development, but none are currently available for treating patients.”

“And because MCL-1 is essential for proper functioning of many normal cell types, there is concern about potential toxicity. We sought to identify drugs that are available now to augment treatment of BCR-ABL+ ALL.”

The search for a drug to sensitize BCR-ABL+ ALL to navitoclax and related compounds led Dr Opferman and his colleagues to DHA. A drug screen showed that DHA killed BCR-ABL+ ALL cells from mice.

The investigators showed how DHA induced expression of the protein CHOP, which is a key regulator of the endoplasmic reticulum stress pathway in cells. CHOP expression triggered the stress pathway in BCR-ABL+ ALL cells from mice and led to the suppression of MCL-1.

“MCL-1 has a short half-life, so the cell’s MCL-1 stores are rapidly depleted if the protein’s translation is repressed,” said study author Amit Budhraja, PhD, a postdoctoral fellow in Dr Opferman’s lab.

Now, the investigators are studying the mechanism in human BCR-ABL+ leukemic cells as well as in other cancers.

“Identifying the mechanism will allow us to study the pathway in detail for other points to target for anticancer drug development,” Dr Opferman said.

Wolfgang Däuble

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Wolfgang Däuble

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Wolfgang Däuble

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

NATIONAL HARBOR, MD. – A new CD22-targeted chimeric antigen receptor (CAR) demonstrated clinical activity in a phase 1 study of adults and children with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), including several who were previously treated with CD19-directed immunotherapy.

In 21 children and adults with B-ALL who were treated with the CD22 CAR, dose-dependent antileukemic activity was observed; complete remission occurred in 11 of 15 (73%) who received bioactive doses (at least 1 x 10⁶ CD22 CAR T-cells per kg of body weight), including 5 of 5 patients with CD19dim or CD19neg B-ALL, Terry J. Fry, MD, of the National Institutes of Health, Bethesda, Md., and colleagues reported in Nature Medicine (2017 Nov 20. doi: 10.1038.nm.4441).

Sharon Worcester/Frontline Medical News

[email protected]

NATIONAL HARBOR, MD. – A new CD22-targeted chimeric antigen receptor (CAR) demonstrated clinical activity in a phase 1 study of adults and children with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), including several who were previously treated with CD19-directed immunotherapy.

In 21 children and adults with B-ALL who were treated with the CD22 CAR, dose-dependent antileukemic activity was observed; complete remission occurred in 11 of 15 (73%) who received bioactive doses (at least 1 x 10⁶ CD22 CAR T-cells per kg of body weight), including 5 of 5 patients with CD19dim or CD19neg B-ALL, Terry J. Fry, MD, of the National Institutes of Health, Bethesda, Md., and colleagues reported in Nature Medicine (2017 Nov 20. doi: 10.1038.nm.4441).

Sharon Worcester/Frontline Medical News

[email protected]

NATIONAL HARBOR, MD. – A new CD22-targeted chimeric antigen receptor (CAR) demonstrated clinical activity in a phase 1 study of adults and children with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), including several who were previously treated with CD19-directed immunotherapy.

In 21 children and adults with B-ALL who were treated with the CD22 CAR, dose-dependent antileukemic activity was observed; complete remission occurred in 11 of 15 (73%) who received bioactive doses (at least 1 x 10⁶ CD22 CAR T-cells per kg of body weight), including 5 of 5 patients with CD19dim or CD19neg B-ALL, Terry J. Fry, MD, of the National Institutes of Health, Bethesda, Md., and colleagues reported in Nature Medicine (2017 Nov 20. doi: 10.1038.nm.4441).

Sharon Worcester/Frontline Medical News

[email protected]

Chimeric antigen receptor (CAR) T-cell therapy has generated a great deal of excitement in recent months with the approval of Novartis’ Kymriah (tisagenlecleucel) for pediatric acute lymphoblastic leukemia and Kite Pharma’s Yescarta (axicabtagene ciloleucel) for relapsed/refractory large B-cell lymphoma in adults, and experts in the field foresee a wave of approvals for additional indications in the coming months.

“CAR T is coming unbelievably fast,” Richard Maziarz, MD, professor of medicine at Oregon Health and Science University, Portland, said in an interview.

In fact, a search of clinicaltrials.gov revealed 120 open CAR T-cell–based therapy trials for cancer and other conditions such as autoimmune diseases, he said.
 

Price tag pressure

During a plenary session on genetically modified cell therapies at the annual meeting of the Society for Immunotherapy of Cancer, experts and investigators provided a glimpse of what’s in store, including new targets and smarter targeting and combinations that incorporate CAR T-cell therapy to treat solid tumors.

Cost-saving proposals

Efforts to address the cost concerns, including proposals for novel payment strategies, are already emerging. One example involves an offer by Novartis to charge for Kymriah only if treated patients go into remission within 1 month. Details of the plan haven’t been released.

Another approach is being considered in Europe and involves a graduated payment system for an investigational regulatory T cell therapy for autoimmune disease, Dr. Maziarz said. For example, if the drug costs $1 million, the government might pay $200,000 the first year and then $100,000 per year if the patient is cured. “If the patient relapses, they can stop their payment, as cure was not achieved,” he explained.

In many discussions about value, the definition is based on quality-adjusted life years (QALY) gained, he said. A recent statement from the American College of Cardiology and the American Heart Association on cost/value methodology, for example, used $50,000 per QALY gained as the cut-off for a good investment. Costs of $50,000 to less than $150,000 per QALY were considered to be of intermediate value, and costs of $150,000 or greater per QALY gained were considered to be of low value.

“A number of payers are using these guidelines to determine what drugs they will put on their portfolio and make available to enrollees,” Dr. Maziarz said.

In anticipation of cost-related issues with CAR T-cell therapy, the Institute for Clinical and Economic Review (ICER) and its California Technology Assessment Forum (CTAP) put out a request for information and input regarding their intent to collaboratively initiate an assessment of CAR T-cell effectiveness and value, he said.

In the meantime, Dr. Maziarz said that most private insurers he’s been in contact with are planning coverage of CAR T-cell therapy but are working out the details of how to do it.

“It’s typically going to involve very, very strict guidelines for the patients who go on therapy – it’s not going to be a liberal use of the product. It will involve strict adherence to the label,” he said.

The real challenge, however, will be in the Medicare and Medicaid programs, because of the current nature of the reimbursement structures and lack of clear procedural codes to define the effort and cost of care associated with the application of these novel cell therapies.

Walid F. Gellad, MD, and Aaron S. Kesselheim, MD, anticipated some of these challenges in light of accelerated approval processes for expensive drugs and proposed in a May 2017 paper that government payers reimburse only the cost of manufacturing and some predetermined mark-up for such drugs until confirmatory trials demonstrate clinical benefit (N Engl J Med. 2017;376[21]:2001-04).

“Both Yescarta and Kymriah are approved with very, very, very limited data – 100 patients, 80 patients. They absolutely look promising. I was part of those studies, so I’m a believer, but the classic approach to determining success in the medical community is a randomized controlled trial,” Dr. Maziarz said.

The proposal by Dr. Gellad and Dr. Kesselheim acknowledged this, and said perhaps full payment isn’t warranted while the drugs remain in development and until they are proven to be a good investment.

Their proposal also calls for an economic impact analysis after 1-2 years on the market for all accelerated-approval pathway drugs that cost over a predetermined amount, timely and optimally designed confirmatory trials following accelerated approval to limit the period of uncertainty about the true clinical effect of the drug, and additional price concessions to public insurance programs for such drugs until the confirmatory trials are completed. Under this proposal, the unpaid portion of drug costs would be held in escrow until the drug’s efficacy is confirmed.

“I think what’s going to happen is that, as prices and costs go up for any therapy, that backlash will occur. These types of proposals to create solutions will come not from individual companies, but from the government,” Dr. Maziarz said. “I’m 100% excited about the work. I’m extremely excited to be part of the explorations. … I just still think we have to at least try to be aware and cognizant of the issues that we’ll be facing.”

Dr. Maziarz has received consulting fees from Novartis, Juno Therapeutics, and Kite Pharma. Dr. Heslop has received consulting fees from Novartis, has conducted research for Cell Medica and holds intellectual property rights/patent from Cell Medica, and has ownership interest in ViraCyte and Marker Therapeutics. Dr. June received royalties from Novartis, has conducted research for Novartis, and has ownership interest in Tmunity Therapeutics.

[email protected]

Chimeric antigen receptor (CAR) T-cell therapy has generated a great deal of excitement in recent months with the approval of Novartis’ Kymriah (tisagenlecleucel) for pediatric acute lymphoblastic leukemia and Kite Pharma’s Yescarta (axicabtagene ciloleucel) for relapsed/refractory large B-cell lymphoma in adults, and experts in the field foresee a wave of approvals for additional indications in the coming months.

“CAR T is coming unbelievably fast,” Richard Maziarz, MD, professor of medicine at Oregon Health and Science University, Portland, said in an interview.

In fact, a search of clinicaltrials.gov revealed 120 open CAR T-cell–based therapy trials for cancer and other conditions such as autoimmune diseases, he said.
 

Price tag pressure

During a plenary session on genetically modified cell therapies at the annual meeting of the Society for Immunotherapy of Cancer, experts and investigators provided a glimpse of what’s in store, including new targets and smarter targeting and combinations that incorporate CAR T-cell therapy to treat solid tumors.

Cost-saving proposals

Efforts to address the cost concerns, including proposals for novel payment strategies, are already emerging. One example involves an offer by Novartis to charge for Kymriah only if treated patients go into remission within 1 month. Details of the plan haven’t been released.

Another approach is being considered in Europe and involves a graduated payment system for an investigational regulatory T cell therapy for autoimmune disease, Dr. Maziarz said. For example, if the drug costs $1 million, the government might pay $200,000 the first year and then $100,000 per year if the patient is cured. “If the patient relapses, they can stop their payment, as cure was not achieved,” he explained.

In many discussions about value, the definition is based on quality-adjusted life years (QALY) gained, he said. A recent statement from the American College of Cardiology and the American Heart Association on cost/value methodology, for example, used $50,000 per QALY gained as the cut-off for a good investment. Costs of $50,000 to less than $150,000 per QALY were considered to be of intermediate value, and costs of $150,000 or greater per QALY gained were considered to be of low value.

“A number of payers are using these guidelines to determine what drugs they will put on their portfolio and make available to enrollees,” Dr. Maziarz said.

In anticipation of cost-related issues with CAR T-cell therapy, the Institute for Clinical and Economic Review (ICER) and its California Technology Assessment Forum (CTAP) put out a request for information and input regarding their intent to collaboratively initiate an assessment of CAR T-cell effectiveness and value, he said.

In the meantime, Dr. Maziarz said that most private insurers he’s been in contact with are planning coverage of CAR T-cell therapy but are working out the details of how to do it.

“It’s typically going to involve very, very strict guidelines for the patients who go on therapy – it’s not going to be a liberal use of the product. It will involve strict adherence to the label,” he said.

The real challenge, however, will be in the Medicare and Medicaid programs, because of the current nature of the reimbursement structures and lack of clear procedural codes to define the effort and cost of care associated with the application of these novel cell therapies.

Walid F. Gellad, MD, and Aaron S. Kesselheim, MD, anticipated some of these challenges in light of accelerated approval processes for expensive drugs and proposed in a May 2017 paper that government payers reimburse only the cost of manufacturing and some predetermined mark-up for such drugs until confirmatory trials demonstrate clinical benefit (N Engl J Med. 2017;376[21]:2001-04).

“Both Yescarta and Kymriah are approved with very, very, very limited data – 100 patients, 80 patients. They absolutely look promising. I was part of those studies, so I’m a believer, but the classic approach to determining success in the medical community is a randomized controlled trial,” Dr. Maziarz said.

The proposal by Dr. Gellad and Dr. Kesselheim acknowledged this, and said perhaps full payment isn’t warranted while the drugs remain in development and until they are proven to be a good investment.

Their proposal also calls for an economic impact analysis after 1-2 years on the market for all accelerated-approval pathway drugs that cost over a predetermined amount, timely and optimally designed confirmatory trials following accelerated approval to limit the period of uncertainty about the true clinical effect of the drug, and additional price concessions to public insurance programs for such drugs until the confirmatory trials are completed. Under this proposal, the unpaid portion of drug costs would be held in escrow until the drug’s efficacy is confirmed.

“I think what’s going to happen is that, as prices and costs go up for any therapy, that backlash will occur. These types of proposals to create solutions will come not from individual companies, but from the government,” Dr. Maziarz said. “I’m 100% excited about the work. I’m extremely excited to be part of the explorations. … I just still think we have to at least try to be aware and cognizant of the issues that we’ll be facing.”

Dr. Maziarz has received consulting fees from Novartis, Juno Therapeutics, and Kite Pharma. Dr. Heslop has received consulting fees from Novartis, has conducted research for Cell Medica and holds intellectual property rights/patent from Cell Medica, and has ownership interest in ViraCyte and Marker Therapeutics. Dr. June received royalties from Novartis, has conducted research for Novartis, and has ownership interest in Tmunity Therapeutics.

[email protected]

Chimeric antigen receptor (CAR) T-cell therapy has generated a great deal of excitement in recent months with the approval of Novartis’ Kymriah (tisagenlecleucel) for pediatric acute lymphoblastic leukemia and Kite Pharma’s Yescarta (axicabtagene ciloleucel) for relapsed/refractory large B-cell lymphoma in adults, and experts in the field foresee a wave of approvals for additional indications in the coming months.

“CAR T is coming unbelievably fast,” Richard Maziarz, MD, professor of medicine at Oregon Health and Science University, Portland, said in an interview.

In fact, a search of clinicaltrials.gov revealed 120 open CAR T-cell–based therapy trials for cancer and other conditions such as autoimmune diseases, he said.
 

Price tag pressure

During a plenary session on genetically modified cell therapies at the annual meeting of the Society for Immunotherapy of Cancer, experts and investigators provided a glimpse of what’s in store, including new targets and smarter targeting and combinations that incorporate CAR T-cell therapy to treat solid tumors.

Cost-saving proposals

Efforts to address the cost concerns, including proposals for novel payment strategies, are already emerging. One example involves an offer by Novartis to charge for Kymriah only if treated patients go into remission within 1 month. Details of the plan haven’t been released.

Another approach is being considered in Europe and involves a graduated payment system for an investigational regulatory T cell therapy for autoimmune disease, Dr. Maziarz said. For example, if the drug costs $1 million, the government might pay $200,000 the first year and then $100,000 per year if the patient is cured. “If the patient relapses, they can stop their payment, as cure was not achieved,” he explained.

In many discussions about value, the definition is based on quality-adjusted life years (QALY) gained, he said. A recent statement from the American College of Cardiology and the American Heart Association on cost/value methodology, for example, used $50,000 per QALY gained as the cut-off for a good investment. Costs of $50,000 to less than $150,000 per QALY were considered to be of intermediate value, and costs of $150,000 or greater per QALY gained were considered to be of low value.

“A number of payers are using these guidelines to determine what drugs they will put on their portfolio and make available to enrollees,” Dr. Maziarz said.

In anticipation of cost-related issues with CAR T-cell therapy, the Institute for Clinical and Economic Review (ICER) and its California Technology Assessment Forum (CTAP) put out a request for information and input regarding their intent to collaboratively initiate an assessment of CAR T-cell effectiveness and value, he said.

In the meantime, Dr. Maziarz said that most private insurers he’s been in contact with are planning coverage of CAR T-cell therapy but are working out the details of how to do it.

“It’s typically going to involve very, very strict guidelines for the patients who go on therapy – it’s not going to be a liberal use of the product. It will involve strict adherence to the label,” he said.

The real challenge, however, will be in the Medicare and Medicaid programs, because of the current nature of the reimbursement structures and lack of clear procedural codes to define the effort and cost of care associated with the application of these novel cell therapies.

Walid F. Gellad, MD, and Aaron S. Kesselheim, MD, anticipated some of these challenges in light of accelerated approval processes for expensive drugs and proposed in a May 2017 paper that government payers reimburse only the cost of manufacturing and some predetermined mark-up for such drugs until confirmatory trials demonstrate clinical benefit (N Engl J Med. 2017;376[21]:2001-04).

“Both Yescarta and Kymriah are approved with very, very, very limited data – 100 patients, 80 patients. They absolutely look promising. I was part of those studies, so I’m a believer, but the classic approach to determining success in the medical community is a randomized controlled trial,” Dr. Maziarz said.

The proposal by Dr. Gellad and Dr. Kesselheim acknowledged this, and said perhaps full payment isn’t warranted while the drugs remain in development and until they are proven to be a good investment.

Their proposal also calls for an economic impact analysis after 1-2 years on the market for all accelerated-approval pathway drugs that cost over a predetermined amount, timely and optimally designed confirmatory trials following accelerated approval to limit the period of uncertainty about the true clinical effect of the drug, and additional price concessions to public insurance programs for such drugs until the confirmatory trials are completed. Under this proposal, the unpaid portion of drug costs would be held in escrow until the drug’s efficacy is confirmed.

“I think what’s going to happen is that, as prices and costs go up for any therapy, that backlash will occur. These types of proposals to create solutions will come not from individual companies, but from the government,” Dr. Maziarz said. “I’m 100% excited about the work. I’m extremely excited to be part of the explorations. … I just still think we have to at least try to be aware and cognizant of the issues that we’ll be facing.”

Dr. Maziarz has received consulting fees from Novartis, Juno Therapeutics, and Kite Pharma. Dr. Heslop has received consulting fees from Novartis, has conducted research for Cell Medica and holds intellectual property rights/patent from Cell Medica, and has ownership interest in ViraCyte and Marker Therapeutics. Dr. June received royalties from Novartis, has conducted research for Novartis, and has ownership interest in Tmunity Therapeutics.

[email protected]

Micrograph showing B-ALL

Researchers say they have reported the first results demonstrating clinical activity of a CD22-directed chimeric antigen receptor (CAR) T-cell therapy in B-cell acute lymphoblastic leukemia (B-ALL).

The team conducted a phase 1 study of the therapy in 21 children and adults with relapsed/refractory B-ALL.

Twelve patients achieved a complete response (CR) to the treatment, with 3 patients still in CR at last follow-up.

Sixteen patients developed cytokine release syndrome (CRS), all grade 1 or 2.

Crystal Mackall, MD, of Stanford University in California, and her colleagues reported these results in Nature Medicine.*

“This is the first time that we’ve seen response rates anything like we achieved when we were first testing the CD19 CAR T therapy,” Dr Mackall said.

“We were all a little worried that we wouldn’t find anything comparable, but this study gives hope to the idea that there may be another similar, very potent treatment.”

Patients

Dr Mackall and her colleagues studied the CD22-CAR T-cell therapy in 21 patients with relapsed/refractory B-ALL. They had a median age of 19 (range, 7 to 30).

All of the patients had received a hematopoietic stem cell transplant at least once, and 2 patients had 2 prior transplants each. Seventeen patients had received prior CD19-directed immunotherapy. Fifteen had received CD19-directed CAR T-cell therapy, and 2 had received blinatumomab.

Lymphoblasts were CD19⁻ or CD19^dim in 10 patients (9 who had received a CD19-CAR and 1 treated with blinatumomab).

The median CD22 site density was 2839 molecules per cell (range, 613 to 13,452).

Dosing and DLTs

Patients received the CD22-CAR T-cell therapy at 1 of 3 dose levels:

• 0.3 × 10⁶ CD22-CAR T cells per kg body weight (n=6)
• 1 × 10⁶ cells per kg (n=13)
• 3 × 10⁶ cells per kg (n=2).

There was 1 dose-limiting toxicity (DLT) at the first dose level. It was grade 3, self-limited, noninfectious diarrhea that occurred during CRS and resolved with supportive care.

The other DLT occurred in a patient who received treatment at the third dose level. This patient had grade 4 hypoxia that was associated with rapid disease progression. The patient required brief intubation, and the hypoxia was resolved within 24 hours of starting steroid treatment.

Based on these results, the second dose level became the recommended phase 2 dose.

Other adverse events

The researchers said the primary toxicity was CRS, which occurred in 16 patients. Nine patients had grade 1 CRS, and 7 had grade 2.

There were no cases of irreversible neurotoxicity or seizure reported. Among the first 16 patients with complete assessments, there were cases of transient visual hallucinations (n=2), mild unresponsiveness (n=1), mild disorientation (n=1), and mild to moderate pain (n=2). However, these incidents resolved by day 28.

One patient died from gram-negative rod sepsis that developed after the resolution of CRS and neutrophil count recovery to >1000 cells/μL blood. The patient had a history of multi-organ failure due to sepsis.

Response

Twelve patients (57%) had a CR, and 9 of them were minimal residual disease negative.

One CR occurred at the lowest dose of therapy, 1 occurred at the highest dose, and the remaining 10 CRs occurred in patients who received dose level 2.

The researchers said there was no evidence to suggest that previous CD19-directed immunotherapy or diminished surface expression of CD19 impacted response to the CD22-CAR T-cell therapy.

Of the 9 patients who did not respond, 4 progressed and 5 had stable disease.

The researchers said 4 non-responders had “very high disease burden with rapid disease progression.” And 2 non-responders expressed diminished or partial CD22 on leukemic blasts at the time of enrollment.

The median duration of response was 6 months (range, 1.5 to 21+ months). Three patients are still in CR at 6, 9, and 21 months of follow-up.

“The take-home message is that we’ve found another CAR T-cell therapy that displays high-level activity in this phase 1 trial,” Dr Mackall said. “But the relapse rate was also high. So this forces the field to get even more sophisticated. How much of a target is needed for successful, long-lasting treatment? What happens if we target both CD19 and CD22 simultaneously?”

The researchers are already tackling the last question by testing a CAR T-cell therapy that recognizes both CD19 and CD22. They’ve confirmed this therapy can kill cancer cells in vitro and in vivo. Now, they’re testing it in a clinical trial that has opened at Stanford University and will open soon at the National Cancer Institute.

*This research was supported, in part, by the Intramural Research Program, National Cancer Institute and NIH Clinical Center, National Institutes of Health; by a Stand Up to Cancer–St. Baldrick’s Pediatric Dream Team translational research grant; and by a St. Baldrick’s Foundation Scholar Award.

Micrograph showing B-ALL

Researchers say they have reported the first results demonstrating clinical activity of a CD22-directed chimeric antigen receptor (CAR) T-cell therapy in B-cell acute lymphoblastic leukemia (B-ALL).

The team conducted a phase 1 study of the therapy in 21 children and adults with relapsed/refractory B-ALL.

Twelve patients achieved a complete response (CR) to the treatment, with 3 patients still in CR at last follow-up.

Sixteen patients developed cytokine release syndrome (CRS), all grade 1 or 2.

Crystal Mackall, MD, of Stanford University in California, and her colleagues reported these results in Nature Medicine.*

“This is the first time that we’ve seen response rates anything like we achieved when we were first testing the CD19 CAR T therapy,” Dr Mackall said.

“We were all a little worried that we wouldn’t find anything comparable, but this study gives hope to the idea that there may be another similar, very potent treatment.”

Patients

Dr Mackall and her colleagues studied the CD22-CAR T-cell therapy in 21 patients with relapsed/refractory B-ALL. They had a median age of 19 (range, 7 to 30).

All of the patients had received a hematopoietic stem cell transplant at least once, and 2 patients had 2 prior transplants each. Seventeen patients had received prior CD19-directed immunotherapy. Fifteen had received CD19-directed CAR T-cell therapy, and 2 had received blinatumomab.

Lymphoblasts were CD19⁻ or CD19^dim in 10 patients (9 who had received a CD19-CAR and 1 treated with blinatumomab).

The median CD22 site density was 2839 molecules per cell (range, 613 to 13,452).

Dosing and DLTs

Patients received the CD22-CAR T-cell therapy at 1 of 3 dose levels:

• 0.3 × 10⁶ CD22-CAR T cells per kg body weight (n=6)
• 1 × 10⁶ cells per kg (n=13)
• 3 × 10⁶ cells per kg (n=2).

There was 1 dose-limiting toxicity (DLT) at the first dose level. It was grade 3, self-limited, noninfectious diarrhea that occurred during CRS and resolved with supportive care.

The other DLT occurred in a patient who received treatment at the third dose level. This patient had grade 4 hypoxia that was associated with rapid disease progression. The patient required brief intubation, and the hypoxia was resolved within 24 hours of starting steroid treatment.

Based on these results, the second dose level became the recommended phase 2 dose.

Other adverse events

The researchers said the primary toxicity was CRS, which occurred in 16 patients. Nine patients had grade 1 CRS, and 7 had grade 2.

There were no cases of irreversible neurotoxicity or seizure reported. Among the first 16 patients with complete assessments, there were cases of transient visual hallucinations (n=2), mild unresponsiveness (n=1), mild disorientation (n=1), and mild to moderate pain (n=2). However, these incidents resolved by day 28.

One patient died from gram-negative rod sepsis that developed after the resolution of CRS and neutrophil count recovery to >1000 cells/μL blood. The patient had a history of multi-organ failure due to sepsis.

Response

Twelve patients (57%) had a CR, and 9 of them were minimal residual disease negative.

One CR occurred at the lowest dose of therapy, 1 occurred at the highest dose, and the remaining 10 CRs occurred in patients who received dose level 2.

The researchers said there was no evidence to suggest that previous CD19-directed immunotherapy or diminished surface expression of CD19 impacted response to the CD22-CAR T-cell therapy.

Of the 9 patients who did not respond, 4 progressed and 5 had stable disease.

The researchers said 4 non-responders had “very high disease burden with rapid disease progression.” And 2 non-responders expressed diminished or partial CD22 on leukemic blasts at the time of enrollment.

The median duration of response was 6 months (range, 1.5 to 21+ months). Three patients are still in CR at 6, 9, and 21 months of follow-up.

“The take-home message is that we’ve found another CAR T-cell therapy that displays high-level activity in this phase 1 trial,” Dr Mackall said. “But the relapse rate was also high. So this forces the field to get even more sophisticated. How much of a target is needed for successful, long-lasting treatment? What happens if we target both CD19 and CD22 simultaneously?”

The researchers are already tackling the last question by testing a CAR T-cell therapy that recognizes both CD19 and CD22. They’ve confirmed this therapy can kill cancer cells in vitro and in vivo. Now, they’re testing it in a clinical trial that has opened at Stanford University and will open soon at the National Cancer Institute.

*This research was supported, in part, by the Intramural Research Program, National Cancer Institute and NIH Clinical Center, National Institutes of Health; by a Stand Up to Cancer–St. Baldrick’s Pediatric Dream Team translational research grant; and by a St. Baldrick’s Foundation Scholar Award.

Micrograph showing B-ALL

Researchers say they have reported the first results demonstrating clinical activity of a CD22-directed chimeric antigen receptor (CAR) T-cell therapy in B-cell acute lymphoblastic leukemia (B-ALL).

The team conducted a phase 1 study of the therapy in 21 children and adults with relapsed/refractory B-ALL.

Twelve patients achieved a complete response (CR) to the treatment, with 3 patients still in CR at last follow-up.

Sixteen patients developed cytokine release syndrome (CRS), all grade 1 or 2.

Crystal Mackall, MD, of Stanford University in California, and her colleagues reported these results in Nature Medicine.*

“This is the first time that we’ve seen response rates anything like we achieved when we were first testing the CD19 CAR T therapy,” Dr Mackall said.

“We were all a little worried that we wouldn’t find anything comparable, but this study gives hope to the idea that there may be another similar, very potent treatment.”

Patients

Dr Mackall and her colleagues studied the CD22-CAR T-cell therapy in 21 patients with relapsed/refractory B-ALL. They had a median age of 19 (range, 7 to 30).

All of the patients had received a hematopoietic stem cell transplant at least once, and 2 patients had 2 prior transplants each. Seventeen patients had received prior CD19-directed immunotherapy. Fifteen had received CD19-directed CAR T-cell therapy, and 2 had received blinatumomab.

Lymphoblasts were CD19⁻ or CD19^dim in 10 patients (9 who had received a CD19-CAR and 1 treated with blinatumomab).

The median CD22 site density was 2839 molecules per cell (range, 613 to 13,452).

Dosing and DLTs

Patients received the CD22-CAR T-cell therapy at 1 of 3 dose levels:

• 0.3 × 10⁶ CD22-CAR T cells per kg body weight (n=6)
• 1 × 10⁶ cells per kg (n=13)
• 3 × 10⁶ cells per kg (n=2).

There was 1 dose-limiting toxicity (DLT) at the first dose level. It was grade 3, self-limited, noninfectious diarrhea that occurred during CRS and resolved with supportive care.

The other DLT occurred in a patient who received treatment at the third dose level. This patient had grade 4 hypoxia that was associated with rapid disease progression. The patient required brief intubation, and the hypoxia was resolved within 24 hours of starting steroid treatment.

Based on these results, the second dose level became the recommended phase 2 dose.

Other adverse events

The researchers said the primary toxicity was CRS, which occurred in 16 patients. Nine patients had grade 1 CRS, and 7 had grade 2.

There were no cases of irreversible neurotoxicity or seizure reported. Among the first 16 patients with complete assessments, there were cases of transient visual hallucinations (n=2), mild unresponsiveness (n=1), mild disorientation (n=1), and mild to moderate pain (n=2). However, these incidents resolved by day 28.

One patient died from gram-negative rod sepsis that developed after the resolution of CRS and neutrophil count recovery to >1000 cells/μL blood. The patient had a history of multi-organ failure due to sepsis.

Response

Twelve patients (57%) had a CR, and 9 of them were minimal residual disease negative.

One CR occurred at the lowest dose of therapy, 1 occurred at the highest dose, and the remaining 10 CRs occurred in patients who received dose level 2.

The researchers said there was no evidence to suggest that previous CD19-directed immunotherapy or diminished surface expression of CD19 impacted response to the CD22-CAR T-cell therapy.

Of the 9 patients who did not respond, 4 progressed and 5 had stable disease.

The researchers said 4 non-responders had “very high disease burden with rapid disease progression.” And 2 non-responders expressed diminished or partial CD22 on leukemic blasts at the time of enrollment.

The median duration of response was 6 months (range, 1.5 to 21+ months). Three patients are still in CR at 6, 9, and 21 months of follow-up.

“The take-home message is that we’ve found another CAR T-cell therapy that displays high-level activity in this phase 1 trial,” Dr Mackall said. “But the relapse rate was also high. So this forces the field to get even more sophisticated. How much of a target is needed for successful, long-lasting treatment? What happens if we target both CD19 and CD22 simultaneously?”

The researchers are already tackling the last question by testing a CAR T-cell therapy that recognizes both CD19 and CD22. They’ve confirmed this therapy can kill cancer cells in vitro and in vivo. Now, they’re testing it in a clinical trial that has opened at Stanford University and will open soon at the National Cancer Institute.

*This research was supported, in part, by the Intramural Research Program, National Cancer Institute and NIH Clinical Center, National Institutes of Health; by a Stand Up to Cancer–St. Baldrick’s Pediatric Dream Team translational research grant; and by a St. Baldrick’s Foundation Scholar Award.

acute lymphoblastic leukemia

The US Food and Drug Administration (FDA) has approved Dr. Reddy’s Laboratories Ltd.’s Clofarabine Injection, a therapeutic equivalent generic version of Clolar® (clofarabine) Injection.

The generic drug is now approved to treat patients age 1 to 21 who have relapsed or refractory acute lymphoblastic leukemia and have received at least 2 prior treatment regimens.

Dr. Reddy’s Clofarabine Injection is available in single-dose, 20 mL flint vials containing 20 mg of clofarabine in 20 mL of solution (1 mg/mL).

acute lymphoblastic leukemia

The US Food and Drug Administration (FDA) has approved Dr. Reddy’s Laboratories Ltd.’s Clofarabine Injection, a therapeutic equivalent generic version of Clolar® (clofarabine) Injection.

The generic drug is now approved to treat patients age 1 to 21 who have relapsed or refractory acute lymphoblastic leukemia and have received at least 2 prior treatment regimens.

Dr. Reddy’s Clofarabine Injection is available in single-dose, 20 mL flint vials containing 20 mg of clofarabine in 20 mL of solution (1 mg/mL).

acute lymphoblastic leukemia

The US Food and Drug Administration (FDA) has approved Dr. Reddy’s Laboratories Ltd.’s Clofarabine Injection, a therapeutic equivalent generic version of Clolar® (clofarabine) Injection.

The generic drug is now approved to treat patients age 1 to 21 who have relapsed or refractory acute lymphoblastic leukemia and have received at least 2 prior treatment regimens.

Dr. Reddy’s Clofarabine Injection is available in single-dose, 20 mL flint vials containing 20 mg of clofarabine in 20 mL of solution (1 mg/mL).

VICTORIA, B.C. – When it comes to the adverse effects of tyrosine kinase inhibitors (TKIs), hypothyroidism appears to have a bright side, according to a retrospective cohort study among patients with nonthyroid cancers.

While taking one of these targeted agents, roughly a quarter of patients became overtly hypothyroid, an adverse effect that appears to be due in part to immune destruction. Risk was higher for women and earlier in therapy.

Relative to counterparts who remained euthyroid, overtly hypothyroid patients were 44% less likely to die after other factors were taken into account.

Susan London, Frontline Medical News

VICTORIA, B.C. – When it comes to the adverse effects of tyrosine kinase inhibitors (TKIs), hypothyroidism appears to have a bright side, according to a retrospective cohort study among patients with nonthyroid cancers.

While taking one of these targeted agents, roughly a quarter of patients became overtly hypothyroid, an adverse effect that appears to be due in part to immune destruction. Risk was higher for women and earlier in therapy.

Relative to counterparts who remained euthyroid, overtly hypothyroid patients were 44% less likely to die after other factors were taken into account.

Susan London, Frontline Medical News

VICTORIA, B.C. – When it comes to the adverse effects of tyrosine kinase inhibitors (TKIs), hypothyroidism appears to have a bright side, according to a retrospective cohort study among patients with nonthyroid cancers.

While taking one of these targeted agents, roughly a quarter of patients became overtly hypothyroid, an adverse effect that appears to be due in part to immune destruction. Risk was higher for women and earlier in therapy.

Relative to counterparts who remained euthyroid, overtly hypothyroid patients were 44% less likely to die after other factors were taken into account.

Susan London, Frontline Medical News

Among children with average-risk acute lymphoblastic leukemia (ALL), those with impairments in physical and emotional functioning at 2 months after diagnosis are likely to have continuing difficulties over 2 years later, based on the results of a 594-patient study published online in Cancer (2017 Nov 7. doi: 10.1002/cncr.31085).

Evaluations of quality of life and family functioning as early as 2 months after diagnosis identified those at highest risk of continued impairment, and can be used to target patients and their families for interventions and risk factor modification, the researchers said.

“These results provide a compelling rationale to screen patients for physical and emotional functioning early in therapy to target interventions toward patients at the highest risk of later impairment,” wrote lead author Daniel J. Zheng, MD, of the section of pediatric hematology-oncology at Yale University, New Haven, Conn., and coauthors.

Dr. Zheng and his colleagues measured impairments in children with average-risk ALL using the Pediatric Quality of Life Inventory Generic Core Scales Version 4.0 (PedsQL4.0), a 23-item survey that measures a child’s quality of life, and the 12-question General Functioning subscale of the McMaster Family Assessment Device (FAD-GF). Both are quick and low-cost screening measures that can be conducted in the clinic, they added. Evaluations occurred at approximately 2 months, 8 months, 17 months, 26 months, and 38 months (boys only) after diagnosis. The mean age of participants at diagnosis was 6.0 years (standard deviation, 1.6 years).

At 2 months after diagnosis, 36.5% of the children had impairments in physical functioning, and 26.2% had impairments in emotional functioning. The population norms for these measures are 2.3% for both scales, investigators wrote. At a 26-month evaluation, levels of impairment were still 11.9% for physical and 9.8% for emotional functioning.

Boys had an additional 38-month evaluation, at which time there were no significant differences in quality of life outcomes versus those observed at 26 months in the girls.

Unhealthy family functioning was a significant predictor of emotional impairment (odds ratio, 1.5; 95% confidence interval, 1.1-2.1) in multivariate models controlling for age and sex.

Strategies are needed to “intervene early and help the substantial proportion of children” with quality of life impairments, the researchers said. In particular, family functioning is “potentially modifiable with early intervention,” as suggested by a series of promising studies of techniques such as stress management sessions for parents. Most techniques feature a “targeted family-centered approach to psychosocial needs” that includes “embedded psychologists” as part of the multidisciplinary cancer care team.

Study funding came from the National Institutes of Health, National Cancer Institute, and the St. Baldrick’s Foundation. Dr. Zheng reported funding from a Yale Medical Student research fellowship, while coauthors reported conflict of interest disclosures from entities including Amgen, Takeda Pharmaceuticals International, and Shire Pharmaceuticals.

Among children with average-risk acute lymphoblastic leukemia (ALL), those with impairments in physical and emotional functioning at 2 months after diagnosis are likely to have continuing difficulties over 2 years later, based on the results of a 594-patient study published online in Cancer (2017 Nov 7. doi: 10.1002/cncr.31085).

Evaluations of quality of life and family functioning as early as 2 months after diagnosis identified those at highest risk of continued impairment, and can be used to target patients and their families for interventions and risk factor modification, the researchers said.

“These results provide a compelling rationale to screen patients for physical and emotional functioning early in therapy to target interventions toward patients at the highest risk of later impairment,” wrote lead author Daniel J. Zheng, MD, of the section of pediatric hematology-oncology at Yale University, New Haven, Conn., and coauthors.

Dr. Zheng and his colleagues measured impairments in children with average-risk ALL using the Pediatric Quality of Life Inventory Generic Core Scales Version 4.0 (PedsQL4.0), a 23-item survey that measures a child’s quality of life, and the 12-question General Functioning subscale of the McMaster Family Assessment Device (FAD-GF). Both are quick and low-cost screening measures that can be conducted in the clinic, they added. Evaluations occurred at approximately 2 months, 8 months, 17 months, 26 months, and 38 months (boys only) after diagnosis. The mean age of participants at diagnosis was 6.0 years (standard deviation, 1.6 years).

At 2 months after diagnosis, 36.5% of the children had impairments in physical functioning, and 26.2% had impairments in emotional functioning. The population norms for these measures are 2.3% for both scales, investigators wrote. At a 26-month evaluation, levels of impairment were still 11.9% for physical and 9.8% for emotional functioning.

Boys had an additional 38-month evaluation, at which time there were no significant differences in quality of life outcomes versus those observed at 26 months in the girls.

Unhealthy family functioning was a significant predictor of emotional impairment (odds ratio, 1.5; 95% confidence interval, 1.1-2.1) in multivariate models controlling for age and sex.

Strategies are needed to “intervene early and help the substantial proportion of children” with quality of life impairments, the researchers said. In particular, family functioning is “potentially modifiable with early intervention,” as suggested by a series of promising studies of techniques such as stress management sessions for parents. Most techniques feature a “targeted family-centered approach to psychosocial needs” that includes “embedded psychologists” as part of the multidisciplinary cancer care team.

Study funding came from the National Institutes of Health, National Cancer Institute, and the St. Baldrick’s Foundation. Dr. Zheng reported funding from a Yale Medical Student research fellowship, while coauthors reported conflict of interest disclosures from entities including Amgen, Takeda Pharmaceuticals International, and Shire Pharmaceuticals.

Among children with average-risk acute lymphoblastic leukemia (ALL), those with impairments in physical and emotional functioning at 2 months after diagnosis are likely to have continuing difficulties over 2 years later, based on the results of a 594-patient study published online in Cancer (2017 Nov 7. doi: 10.1002/cncr.31085).

Evaluations of quality of life and family functioning as early as 2 months after diagnosis identified those at highest risk of continued impairment, and can be used to target patients and their families for interventions and risk factor modification, the researchers said.

“These results provide a compelling rationale to screen patients for physical and emotional functioning early in therapy to target interventions toward patients at the highest risk of later impairment,” wrote lead author Daniel J. Zheng, MD, of the section of pediatric hematology-oncology at Yale University, New Haven, Conn., and coauthors.

Dr. Zheng and his colleagues measured impairments in children with average-risk ALL using the Pediatric Quality of Life Inventory Generic Core Scales Version 4.0 (PedsQL4.0), a 23-item survey that measures a child’s quality of life, and the 12-question General Functioning subscale of the McMaster Family Assessment Device (FAD-GF). Both are quick and low-cost screening measures that can be conducted in the clinic, they added. Evaluations occurred at approximately 2 months, 8 months, 17 months, 26 months, and 38 months (boys only) after diagnosis. The mean age of participants at diagnosis was 6.0 years (standard deviation, 1.6 years).

At 2 months after diagnosis, 36.5% of the children had impairments in physical functioning, and 26.2% had impairments in emotional functioning. The population norms for these measures are 2.3% for both scales, investigators wrote. At a 26-month evaluation, levels of impairment were still 11.9% for physical and 9.8% for emotional functioning.

Boys had an additional 38-month evaluation, at which time there were no significant differences in quality of life outcomes versus those observed at 26 months in the girls.

Unhealthy family functioning was a significant predictor of emotional impairment (odds ratio, 1.5; 95% confidence interval, 1.1-2.1) in multivariate models controlling for age and sex.

Strategies are needed to “intervene early and help the substantial proportion of children” with quality of life impairments, the researchers said. In particular, family functioning is “potentially modifiable with early intervention,” as suggested by a series of promising studies of techniques such as stress management sessions for parents. Most techniques feature a “targeted family-centered approach to psychosocial needs” that includes “embedded psychologists” as part of the multidisciplinary cancer care team.

Study funding came from the National Institutes of Health, National Cancer Institute, and the St. Baldrick’s Foundation. Dr. Zheng reported funding from a Yale Medical Student research fellowship, while coauthors reported conflict of interest disclosures from entities including Amgen, Takeda Pharmaceuticals International, and Shire Pharmaceuticals.