Aggressive Lymphomas

Micrograph showing DLBCL

Preclinical research suggests the dual PI3K/mTOR inhibitor PQR309 has activity against several types of lymphoma and works well in combination with other agents.

PQR309 exhibited anti-lymphoma activity as a single agent and in combination with venetoclax, panobinostat, ibrutinib, lenalidomide, ARV-825, marizomib, and rituximab.

PQR309 demonstrated greater activity against B-cell lymphoma than T-cell lymphoma, and the inhibitor was able to overcome both primary and acquired resistance to idelalisib.

Francesco Bertoni, MD, of the Institute of Oncology Research in Bellinzona, Switzerland, and his colleagues conducted this research and reported the results in Clinical Cancer Research.

The work was funded by PIQUR Therapeutics AG, the company developing PQR309, and some study authors are PIQUR employees.

The researchers tested PQR309 in 49 human lymphoma cell lines—7 activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL), 18 germinal center B-cell (GCB) DLBCL, 10 mantle cell lymphoma (MCL), 3 splenic marginal zone lymphoma (SMZL), 2 chronic lymphocytic leukemia (CLL), 4 Hodgkin lymphoma, and 5 anaplastic large-cell lymphoma (ALCL).

In most cell lines, PQR309 halted proliferation, mainly due to cell-cycle arrest with a block in G1. However, PQR309 induced apoptosis in 2 cell lines tested—SU-DHL-4 and TMD8.

The researchers noted that PQR309 was significantly more active in the B-cell lymphoma cell lines (DLBCL, MCL, CLL, and SMZL) than in the T-cell lymphoma cell line ALCL (P=0.028).

PQR309 exhibited similar activity in ABC and GCB DLBCL cell lines, de novo DLBCL, and DLBCL derived from transformed follicular lymphoma. TP53, MYC, and BCL2 status also had no significant effect on PQR309 activity.

The researchers compared cell lines that were very sensitive to PQR309 to those with low sensitivity to the drug and identified differences.

The team said that transcripts preferentially expressed in PQR309-sensitive cell lines were significantly enriched of genes involved in BCR pathway/signaling and BLIMP1 targets. Transcripts associated with less sensitive cell lines were enriched of members of proteasome pathway, response to unfolded proteins, MYC targets, XBP1 targets, genes downregulated by mTOR inhibitors, and genes involved in oxidative phosphorylation.

PQR309 demonstrated synergistic effects when combined with the BTK inhibitor ibrutinib, the immunomodulatory drug lenalidomide, the anti-CD20 monoclonal antibody rituximab, and the proteasome inhibitor marizomib.

PQR309 demonstrated synergistic or additive effects when combined with the BCL2 inhibitor venetoclax, the HDAC inhibitor panobinostat, and the PROTAC BET inhibitor ARV-825.

In addition, PQR309 was active in lymphoma cell lines with primary and secondary resistance to the PI3K inhibitor idelalisib.

The researchers believe the results of this study, together with ongoing clinical studies of PQR309, can lead to better treatments for lymphoma patients and better understanding of the mechanisms of anti-lymphoma agents.

Micrograph showing DLBCL

Preclinical research suggests the dual PI3K/mTOR inhibitor PQR309 has activity against several types of lymphoma and works well in combination with other agents.

PQR309 exhibited anti-lymphoma activity as a single agent and in combination with venetoclax, panobinostat, ibrutinib, lenalidomide, ARV-825, marizomib, and rituximab.

PQR309 demonstrated greater activity against B-cell lymphoma than T-cell lymphoma, and the inhibitor was able to overcome both primary and acquired resistance to idelalisib.

Francesco Bertoni, MD, of the Institute of Oncology Research in Bellinzona, Switzerland, and his colleagues conducted this research and reported the results in Clinical Cancer Research.

The work was funded by PIQUR Therapeutics AG, the company developing PQR309, and some study authors are PIQUR employees.

The researchers tested PQR309 in 49 human lymphoma cell lines—7 activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL), 18 germinal center B-cell (GCB) DLBCL, 10 mantle cell lymphoma (MCL), 3 splenic marginal zone lymphoma (SMZL), 2 chronic lymphocytic leukemia (CLL), 4 Hodgkin lymphoma, and 5 anaplastic large-cell lymphoma (ALCL).

In most cell lines, PQR309 halted proliferation, mainly due to cell-cycle arrest with a block in G1. However, PQR309 induced apoptosis in 2 cell lines tested—SU-DHL-4 and TMD8.

The researchers noted that PQR309 was significantly more active in the B-cell lymphoma cell lines (DLBCL, MCL, CLL, and SMZL) than in the T-cell lymphoma cell line ALCL (P=0.028).

PQR309 exhibited similar activity in ABC and GCB DLBCL cell lines, de novo DLBCL, and DLBCL derived from transformed follicular lymphoma. TP53, MYC, and BCL2 status also had no significant effect on PQR309 activity.

The researchers compared cell lines that were very sensitive to PQR309 to those with low sensitivity to the drug and identified differences.

The team said that transcripts preferentially expressed in PQR309-sensitive cell lines were significantly enriched of genes involved in BCR pathway/signaling and BLIMP1 targets. Transcripts associated with less sensitive cell lines were enriched of members of proteasome pathway, response to unfolded proteins, MYC targets, XBP1 targets, genes downregulated by mTOR inhibitors, and genes involved in oxidative phosphorylation.

PQR309 demonstrated synergistic effects when combined with the BTK inhibitor ibrutinib, the immunomodulatory drug lenalidomide, the anti-CD20 monoclonal antibody rituximab, and the proteasome inhibitor marizomib.

PQR309 demonstrated synergistic or additive effects when combined with the BCL2 inhibitor venetoclax, the HDAC inhibitor panobinostat, and the PROTAC BET inhibitor ARV-825.

In addition, PQR309 was active in lymphoma cell lines with primary and secondary resistance to the PI3K inhibitor idelalisib.

The researchers believe the results of this study, together with ongoing clinical studies of PQR309, can lead to better treatments for lymphoma patients and better understanding of the mechanisms of anti-lymphoma agents.

Micrograph showing DLBCL

Preclinical research suggests the dual PI3K/mTOR inhibitor PQR309 has activity against several types of lymphoma and works well in combination with other agents.

PQR309 exhibited anti-lymphoma activity as a single agent and in combination with venetoclax, panobinostat, ibrutinib, lenalidomide, ARV-825, marizomib, and rituximab.

PQR309 demonstrated greater activity against B-cell lymphoma than T-cell lymphoma, and the inhibitor was able to overcome both primary and acquired resistance to idelalisib.

Francesco Bertoni, MD, of the Institute of Oncology Research in Bellinzona, Switzerland, and his colleagues conducted this research and reported the results in Clinical Cancer Research.

The work was funded by PIQUR Therapeutics AG, the company developing PQR309, and some study authors are PIQUR employees.

The researchers tested PQR309 in 49 human lymphoma cell lines—7 activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL), 18 germinal center B-cell (GCB) DLBCL, 10 mantle cell lymphoma (MCL), 3 splenic marginal zone lymphoma (SMZL), 2 chronic lymphocytic leukemia (CLL), 4 Hodgkin lymphoma, and 5 anaplastic large-cell lymphoma (ALCL).

In most cell lines, PQR309 halted proliferation, mainly due to cell-cycle arrest with a block in G1. However, PQR309 induced apoptosis in 2 cell lines tested—SU-DHL-4 and TMD8.

The researchers noted that PQR309 was significantly more active in the B-cell lymphoma cell lines (DLBCL, MCL, CLL, and SMZL) than in the T-cell lymphoma cell line ALCL (P=0.028).

PQR309 exhibited similar activity in ABC and GCB DLBCL cell lines, de novo DLBCL, and DLBCL derived from transformed follicular lymphoma. TP53, MYC, and BCL2 status also had no significant effect on PQR309 activity.

The researchers compared cell lines that were very sensitive to PQR309 to those with low sensitivity to the drug and identified differences.

The team said that transcripts preferentially expressed in PQR309-sensitive cell lines were significantly enriched of genes involved in BCR pathway/signaling and BLIMP1 targets. Transcripts associated with less sensitive cell lines were enriched of members of proteasome pathway, response to unfolded proteins, MYC targets, XBP1 targets, genes downregulated by mTOR inhibitors, and genes involved in oxidative phosphorylation.

PQR309 demonstrated synergistic effects when combined with the BTK inhibitor ibrutinib, the immunomodulatory drug lenalidomide, the anti-CD20 monoclonal antibody rituximab, and the proteasome inhibitor marizomib.

PQR309 demonstrated synergistic or additive effects when combined with the BCL2 inhibitor venetoclax, the HDAC inhibitor panobinostat, and the PROTAC BET inhibitor ARV-825.

In addition, PQR309 was active in lymphoma cell lines with primary and secondary resistance to the PI3K inhibitor idelalisib.

The researchers believe the results of this study, together with ongoing clinical studies of PQR309, can lead to better treatments for lymphoma patients and better understanding of the mechanisms of anti-lymphoma agents.

Photo from NIH

A study of childhood cancer survivors (CCSs) suggests these individuals have an increased risk of developing hypertension as adults.

The CCSs studied had more than double the rate of hypertension observed in the matched general population.

Sex, age, race, and weight were all significantly associated with hypertension among CCSs, but most treatment types were not.

The exception was nephrectomy, which was associated with an increased risk of hypertension.

Todd M. Gibson, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and reported the results in Cancer Epidemiology, Biomarkers & Prevention.

“High blood pressure is an important modifiable risk factor that increases the risk of heart problems in everyone,” Dr Gibson said. “Research has shown that high blood pressure can have an even greater negative impact on survivors of childhood cancer who were treated with cardiotoxic therapies such as anthracyclines or chest radiation.”

To assess the prevalence of hypertension among CCSs, Dr Gibson and his colleagues examined 3016 adults who were 10-year survivors of childhood cancers. The subjects were enrolled in the St. Jude Lifetime Cohort Study, which provides ongoing medical assessments of CCSs to advance knowledge of their long-term health outcomes.

The subjects’ mean age at the initial study assessment was 32, and 52% were male. Most (83%) were non-Hispanic white, 14% were non-Hispanic black, 2% were Hispanic, and 1% were “other.”

Thirty-seven percent of subjects had leukemia, 12% had Hodgkin lymphoma, and 7% had non-Hodgkin lymphoma.

Eighty-six percent of subjects had received chemotherapy, and 59% received radiation.

Results

Subjects were considered to have hypertension if their systolic blood pressure was 140 or greater, their diastolic blood pressure was 90 or greater, or if they had been previously diagnosed with hypertension and were taking antihypertensive medication.

The prevalence of hypertension was 2.6 times higher among CCSs than expected, based on age-, sex-, race- and body mass index-specific rates in the general population.

In addition, the incidence of hypertension increased for CCSs over time. Thirteen percent of CCSs had hypertension at age 30, 37% had it at age 40, and more than 70% had it at age 50.

Dr Gibson said rates of hypertension in CCSs matched rates in the general population of people about a decade older.

The researchers identified several factors that were significantly associated with hypertension among CCSs, including:

• Male sex (odd ratio [OR], 1.38; 95% CI, 1.14–1.67)
• Non-Hispanic black race (OR, 1.66; 95% CI, 1.28–2.16)
• Older age at assessment (OR per 1 year of age, 1.10; 95% CI, 1.08–1.11)
• Being overweight (OR, 1.58; 95% CI, 1.21–2.07)
• Obesity (OR, 3.02; 95% CI, 2.34–3.88).

Exposure to any type of radiation or chemotherapy was not significantly associated with hypertension, but nephrectomy was (OR, 1.68; 95% CI, 1.11–2.53).

Dr Gibson said the lack of an association between hypertension and radiation/chemotherapy was surprising. It suggests the connection between childhood cancer survival and adult hypertension is multifactorial and worthy of future research.

In the meantime, he said, clinicians should be mindful that CCSs are more likely than the general public to develop hypertension.

“The good news is that, unlike prior cancer therapy, high blood pressure is a modifiable risk factor,” Dr Gibson noted. “Research is needed to identify effective interventions to prevent hypertension in survivors, but our results emphasize the importance of blood pressure surveillance and management.”

Dr Gibson said a limitation of this study is that it was based on blood pressure measurements taken at a single study visit. A clinical diagnosis of hypertension typically requires measurements taken at multiple intervals.

In addition, the St. Jude Lifetime Cohort is a group of CCSs who undergo frequent clinical follow-up, so its participants may have benefited from being monitored and may therefore be in better health than CCSs who have less comprehensive follow-up.

Photo from NIH

A study of childhood cancer survivors (CCSs) suggests these individuals have an increased risk of developing hypertension as adults.

The CCSs studied had more than double the rate of hypertension observed in the matched general population.

Sex, age, race, and weight were all significantly associated with hypertension among CCSs, but most treatment types were not.

The exception was nephrectomy, which was associated with an increased risk of hypertension.

Todd M. Gibson, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and reported the results in Cancer Epidemiology, Biomarkers & Prevention.

“High blood pressure is an important modifiable risk factor that increases the risk of heart problems in everyone,” Dr Gibson said. “Research has shown that high blood pressure can have an even greater negative impact on survivors of childhood cancer who were treated with cardiotoxic therapies such as anthracyclines or chest radiation.”

To assess the prevalence of hypertension among CCSs, Dr Gibson and his colleagues examined 3016 adults who were 10-year survivors of childhood cancers. The subjects were enrolled in the St. Jude Lifetime Cohort Study, which provides ongoing medical assessments of CCSs to advance knowledge of their long-term health outcomes.

The subjects’ mean age at the initial study assessment was 32, and 52% were male. Most (83%) were non-Hispanic white, 14% were non-Hispanic black, 2% were Hispanic, and 1% were “other.”

Thirty-seven percent of subjects had leukemia, 12% had Hodgkin lymphoma, and 7% had non-Hodgkin lymphoma.

Eighty-six percent of subjects had received chemotherapy, and 59% received radiation.

Results

Subjects were considered to have hypertension if their systolic blood pressure was 140 or greater, their diastolic blood pressure was 90 or greater, or if they had been previously diagnosed with hypertension and were taking antihypertensive medication.

The prevalence of hypertension was 2.6 times higher among CCSs than expected, based on age-, sex-, race- and body mass index-specific rates in the general population.

In addition, the incidence of hypertension increased for CCSs over time. Thirteen percent of CCSs had hypertension at age 30, 37% had it at age 40, and more than 70% had it at age 50.

Dr Gibson said rates of hypertension in CCSs matched rates in the general population of people about a decade older.

The researchers identified several factors that were significantly associated with hypertension among CCSs, including:

• Male sex (odd ratio [OR], 1.38; 95% CI, 1.14–1.67)
• Non-Hispanic black race (OR, 1.66; 95% CI, 1.28–2.16)
• Older age at assessment (OR per 1 year of age, 1.10; 95% CI, 1.08–1.11)
• Being overweight (OR, 1.58; 95% CI, 1.21–2.07)
• Obesity (OR, 3.02; 95% CI, 2.34–3.88).

Exposure to any type of radiation or chemotherapy was not significantly associated with hypertension, but nephrectomy was (OR, 1.68; 95% CI, 1.11–2.53).

Dr Gibson said the lack of an association between hypertension and radiation/chemotherapy was surprising. It suggests the connection between childhood cancer survival and adult hypertension is multifactorial and worthy of future research.

In the meantime, he said, clinicians should be mindful that CCSs are more likely than the general public to develop hypertension.

“The good news is that, unlike prior cancer therapy, high blood pressure is a modifiable risk factor,” Dr Gibson noted. “Research is needed to identify effective interventions to prevent hypertension in survivors, but our results emphasize the importance of blood pressure surveillance and management.”

Dr Gibson said a limitation of this study is that it was based on blood pressure measurements taken at a single study visit. A clinical diagnosis of hypertension typically requires measurements taken at multiple intervals.

In addition, the St. Jude Lifetime Cohort is a group of CCSs who undergo frequent clinical follow-up, so its participants may have benefited from being monitored and may therefore be in better health than CCSs who have less comprehensive follow-up.

Photo from NIH

A study of childhood cancer survivors (CCSs) suggests these individuals have an increased risk of developing hypertension as adults.

The CCSs studied had more than double the rate of hypertension observed in the matched general population.

Sex, age, race, and weight were all significantly associated with hypertension among CCSs, but most treatment types were not.

The exception was nephrectomy, which was associated with an increased risk of hypertension.

Todd M. Gibson, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and reported the results in Cancer Epidemiology, Biomarkers & Prevention.

“High blood pressure is an important modifiable risk factor that increases the risk of heart problems in everyone,” Dr Gibson said. “Research has shown that high blood pressure can have an even greater negative impact on survivors of childhood cancer who were treated with cardiotoxic therapies such as anthracyclines or chest radiation.”

To assess the prevalence of hypertension among CCSs, Dr Gibson and his colleagues examined 3016 adults who were 10-year survivors of childhood cancers. The subjects were enrolled in the St. Jude Lifetime Cohort Study, which provides ongoing medical assessments of CCSs to advance knowledge of their long-term health outcomes.

The subjects’ mean age at the initial study assessment was 32, and 52% were male. Most (83%) were non-Hispanic white, 14% were non-Hispanic black, 2% were Hispanic, and 1% were “other.”

Thirty-seven percent of subjects had leukemia, 12% had Hodgkin lymphoma, and 7% had non-Hodgkin lymphoma.

Eighty-six percent of subjects had received chemotherapy, and 59% received radiation.

Results

Subjects were considered to have hypertension if their systolic blood pressure was 140 or greater, their diastolic blood pressure was 90 or greater, or if they had been previously diagnosed with hypertension and were taking antihypertensive medication.

The prevalence of hypertension was 2.6 times higher among CCSs than expected, based on age-, sex-, race- and body mass index-specific rates in the general population.

In addition, the incidence of hypertension increased for CCSs over time. Thirteen percent of CCSs had hypertension at age 30, 37% had it at age 40, and more than 70% had it at age 50.

Dr Gibson said rates of hypertension in CCSs matched rates in the general population of people about a decade older.

The researchers identified several factors that were significantly associated with hypertension among CCSs, including:

• Male sex (odd ratio [OR], 1.38; 95% CI, 1.14–1.67)
• Non-Hispanic black race (OR, 1.66; 95% CI, 1.28–2.16)
• Older age at assessment (OR per 1 year of age, 1.10; 95% CI, 1.08–1.11)
• Being overweight (OR, 1.58; 95% CI, 1.21–2.07)
• Obesity (OR, 3.02; 95% CI, 2.34–3.88).

Exposure to any type of radiation or chemotherapy was not significantly associated with hypertension, but nephrectomy was (OR, 1.68; 95% CI, 1.11–2.53).

Dr Gibson said the lack of an association between hypertension and radiation/chemotherapy was surprising. It suggests the connection between childhood cancer survival and adult hypertension is multifactorial and worthy of future research.

In the meantime, he said, clinicians should be mindful that CCSs are more likely than the general public to develop hypertension.

“The good news is that, unlike prior cancer therapy, high blood pressure is a modifiable risk factor,” Dr Gibson noted. “Research is needed to identify effective interventions to prevent hypertension in survivors, but our results emphasize the importance of blood pressure surveillance and management.”

Dr Gibson said a limitation of this study is that it was based on blood pressure measurements taken at a single study visit. A clinical diagnosis of hypertension typically requires measurements taken at multiple intervals.

In addition, the St. Jude Lifetime Cohort is a group of CCSs who undergo frequent clinical follow-up, so its participants may have benefited from being monitored and may therefore be in better health than CCSs who have less comprehensive follow-up.

Chimeric antigen receptor (CAR) T-cell therapies are driving ever faster forward, with impressive response rates – including a high level of complete responses – in treatment of patients with lymphomas and multiple myeloma as shown by clinical trial results to be presented at the annual meeting of the American Society of Hematology.

Investigators will be presenting data on the first two CAR T constructs to receive Food and Drug Administration approval, each directed against CD19.
 

ZUMA-1 for non-Hodgkin lymphoma

Long-term follow-up results with the use of axicabtagene ciloleucel (Yescarta; axi-cel) in patients with refractory aggressive non-Hodgkin lymphoma will be presented by Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center in Houston, on behalf of colleagues in the ZUMA-1 trial (Abstract 578).

At the 2017 European Hematology Association Congress in Madrid, ZUMA-1 investigators reported that axi-cel, an autologous anti-CD19 CAR-T product, was associated with an 82% objective response rate (ORR), including 54% complete responses, in patients with refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, or transformed follicular lymphoma. The 54% complete response rate was nearly sevenfold higher than that reported for historical controls, according to coinvestigator Yi Lin, MD, PhD, of the Mayo Clinic, Rochester, Minn.

The treatment was generally safe, with 13% of patients experiencing grade 3 or greater cytokine release syndrome (CRS), and 28% having grade 3 or greater neurologic events. The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.

This CAR T-cell construct received FDA approval in October 2017.

At ASH 2017, Dr. Neelapu will present 1-year follow-up data from the trial which will include both data on responses and toxicity, “but also some very interesting information on mechanisms of resistance, whether patients’ tumor cells become CD19 negative, or checkpoint, like PD-L1, positive,” said Kenneth Anderson, MD, of the Dana-Farber Cancer Institute in Boston, who discussed noteworthy abstracts in a media briefing prior to the meeting.
 

JULIET for DLBCL

Data on the use of another anti-CD19 CAR construct, tisagenlecleucel (Kymriah) in adults with relapsed or refractory DLBCL will be presented by Stephen J. Schuster, MD, of the University of Pennsylvania, Philadelphia, on behalf of investigators in the JULIET trial.

At the 2017 European Hematology Association Congress, coinvestigator Gilles Salles, MD, PhD, of the University of Lyon, France, reported an interim analysis from the trial, showing that the CAR T construct was associated with a 59% ORR, consisting of 43% complete responses and 16% partial responses in patients with relapsed or refractory DLBCL. The analysis “confirms the high response rates and durable responses observed in the previous single-center trial,” Dr. Salles said.

Dr. Schuster will present the primary analysis of the global phase 2 pivotal trial at ASH 2017 (Abstract 577), looking at patients who received the product from the U.S. manufacturing site.

As of the data cutoff in March 2017, the best ORR among 81 patients with at least 3 months of follow-up, or earlier discontinuation, was 53.1% with 39.5% complete responses and 13.6% partial responses. For 46 patients evaluable at 6 months, the complete response rate was 30% and partial response rate was 7%.

The response rates were consistent across subgroups, including patients who had previously undergone autologous stem cell transplant and those with double-hit lymphoma (i.e, with mutation in MYC and BCL2 or BCL6).

The responses also appeared to be durable, with the median duration not reached. The 6-month probability of being relapse free was 73.5%. Similarly, median overall survival was not reached; the 6-month probability of overall survival was 64.5%, according to the published abstract.

Adverse events included CRS in 58% of infused patients, with 15% grade 3 and 8% grade 4 in severity. CRS was managed according to protocol with tocilizumab and/or corticosteroids. There were no deaths associated with either the CRS or neurologic toxicities.

“This is a multicenter trial: 27 centers, 10 countries, 4 continents, so it sort of demonstrates to all of us that this technology can be done in an international scope,” Dr. Anderson said.
 

Anti-BCMA for multiple myeloma

CAR T-cells are relative newcomers in the treatment of multiple myeloma, but James N. Kochenderfer, MD, of the National Cancer Institute, Bethesda, Md., will be presenting updated results from a multicenter study of bb2121, a CAR T-cell construct directed against B-cell maturation antigen (BCMA).

BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. As previously reported, a different anti-BCMA T-cell product induced clinical remissions in 33 of 35 patients with relapsed/refractory multiple myeloma who were treated in an early clinical trial.

With the construct being investigated by Dr. Kochenderfer and colleagues, 21 patients (median 58 years old) with a median of 5 years since a diagnosis of multiple myeloma were infused with bb2121. One-month data on clinical response was available for 18 patients at the time of data cutoff in May 2017 (Abstract 740).

In this heavily pretreated population, the ORR was 89% overall, and was 100% for patients treated with doses of 150 x 10⁶ CAR+ T cells or higher. At this dose range or higher no patients had disease progression at up to 54 weeks after infusion. Of the four patients evaluable for minimal residual disease (MRD), all were MRD negative.

As of the data cut-off there were no dose-limiting toxicities and no treatment-related grade 3 or higher neurotoxicities. CRS was primarily grade 1 or 2 and was reported in 15 of 21 patients. Two patients had grade 3 CRS that resolved in 24 hours, and four patients received tocilizumab (one with steroids) for CRS management.

There was one on-study death, from cardiopulmonary arrest more than 4 months after bb2121 infusion in a patient with an extensive cardiac history. The death was judged to be unrelated to CAR T-cell therapy.

Dr. Kochenderfer will present data and analysis on an additional 5 months of follow-up.

“This abstract demonstrates that again, in patients, this time with myeloma with literally no other option, you can achieve very impressive response,” Dr. Anderson said.

The ZUMA-1 study is funded by Kite Pharma. Dr. Neelapu reported research funding from BMS, Poseida, Merck, Kite Pharma, and Cellectis. He reported consultancy and membership on the board of directors or advisory committees for Merck, Kite Pharma, and Celgene.

The JULIET study is funded by Novartis. Dr. Schuster reported consultancy and research funding from Novartis Pharmaceuticals, Celgene, Genentech, Bristol-Myers Squibb, Janssen R&D, and Gilead. He reported consultancy with Seattle Genetics and Nordic Nanovector, and research funding from Merck.

The multicenter study of bb2121 is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported research funding from bluebird bio and Kite Pharma. He reported having multiple patents in the CAR field.


Abstract 578 Long-Term Follow-up ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel (Axi-Cel; KTE-C19) in Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL) will be presented in session 626, Monday, Dec. 11, 2017, at 7:15 a.m.

Abstract 577 Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma will be presented in session 626, Monday, Dec. 11, 2017 at 7:00 a.m.

Abstract 740 Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-BCMA CAR T Cell Therapy will be presented in session 653, Monday, Dec. 11, 2017 at 3:00 p.m.

Chimeric antigen receptor (CAR) T-cell therapies are driving ever faster forward, with impressive response rates – including a high level of complete responses – in treatment of patients with lymphomas and multiple myeloma as shown by clinical trial results to be presented at the annual meeting of the American Society of Hematology.

Investigators will be presenting data on the first two CAR T constructs to receive Food and Drug Administration approval, each directed against CD19.
 

ZUMA-1 for non-Hodgkin lymphoma

Long-term follow-up results with the use of axicabtagene ciloleucel (Yescarta; axi-cel) in patients with refractory aggressive non-Hodgkin lymphoma will be presented by Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center in Houston, on behalf of colleagues in the ZUMA-1 trial (Abstract 578).

At the 2017 European Hematology Association Congress in Madrid, ZUMA-1 investigators reported that axi-cel, an autologous anti-CD19 CAR-T product, was associated with an 82% objective response rate (ORR), including 54% complete responses, in patients with refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, or transformed follicular lymphoma. The 54% complete response rate was nearly sevenfold higher than that reported for historical controls, according to coinvestigator Yi Lin, MD, PhD, of the Mayo Clinic, Rochester, Minn.

The treatment was generally safe, with 13% of patients experiencing grade 3 or greater cytokine release syndrome (CRS), and 28% having grade 3 or greater neurologic events. The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.

This CAR T-cell construct received FDA approval in October 2017.

At ASH 2017, Dr. Neelapu will present 1-year follow-up data from the trial which will include both data on responses and toxicity, “but also some very interesting information on mechanisms of resistance, whether patients’ tumor cells become CD19 negative, or checkpoint, like PD-L1, positive,” said Kenneth Anderson, MD, of the Dana-Farber Cancer Institute in Boston, who discussed noteworthy abstracts in a media briefing prior to the meeting.
 

JULIET for DLBCL

Data on the use of another anti-CD19 CAR construct, tisagenlecleucel (Kymriah) in adults with relapsed or refractory DLBCL will be presented by Stephen J. Schuster, MD, of the University of Pennsylvania, Philadelphia, on behalf of investigators in the JULIET trial.

At the 2017 European Hematology Association Congress, coinvestigator Gilles Salles, MD, PhD, of the University of Lyon, France, reported an interim analysis from the trial, showing that the CAR T construct was associated with a 59% ORR, consisting of 43% complete responses and 16% partial responses in patients with relapsed or refractory DLBCL. The analysis “confirms the high response rates and durable responses observed in the previous single-center trial,” Dr. Salles said.

Dr. Schuster will present the primary analysis of the global phase 2 pivotal trial at ASH 2017 (Abstract 577), looking at patients who received the product from the U.S. manufacturing site.

As of the data cutoff in March 2017, the best ORR among 81 patients with at least 3 months of follow-up, or earlier discontinuation, was 53.1% with 39.5% complete responses and 13.6% partial responses. For 46 patients evaluable at 6 months, the complete response rate was 30% and partial response rate was 7%.

The response rates were consistent across subgroups, including patients who had previously undergone autologous stem cell transplant and those with double-hit lymphoma (i.e, with mutation in MYC and BCL2 or BCL6).

The responses also appeared to be durable, with the median duration not reached. The 6-month probability of being relapse free was 73.5%. Similarly, median overall survival was not reached; the 6-month probability of overall survival was 64.5%, according to the published abstract.

Adverse events included CRS in 58% of infused patients, with 15% grade 3 and 8% grade 4 in severity. CRS was managed according to protocol with tocilizumab and/or corticosteroids. There were no deaths associated with either the CRS or neurologic toxicities.

“This is a multicenter trial: 27 centers, 10 countries, 4 continents, so it sort of demonstrates to all of us that this technology can be done in an international scope,” Dr. Anderson said.
 

Anti-BCMA for multiple myeloma

CAR T-cells are relative newcomers in the treatment of multiple myeloma, but James N. Kochenderfer, MD, of the National Cancer Institute, Bethesda, Md., will be presenting updated results from a multicenter study of bb2121, a CAR T-cell construct directed against B-cell maturation antigen (BCMA).

BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. As previously reported, a different anti-BCMA T-cell product induced clinical remissions in 33 of 35 patients with relapsed/refractory multiple myeloma who were treated in an early clinical trial.

With the construct being investigated by Dr. Kochenderfer and colleagues, 21 patients (median 58 years old) with a median of 5 years since a diagnosis of multiple myeloma were infused with bb2121. One-month data on clinical response was available for 18 patients at the time of data cutoff in May 2017 (Abstract 740).

In this heavily pretreated population, the ORR was 89% overall, and was 100% for patients treated with doses of 150 x 10⁶ CAR+ T cells or higher. At this dose range or higher no patients had disease progression at up to 54 weeks after infusion. Of the four patients evaluable for minimal residual disease (MRD), all were MRD negative.

As of the data cut-off there were no dose-limiting toxicities and no treatment-related grade 3 or higher neurotoxicities. CRS was primarily grade 1 or 2 and was reported in 15 of 21 patients. Two patients had grade 3 CRS that resolved in 24 hours, and four patients received tocilizumab (one with steroids) for CRS management.

There was one on-study death, from cardiopulmonary arrest more than 4 months after bb2121 infusion in a patient with an extensive cardiac history. The death was judged to be unrelated to CAR T-cell therapy.

Dr. Kochenderfer will present data and analysis on an additional 5 months of follow-up.

“This abstract demonstrates that again, in patients, this time with myeloma with literally no other option, you can achieve very impressive response,” Dr. Anderson said.

The ZUMA-1 study is funded by Kite Pharma. Dr. Neelapu reported research funding from BMS, Poseida, Merck, Kite Pharma, and Cellectis. He reported consultancy and membership on the board of directors or advisory committees for Merck, Kite Pharma, and Celgene.

The JULIET study is funded by Novartis. Dr. Schuster reported consultancy and research funding from Novartis Pharmaceuticals, Celgene, Genentech, Bristol-Myers Squibb, Janssen R&D, and Gilead. He reported consultancy with Seattle Genetics and Nordic Nanovector, and research funding from Merck.

The multicenter study of bb2121 is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported research funding from bluebird bio and Kite Pharma. He reported having multiple patents in the CAR field.


Abstract 578 Long-Term Follow-up ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel (Axi-Cel; KTE-C19) in Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL) will be presented in session 626, Monday, Dec. 11, 2017, at 7:15 a.m.

Abstract 577 Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma will be presented in session 626, Monday, Dec. 11, 2017 at 7:00 a.m.

Abstract 740 Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-BCMA CAR T Cell Therapy will be presented in session 653, Monday, Dec. 11, 2017 at 3:00 p.m.

Chimeric antigen receptor (CAR) T-cell therapies are driving ever faster forward, with impressive response rates – including a high level of complete responses – in treatment of patients with lymphomas and multiple myeloma as shown by clinical trial results to be presented at the annual meeting of the American Society of Hematology.

Investigators will be presenting data on the first two CAR T constructs to receive Food and Drug Administration approval, each directed against CD19.
 

ZUMA-1 for non-Hodgkin lymphoma

Long-term follow-up results with the use of axicabtagene ciloleucel (Yescarta; axi-cel) in patients with refractory aggressive non-Hodgkin lymphoma will be presented by Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center in Houston, on behalf of colleagues in the ZUMA-1 trial (Abstract 578).

At the 2017 European Hematology Association Congress in Madrid, ZUMA-1 investigators reported that axi-cel, an autologous anti-CD19 CAR-T product, was associated with an 82% objective response rate (ORR), including 54% complete responses, in patients with refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, or transformed follicular lymphoma. The 54% complete response rate was nearly sevenfold higher than that reported for historical controls, according to coinvestigator Yi Lin, MD, PhD, of the Mayo Clinic, Rochester, Minn.

The treatment was generally safe, with 13% of patients experiencing grade 3 or greater cytokine release syndrome (CRS), and 28% having grade 3 or greater neurologic events. The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.

This CAR T-cell construct received FDA approval in October 2017.

At ASH 2017, Dr. Neelapu will present 1-year follow-up data from the trial which will include both data on responses and toxicity, “but also some very interesting information on mechanisms of resistance, whether patients’ tumor cells become CD19 negative, or checkpoint, like PD-L1, positive,” said Kenneth Anderson, MD, of the Dana-Farber Cancer Institute in Boston, who discussed noteworthy abstracts in a media briefing prior to the meeting.
 

JULIET for DLBCL

Data on the use of another anti-CD19 CAR construct, tisagenlecleucel (Kymriah) in adults with relapsed or refractory DLBCL will be presented by Stephen J. Schuster, MD, of the University of Pennsylvania, Philadelphia, on behalf of investigators in the JULIET trial.

At the 2017 European Hematology Association Congress, coinvestigator Gilles Salles, MD, PhD, of the University of Lyon, France, reported an interim analysis from the trial, showing that the CAR T construct was associated with a 59% ORR, consisting of 43% complete responses and 16% partial responses in patients with relapsed or refractory DLBCL. The analysis “confirms the high response rates and durable responses observed in the previous single-center trial,” Dr. Salles said.

Dr. Schuster will present the primary analysis of the global phase 2 pivotal trial at ASH 2017 (Abstract 577), looking at patients who received the product from the U.S. manufacturing site.

As of the data cutoff in March 2017, the best ORR among 81 patients with at least 3 months of follow-up, or earlier discontinuation, was 53.1% with 39.5% complete responses and 13.6% partial responses. For 46 patients evaluable at 6 months, the complete response rate was 30% and partial response rate was 7%.

The response rates were consistent across subgroups, including patients who had previously undergone autologous stem cell transplant and those with double-hit lymphoma (i.e, with mutation in MYC and BCL2 or BCL6).

The responses also appeared to be durable, with the median duration not reached. The 6-month probability of being relapse free was 73.5%. Similarly, median overall survival was not reached; the 6-month probability of overall survival was 64.5%, according to the published abstract.

Adverse events included CRS in 58% of infused patients, with 15% grade 3 and 8% grade 4 in severity. CRS was managed according to protocol with tocilizumab and/or corticosteroids. There were no deaths associated with either the CRS or neurologic toxicities.

“This is a multicenter trial: 27 centers, 10 countries, 4 continents, so it sort of demonstrates to all of us that this technology can be done in an international scope,” Dr. Anderson said.
 

Anti-BCMA for multiple myeloma

CAR T-cells are relative newcomers in the treatment of multiple myeloma, but James N. Kochenderfer, MD, of the National Cancer Institute, Bethesda, Md., will be presenting updated results from a multicenter study of bb2121, a CAR T-cell construct directed against B-cell maturation antigen (BCMA).

BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. As previously reported, a different anti-BCMA T-cell product induced clinical remissions in 33 of 35 patients with relapsed/refractory multiple myeloma who were treated in an early clinical trial.

With the construct being investigated by Dr. Kochenderfer and colleagues, 21 patients (median 58 years old) with a median of 5 years since a diagnosis of multiple myeloma were infused with bb2121. One-month data on clinical response was available for 18 patients at the time of data cutoff in May 2017 (Abstract 740).

In this heavily pretreated population, the ORR was 89% overall, and was 100% for patients treated with doses of 150 x 10⁶ CAR+ T cells or higher. At this dose range or higher no patients had disease progression at up to 54 weeks after infusion. Of the four patients evaluable for minimal residual disease (MRD), all were MRD negative.

As of the data cut-off there were no dose-limiting toxicities and no treatment-related grade 3 or higher neurotoxicities. CRS was primarily grade 1 or 2 and was reported in 15 of 21 patients. Two patients had grade 3 CRS that resolved in 24 hours, and four patients received tocilizumab (one with steroids) for CRS management.

There was one on-study death, from cardiopulmonary arrest more than 4 months after bb2121 infusion in a patient with an extensive cardiac history. The death was judged to be unrelated to CAR T-cell therapy.

Dr. Kochenderfer will present data and analysis on an additional 5 months of follow-up.

“This abstract demonstrates that again, in patients, this time with myeloma with literally no other option, you can achieve very impressive response,” Dr. Anderson said.

The ZUMA-1 study is funded by Kite Pharma. Dr. Neelapu reported research funding from BMS, Poseida, Merck, Kite Pharma, and Cellectis. He reported consultancy and membership on the board of directors or advisory committees for Merck, Kite Pharma, and Celgene.

The JULIET study is funded by Novartis. Dr. Schuster reported consultancy and research funding from Novartis Pharmaceuticals, Celgene, Genentech, Bristol-Myers Squibb, Janssen R&D, and Gilead. He reported consultancy with Seattle Genetics and Nordic Nanovector, and research funding from Merck.

The multicenter study of bb2121 is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported research funding from bluebird bio and Kite Pharma. He reported having multiple patents in the CAR field.


Abstract 578 Long-Term Follow-up ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel (Axi-Cel; KTE-C19) in Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL) will be presented in session 626, Monday, Dec. 11, 2017, at 7:15 a.m.

Abstract 577 Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma will be presented in session 626, Monday, Dec. 11, 2017 at 7:00 a.m.

Abstract 740 Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-BCMA CAR T Cell Therapy will be presented in session 653, Monday, Dec. 11, 2017 at 3:00 p.m.

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.”

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]

Obinutuzumab (Gazyva)

The US Food and Drug Administration (FDA) has expanded the approved use of obinutuzumab (Gazyva®).

The drug is now approved for use in combination with chemotherapy to treat patients with previously untreated follicular lymphoma (FL) that is advanced (stage II bulky, stage III, or stage IV) .

In patients who respond to this treatment, obinutuzumab monotherapy can be given as maintenance.

The FDA granted this new approval of obinutuzumab to Genentech, Inc. The application for obinutuzumab in this indication received priority review.

The latest FDA approval means obinutuzumab is available in the US for the following indications:

• In combination with chlorambucil to treat chronic lymphocytic leukemia (CLL) in adults who have not had previous CLL treatment
• In combination with bendamustine, followed by obinutuzumab alone, to treat FL in adults who did not respond to a rituximab-containing regimen or whose FL returned after such treatment
• In combination with chemotherapy, followed by obinutuzumab alone in responders, to treat stage II bulky, stage III, or stage IV FL in adults who have not had previous FL treatment.

Phase 3 results

The latest approval of obinutuzumab is based on results from the phase 3 GALLIUM study, which were presented at the 2016 ASH Annual Meeting and published in NEJM in October.

The following are updated data from the obinutuzumab prescribing information.

GALLIUM included 1385 patients with previously untreated non-Hodgkin lymphoma, and 1202 of these patients had advanced FL.

Half of the FL patients (n=601) were randomized to receive obinutuzumab plus chemotherapy (followed by obinutuzumab maintenance for up to 2 years), and half were randomized to rituximab plus chemotherapy (followed by rituximab maintenance for up to 2 years).

The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone), CVP (cyclophosphamide, vincristine, and prednisolone), and bendamustine.

At a median observation time of 38 months, the overall response rate was 91% in the obinutuzumab arm and 88% in the rituximab arm. The complete response rates were 28% and 27%, respectively.

The median progression-free survival was not reached in either arm. The hazard ratio, for obinutuzumab compared to rituximab, was 0.72 (95% CI, 0.56-0.93, P=0.0118).

Safety was evaluated based on all 1385 patients in the study, 86% of whom had previously untreated FL and 14% of whom had marginal zone lymphoma.

Serious adverse events (AEs) occurred in 50% of patients in the obinutuzumab arm and 43% in the rituximab arm. Fatal AEs occurred in 5% and 4%, respectively. Infections and second malignancies were the leading causes of these deaths.

The most common AEs (incidence ≥ 20%) observed at least 2% more patients in the obinutuzumab arm were infusion-related reactions, neutropenia, upper respiratory tract infection, cough, constipation, and diarrhea.

The most common grade 3 to 5 AEs (incidence ≥ 5%) observed more frequently in the obinutuzumab arm were neutropenia, infusion-related reactions, febrile neutropenia, and thrombocytopenia.

Obinutuzumab (Gazyva)

The US Food and Drug Administration (FDA) has expanded the approved use of obinutuzumab (Gazyva®).

The drug is now approved for use in combination with chemotherapy to treat patients with previously untreated follicular lymphoma (FL) that is advanced (stage II bulky, stage III, or stage IV) .

In patients who respond to this treatment, obinutuzumab monotherapy can be given as maintenance.

The FDA granted this new approval of obinutuzumab to Genentech, Inc. The application for obinutuzumab in this indication received priority review.

The latest FDA approval means obinutuzumab is available in the US for the following indications:

• In combination with chlorambucil to treat chronic lymphocytic leukemia (CLL) in adults who have not had previous CLL treatment
• In combination with bendamustine, followed by obinutuzumab alone, to treat FL in adults who did not respond to a rituximab-containing regimen or whose FL returned after such treatment
• In combination with chemotherapy, followed by obinutuzumab alone in responders, to treat stage II bulky, stage III, or stage IV FL in adults who have not had previous FL treatment.

Phase 3 results

The latest approval of obinutuzumab is based on results from the phase 3 GALLIUM study, which were presented at the 2016 ASH Annual Meeting and published in NEJM in October.

The following are updated data from the obinutuzumab prescribing information.

GALLIUM included 1385 patients with previously untreated non-Hodgkin lymphoma, and 1202 of these patients had advanced FL.

Half of the FL patients (n=601) were randomized to receive obinutuzumab plus chemotherapy (followed by obinutuzumab maintenance for up to 2 years), and half were randomized to rituximab plus chemotherapy (followed by rituximab maintenance for up to 2 years).

The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone), CVP (cyclophosphamide, vincristine, and prednisolone), and bendamustine.

At a median observation time of 38 months, the overall response rate was 91% in the obinutuzumab arm and 88% in the rituximab arm. The complete response rates were 28% and 27%, respectively.

The median progression-free survival was not reached in either arm. The hazard ratio, for obinutuzumab compared to rituximab, was 0.72 (95% CI, 0.56-0.93, P=0.0118).

Safety was evaluated based on all 1385 patients in the study, 86% of whom had previously untreated FL and 14% of whom had marginal zone lymphoma.

Serious adverse events (AEs) occurred in 50% of patients in the obinutuzumab arm and 43% in the rituximab arm. Fatal AEs occurred in 5% and 4%, respectively. Infections and second malignancies were the leading causes of these deaths.

The most common AEs (incidence ≥ 20%) observed at least 2% more patients in the obinutuzumab arm were infusion-related reactions, neutropenia, upper respiratory tract infection, cough, constipation, and diarrhea.

The most common grade 3 to 5 AEs (incidence ≥ 5%) observed more frequently in the obinutuzumab arm were neutropenia, infusion-related reactions, febrile neutropenia, and thrombocytopenia.

Obinutuzumab (Gazyva)

The US Food and Drug Administration (FDA) has expanded the approved use of obinutuzumab (Gazyva®).

The drug is now approved for use in combination with chemotherapy to treat patients with previously untreated follicular lymphoma (FL) that is advanced (stage II bulky, stage III, or stage IV) .

In patients who respond to this treatment, obinutuzumab monotherapy can be given as maintenance.

The FDA granted this new approval of obinutuzumab to Genentech, Inc. The application for obinutuzumab in this indication received priority review.

The latest FDA approval means obinutuzumab is available in the US for the following indications:

• In combination with chlorambucil to treat chronic lymphocytic leukemia (CLL) in adults who have not had previous CLL treatment
• In combination with bendamustine, followed by obinutuzumab alone, to treat FL in adults who did not respond to a rituximab-containing regimen or whose FL returned after such treatment
• In combination with chemotherapy, followed by obinutuzumab alone in responders, to treat stage II bulky, stage III, or stage IV FL in adults who have not had previous FL treatment.

Phase 3 results

The latest approval of obinutuzumab is based on results from the phase 3 GALLIUM study, which were presented at the 2016 ASH Annual Meeting and published in NEJM in October.

The following are updated data from the obinutuzumab prescribing information.

GALLIUM included 1385 patients with previously untreated non-Hodgkin lymphoma, and 1202 of these patients had advanced FL.

Half of the FL patients (n=601) were randomized to receive obinutuzumab plus chemotherapy (followed by obinutuzumab maintenance for up to 2 years), and half were randomized to rituximab plus chemotherapy (followed by rituximab maintenance for up to 2 years).

The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone), CVP (cyclophosphamide, vincristine, and prednisolone), and bendamustine.

At a median observation time of 38 months, the overall response rate was 91% in the obinutuzumab arm and 88% in the rituximab arm. The complete response rates were 28% and 27%, respectively.

The median progression-free survival was not reached in either arm. The hazard ratio, for obinutuzumab compared to rituximab, was 0.72 (95% CI, 0.56-0.93, P=0.0118).

Safety was evaluated based on all 1385 patients in the study, 86% of whom had previously untreated FL and 14% of whom had marginal zone lymphoma.

Serious adverse events (AEs) occurred in 50% of patients in the obinutuzumab arm and 43% in the rituximab arm. Fatal AEs occurred in 5% and 4%, respectively. Infections and second malignancies were the leading causes of these deaths.

The most common AEs (incidence ≥ 20%) observed at least 2% more patients in the obinutuzumab arm were infusion-related reactions, neutropenia, upper respiratory tract infection, cough, constipation, and diarrhea.

The most common grade 3 to 5 AEs (incidence ≥ 5%) observed more frequently in the obinutuzumab arm were neutropenia, infusion-related reactions, febrile neutropenia, and thrombocytopenia.

Rituximab maintenance was a key factor influencing survival in patients with mantle cell lymphoma (MCL) who had undergone autologous stem cell transplant (ASCT), according to results from a retrospective, single-center study of 191 patients.

The study, which outlines the experience across a variety of different treatment patterns at City of Hope National Medical Center, Duarte, Calif., between January 1997 and November 2013, suggests a “large benefit” of adding rituximab, wrote Matthew G. Mei, MD, of the center’s department of hematology and hematopoietic cell transplantation, and his colleagues. Further, maintenance rituximab was associated with improved survival outcomes in patients with positron emission tomography (PET)-negative status at first complete remission.

The benefit of rituximab “stands out, and adds to the increasing body of evidence supporting this practice for all MCL patients after ASCT, regardless of age and frontline induction regimens,” wrote Dr. Mei and his colleagues (Biol Blood Marrow Transplant 2017 November. doi: 10.1016/j.bbmt.2017.07.006). This was the case even with improvements in early diagnosis and supportive care, and the incorporation of novel agents such as bortezomib, lenalidomide, and ibrutinib, they wrote, noting significantly better outcomes for patients who underwent ASCT after 2007.

Wikimedia Commons/TexasPathologistMSW/CC-ASA 4.0 International

Rituximab maintenance was a key factor influencing survival in patients with mantle cell lymphoma (MCL) who had undergone autologous stem cell transplant (ASCT), according to results from a retrospective, single-center study of 191 patients.

The study, which outlines the experience across a variety of different treatment patterns at City of Hope National Medical Center, Duarte, Calif., between January 1997 and November 2013, suggests a “large benefit” of adding rituximab, wrote Matthew G. Mei, MD, of the center’s department of hematology and hematopoietic cell transplantation, and his colleagues. Further, maintenance rituximab was associated with improved survival outcomes in patients with positron emission tomography (PET)-negative status at first complete remission.

The benefit of rituximab “stands out, and adds to the increasing body of evidence supporting this practice for all MCL patients after ASCT, regardless of age and frontline induction regimens,” wrote Dr. Mei and his colleagues (Biol Blood Marrow Transplant 2017 November. doi: 10.1016/j.bbmt.2017.07.006). This was the case even with improvements in early diagnosis and supportive care, and the incorporation of novel agents such as bortezomib, lenalidomide, and ibrutinib, they wrote, noting significantly better outcomes for patients who underwent ASCT after 2007.

Wikimedia Commons/TexasPathologistMSW/CC-ASA 4.0 International

Rituximab maintenance was a key factor influencing survival in patients with mantle cell lymphoma (MCL) who had undergone autologous stem cell transplant (ASCT), according to results from a retrospective, single-center study of 191 patients.

The study, which outlines the experience across a variety of different treatment patterns at City of Hope National Medical Center, Duarte, Calif., between January 1997 and November 2013, suggests a “large benefit” of adding rituximab, wrote Matthew G. Mei, MD, of the center’s department of hematology and hematopoietic cell transplantation, and his colleagues. Further, maintenance rituximab was associated with improved survival outcomes in patients with positron emission tomography (PET)-negative status at first complete remission.

The benefit of rituximab “stands out, and adds to the increasing body of evidence supporting this practice for all MCL patients after ASCT, regardless of age and frontline induction regimens,” wrote Dr. Mei and his colleagues (Biol Blood Marrow Transplant 2017 November. doi: 10.1016/j.bbmt.2017.07.006). This was the case even with improvements in early diagnosis and supportive care, and the incorporation of novel agents such as bortezomib, lenalidomide, and ibrutinib, they wrote, noting significantly better outcomes for patients who underwent ASCT after 2007.

Wikimedia Commons/TexasPathologistMSW/CC-ASA 4.0 International

NATIONAL HARBOR, MD. – The immune checkpoint inhibitor nivolumab has promising activity in mismatch repair–deficient noncolorectal cancers, according to preliminary findings from the first sub-arm of the National Cancer Institute’s landmark Molecular Analysis for Therapy Choice (NCI-MATCH) trial.

NCI-MATCH is a 1,173-site precision medicine trial launched in 2015 to study targeted therapies for patients with relapsed/refractory solid tumors, lymphomas, and myelomas. In the first substudy (arm Z1D), the investigators identified 4,900 subjects with samples that could be tested for “actionable molecular abnormalities,” and from among those, they identified 77 with loss of mismatch repair proteins MLH1 or MSH2. Ultimately 47 patients were treated with nivolumab in the substudy.

Sharon Worcester/Frontline Medical News

[email protected]

NATIONAL HARBOR, MD. – The immune checkpoint inhibitor nivolumab has promising activity in mismatch repair–deficient noncolorectal cancers, according to preliminary findings from the first sub-arm of the National Cancer Institute’s landmark Molecular Analysis for Therapy Choice (NCI-MATCH) trial.

NCI-MATCH is a 1,173-site precision medicine trial launched in 2015 to study targeted therapies for patients with relapsed/refractory solid tumors, lymphomas, and myelomas. In the first substudy (arm Z1D), the investigators identified 4,900 subjects with samples that could be tested for “actionable molecular abnormalities,” and from among those, they identified 77 with loss of mismatch repair proteins MLH1 or MSH2. Ultimately 47 patients were treated with nivolumab in the substudy.

Sharon Worcester/Frontline Medical News

[email protected]

NATIONAL HARBOR, MD. – The immune checkpoint inhibitor nivolumab has promising activity in mismatch repair–deficient noncolorectal cancers, according to preliminary findings from the first sub-arm of the National Cancer Institute’s landmark Molecular Analysis for Therapy Choice (NCI-MATCH) trial.

NCI-MATCH is a 1,173-site precision medicine trial launched in 2015 to study targeted therapies for patients with relapsed/refractory solid tumors, lymphomas, and myelomas. In the first substudy (arm Z1D), the investigators identified 4,900 subjects with samples that could be tested for “actionable molecular abnormalities,” and from among those, they identified 77 with loss of mismatch repair proteins MLH1 or MSH2. Ultimately 47 patients were treated with nivolumab in the substudy.

Sharon Worcester/Frontline Medical News

[email protected]

Photo by Bill Branson

Cancer drug costs in the US increase substantially after launch, regardless of competition, according to a study published in the Journal of Clinical Oncology.*

Researchers studied 24 cancer drugs approved over the last 20 years and found a mean cumulative cost increase of about 37%, or 19% when adjusted for inflation.

Among drugs approved to treat hematologic malignancies, the greatest inflation-adjusted price increases were for arsenic trioxide (57%), nelarabine (55%), and rituximab (49%).

The lowest inflation-adjusted price increases were for ofatumumab (8%), clofarabine (8%), and liposomal vincristine (18%).

For this study, Daniel A. Goldstein, MD, of Emory University in Atlanta, Georgia, and his colleagues measured the monthly price trajectories of 24 cancer drugs approved by the US Food and Drug Administration. This included 10 drugs approved to treat hematologic malignancies between 1997 and 2011.

To account for discounts and rebates, the researchers used the average sales prices published by the Centers for Medicare and Medicaid Services and adjusted to general and health-related inflation rates. For each drug, the researchers calculated the cumulative and annual drug cost changes.

Results

The mean follow-up was 8 years. The mean cumulative cost increase for all 24 drugs was +36.5% (95% CI, 24.7% to 48.3%).

The general inflation-adjusted increase was +19.1% (95% CI, 11.0% to 27.2%), and the health-related inflation-adjusted increase was +8.4% (95% CI, 1.4% to 15.4%).

Only 1 of the 24 drugs studied had a price decrease over time. That drug is ziv-aflibercept, which was approved to treat metastatic colorectal cancer in 2012.

Ziv-aflibercept was launched with an annual price exceeding $110,000. After public outcry, the drug’s manufacturer, Sanofi, cut the price in half. By the end of the study’s follow-up period in 2017, the cost of ziv-aflibercept had decreased 13% (inflation-adjusted decrease of 15%, health-related inflation-adjusted decrease of 20%).

Cost changes for the drugs approved to treat hematologic malignancies are listed in the following table.

Abbreviations: ALL, acute lymphoblastic leukemia; APL, acute promyelocytic leukemia; CLL, chronic lymphocytic leukemia; MCL, mantle cell lymphoma; MM, multiple myeloma; NHL, non-Hodgkin lymphoma; SD, standard deviation.

The researchers noted that there was a steady increase in drug costs over the study period, regardless of whether a drug was granted a new supplemental indication, the drug had a new off-label indication, or a competitor drug was approved.

The only variable that was significantly associated with price change was the amount of time that had elapsed from a drug’s launch.

This association was significant in models in which the researchers used prices adjusted to inflation (P=0.002) and health-related inflation (P=0.023). However, it was not significant when the researchers used the actual drug price (P=0.085).

*Data in the abstract differ from data in the body of the JCO paper. This article includes data from the body of the JCO paper.

Photo by Bill Branson

Cancer drug costs in the US increase substantially after launch, regardless of competition, according to a study published in the Journal of Clinical Oncology.*

Researchers studied 24 cancer drugs approved over the last 20 years and found a mean cumulative cost increase of about 37%, or 19% when adjusted for inflation.

Among drugs approved to treat hematologic malignancies, the greatest inflation-adjusted price increases were for arsenic trioxide (57%), nelarabine (55%), and rituximab (49%).

The lowest inflation-adjusted price increases were for ofatumumab (8%), clofarabine (8%), and liposomal vincristine (18%).

For this study, Daniel A. Goldstein, MD, of Emory University in Atlanta, Georgia, and his colleagues measured the monthly price trajectories of 24 cancer drugs approved by the US Food and Drug Administration. This included 10 drugs approved to treat hematologic malignancies between 1997 and 2011.

To account for discounts and rebates, the researchers used the average sales prices published by the Centers for Medicare and Medicaid Services and adjusted to general and health-related inflation rates. For each drug, the researchers calculated the cumulative and annual drug cost changes.

Results

The mean follow-up was 8 years. The mean cumulative cost increase for all 24 drugs was +36.5% (95% CI, 24.7% to 48.3%).

The general inflation-adjusted increase was +19.1% (95% CI, 11.0% to 27.2%), and the health-related inflation-adjusted increase was +8.4% (95% CI, 1.4% to 15.4%).

Only 1 of the 24 drugs studied had a price decrease over time. That drug is ziv-aflibercept, which was approved to treat metastatic colorectal cancer in 2012.

Ziv-aflibercept was launched with an annual price exceeding $110,000. After public outcry, the drug’s manufacturer, Sanofi, cut the price in half. By the end of the study’s follow-up period in 2017, the cost of ziv-aflibercept had decreased 13% (inflation-adjusted decrease of 15%, health-related inflation-adjusted decrease of 20%).

Cost changes for the drugs approved to treat hematologic malignancies are listed in the following table.

Abbreviations: ALL, acute lymphoblastic leukemia; APL, acute promyelocytic leukemia; CLL, chronic lymphocytic leukemia; MCL, mantle cell lymphoma; MM, multiple myeloma; NHL, non-Hodgkin lymphoma; SD, standard deviation.

The researchers noted that there was a steady increase in drug costs over the study period, regardless of whether a drug was granted a new supplemental indication, the drug had a new off-label indication, or a competitor drug was approved.

The only variable that was significantly associated with price change was the amount of time that had elapsed from a drug’s launch.

This association was significant in models in which the researchers used prices adjusted to inflation (P=0.002) and health-related inflation (P=0.023). However, it was not significant when the researchers used the actual drug price (P=0.085).

*Data in the abstract differ from data in the body of the JCO paper. This article includes data from the body of the JCO paper.

Photo by Bill Branson

Cancer drug costs in the US increase substantially after launch, regardless of competition, according to a study published in the Journal of Clinical Oncology.*

Researchers studied 24 cancer drugs approved over the last 20 years and found a mean cumulative cost increase of about 37%, or 19% when adjusted for inflation.

Among drugs approved to treat hematologic malignancies, the greatest inflation-adjusted price increases were for arsenic trioxide (57%), nelarabine (55%), and rituximab (49%).

The lowest inflation-adjusted price increases were for ofatumumab (8%), clofarabine (8%), and liposomal vincristine (18%).

For this study, Daniel A. Goldstein, MD, of Emory University in Atlanta, Georgia, and his colleagues measured the monthly price trajectories of 24 cancer drugs approved by the US Food and Drug Administration. This included 10 drugs approved to treat hematologic malignancies between 1997 and 2011.

To account for discounts and rebates, the researchers used the average sales prices published by the Centers for Medicare and Medicaid Services and adjusted to general and health-related inflation rates. For each drug, the researchers calculated the cumulative and annual drug cost changes.

Results

The mean follow-up was 8 years. The mean cumulative cost increase for all 24 drugs was +36.5% (95% CI, 24.7% to 48.3%).

The general inflation-adjusted increase was +19.1% (95% CI, 11.0% to 27.2%), and the health-related inflation-adjusted increase was +8.4% (95% CI, 1.4% to 15.4%).

Only 1 of the 24 drugs studied had a price decrease over time. That drug is ziv-aflibercept, which was approved to treat metastatic colorectal cancer in 2012.

Ziv-aflibercept was launched with an annual price exceeding $110,000. After public outcry, the drug’s manufacturer, Sanofi, cut the price in half. By the end of the study’s follow-up period in 2017, the cost of ziv-aflibercept had decreased 13% (inflation-adjusted decrease of 15%, health-related inflation-adjusted decrease of 20%).

Cost changes for the drugs approved to treat hematologic malignancies are listed in the following table.

Abbreviations: ALL, acute lymphoblastic leukemia; APL, acute promyelocytic leukemia; CLL, chronic lymphocytic leukemia; MCL, mantle cell lymphoma; MM, multiple myeloma; NHL, non-Hodgkin lymphoma; SD, standard deviation.

The researchers noted that there was a steady increase in drug costs over the study period, regardless of whether a drug was granted a new supplemental indication, the drug had a new off-label indication, or a competitor drug was approved.

The only variable that was significantly associated with price change was the amount of time that had elapsed from a drug’s launch.

This association was significant in models in which the researchers used prices adjusted to inflation (P=0.002) and health-related inflation (P=0.023). However, it was not significant when the researchers used the actual drug price (P=0.085).

*Data in the abstract differ from data in the body of the JCO paper. This article includes data from the body of the JCO paper.

Event-free survival at 24 months (EFS24) is predictive of survival in patients with peripheral T-cell lymphomas (PTCLs), according to new findings published in the Journal of Clinical Oncology.

Patients who were event free 2 years after diagnosis had a more favorable outcome, compared with those who relapsed within that time period. Some patients who remained event free for 24 months were potentially cured; conversely, events within 2 years were associated with an early death in almost all of those patients.

“Thus, EFS24 is a dichotomous end point that allows individualized risk prediction in patients with PTCL and can help inform patient counseling, biomarker discovery, clinical trial design, and precision medicine approaches,” wrote Matthew J. Maurer, MS, of the Mayo Clinic, Rochester, MN, and his coauthors (J Clin Oncol. 2017 Oct 26. doi: 10.1200/JCO.2017.73.8195).

PTCL is an uncommon and heterogeneous group of non-Hodgkin lymphomas that carry a very poor prognosis; most systemic cases are treated with anthracycline-based combination chemotherapy. Previous studies have reported that achieving EFS24 is predictive of excellent long-term outcomes, independent of baseline prognostic factors.

In this study Mr. Maurer and his coauthors assessed the association between EFS24 and overall survival in 775 patients with newly systemic PTCL who were diagnosed during 2000-2012 and received treatment with curative intent.

Among the entire cohort, 36% of patients achieved EFS24 while 64% did not, and the median overall survival following progression within that 2-year time period was 4.9 months (95% confidence interval, 3.8-5.9 months). The 5-year overall survival in the group that relapsed was 11%, with a standardized mortality ratio of 46.4 (95% CI, 41.8-51.3).

Conversely, among patients with EFS24, the median overall survival was not reached, and the 5-year overall survival was 78% (95% CI, 73%-84%). In this group, the 5-year risk of subsequent lymphoma relapse was 23%, and survival following a late relapse was generally poor (median of 10.3 months; 95% CI, 5.7-19.1 months). The best outcomes after achieving EFS24 were observed among patients aged 60 years or younger: These patients had a 5-year overall survival of 91%.

“The use of a dichotomous end point that allows individualized risk prediction is particularly important in rare diseases such as PTCL, where limited numbers of patients may make formal surrogate end point analysis difficult,” wrote the authors.

The study was supported by grants from the National Cancer Institute, the Terry Fox Research Institute, and the BC Cancer Foundation. Dr. Maurer reported research funding from Kite Pharma and Celgene, and several of the coauthors reported relationships with industry.

Event-free survival at 24 months (EFS24) is predictive of survival in patients with peripheral T-cell lymphomas (PTCLs), according to new findings published in the Journal of Clinical Oncology.

Patients who were event free 2 years after diagnosis had a more favorable outcome, compared with those who relapsed within that time period. Some patients who remained event free for 24 months were potentially cured; conversely, events within 2 years were associated with an early death in almost all of those patients.

“Thus, EFS24 is a dichotomous end point that allows individualized risk prediction in patients with PTCL and can help inform patient counseling, biomarker discovery, clinical trial design, and precision medicine approaches,” wrote Matthew J. Maurer, MS, of the Mayo Clinic, Rochester, MN, and his coauthors (J Clin Oncol. 2017 Oct 26. doi: 10.1200/JCO.2017.73.8195).

PTCL is an uncommon and heterogeneous group of non-Hodgkin lymphomas that carry a very poor prognosis; most systemic cases are treated with anthracycline-based combination chemotherapy. Previous studies have reported that achieving EFS24 is predictive of excellent long-term outcomes, independent of baseline prognostic factors.

In this study Mr. Maurer and his coauthors assessed the association between EFS24 and overall survival in 775 patients with newly systemic PTCL who were diagnosed during 2000-2012 and received treatment with curative intent.

Among the entire cohort, 36% of patients achieved EFS24 while 64% did not, and the median overall survival following progression within that 2-year time period was 4.9 months (95% confidence interval, 3.8-5.9 months). The 5-year overall survival in the group that relapsed was 11%, with a standardized mortality ratio of 46.4 (95% CI, 41.8-51.3).

Conversely, among patients with EFS24, the median overall survival was not reached, and the 5-year overall survival was 78% (95% CI, 73%-84%). In this group, the 5-year risk of subsequent lymphoma relapse was 23%, and survival following a late relapse was generally poor (median of 10.3 months; 95% CI, 5.7-19.1 months). The best outcomes after achieving EFS24 were observed among patients aged 60 years or younger: These patients had a 5-year overall survival of 91%.

“The use of a dichotomous end point that allows individualized risk prediction is particularly important in rare diseases such as PTCL, where limited numbers of patients may make formal surrogate end point analysis difficult,” wrote the authors.

The study was supported by grants from the National Cancer Institute, the Terry Fox Research Institute, and the BC Cancer Foundation. Dr. Maurer reported research funding from Kite Pharma and Celgene, and several of the coauthors reported relationships with industry.

Event-free survival at 24 months (EFS24) is predictive of survival in patients with peripheral T-cell lymphomas (PTCLs), according to new findings published in the Journal of Clinical Oncology.

Patients who were event free 2 years after diagnosis had a more favorable outcome, compared with those who relapsed within that time period. Some patients who remained event free for 24 months were potentially cured; conversely, events within 2 years were associated with an early death in almost all of those patients.

“Thus, EFS24 is a dichotomous end point that allows individualized risk prediction in patients with PTCL and can help inform patient counseling, biomarker discovery, clinical trial design, and precision medicine approaches,” wrote Matthew J. Maurer, MS, of the Mayo Clinic, Rochester, MN, and his coauthors (J Clin Oncol. 2017 Oct 26. doi: 10.1200/JCO.2017.73.8195).

PTCL is an uncommon and heterogeneous group of non-Hodgkin lymphomas that carry a very poor prognosis; most systemic cases are treated with anthracycline-based combination chemotherapy. Previous studies have reported that achieving EFS24 is predictive of excellent long-term outcomes, independent of baseline prognostic factors.

In this study Mr. Maurer and his coauthors assessed the association between EFS24 and overall survival in 775 patients with newly systemic PTCL who were diagnosed during 2000-2012 and received treatment with curative intent.

Among the entire cohort, 36% of patients achieved EFS24 while 64% did not, and the median overall survival following progression within that 2-year time period was 4.9 months (95% confidence interval, 3.8-5.9 months). The 5-year overall survival in the group that relapsed was 11%, with a standardized mortality ratio of 46.4 (95% CI, 41.8-51.3).

Conversely, among patients with EFS24, the median overall survival was not reached, and the 5-year overall survival was 78% (95% CI, 73%-84%). In this group, the 5-year risk of subsequent lymphoma relapse was 23%, and survival following a late relapse was generally poor (median of 10.3 months; 95% CI, 5.7-19.1 months). The best outcomes after achieving EFS24 were observed among patients aged 60 years or younger: These patients had a 5-year overall survival of 91%.

“The use of a dichotomous end point that allows individualized risk prediction is particularly important in rare diseases such as PTCL, where limited numbers of patients may make formal surrogate end point analysis difficult,” wrote the authors.

The study was supported by grants from the National Cancer Institute, the Terry Fox Research Institute, and the BC Cancer Foundation. Dr. Maurer reported research funding from Kite Pharma and Celgene, and several of the coauthors reported relationships with industry.