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Acalabrutinib shows efficacy as monotherapy in untreated CLL
CHICAGO – Acalabrutinib, which has shown efficacy in relapsed chronic lymphocytic leukemia, has now shown efficacy as a monotherapy for patients with previously untreated CLL, based on results from an ongoing phase I-II study presented as a poster at the annual meeting of the American Society of Clinical Oncology.
In a 74-patient study, best overall response rate was 96%, and median time to response was 2 months. CLL has not progressed in any of the patients, and none have experienced Richter’s transformation, Dr. John C. Byrd, the D. Warren Brown Chair of Leukemia Research at The Ohio State University, Columbus, and his colleagues reported. Based on its favorable safety profile and durable response rates, a phase III trialof acalabrutinib therapy has been initiated (NCT02475681).
Oral acalabrutinib was given at doses of 100 mg twice daily to 37 patients or 200 mg daily to 37 other patients. About half of the patients had bulky lymph nodes of at least 5 cm and 38 of 67 patients had an unmutated IGHV gene. Median time on the study was 11 months.
All patients had rapid declines in lymphadenopathy. Both dose schedules were associated with clinical activity, with Bruton’s tyrosine kinase occupancy highest at 98% with twice-daily dosing and 93% with once-daily dosing. Treatment-related lymphocytosis occurred in 39 of 74 patients and resolved in 38 of the 39. In general, lymphocytosis peaked at a median of 1 week and resolved by a median of 7 weeks.
Acalabrutinib was well tolerated with 72 of 74 patients continuing on the drug. Most adverse events were grade 2 or less, and included headache (42%), diarrhea (35%), arthralgia (22%), contusion (18%), nausea (18%) and increased weight (18%). Grade 3-4 adverse events that occurred in at least two patients included syncope (two patients) and hypertension (two patients). There was one grade 3 upper GI bleed from a gastric ulcer and aspirin use, and one grade 5 case of pneumonia. No atrial fibrillation was reported.
Dr. Byrd receives research funding from Acerta Pharma, the maker of acalabrutinib, as well as from Genentech and Pharmacyclics.
On Twitter @maryjodales
CHICAGO – Acalabrutinib, which has shown efficacy in relapsed chronic lymphocytic leukemia, has now shown efficacy as a monotherapy for patients with previously untreated CLL, based on results from an ongoing phase I-II study presented as a poster at the annual meeting of the American Society of Clinical Oncology.
In a 74-patient study, best overall response rate was 96%, and median time to response was 2 months. CLL has not progressed in any of the patients, and none have experienced Richter’s transformation, Dr. John C. Byrd, the D. Warren Brown Chair of Leukemia Research at The Ohio State University, Columbus, and his colleagues reported. Based on its favorable safety profile and durable response rates, a phase III trialof acalabrutinib therapy has been initiated (NCT02475681).
Oral acalabrutinib was given at doses of 100 mg twice daily to 37 patients or 200 mg daily to 37 other patients. About half of the patients had bulky lymph nodes of at least 5 cm and 38 of 67 patients had an unmutated IGHV gene. Median time on the study was 11 months.
All patients had rapid declines in lymphadenopathy. Both dose schedules were associated with clinical activity, with Bruton’s tyrosine kinase occupancy highest at 98% with twice-daily dosing and 93% with once-daily dosing. Treatment-related lymphocytosis occurred in 39 of 74 patients and resolved in 38 of the 39. In general, lymphocytosis peaked at a median of 1 week and resolved by a median of 7 weeks.
Acalabrutinib was well tolerated with 72 of 74 patients continuing on the drug. Most adverse events were grade 2 or less, and included headache (42%), diarrhea (35%), arthralgia (22%), contusion (18%), nausea (18%) and increased weight (18%). Grade 3-4 adverse events that occurred in at least two patients included syncope (two patients) and hypertension (two patients). There was one grade 3 upper GI bleed from a gastric ulcer and aspirin use, and one grade 5 case of pneumonia. No atrial fibrillation was reported.
Dr. Byrd receives research funding from Acerta Pharma, the maker of acalabrutinib, as well as from Genentech and Pharmacyclics.
On Twitter @maryjodales
CHICAGO – Acalabrutinib, which has shown efficacy in relapsed chronic lymphocytic leukemia, has now shown efficacy as a monotherapy for patients with previously untreated CLL, based on results from an ongoing phase I-II study presented as a poster at the annual meeting of the American Society of Clinical Oncology.
In a 74-patient study, best overall response rate was 96%, and median time to response was 2 months. CLL has not progressed in any of the patients, and none have experienced Richter’s transformation, Dr. John C. Byrd, the D. Warren Brown Chair of Leukemia Research at The Ohio State University, Columbus, and his colleagues reported. Based on its favorable safety profile and durable response rates, a phase III trialof acalabrutinib therapy has been initiated (NCT02475681).
Oral acalabrutinib was given at doses of 100 mg twice daily to 37 patients or 200 mg daily to 37 other patients. About half of the patients had bulky lymph nodes of at least 5 cm and 38 of 67 patients had an unmutated IGHV gene. Median time on the study was 11 months.
All patients had rapid declines in lymphadenopathy. Both dose schedules were associated with clinical activity, with Bruton’s tyrosine kinase occupancy highest at 98% with twice-daily dosing and 93% with once-daily dosing. Treatment-related lymphocytosis occurred in 39 of 74 patients and resolved in 38 of the 39. In general, lymphocytosis peaked at a median of 1 week and resolved by a median of 7 weeks.
Acalabrutinib was well tolerated with 72 of 74 patients continuing on the drug. Most adverse events were grade 2 or less, and included headache (42%), diarrhea (35%), arthralgia (22%), contusion (18%), nausea (18%) and increased weight (18%). Grade 3-4 adverse events that occurred in at least two patients included syncope (two patients) and hypertension (two patients). There was one grade 3 upper GI bleed from a gastric ulcer and aspirin use, and one grade 5 case of pneumonia. No atrial fibrillation was reported.
Dr. Byrd receives research funding from Acerta Pharma, the maker of acalabrutinib, as well as from Genentech and Pharmacyclics.
On Twitter @maryjodales
FROM 2016 ASCO ANNUAL MEETING
Key clinical point: Acalabrutinib, which has shown efficacy in relapsed CLL, has now shown efficacy as a monotherapy for patients with previously untreated CLL.
Major finding: In a 74-patient study, best overall response rate was 96%, and median time to response was 2 months.
Data source: An ongoing phase I-II study.
Disclosures: Dr. Byrd receives research funding from Acerta Pharma, the maker of acalabrutinib, as well as from Genentech and Pharmacyclics.
Ibrutinib at below standard dose may achieve good survival in CLL
Ibrutinib given at doses lower than the standard dose of 420 mg/day was associated with comparable overall survival and progression-free survival as the standard dose in patients with chronic lymphocytic leukemia (CLL), based on the results of a multicenter, retrospective study submitted as a poster at the annual meeting of the American Society of Clinical Oncology.
The initial findings indicate patients who experience toxicity on the 420 mg/day dosage can still do well on a slightly lower dose of ibrutinib, reported Colleen Timlin, Pharm.D., of the Hospital of the University of Pennsylvania, Philadelphia, and her associates.
At a median follow-up of 13.5 months, the median progression-free survival was 37.4 months in the standard dose group and the median progression-free survival had not been reached in the reduced-dose group. The median overall survival had not been reached in either group. The hazard ratio in the reduced-dose group was 1.2 for progression-free survival and 0.6 for overall survival; neither difference was statistically significant. Best overall response rate was 85% in the standard-dose group and 84% in the reduced-dose group.
The study included 197 patients, 37 of whom were shifted to reduced doses of ibrutinib within 3 months of initiating therapy at the recommended 420 mg/day dosage. For reduced-dose patients, the median ibrutinib dose was 4.3 mg/kg per day. The most common reasons for reducing the ibrutinib dose were gastrointestinal toxicity, bleeding, rash, cardiotoxicity, and renal insufficiency, the researchers said.
Most of the patients treated with doses less than 420 mg/day still maintained a dose of greater than 2.5 mg/kg per day, which assured adequate Bruton’s tyrosine kinase occupancy. The 420 mg/day dosage noted in the labeling was established, based on achievement of greater than 90% Bruton’s tyrosine kinase occupancy. Fewer patients achieve greater than 90% occupancy at lower doses, but lower doses may not translate into inferior outcomes.
Weight-based dosing should be considered in future studies and pharmacoeconomic analyses. Comparative analyses of toxicity profiles stratified by ibrutinib dose are underway, according to Dr. Timlin and her colleagues.
Dr. Timlin had no relevant disclosures. Several of her colleagues had multiple financial disclosures.
On Twitter @maryjodales
Ibrutinib given at doses lower than the standard dose of 420 mg/day was associated with comparable overall survival and progression-free survival as the standard dose in patients with chronic lymphocytic leukemia (CLL), based on the results of a multicenter, retrospective study submitted as a poster at the annual meeting of the American Society of Clinical Oncology.
The initial findings indicate patients who experience toxicity on the 420 mg/day dosage can still do well on a slightly lower dose of ibrutinib, reported Colleen Timlin, Pharm.D., of the Hospital of the University of Pennsylvania, Philadelphia, and her associates.
At a median follow-up of 13.5 months, the median progression-free survival was 37.4 months in the standard dose group and the median progression-free survival had not been reached in the reduced-dose group. The median overall survival had not been reached in either group. The hazard ratio in the reduced-dose group was 1.2 for progression-free survival and 0.6 for overall survival; neither difference was statistically significant. Best overall response rate was 85% in the standard-dose group and 84% in the reduced-dose group.
The study included 197 patients, 37 of whom were shifted to reduced doses of ibrutinib within 3 months of initiating therapy at the recommended 420 mg/day dosage. For reduced-dose patients, the median ibrutinib dose was 4.3 mg/kg per day. The most common reasons for reducing the ibrutinib dose were gastrointestinal toxicity, bleeding, rash, cardiotoxicity, and renal insufficiency, the researchers said.
Most of the patients treated with doses less than 420 mg/day still maintained a dose of greater than 2.5 mg/kg per day, which assured adequate Bruton’s tyrosine kinase occupancy. The 420 mg/day dosage noted in the labeling was established, based on achievement of greater than 90% Bruton’s tyrosine kinase occupancy. Fewer patients achieve greater than 90% occupancy at lower doses, but lower doses may not translate into inferior outcomes.
Weight-based dosing should be considered in future studies and pharmacoeconomic analyses. Comparative analyses of toxicity profiles stratified by ibrutinib dose are underway, according to Dr. Timlin and her colleagues.
Dr. Timlin had no relevant disclosures. Several of her colleagues had multiple financial disclosures.
On Twitter @maryjodales
Ibrutinib given at doses lower than the standard dose of 420 mg/day was associated with comparable overall survival and progression-free survival as the standard dose in patients with chronic lymphocytic leukemia (CLL), based on the results of a multicenter, retrospective study submitted as a poster at the annual meeting of the American Society of Clinical Oncology.
The initial findings indicate patients who experience toxicity on the 420 mg/day dosage can still do well on a slightly lower dose of ibrutinib, reported Colleen Timlin, Pharm.D., of the Hospital of the University of Pennsylvania, Philadelphia, and her associates.
At a median follow-up of 13.5 months, the median progression-free survival was 37.4 months in the standard dose group and the median progression-free survival had not been reached in the reduced-dose group. The median overall survival had not been reached in either group. The hazard ratio in the reduced-dose group was 1.2 for progression-free survival and 0.6 for overall survival; neither difference was statistically significant. Best overall response rate was 85% in the standard-dose group and 84% in the reduced-dose group.
The study included 197 patients, 37 of whom were shifted to reduced doses of ibrutinib within 3 months of initiating therapy at the recommended 420 mg/day dosage. For reduced-dose patients, the median ibrutinib dose was 4.3 mg/kg per day. The most common reasons for reducing the ibrutinib dose were gastrointestinal toxicity, bleeding, rash, cardiotoxicity, and renal insufficiency, the researchers said.
Most of the patients treated with doses less than 420 mg/day still maintained a dose of greater than 2.5 mg/kg per day, which assured adequate Bruton’s tyrosine kinase occupancy. The 420 mg/day dosage noted in the labeling was established, based on achievement of greater than 90% Bruton’s tyrosine kinase occupancy. Fewer patients achieve greater than 90% occupancy at lower doses, but lower doses may not translate into inferior outcomes.
Weight-based dosing should be considered in future studies and pharmacoeconomic analyses. Comparative analyses of toxicity profiles stratified by ibrutinib dose are underway, according to Dr. Timlin and her colleagues.
Dr. Timlin had no relevant disclosures. Several of her colleagues had multiple financial disclosures.
On Twitter @maryjodales
Key clinical point: Ibrutinib given at doses lower than the standard dose of 420 mg/day may achieve comparable overall survival and progression-free survival.
Major finding: At a median follow-up of 13.5 months, the median progression-free survival was 37.4 months in the standard dose group, and the median progression-free survival had not been reached in the reduced-dose group.
Data source: A multicenter, retrospective study of 197 patients.
Disclosures: Dr. Timlin had no relevant disclosures. Several of her colleagues had multiple financial disclosures.
Maintenance rituximab extends progression-free but not overall survival in CLL
CHICAGO – After 2 years of maintenance immunotherapy with rituximab, elderly patients with chronic lymphocytic leukemia had better rates of progression-free survival than did patients in an observation group, based on results of the CLL 2007 SA trial from the French FILO (French Innovative Leukemia Organisation) Group.
The two groups did not significantly differ in overall survival, however, with 92.6% estimated 3-year overall survival in the rituximab group and 87.2% in the observation group. Further, the patients given rituximab had more adverse events, based on data presented by Dr. Caroline Dartigeas of the University Hospital in Tours, France, at the annual meeting of the American Society of Clinical Oncology.
Given the cost and risk for events with rituximab, the findings raise the question of whether there are any meaningful benefits for maintenance rituximab after induction therapy, Dr. Jonathan W. Friedberg of the University of Rochester, N.Y., who was the discussant of the paper, remarked after the presentation. He asked whether there is any evidence that patients feel better if they’re in remission and, thus, their quality of life is improved.
The study included fit, treatment-naive patients aged 65 years and older with B-cell CLL who lacked del17p. Median patient age was 71.3 years, and two-thirds of the patients were men.
Patients received four cycles of induction therapy with fludarabine, cyclophosphamide, and rituximab on a shortened schedule chosen to reduce the risk of cumulative toxicity. At randomization, patients were stratified for immunoglobulin heavy chain variable (IGHV) status (54.8% of patients had unmutated status) and del11q (21.3% of patients had the deletion). Patients who had complete (25.7% of patients) or partial (62.8% of patients) responses were randomly allocated to either maintenance rituximab (202 patients given 500 mg/m2 twice per month for 2 years) or to observation (207 patients). Median follow-up from randomization was 43.6 months.
Median progression-free survival in the rituximab arm was 59.3 months (95% confidence interval, 49.6; not reached), compared with 49 months (95% CI, 40.9-60.5) in the observation group (hazard ratio, 0.597; 95% CI, 0.437-0.814; P = .0011), corresponding to 3-year progression-free survival of 83% and 64.2% in each arm, respectively.
Estimated overall survival at 3 years was 92.6% with rituximab maintenance and 87.2% in the observation group. Rituximab maintenance significantly improved progression-free survival in patients with and without del11q and in those with unmutated IGHV.
Serious adverse events for hematologic toxicity were seen in 6.9% of rituximab-treated patients and 1.9% of patients in the observation group (P = .027). Serious adverse events for infectious toxicity occurred in 18.8% of rituximab-treated patients and 10.1% of the observation group (P = .036). There were 69 deaths post randomization: 32 in the rituximab-treated group and 37 in the observation group. Secondary cancers, excluding basal cell carcinomas of the skin, occurred in 15.3% of the rituximab arm, including five cases of myelodysplastic syndrome, and in 11.1% of the observation group, including three cases of myelodysplastic syndrome.
Dr. Dartigeas is a consultant to Gilead Sciences and has provided expert testimony for Roche/Genentech. Genentech and Biogen jointly market rituximab (Rituxan).
On Twitter @maryjodales
CHICAGO – After 2 years of maintenance immunotherapy with rituximab, elderly patients with chronic lymphocytic leukemia had better rates of progression-free survival than did patients in an observation group, based on results of the CLL 2007 SA trial from the French FILO (French Innovative Leukemia Organisation) Group.
The two groups did not significantly differ in overall survival, however, with 92.6% estimated 3-year overall survival in the rituximab group and 87.2% in the observation group. Further, the patients given rituximab had more adverse events, based on data presented by Dr. Caroline Dartigeas of the University Hospital in Tours, France, at the annual meeting of the American Society of Clinical Oncology.
Given the cost and risk for events with rituximab, the findings raise the question of whether there are any meaningful benefits for maintenance rituximab after induction therapy, Dr. Jonathan W. Friedberg of the University of Rochester, N.Y., who was the discussant of the paper, remarked after the presentation. He asked whether there is any evidence that patients feel better if they’re in remission and, thus, their quality of life is improved.
The study included fit, treatment-naive patients aged 65 years and older with B-cell CLL who lacked del17p. Median patient age was 71.3 years, and two-thirds of the patients were men.
Patients received four cycles of induction therapy with fludarabine, cyclophosphamide, and rituximab on a shortened schedule chosen to reduce the risk of cumulative toxicity. At randomization, patients were stratified for immunoglobulin heavy chain variable (IGHV) status (54.8% of patients had unmutated status) and del11q (21.3% of patients had the deletion). Patients who had complete (25.7% of patients) or partial (62.8% of patients) responses were randomly allocated to either maintenance rituximab (202 patients given 500 mg/m2 twice per month for 2 years) or to observation (207 patients). Median follow-up from randomization was 43.6 months.
Median progression-free survival in the rituximab arm was 59.3 months (95% confidence interval, 49.6; not reached), compared with 49 months (95% CI, 40.9-60.5) in the observation group (hazard ratio, 0.597; 95% CI, 0.437-0.814; P = .0011), corresponding to 3-year progression-free survival of 83% and 64.2% in each arm, respectively.
Estimated overall survival at 3 years was 92.6% with rituximab maintenance and 87.2% in the observation group. Rituximab maintenance significantly improved progression-free survival in patients with and without del11q and in those with unmutated IGHV.
Serious adverse events for hematologic toxicity were seen in 6.9% of rituximab-treated patients and 1.9% of patients in the observation group (P = .027). Serious adverse events for infectious toxicity occurred in 18.8% of rituximab-treated patients and 10.1% of the observation group (P = .036). There were 69 deaths post randomization: 32 in the rituximab-treated group and 37 in the observation group. Secondary cancers, excluding basal cell carcinomas of the skin, occurred in 15.3% of the rituximab arm, including five cases of myelodysplastic syndrome, and in 11.1% of the observation group, including three cases of myelodysplastic syndrome.
Dr. Dartigeas is a consultant to Gilead Sciences and has provided expert testimony for Roche/Genentech. Genentech and Biogen jointly market rituximab (Rituxan).
On Twitter @maryjodales
CHICAGO – After 2 years of maintenance immunotherapy with rituximab, elderly patients with chronic lymphocytic leukemia had better rates of progression-free survival than did patients in an observation group, based on results of the CLL 2007 SA trial from the French FILO (French Innovative Leukemia Organisation) Group.
The two groups did not significantly differ in overall survival, however, with 92.6% estimated 3-year overall survival in the rituximab group and 87.2% in the observation group. Further, the patients given rituximab had more adverse events, based on data presented by Dr. Caroline Dartigeas of the University Hospital in Tours, France, at the annual meeting of the American Society of Clinical Oncology.
Given the cost and risk for events with rituximab, the findings raise the question of whether there are any meaningful benefits for maintenance rituximab after induction therapy, Dr. Jonathan W. Friedberg of the University of Rochester, N.Y., who was the discussant of the paper, remarked after the presentation. He asked whether there is any evidence that patients feel better if they’re in remission and, thus, their quality of life is improved.
The study included fit, treatment-naive patients aged 65 years and older with B-cell CLL who lacked del17p. Median patient age was 71.3 years, and two-thirds of the patients were men.
Patients received four cycles of induction therapy with fludarabine, cyclophosphamide, and rituximab on a shortened schedule chosen to reduce the risk of cumulative toxicity. At randomization, patients were stratified for immunoglobulin heavy chain variable (IGHV) status (54.8% of patients had unmutated status) and del11q (21.3% of patients had the deletion). Patients who had complete (25.7% of patients) or partial (62.8% of patients) responses were randomly allocated to either maintenance rituximab (202 patients given 500 mg/m2 twice per month for 2 years) or to observation (207 patients). Median follow-up from randomization was 43.6 months.
Median progression-free survival in the rituximab arm was 59.3 months (95% confidence interval, 49.6; not reached), compared with 49 months (95% CI, 40.9-60.5) in the observation group (hazard ratio, 0.597; 95% CI, 0.437-0.814; P = .0011), corresponding to 3-year progression-free survival of 83% and 64.2% in each arm, respectively.
Estimated overall survival at 3 years was 92.6% with rituximab maintenance and 87.2% in the observation group. Rituximab maintenance significantly improved progression-free survival in patients with and without del11q and in those with unmutated IGHV.
Serious adverse events for hematologic toxicity were seen in 6.9% of rituximab-treated patients and 1.9% of patients in the observation group (P = .027). Serious adverse events for infectious toxicity occurred in 18.8% of rituximab-treated patients and 10.1% of the observation group (P = .036). There were 69 deaths post randomization: 32 in the rituximab-treated group and 37 in the observation group. Secondary cancers, excluding basal cell carcinomas of the skin, occurred in 15.3% of the rituximab arm, including five cases of myelodysplastic syndrome, and in 11.1% of the observation group, including three cases of myelodysplastic syndrome.
Dr. Dartigeas is a consultant to Gilead Sciences and has provided expert testimony for Roche/Genentech. Genentech and Biogen jointly market rituximab (Rituxan).
On Twitter @maryjodales
AT 2016 ASCO ANNUAL MEETING
Key clinical point: Progression-free survival, but not overall survival, was improved after 2 years of maintenance immunotherapy with rituximab.
Major finding: Median progression-free survival in the rituximab arm was 59.3 months (95% CI, 49.6; not reached), compared with 49 months (95% CI, 40.9-60.5) in the observation group (HR, 0.597; 95% CI, 0.437-0.814; P = .0011), corresponding to a 3-year progression-free survival of 83% and 64.2% in each arm, respectively.
Data source: Maintenance rituximab (202 patients given 500 mg/m2 twice a month for 2 years) and observation (207 patients) in the CLL 2007 SA trial from the French FILO Group.
Disclosures: Dr. Dartigeas is a consultant to Gilead Sciences and has provided expert testimony for Roche/Genentech. Genentech and Biogen jointly market rituximab (Rituxan).
Dr. Matt Kalaycio’s top 10 hematologic oncology abstracts for ASCO 2016
Hematology News’ Editor-in-Chief Matt Kalaycio selected the following as his “top 10” picks for hematologic oncology abstracts at ASCO 2016:
Abstract 7000: Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML
Comment: When any treatment appears to improve survival, compared with 7+3 for AML, all must take notice.
Abstract 7001: Treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) treated with frontline nilotinib: Results from the ENESTFreedom study
Comment: About 50% of the CML patients treated with frontline nilotinib are eventually able to stop the drug and successfully stay off of it. That means more patients in treatment-free remission, compared with those initially treated with imatinib.
Link to abstract 7001
Abstract 7007: Phase Ib/2 study of venetoclax with low-dose cytarabine in treatment-naive patients age ≥ 65 with acute myelogenous leukemia
Abstract 7009: Results of a phase 1b study of venetoclax plus decitabine or azacitidine in untreated acute myeloid leukemia patients ≥ 65 years ineligible for standard induction therapy
Comment: The response rates in these older AML patients are remarkable and challenge results typically seen with 7+3 in a younger population.
Link to abstract 7007 and 7009
Abstract 7501: A prospective, multicenter, randomized study of anti-CCR4 monoclonal antibody mogamulizumab (moga) vs investigator’s choice (IC) in the treatment of patients (pts) with relapsed/refractory (R/R) adult T-cell leukemia-lymphoma (ATL)
Comment: The response rate to mogamulizumab was outstanding in the largest randomized clinical trial thus far conducted for this cancer. Although rare in the USA, ATL is more common in Asia.
Link to abstract 7501
Abstract 7507: Effect of bortezomib on complete remission (CR) rate when added to bendamustine-rituximab (BR) in previously untreated high-risk (HR) follicular lymphoma (FL): A randomized phase II trial of the ECOG-ACRIN Cancer Research Group (E2408)
Comment: This interesting observation of improved complete remission needs longer follow-up.
Link to abstract 7507
Abstract 7519: Venetoclax activity in CLL patients who have relapsed after or are refractory to ibrutinib or idelalisib
Comment: This study has implications for practice. Venetoclax elicits a 50%-60% response rate after patients with CLL progress during treatment with B-cell receptor pathway inhibitors.
Link to abstract 7519
Abstract 7521: Acalabrutinib, a second-generation bruton tyrosine kinase (Btk) inhibitor, in previously untreated chronic lymphocytic leukemia (CLL)
Comment: This next-generation variation on ibrutinib was associated with a 96% overall response rate with fewer adverse effects such as atrial fibrillation.
Link to abstract 7521
Abstract 8000: Upfront autologous stem cell transplantation (ASCT) versus novel agent-based therapy for multiple myeloma (MM): A randomized phase 3 study of the European Myeloma Network (EMN02/HO95 MM trial)
Comment: Other trials are underway to address the role of upfront ASCT for newly diagnosed multiple myeloma. While the last word on this issue has yet to be written, ASCT remains the standard of care for MM patients after induction.
Link to abstract 8000
LBA4: Phase III randomized controlled study of daratumumab, bortezomib, and dexamethasone (DVd) versus bortezomib and dexamethasone (Vd) in patients (pts) with relapsed or refractory multiple myeloma (RRMM): CASTOR study
Comment: As predicted by most, the addition of daratumumab to bortezomib-based therapy increases response rates, compared with bortezomib-based alone. Efficacy is becoming less of a concern with myeloma treatment than is economics..
Look for the full, final text of this abstract to be posted online at 7:30 AM (EDT) on Sunday, June 5.
Hematology News’ Editor-in-Chief Matt Kalaycio selected the following as his “top 10” picks for hematologic oncology abstracts at ASCO 2016:
Abstract 7000: Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML
Comment: When any treatment appears to improve survival, compared with 7+3 for AML, all must take notice.
Abstract 7001: Treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) treated with frontline nilotinib: Results from the ENESTFreedom study
Comment: About 50% of the CML patients treated with frontline nilotinib are eventually able to stop the drug and successfully stay off of it. That means more patients in treatment-free remission, compared with those initially treated with imatinib.
Link to abstract 7001
Abstract 7007: Phase Ib/2 study of venetoclax with low-dose cytarabine in treatment-naive patients age ≥ 65 with acute myelogenous leukemia
Abstract 7009: Results of a phase 1b study of venetoclax plus decitabine or azacitidine in untreated acute myeloid leukemia patients ≥ 65 years ineligible for standard induction therapy
Comment: The response rates in these older AML patients are remarkable and challenge results typically seen with 7+3 in a younger population.
Link to abstract 7007 and 7009
Abstract 7501: A prospective, multicenter, randomized study of anti-CCR4 monoclonal antibody mogamulizumab (moga) vs investigator’s choice (IC) in the treatment of patients (pts) with relapsed/refractory (R/R) adult T-cell leukemia-lymphoma (ATL)
Comment: The response rate to mogamulizumab was outstanding in the largest randomized clinical trial thus far conducted for this cancer. Although rare in the USA, ATL is more common in Asia.
Link to abstract 7501
Abstract 7507: Effect of bortezomib on complete remission (CR) rate when added to bendamustine-rituximab (BR) in previously untreated high-risk (HR) follicular lymphoma (FL): A randomized phase II trial of the ECOG-ACRIN Cancer Research Group (E2408)
Comment: This interesting observation of improved complete remission needs longer follow-up.
Link to abstract 7507
Abstract 7519: Venetoclax activity in CLL patients who have relapsed after or are refractory to ibrutinib or idelalisib
Comment: This study has implications for practice. Venetoclax elicits a 50%-60% response rate after patients with CLL progress during treatment with B-cell receptor pathway inhibitors.
Link to abstract 7519
Abstract 7521: Acalabrutinib, a second-generation bruton tyrosine kinase (Btk) inhibitor, in previously untreated chronic lymphocytic leukemia (CLL)
Comment: This next-generation variation on ibrutinib was associated with a 96% overall response rate with fewer adverse effects such as atrial fibrillation.
Link to abstract 7521
Abstract 8000: Upfront autologous stem cell transplantation (ASCT) versus novel agent-based therapy for multiple myeloma (MM): A randomized phase 3 study of the European Myeloma Network (EMN02/HO95 MM trial)
Comment: Other trials are underway to address the role of upfront ASCT for newly diagnosed multiple myeloma. While the last word on this issue has yet to be written, ASCT remains the standard of care for MM patients after induction.
Link to abstract 8000
LBA4: Phase III randomized controlled study of daratumumab, bortezomib, and dexamethasone (DVd) versus bortezomib and dexamethasone (Vd) in patients (pts) with relapsed or refractory multiple myeloma (RRMM): CASTOR study
Comment: As predicted by most, the addition of daratumumab to bortezomib-based therapy increases response rates, compared with bortezomib-based alone. Efficacy is becoming less of a concern with myeloma treatment than is economics..
Look for the full, final text of this abstract to be posted online at 7:30 AM (EDT) on Sunday, June 5.
Hematology News’ Editor-in-Chief Matt Kalaycio selected the following as his “top 10” picks for hematologic oncology abstracts at ASCO 2016:
Abstract 7000: Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML
Comment: When any treatment appears to improve survival, compared with 7+3 for AML, all must take notice.
Abstract 7001: Treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) treated with frontline nilotinib: Results from the ENESTFreedom study
Comment: About 50% of the CML patients treated with frontline nilotinib are eventually able to stop the drug and successfully stay off of it. That means more patients in treatment-free remission, compared with those initially treated with imatinib.
Link to abstract 7001
Abstract 7007: Phase Ib/2 study of venetoclax with low-dose cytarabine in treatment-naive patients age ≥ 65 with acute myelogenous leukemia
Abstract 7009: Results of a phase 1b study of venetoclax plus decitabine or azacitidine in untreated acute myeloid leukemia patients ≥ 65 years ineligible for standard induction therapy
Comment: The response rates in these older AML patients are remarkable and challenge results typically seen with 7+3 in a younger population.
Link to abstract 7007 and 7009
Abstract 7501: A prospective, multicenter, randomized study of anti-CCR4 monoclonal antibody mogamulizumab (moga) vs investigator’s choice (IC) in the treatment of patients (pts) with relapsed/refractory (R/R) adult T-cell leukemia-lymphoma (ATL)
Comment: The response rate to mogamulizumab was outstanding in the largest randomized clinical trial thus far conducted for this cancer. Although rare in the USA, ATL is more common in Asia.
Link to abstract 7501
Abstract 7507: Effect of bortezomib on complete remission (CR) rate when added to bendamustine-rituximab (BR) in previously untreated high-risk (HR) follicular lymphoma (FL): A randomized phase II trial of the ECOG-ACRIN Cancer Research Group (E2408)
Comment: This interesting observation of improved complete remission needs longer follow-up.
Link to abstract 7507
Abstract 7519: Venetoclax activity in CLL patients who have relapsed after or are refractory to ibrutinib or idelalisib
Comment: This study has implications for practice. Venetoclax elicits a 50%-60% response rate after patients with CLL progress during treatment with B-cell receptor pathway inhibitors.
Link to abstract 7519
Abstract 7521: Acalabrutinib, a second-generation bruton tyrosine kinase (Btk) inhibitor, in previously untreated chronic lymphocytic leukemia (CLL)
Comment: This next-generation variation on ibrutinib was associated with a 96% overall response rate with fewer adverse effects such as atrial fibrillation.
Link to abstract 7521
Abstract 8000: Upfront autologous stem cell transplantation (ASCT) versus novel agent-based therapy for multiple myeloma (MM): A randomized phase 3 study of the European Myeloma Network (EMN02/HO95 MM trial)
Comment: Other trials are underway to address the role of upfront ASCT for newly diagnosed multiple myeloma. While the last word on this issue has yet to be written, ASCT remains the standard of care for MM patients after induction.
Link to abstract 8000
LBA4: Phase III randomized controlled study of daratumumab, bortezomib, and dexamethasone (DVd) versus bortezomib and dexamethasone (Vd) in patients (pts) with relapsed or refractory multiple myeloma (RRMM): CASTOR study
Comment: As predicted by most, the addition of daratumumab to bortezomib-based therapy increases response rates, compared with bortezomib-based alone. Efficacy is becoming less of a concern with myeloma treatment than is economics..
Look for the full, final text of this abstract to be posted online at 7:30 AM (EDT) on Sunday, June 5.
Venetoclax achieves responses in CLL refractory to ibrutinib, idelalisib
Venetoclax monotherapy was active, and even elicited minimal residual disease negativity in a proportion of patients with chronic lymphocytic leukemia (CLL) that was resistant or refractory to ibrutinib or idelalisib, Dr. Jeffrey Alan Jones of the Ohio State University Comprehensive Cancer Center, Columbus, and colleagues wrote in an abstract to be presented at the annual meeting of the American Society of Clinical Oncology.
The findings from their ongoing phase II study are the first prospective results to demonstrate efficacy in this poor-prognosis population, the researchers wrote. Earlier results from the study were reported at the American Society of Hematology meeting.
The 54 patients in the study, 25 of them refractory to ibrutinib and 6 to idelalisib, received venetoclax 20 mg daily followed by a 5-week ramp up in dosage to 400 mg daily. Over half of the patients had received more than five prior therapies; 83% did not have IGHV mutations, 20% had absolute lymphocyte counts exceeding 100 x 109, 35% had 17p deletions, and 24% had at least one node that was 10 cm or larger.
Of the patients who had previously received ibrutinib, four discontinued venetoclax because of progressive disease and four others had respiratory failure, multiorgan failure, death of unknown cause, or consent withdrawal. Of those who previously received idelalisib, four halted therapy because of progressive disease and failure to respond. Of 48 evaluable patients, 38 previously received ibrutinib, and 10 previously received idelalisib.
The overall response rate was 61% (23 of 38 patients) for patients refractory to ibrutinib and 50% (5 of 10 patients) for those refractory to idelalisib. A complete response was seen in three patients, all refractory to ibrutinib.
Grade 3/4 adverse events were seen in over 10% of patients and included neutropenia (39%), thrombocytopenia (22%), anemia (20%), leukopenia (13%), and pneumonia (13%). Significant adverse events seen in at least two patients included pneumonia (9%), febrile neutropenia (7%), increased potassium, multiorgan failure, and septic shock (4% each).
The study is sponsored by AbbVie.
Venetoclax monotherapy was active, and even elicited minimal residual disease negativity in a proportion of patients with chronic lymphocytic leukemia (CLL) that was resistant or refractory to ibrutinib or idelalisib, Dr. Jeffrey Alan Jones of the Ohio State University Comprehensive Cancer Center, Columbus, and colleagues wrote in an abstract to be presented at the annual meeting of the American Society of Clinical Oncology.
The findings from their ongoing phase II study are the first prospective results to demonstrate efficacy in this poor-prognosis population, the researchers wrote. Earlier results from the study were reported at the American Society of Hematology meeting.
The 54 patients in the study, 25 of them refractory to ibrutinib and 6 to idelalisib, received venetoclax 20 mg daily followed by a 5-week ramp up in dosage to 400 mg daily. Over half of the patients had received more than five prior therapies; 83% did not have IGHV mutations, 20% had absolute lymphocyte counts exceeding 100 x 109, 35% had 17p deletions, and 24% had at least one node that was 10 cm or larger.
Of the patients who had previously received ibrutinib, four discontinued venetoclax because of progressive disease and four others had respiratory failure, multiorgan failure, death of unknown cause, or consent withdrawal. Of those who previously received idelalisib, four halted therapy because of progressive disease and failure to respond. Of 48 evaluable patients, 38 previously received ibrutinib, and 10 previously received idelalisib.
The overall response rate was 61% (23 of 38 patients) for patients refractory to ibrutinib and 50% (5 of 10 patients) for those refractory to idelalisib. A complete response was seen in three patients, all refractory to ibrutinib.
Grade 3/4 adverse events were seen in over 10% of patients and included neutropenia (39%), thrombocytopenia (22%), anemia (20%), leukopenia (13%), and pneumonia (13%). Significant adverse events seen in at least two patients included pneumonia (9%), febrile neutropenia (7%), increased potassium, multiorgan failure, and septic shock (4% each).
The study is sponsored by AbbVie.
Venetoclax monotherapy was active, and even elicited minimal residual disease negativity in a proportion of patients with chronic lymphocytic leukemia (CLL) that was resistant or refractory to ibrutinib or idelalisib, Dr. Jeffrey Alan Jones of the Ohio State University Comprehensive Cancer Center, Columbus, and colleagues wrote in an abstract to be presented at the annual meeting of the American Society of Clinical Oncology.
The findings from their ongoing phase II study are the first prospective results to demonstrate efficacy in this poor-prognosis population, the researchers wrote. Earlier results from the study were reported at the American Society of Hematology meeting.
The 54 patients in the study, 25 of them refractory to ibrutinib and 6 to idelalisib, received venetoclax 20 mg daily followed by a 5-week ramp up in dosage to 400 mg daily. Over half of the patients had received more than five prior therapies; 83% did not have IGHV mutations, 20% had absolute lymphocyte counts exceeding 100 x 109, 35% had 17p deletions, and 24% had at least one node that was 10 cm or larger.
Of the patients who had previously received ibrutinib, four discontinued venetoclax because of progressive disease and four others had respiratory failure, multiorgan failure, death of unknown cause, or consent withdrawal. Of those who previously received idelalisib, four halted therapy because of progressive disease and failure to respond. Of 48 evaluable patients, 38 previously received ibrutinib, and 10 previously received idelalisib.
The overall response rate was 61% (23 of 38 patients) for patients refractory to ibrutinib and 50% (5 of 10 patients) for those refractory to idelalisib. A complete response was seen in three patients, all refractory to ibrutinib.
Grade 3/4 adverse events were seen in over 10% of patients and included neutropenia (39%), thrombocytopenia (22%), anemia (20%), leukopenia (13%), and pneumonia (13%). Significant adverse events seen in at least two patients included pneumonia (9%), febrile neutropenia (7%), increased potassium, multiorgan failure, and septic shock (4% each).
The study is sponsored by AbbVie.
FROM ASCO 2016
Key clinical point: Venetoclax can achieve responses in patients who are refractory to ibrutinib.
Major finding: The overall response rate was 61% (23 of 38 patients) for patients refractory to ibrutinib and 50% (5 of 10 patients) for those refractory to idelalisib. A complete response was seen in three patients, all refractory to ibrutinib..
Data source: Data on 54 patients in an ongoing phase II study.
Disclosures: The study is sponsored by AbbVie.
CAR T-cell start-up launched
Dr. Siddhartha Mukherjee has partnered with Puretech Health to launch a new biotechnology and immuno-oncology company to broaden the use of chimeric antigen receptor (CAR) T-cell therapy. Dr. Mukherjee, a Columbia University researcher, hematologist, oncologist, and Pulitzer Prize–winning author of “The Emperor of All Maladies: A Biography of Cancer,” (New York: Scribner, a division of Simon & Schuster, 2011) is licensing his CAR T-cell technology to the joint venture, called Vor BioPharma.
Vor BioPharma will focus on advancing and expanding CAR T-cell therapy, a relatively new cancer treatment where T cells are first collected from a patient’s blood and then genetically engineered to produce CAR proteins on their surface. The CAR proteins are designed to bind specific antigens found on the patient’s cancer cells. These genetically engineered T cells are grown in a laboratory and then infused into the patient. As of now, CAR T-cell therapy is primarily used to treat B-cell leukemias and other chronic lymphocytic leukemia.
“We continue to make great strides in developing new ways to treat cancer using the body’s immune system,” said Dr. Mukherjee in a written statement announcing the partnership. “The positive clinical response researchers have achieved with CAR T-cell therapies in B-cell leukemias has led to great interest within the oncology community and is something we hope to achieve in other cancers over time,” he said.
“CAR T-cell therapies have shown remarkable progress in the clinic, yet their applicability beyond a small subset of cancers is currently very limited,” said Dr. Sanjiv Sam Gambhir of Stanford University and a member of the Vor Scientific Advisory Board. “This technology seeks to address bottlenecks that prevent CAR T-cell therapy from becoming more broadly useful in treating cancers outside of B-cell cancers.”
Other Vor BioPharma employees and Scientific Advisory Board members include Dr. Joseph Bolen, former President and Chief Scientific Officer of Moderna Therapeutics; Dr. Dan Littman of the Howard Hughes Medical Institute; and Dr. Derrick Rossi of Harvard University.
On Twitter @jess_craig94
Dr. Siddhartha Mukherjee has partnered with Puretech Health to launch a new biotechnology and immuno-oncology company to broaden the use of chimeric antigen receptor (CAR) T-cell therapy. Dr. Mukherjee, a Columbia University researcher, hematologist, oncologist, and Pulitzer Prize–winning author of “The Emperor of All Maladies: A Biography of Cancer,” (New York: Scribner, a division of Simon & Schuster, 2011) is licensing his CAR T-cell technology to the joint venture, called Vor BioPharma.
Vor BioPharma will focus on advancing and expanding CAR T-cell therapy, a relatively new cancer treatment where T cells are first collected from a patient’s blood and then genetically engineered to produce CAR proteins on their surface. The CAR proteins are designed to bind specific antigens found on the patient’s cancer cells. These genetically engineered T cells are grown in a laboratory and then infused into the patient. As of now, CAR T-cell therapy is primarily used to treat B-cell leukemias and other chronic lymphocytic leukemia.
“We continue to make great strides in developing new ways to treat cancer using the body’s immune system,” said Dr. Mukherjee in a written statement announcing the partnership. “The positive clinical response researchers have achieved with CAR T-cell therapies in B-cell leukemias has led to great interest within the oncology community and is something we hope to achieve in other cancers over time,” he said.
“CAR T-cell therapies have shown remarkable progress in the clinic, yet their applicability beyond a small subset of cancers is currently very limited,” said Dr. Sanjiv Sam Gambhir of Stanford University and a member of the Vor Scientific Advisory Board. “This technology seeks to address bottlenecks that prevent CAR T-cell therapy from becoming more broadly useful in treating cancers outside of B-cell cancers.”
Other Vor BioPharma employees and Scientific Advisory Board members include Dr. Joseph Bolen, former President and Chief Scientific Officer of Moderna Therapeutics; Dr. Dan Littman of the Howard Hughes Medical Institute; and Dr. Derrick Rossi of Harvard University.
On Twitter @jess_craig94
Dr. Siddhartha Mukherjee has partnered with Puretech Health to launch a new biotechnology and immuno-oncology company to broaden the use of chimeric antigen receptor (CAR) T-cell therapy. Dr. Mukherjee, a Columbia University researcher, hematologist, oncologist, and Pulitzer Prize–winning author of “The Emperor of All Maladies: A Biography of Cancer,” (New York: Scribner, a division of Simon & Schuster, 2011) is licensing his CAR T-cell technology to the joint venture, called Vor BioPharma.
Vor BioPharma will focus on advancing and expanding CAR T-cell therapy, a relatively new cancer treatment where T cells are first collected from a patient’s blood and then genetically engineered to produce CAR proteins on their surface. The CAR proteins are designed to bind specific antigens found on the patient’s cancer cells. These genetically engineered T cells are grown in a laboratory and then infused into the patient. As of now, CAR T-cell therapy is primarily used to treat B-cell leukemias and other chronic lymphocytic leukemia.
“We continue to make great strides in developing new ways to treat cancer using the body’s immune system,” said Dr. Mukherjee in a written statement announcing the partnership. “The positive clinical response researchers have achieved with CAR T-cell therapies in B-cell leukemias has led to great interest within the oncology community and is something we hope to achieve in other cancers over time,” he said.
“CAR T-cell therapies have shown remarkable progress in the clinic, yet their applicability beyond a small subset of cancers is currently very limited,” said Dr. Sanjiv Sam Gambhir of Stanford University and a member of the Vor Scientific Advisory Board. “This technology seeks to address bottlenecks that prevent CAR T-cell therapy from becoming more broadly useful in treating cancers outside of B-cell cancers.”
Other Vor BioPharma employees and Scientific Advisory Board members include Dr. Joseph Bolen, former President and Chief Scientific Officer of Moderna Therapeutics; Dr. Dan Littman of the Howard Hughes Medical Institute; and Dr. Derrick Rossi of Harvard University.
On Twitter @jess_craig94
‘Universal’ CAR T cell may overcome limitations
FROM THE AACR ANNUAL MEETING
A differently engineered chimeric antigen receptor (CAR) T cell promises to overcome major limitations of current CAR T cell therapies. Rather than engineer the CAR T cells to have a receptor that recognizes specific tumor antigens one at a time and requiring different CAR T cells for every antigen, this technique engineers a T cell receptor that can bind one invariant end of a bifunctional molecule. The molecule is constructed such that the other end can bind to whatever tumor cell surface marker is of interest. In this way, the CAR T cells can be constructed once and be directed to various tumor markers.
Standard CAR T cells are engineered to express on their surfaces receptors that recognize a specific antigen. These cells have been used up to now to recognize and kill tumor cells – for example, B cell leukemias carrying the pan-B cell marker CD19. The CAR T cells and their progeny, including memory T cells, remain in the body and continue to carry out their functions, potentially providing immune surveillance in case cancer cells arise again. But they uniquely recognize just CD19 – a problem, in that they kill even normal B cells, so-called off-target toxicity.
Beyond the unique specificity of standard CAR T cells, Philip Low, Ph.D., director of the Center for Drug Discovery at Purdue University in West Lafayette, Indiana, said these cells have three major limitations. First, they may lyse tumor cells so rapidly that a systemic tumor lysis syndrome or “cytokine storm” occurs. Second, the persisting CAR T cells can kill normal cells – for example, ones directed against CD19 killing normal B cells. Third, tumor cells have unstable genomes, leading to tumor heterogeneity, with some cells potentially losing the targeted antigens and therefore becoming “invisible” to the CAR T cells.
“So what we have done is basically designed a solution to all three, and we call it a universal CAR T cell because of its ability, with the help of an adapter molecule, to recognize all of these mutated tumor cells within a heterogeneous tumor,” he said at the annual meeting of the American Association for Cancer Research. The key was to make a CAR T cell with a surface receptor that binds to the dye fluorescein. Then fluorescein is coupled through a short linker to a molecule that binds specifically to a molecule expressed on tumor cells. In this way the CAR T cell can be made to interact with any tumor cell, depending on what is coupled to the fluorescein. The technique is analogous to a socket wrench. Every socket has the same size hole that the ratchet handle fits into regardless of the size of the “business end” of the sockets, which recognize different size nuts.
Dr. Low gave an example of folic acid, for which he says a receptor is overexpressed on about 40% of human tumors but almost never on normal cells. “We link fluorescein to the vitamin folic acid,” he said. CAR T cells are injected into an animal, and nothing happens unless a folate-fluorescein conjugate is also injected. “As soon as we inject folate-fluorescein, the folate binds to the tumor cell surface, the fluorescein part of the folate-fluorescein binds to the CAR T cell, this forces a very tight interaction between the engineered T cell and the cancer cell, and we found it leads to melting away of the tumor,” he said.
This technique addresses the three major problems with standard CAR T cell therapy. By titrating the binding affinity, concentration, and rate of administration of the fluorescein conjugate, the rate of tumor killing can be controlled, mitigating tumor lysis syndrome. Plus, normal cells may be spared if the parameters are adjusted so that the conjugate binds only to cells with high levels of the target molecule, such as tumor cells.
Because its low molecular weight, the bi-specific conjugate rapidly disappears from the circulation, and the cell killing can be terminated, allowing normal cells to regenerate – for example, in the case of normal B cells that carry CD19. Since CAR T cells generate progeny that stay in the body, the progeny remain “dormant” but are ready to be activated again by addition of the conjugate to attack tumor cells if they arise.
A major issue is dealing with tumor heterogeneity; Dr. Low’s method seems to address that, as well. “We have tumor-specific ligands for over 90% of all human cancers,” he said. “Within another couple of months we’ll have them for 100%.”
Tumors typically contain lots of hypoxic cells, and hypoxic cells overexpress carbonic anhydrase-9. “Virtually every tumor has large fractions of the tumor mass that overexpress carbonic anhydrase-9, and we have a ligand that binds very specifically to that,” Dr. Low said.
To address the problem of tumor heterogeneity, with different mutations within different areas of the tumor or over time because of genetic instability in the cells, Dr. Low said, “We have a cocktail of about five of these small molecules… they are inexpensive to produce… and they clear very rapidly… and with the cocktail we can hit nearly all cancer cells, even in heterogeneous cancers.”
One limitation, as with standard CAR T cell therapy, is that the technique will still depend on using an individual patient’s T cells to modify through use of a lentiviral vector, so there would not be a universal, off-the-shelf T cell to use for everyone.
The technique and materials have been tested only in animals so far, using tumor-specific ligands for the folate receptor, a prostate-specific membrane antigen, and an antigen overexpressed on neuroendocrine tumors. Dr. Low has intentions to move the technology into human trials. He said the bridging molecules exist in highly purified form, and CAR T cell technology has already been developed by others. “Today we see great success in animal models and have no reason to believe that it won’t translate at least to a good extent to the clinic,” he said. Still, he expects some obstacles along the way and is willing to partner with others working on similar problems as well as large pharmaceutical companies.
The research has been supported by Endocyte, a company that Dr. Low founded and for which he is Chief Scientific Officer and a member of the board of directors. He has filed two patents on the technology, which are held by Purdue University and licensed to Endocyte.
FROM THE AACR ANNUAL MEETING
A differently engineered chimeric antigen receptor (CAR) T cell promises to overcome major limitations of current CAR T cell therapies. Rather than engineer the CAR T cells to have a receptor that recognizes specific tumor antigens one at a time and requiring different CAR T cells for every antigen, this technique engineers a T cell receptor that can bind one invariant end of a bifunctional molecule. The molecule is constructed such that the other end can bind to whatever tumor cell surface marker is of interest. In this way, the CAR T cells can be constructed once and be directed to various tumor markers.
Standard CAR T cells are engineered to express on their surfaces receptors that recognize a specific antigen. These cells have been used up to now to recognize and kill tumor cells – for example, B cell leukemias carrying the pan-B cell marker CD19. The CAR T cells and their progeny, including memory T cells, remain in the body and continue to carry out their functions, potentially providing immune surveillance in case cancer cells arise again. But they uniquely recognize just CD19 – a problem, in that they kill even normal B cells, so-called off-target toxicity.
Beyond the unique specificity of standard CAR T cells, Philip Low, Ph.D., director of the Center for Drug Discovery at Purdue University in West Lafayette, Indiana, said these cells have three major limitations. First, they may lyse tumor cells so rapidly that a systemic tumor lysis syndrome or “cytokine storm” occurs. Second, the persisting CAR T cells can kill normal cells – for example, ones directed against CD19 killing normal B cells. Third, tumor cells have unstable genomes, leading to tumor heterogeneity, with some cells potentially losing the targeted antigens and therefore becoming “invisible” to the CAR T cells.
“So what we have done is basically designed a solution to all three, and we call it a universal CAR T cell because of its ability, with the help of an adapter molecule, to recognize all of these mutated tumor cells within a heterogeneous tumor,” he said at the annual meeting of the American Association for Cancer Research. The key was to make a CAR T cell with a surface receptor that binds to the dye fluorescein. Then fluorescein is coupled through a short linker to a molecule that binds specifically to a molecule expressed on tumor cells. In this way the CAR T cell can be made to interact with any tumor cell, depending on what is coupled to the fluorescein. The technique is analogous to a socket wrench. Every socket has the same size hole that the ratchet handle fits into regardless of the size of the “business end” of the sockets, which recognize different size nuts.
Dr. Low gave an example of folic acid, for which he says a receptor is overexpressed on about 40% of human tumors but almost never on normal cells. “We link fluorescein to the vitamin folic acid,” he said. CAR T cells are injected into an animal, and nothing happens unless a folate-fluorescein conjugate is also injected. “As soon as we inject folate-fluorescein, the folate binds to the tumor cell surface, the fluorescein part of the folate-fluorescein binds to the CAR T cell, this forces a very tight interaction between the engineered T cell and the cancer cell, and we found it leads to melting away of the tumor,” he said.
This technique addresses the three major problems with standard CAR T cell therapy. By titrating the binding affinity, concentration, and rate of administration of the fluorescein conjugate, the rate of tumor killing can be controlled, mitigating tumor lysis syndrome. Plus, normal cells may be spared if the parameters are adjusted so that the conjugate binds only to cells with high levels of the target molecule, such as tumor cells.
Because its low molecular weight, the bi-specific conjugate rapidly disappears from the circulation, and the cell killing can be terminated, allowing normal cells to regenerate – for example, in the case of normal B cells that carry CD19. Since CAR T cells generate progeny that stay in the body, the progeny remain “dormant” but are ready to be activated again by addition of the conjugate to attack tumor cells if they arise.
A major issue is dealing with tumor heterogeneity; Dr. Low’s method seems to address that, as well. “We have tumor-specific ligands for over 90% of all human cancers,” he said. “Within another couple of months we’ll have them for 100%.”
Tumors typically contain lots of hypoxic cells, and hypoxic cells overexpress carbonic anhydrase-9. “Virtually every tumor has large fractions of the tumor mass that overexpress carbonic anhydrase-9, and we have a ligand that binds very specifically to that,” Dr. Low said.
To address the problem of tumor heterogeneity, with different mutations within different areas of the tumor or over time because of genetic instability in the cells, Dr. Low said, “We have a cocktail of about five of these small molecules… they are inexpensive to produce… and they clear very rapidly… and with the cocktail we can hit nearly all cancer cells, even in heterogeneous cancers.”
One limitation, as with standard CAR T cell therapy, is that the technique will still depend on using an individual patient’s T cells to modify through use of a lentiviral vector, so there would not be a universal, off-the-shelf T cell to use for everyone.
The technique and materials have been tested only in animals so far, using tumor-specific ligands for the folate receptor, a prostate-specific membrane antigen, and an antigen overexpressed on neuroendocrine tumors. Dr. Low has intentions to move the technology into human trials. He said the bridging molecules exist in highly purified form, and CAR T cell technology has already been developed by others. “Today we see great success in animal models and have no reason to believe that it won’t translate at least to a good extent to the clinic,” he said. Still, he expects some obstacles along the way and is willing to partner with others working on similar problems as well as large pharmaceutical companies.
The research has been supported by Endocyte, a company that Dr. Low founded and for which he is Chief Scientific Officer and a member of the board of directors. He has filed two patents on the technology, which are held by Purdue University and licensed to Endocyte.
FROM THE AACR ANNUAL MEETING
A differently engineered chimeric antigen receptor (CAR) T cell promises to overcome major limitations of current CAR T cell therapies. Rather than engineer the CAR T cells to have a receptor that recognizes specific tumor antigens one at a time and requiring different CAR T cells for every antigen, this technique engineers a T cell receptor that can bind one invariant end of a bifunctional molecule. The molecule is constructed such that the other end can bind to whatever tumor cell surface marker is of interest. In this way, the CAR T cells can be constructed once and be directed to various tumor markers.
Standard CAR T cells are engineered to express on their surfaces receptors that recognize a specific antigen. These cells have been used up to now to recognize and kill tumor cells – for example, B cell leukemias carrying the pan-B cell marker CD19. The CAR T cells and their progeny, including memory T cells, remain in the body and continue to carry out their functions, potentially providing immune surveillance in case cancer cells arise again. But they uniquely recognize just CD19 – a problem, in that they kill even normal B cells, so-called off-target toxicity.
Beyond the unique specificity of standard CAR T cells, Philip Low, Ph.D., director of the Center for Drug Discovery at Purdue University in West Lafayette, Indiana, said these cells have three major limitations. First, they may lyse tumor cells so rapidly that a systemic tumor lysis syndrome or “cytokine storm” occurs. Second, the persisting CAR T cells can kill normal cells – for example, ones directed against CD19 killing normal B cells. Third, tumor cells have unstable genomes, leading to tumor heterogeneity, with some cells potentially losing the targeted antigens and therefore becoming “invisible” to the CAR T cells.
“So what we have done is basically designed a solution to all three, and we call it a universal CAR T cell because of its ability, with the help of an adapter molecule, to recognize all of these mutated tumor cells within a heterogeneous tumor,” he said at the annual meeting of the American Association for Cancer Research. The key was to make a CAR T cell with a surface receptor that binds to the dye fluorescein. Then fluorescein is coupled through a short linker to a molecule that binds specifically to a molecule expressed on tumor cells. In this way the CAR T cell can be made to interact with any tumor cell, depending on what is coupled to the fluorescein. The technique is analogous to a socket wrench. Every socket has the same size hole that the ratchet handle fits into regardless of the size of the “business end” of the sockets, which recognize different size nuts.
Dr. Low gave an example of folic acid, for which he says a receptor is overexpressed on about 40% of human tumors but almost never on normal cells. “We link fluorescein to the vitamin folic acid,” he said. CAR T cells are injected into an animal, and nothing happens unless a folate-fluorescein conjugate is also injected. “As soon as we inject folate-fluorescein, the folate binds to the tumor cell surface, the fluorescein part of the folate-fluorescein binds to the CAR T cell, this forces a very tight interaction between the engineered T cell and the cancer cell, and we found it leads to melting away of the tumor,” he said.
This technique addresses the three major problems with standard CAR T cell therapy. By titrating the binding affinity, concentration, and rate of administration of the fluorescein conjugate, the rate of tumor killing can be controlled, mitigating tumor lysis syndrome. Plus, normal cells may be spared if the parameters are adjusted so that the conjugate binds only to cells with high levels of the target molecule, such as tumor cells.
Because its low molecular weight, the bi-specific conjugate rapidly disappears from the circulation, and the cell killing can be terminated, allowing normal cells to regenerate – for example, in the case of normal B cells that carry CD19. Since CAR T cells generate progeny that stay in the body, the progeny remain “dormant” but are ready to be activated again by addition of the conjugate to attack tumor cells if they arise.
A major issue is dealing with tumor heterogeneity; Dr. Low’s method seems to address that, as well. “We have tumor-specific ligands for over 90% of all human cancers,” he said. “Within another couple of months we’ll have them for 100%.”
Tumors typically contain lots of hypoxic cells, and hypoxic cells overexpress carbonic anhydrase-9. “Virtually every tumor has large fractions of the tumor mass that overexpress carbonic anhydrase-9, and we have a ligand that binds very specifically to that,” Dr. Low said.
To address the problem of tumor heterogeneity, with different mutations within different areas of the tumor or over time because of genetic instability in the cells, Dr. Low said, “We have a cocktail of about five of these small molecules… they are inexpensive to produce… and they clear very rapidly… and with the cocktail we can hit nearly all cancer cells, even in heterogeneous cancers.”
One limitation, as with standard CAR T cell therapy, is that the technique will still depend on using an individual patient’s T cells to modify through use of a lentiviral vector, so there would not be a universal, off-the-shelf T cell to use for everyone.
The technique and materials have been tested only in animals so far, using tumor-specific ligands for the folate receptor, a prostate-specific membrane antigen, and an antigen overexpressed on neuroendocrine tumors. Dr. Low has intentions to move the technology into human trials. He said the bridging molecules exist in highly purified form, and CAR T cell technology has already been developed by others. “Today we see great success in animal models and have no reason to believe that it won’t translate at least to a good extent to the clinic,” he said. Still, he expects some obstacles along the way and is willing to partner with others working on similar problems as well as large pharmaceutical companies.
The research has been supported by Endocyte, a company that Dr. Low founded and for which he is Chief Scientific Officer and a member of the board of directors. He has filed two patents on the technology, which are held by Purdue University and licensed to Endocyte.
New single-tube assay detects one CLL cell in 1 million leukocytes
Chronic lymphocytic leukemia cells can be identified at levels as low as 0.0010% with a newly developed and validated single-tube assay, Dr. Andy C. Rawstro of St. James’s Institute of Oncology, Leeds, England, and his colleagues said in a European Research Initiative on CLL (ERIC) project report in Leukemia.
The high-throughput sequencing assay consists of a core panel of six markers – CD19, CD20, CD5, CD43, CD79b and CD81 – with a component specification independent of instrument and reagents. The new assay eliminates the need to distribute the blood sample across multiple tubes, which can impair sensitivity in cases with poor cellularity. The assay can be locally revalidated using normal peripheral blood and can be used to investigate new markers.
The new assay was validated in a multicenter study of 128 samples from 108 patients with CLL or monoclonal B-cell lymphocytosis, studied either at diagnosis or after FCR-based (fludarabine, cyclophosphamide, rituximab) treatment and compared with peripheral blood samples from healthy young women. In a parallel analysis, the assay compared with flow cytometry results at the 0.010% level, the minimal residual disease threshold defined in the 2008 International Workshop on CLL guidelines. The new assay, however, also was able to detect disease at the 0.0010% (one CLL cell in 1 million leukocytes) level.
The ability to detect disease below the levels that can be assessed by flow cytometry may prove to be a valuable resource to improve quantification of minimal residual disease and evaluate treatment response in CLL. Using minimal residual disease as a surrogate measure for treatment effectiveness would avoid the need for prolonged observation times in assessing new therapies, the researchers said (Leukemia 2016;30:929-36).
Dr. Rawstro disclosed receiving honoraria from Celgene, Abbvie, Gilead, Roche, and GSK. He receives royalty payments from BD Biosciences (Intrasure reagent) and study reagents. He is a consultant for Gilead and Biogen Idec.
On Twitter @maryjodales
Chronic lymphocytic leukemia cells can be identified at levels as low as 0.0010% with a newly developed and validated single-tube assay, Dr. Andy C. Rawstro of St. James’s Institute of Oncology, Leeds, England, and his colleagues said in a European Research Initiative on CLL (ERIC) project report in Leukemia.
The high-throughput sequencing assay consists of a core panel of six markers – CD19, CD20, CD5, CD43, CD79b and CD81 – with a component specification independent of instrument and reagents. The new assay eliminates the need to distribute the blood sample across multiple tubes, which can impair sensitivity in cases with poor cellularity. The assay can be locally revalidated using normal peripheral blood and can be used to investigate new markers.
The new assay was validated in a multicenter study of 128 samples from 108 patients with CLL or monoclonal B-cell lymphocytosis, studied either at diagnosis or after FCR-based (fludarabine, cyclophosphamide, rituximab) treatment and compared with peripheral blood samples from healthy young women. In a parallel analysis, the assay compared with flow cytometry results at the 0.010% level, the minimal residual disease threshold defined in the 2008 International Workshop on CLL guidelines. The new assay, however, also was able to detect disease at the 0.0010% (one CLL cell in 1 million leukocytes) level.
The ability to detect disease below the levels that can be assessed by flow cytometry may prove to be a valuable resource to improve quantification of minimal residual disease and evaluate treatment response in CLL. Using minimal residual disease as a surrogate measure for treatment effectiveness would avoid the need for prolonged observation times in assessing new therapies, the researchers said (Leukemia 2016;30:929-36).
Dr. Rawstro disclosed receiving honoraria from Celgene, Abbvie, Gilead, Roche, and GSK. He receives royalty payments from BD Biosciences (Intrasure reagent) and study reagents. He is a consultant for Gilead and Biogen Idec.
On Twitter @maryjodales
Chronic lymphocytic leukemia cells can be identified at levels as low as 0.0010% with a newly developed and validated single-tube assay, Dr. Andy C. Rawstro of St. James’s Institute of Oncology, Leeds, England, and his colleagues said in a European Research Initiative on CLL (ERIC) project report in Leukemia.
The high-throughput sequencing assay consists of a core panel of six markers – CD19, CD20, CD5, CD43, CD79b and CD81 – with a component specification independent of instrument and reagents. The new assay eliminates the need to distribute the blood sample across multiple tubes, which can impair sensitivity in cases with poor cellularity. The assay can be locally revalidated using normal peripheral blood and can be used to investigate new markers.
The new assay was validated in a multicenter study of 128 samples from 108 patients with CLL or monoclonal B-cell lymphocytosis, studied either at diagnosis or after FCR-based (fludarabine, cyclophosphamide, rituximab) treatment and compared with peripheral blood samples from healthy young women. In a parallel analysis, the assay compared with flow cytometry results at the 0.010% level, the minimal residual disease threshold defined in the 2008 International Workshop on CLL guidelines. The new assay, however, also was able to detect disease at the 0.0010% (one CLL cell in 1 million leukocytes) level.
The ability to detect disease below the levels that can be assessed by flow cytometry may prove to be a valuable resource to improve quantification of minimal residual disease and evaluate treatment response in CLL. Using minimal residual disease as a surrogate measure for treatment effectiveness would avoid the need for prolonged observation times in assessing new therapies, the researchers said (Leukemia 2016;30:929-36).
Dr. Rawstro disclosed receiving honoraria from Celgene, Abbvie, Gilead, Roche, and GSK. He receives royalty payments from BD Biosciences (Intrasure reagent) and study reagents. He is a consultant for Gilead and Biogen Idec.
On Twitter @maryjodales
FROM LEUKEMIA
Key clinical point: Chronic lymphocytic leukemia cells can be identified at levels as low as 0.0010% with a newly developed and validated single-tube assay.
Major finding: In a parallel analysis, the assay compared with flow cytometry results at the 0.010% level, and also was able to detect disease at the 0.0010% (one CLL cell in 1 million leukocytes) level.
Data source: The new assay was validated in a multicenter study of 128 samples from 108 patients with CLL or monoclonal B-cell lymphocytosis.
Disclosures: Dr. Rawstro disclosed receiving honoraria from Celgene, Abbvie, Gilead, Roche, and GSK. He receives royalty payments from BD Biosciences (Intrasure reagent) and study reagents. He is a consultant for Gilead and Biogen Idec.
VP Biden to AACR: Help me help you
Stronger teamwork among researchers, sharing data, and realignment of incentives for scientific breakthroughs, in addition to more funding, are key steps needed to advance cancer research, Vice President Joe Biden said during the annual meeting of the American Association for Cancer Research (AACR).
During a plenary speech to close the meeting, Vice President Biden praised the dedication of current cancer researchers and pledged to break down the walls that prevent them from achieving more progress in the field.
“I made a commitment that I will – as I gain this information and knowledge – I will eliminate the barriers that get in your way, get in the way of science and research and development,” he said. “I had to ... learn from all of you how we can proceed, how we can break down silos, how we can accommodate more rapidly the efforts you’re making.”
Vice President Biden, who is leading a new $1 billion initiative to eliminate cancer called “Moonshot,” outlined the top obstacles to cancer research he has garnered from recent visits with renowned cancer scientists and research leaders around the world. This includes a lack of unity among researchers, poor rewards for novel research, and limited data sharing, he said.
“The way the system now is set up, researchers are not incentivized to share their data,” Vice President Biden said, acknowledging that some medical experts are against the idea. “But every expert I’ve spoken to said you need to share these data to move this process rapidly.”
Involving patients earlier in clinical trials design is also a primary focus, he said. Patients should understand more about trials and be more open to signing up.
He noted the “incredible” research currently being conducted by various entities, such as AACR’s Project Genie, Orion Foundation, and The Parker Institute. Mr. Biden stressed however, that such efforts are too isolated.
“It raises [the] question: ‘Why is all this being done separately?’ ” Vice President Biden said. “Why is so much money being spent when if it’s aggregated, everyone acknowledges, the answers would come more quickly?”
Incentives for new research and the way in which funding is alloted must also be redesigned, he stressed. Today, it takes too long for researchers to get projects approved by the government and funding dispersed. He acknowledged the difficulty researchers face in obtaining grants and the fact that those who think “outside the box” are less likely to receive funding.
“It seems to me that we slow down our best minds by making them spend years in the lab before they can get their own grants and, when they do, they spend a third of their time writing a grant that takes months to be approved and awarded,” he said. “It’s like asking Derek Jeter to take several years off to sell bonds to build Yankee stadium.”
The Vice President did not purport to have all the answers, and asked those at the AARC meeting to provide feedback on his suggestions.
“The question I’d ask you to contemplate, because I’d like you to communicate with us, is, ‘Does it require realigning incentives; changing behaviors to take advantage of this inflection point? Does it require sharing more knowledge, treatment, and understanding? Or does that slow the process up?’ ”
He added,“I hope you all know it, but you’re one of the most valuable resources that our great country has, those of you sitting in this room. So ask your institutions, your colleagues, your mentors, your administrators: How can we move your ideas faster together in the interest of patients?”
The Vice President’s Moonshot initiative was announced during President Obama’s 2016 State of the Union Address. The effort includes a new Cancer Moonshot Task Force that will focus on federal investments, targeted incentives, private sector efforts from industry and philanthropy, patient engagement initiatives, and other mechanisms to support cancer research and enable progress in treatment and care, according to the White House. As part of the plan, the President’s fiscal 2017 budget proposes $755 million in mandatory funds for new cancer-related research activities at the National Institutes of Health and the Food and Drug Administration. The initiative also includes increased investments by the Department of Defense and the Department of Veterans Affairs in cancer research, including through funding centers of excellence focused on specific cancers and conducting longitudinal studies to determine risk factors and enhance treatment.
On Twitter @legal_med
Stronger teamwork among researchers, sharing data, and realignment of incentives for scientific breakthroughs, in addition to more funding, are key steps needed to advance cancer research, Vice President Joe Biden said during the annual meeting of the American Association for Cancer Research (AACR).
During a plenary speech to close the meeting, Vice President Biden praised the dedication of current cancer researchers and pledged to break down the walls that prevent them from achieving more progress in the field.
“I made a commitment that I will – as I gain this information and knowledge – I will eliminate the barriers that get in your way, get in the way of science and research and development,” he said. “I had to ... learn from all of you how we can proceed, how we can break down silos, how we can accommodate more rapidly the efforts you’re making.”
Vice President Biden, who is leading a new $1 billion initiative to eliminate cancer called “Moonshot,” outlined the top obstacles to cancer research he has garnered from recent visits with renowned cancer scientists and research leaders around the world. This includes a lack of unity among researchers, poor rewards for novel research, and limited data sharing, he said.
“The way the system now is set up, researchers are not incentivized to share their data,” Vice President Biden said, acknowledging that some medical experts are against the idea. “But every expert I’ve spoken to said you need to share these data to move this process rapidly.”
Involving patients earlier in clinical trials design is also a primary focus, he said. Patients should understand more about trials and be more open to signing up.
He noted the “incredible” research currently being conducted by various entities, such as AACR’s Project Genie, Orion Foundation, and The Parker Institute. Mr. Biden stressed however, that such efforts are too isolated.
“It raises [the] question: ‘Why is all this being done separately?’ ” Vice President Biden said. “Why is so much money being spent when if it’s aggregated, everyone acknowledges, the answers would come more quickly?”
Incentives for new research and the way in which funding is alloted must also be redesigned, he stressed. Today, it takes too long for researchers to get projects approved by the government and funding dispersed. He acknowledged the difficulty researchers face in obtaining grants and the fact that those who think “outside the box” are less likely to receive funding.
“It seems to me that we slow down our best minds by making them spend years in the lab before they can get their own grants and, when they do, they spend a third of their time writing a grant that takes months to be approved and awarded,” he said. “It’s like asking Derek Jeter to take several years off to sell bonds to build Yankee stadium.”
The Vice President did not purport to have all the answers, and asked those at the AARC meeting to provide feedback on his suggestions.
“The question I’d ask you to contemplate, because I’d like you to communicate with us, is, ‘Does it require realigning incentives; changing behaviors to take advantage of this inflection point? Does it require sharing more knowledge, treatment, and understanding? Or does that slow the process up?’ ”
He added,“I hope you all know it, but you’re one of the most valuable resources that our great country has, those of you sitting in this room. So ask your institutions, your colleagues, your mentors, your administrators: How can we move your ideas faster together in the interest of patients?”
The Vice President’s Moonshot initiative was announced during President Obama’s 2016 State of the Union Address. The effort includes a new Cancer Moonshot Task Force that will focus on federal investments, targeted incentives, private sector efforts from industry and philanthropy, patient engagement initiatives, and other mechanisms to support cancer research and enable progress in treatment and care, according to the White House. As part of the plan, the President’s fiscal 2017 budget proposes $755 million in mandatory funds for new cancer-related research activities at the National Institutes of Health and the Food and Drug Administration. The initiative also includes increased investments by the Department of Defense and the Department of Veterans Affairs in cancer research, including through funding centers of excellence focused on specific cancers and conducting longitudinal studies to determine risk factors and enhance treatment.
On Twitter @legal_med
Stronger teamwork among researchers, sharing data, and realignment of incentives for scientific breakthroughs, in addition to more funding, are key steps needed to advance cancer research, Vice President Joe Biden said during the annual meeting of the American Association for Cancer Research (AACR).
During a plenary speech to close the meeting, Vice President Biden praised the dedication of current cancer researchers and pledged to break down the walls that prevent them from achieving more progress in the field.
“I made a commitment that I will – as I gain this information and knowledge – I will eliminate the barriers that get in your way, get in the way of science and research and development,” he said. “I had to ... learn from all of you how we can proceed, how we can break down silos, how we can accommodate more rapidly the efforts you’re making.”
Vice President Biden, who is leading a new $1 billion initiative to eliminate cancer called “Moonshot,” outlined the top obstacles to cancer research he has garnered from recent visits with renowned cancer scientists and research leaders around the world. This includes a lack of unity among researchers, poor rewards for novel research, and limited data sharing, he said.
“The way the system now is set up, researchers are not incentivized to share their data,” Vice President Biden said, acknowledging that some medical experts are against the idea. “But every expert I’ve spoken to said you need to share these data to move this process rapidly.”
Involving patients earlier in clinical trials design is also a primary focus, he said. Patients should understand more about trials and be more open to signing up.
He noted the “incredible” research currently being conducted by various entities, such as AACR’s Project Genie, Orion Foundation, and The Parker Institute. Mr. Biden stressed however, that such efforts are too isolated.
“It raises [the] question: ‘Why is all this being done separately?’ ” Vice President Biden said. “Why is so much money being spent when if it’s aggregated, everyone acknowledges, the answers would come more quickly?”
Incentives for new research and the way in which funding is alloted must also be redesigned, he stressed. Today, it takes too long for researchers to get projects approved by the government and funding dispersed. He acknowledged the difficulty researchers face in obtaining grants and the fact that those who think “outside the box” are less likely to receive funding.
“It seems to me that we slow down our best minds by making them spend years in the lab before they can get their own grants and, when they do, they spend a third of their time writing a grant that takes months to be approved and awarded,” he said. “It’s like asking Derek Jeter to take several years off to sell bonds to build Yankee stadium.”
The Vice President did not purport to have all the answers, and asked those at the AARC meeting to provide feedback on his suggestions.
“The question I’d ask you to contemplate, because I’d like you to communicate with us, is, ‘Does it require realigning incentives; changing behaviors to take advantage of this inflection point? Does it require sharing more knowledge, treatment, and understanding? Or does that slow the process up?’ ”
He added,“I hope you all know it, but you’re one of the most valuable resources that our great country has, those of you sitting in this room. So ask your institutions, your colleagues, your mentors, your administrators: How can we move your ideas faster together in the interest of patients?”
The Vice President’s Moonshot initiative was announced during President Obama’s 2016 State of the Union Address. The effort includes a new Cancer Moonshot Task Force that will focus on federal investments, targeted incentives, private sector efforts from industry and philanthropy, patient engagement initiatives, and other mechanisms to support cancer research and enable progress in treatment and care, according to the White House. As part of the plan, the President’s fiscal 2017 budget proposes $755 million in mandatory funds for new cancer-related research activities at the National Institutes of Health and the Food and Drug Administration. The initiative also includes increased investments by the Department of Defense and the Department of Veterans Affairs in cancer research, including through funding centers of excellence focused on specific cancers and conducting longitudinal studies to determine risk factors and enhance treatment.
On Twitter @legal_med
FROM THE AACR ANNUAL MEETING
In newly diagnosed CLL, mutation tests are advised
Patients with newly diagnosed chronic lymphocytic leukemia should standardly undergo immunoglobulin heavy-chain variable region gene (IGHV) mutation status and interphase fluorescence in situ hybridization (FISH) tests, based on the results of a meta-analysis published in Blood.
“This change will help define the minimal standard initial prognostic evaluation for patients with CLL and help facilitate use of the powerful, recently developed, integrated prognostic indices, all of which are dependent on these 2 variables,” wrote Dr. Sameer A. Parikh of Mayo Clinic, Rochester, Minn., and associates.
IGHV and FISH have prognostic value independent of clinical stage in patients with newly diagnosed and previously untreated CLL, they said (Blood. 2016;127[14]:1752-60). Better understanding of the patient’s risk of disease progression at diagnosis can guide counseling and follow-up intervals, and could potentially influence the decision to treat high-risk patients on early intervention protocols.
IGHV and FISH also appear to provide additional information on progression-free and overall survival.
The researchers cautioned, however, that the results of these tests should not be used to initiate CLL-specific therapy. Only patients who meet indications for therapy based on the 2008 International Workshop on Chronic Lymphocytic Leukemia guidelines should receive treatment.
Further, they noted, the median age of patients included in studies that they analyzed was 64 years; the median age of patients with CLL is 72 years. The prognostic abilities of IGHV mutation and FISH may differ in these older individuals with CLL.
The researchers analyzed 31 studies that met the criteria for inclusion – full-length publications that included at least 200 patients and reported on the prognostic value of IGHV and/or FISH for predicting progression-free or overall survival in patients with newly diagnosed CLL.
They found that the median progression-free survival (range, about 1-5 years) was significantly shorter for patients with unmutated IGHV genes, than was the median progression-free survival (range, about 9-19 years) for those with mutated IGHV genes. Similarly, the median overall survival was significantly shorter for patients with unmutated IGHV (range, about 3-10 years) than for those with mutated IGHV (range, about 18-26 years).
For patients with high-risk FISH (including del17p13 and del11q23), the median progression-free survival was significantly shorter (range, about 0.1-5 years) than for those with low/intermediate-risk FISH (including del13q, normal, and trisomy 12; range, about 1.5-22 years). Median overall survival also significantly differed, ranging from about 3-10 years for patients with high-risk FISH and from about 7.5-20.5 years for those with low/intermediate-risk FISH.
In multivariable analyses, the hazard ratio for high-risk FISH ranged from 1.3 to 4.7 for progression-free survival and from 0.9 to 8.2 for overall survival. In studies reporting the results of multivariable analysis, high-risk FISH remained an independent predictor of progression-free survival in 8 of 17 studies and of overall survival in 10 of 14 studies, including in 10 of 13 studies adjusting for the prognostic impact of IGHV.
In multivariable analyses, IGHV remained an independent predictor of progression-free survival in 15 of 18 studies, including 12 of 15 studies adjusting for the prognostic impact of FISH. IGHV remained an independent predictor of overall survival in 11 of 15 studies reporting the results of multivariable analysis, including 10 of 14 studies adjusting for the prognostic impact of FISH.
Patients with newly diagnosed chronic lymphocytic leukemia should standardly undergo immunoglobulin heavy-chain variable region gene (IGHV) mutation status and interphase fluorescence in situ hybridization (FISH) tests, based on the results of a meta-analysis published in Blood.
“This change will help define the minimal standard initial prognostic evaluation for patients with CLL and help facilitate use of the powerful, recently developed, integrated prognostic indices, all of which are dependent on these 2 variables,” wrote Dr. Sameer A. Parikh of Mayo Clinic, Rochester, Minn., and associates.
IGHV and FISH have prognostic value independent of clinical stage in patients with newly diagnosed and previously untreated CLL, they said (Blood. 2016;127[14]:1752-60). Better understanding of the patient’s risk of disease progression at diagnosis can guide counseling and follow-up intervals, and could potentially influence the decision to treat high-risk patients on early intervention protocols.
IGHV and FISH also appear to provide additional information on progression-free and overall survival.
The researchers cautioned, however, that the results of these tests should not be used to initiate CLL-specific therapy. Only patients who meet indications for therapy based on the 2008 International Workshop on Chronic Lymphocytic Leukemia guidelines should receive treatment.
Further, they noted, the median age of patients included in studies that they analyzed was 64 years; the median age of patients with CLL is 72 years. The prognostic abilities of IGHV mutation and FISH may differ in these older individuals with CLL.
The researchers analyzed 31 studies that met the criteria for inclusion – full-length publications that included at least 200 patients and reported on the prognostic value of IGHV and/or FISH for predicting progression-free or overall survival in patients with newly diagnosed CLL.
They found that the median progression-free survival (range, about 1-5 years) was significantly shorter for patients with unmutated IGHV genes, than was the median progression-free survival (range, about 9-19 years) for those with mutated IGHV genes. Similarly, the median overall survival was significantly shorter for patients with unmutated IGHV (range, about 3-10 years) than for those with mutated IGHV (range, about 18-26 years).
For patients with high-risk FISH (including del17p13 and del11q23), the median progression-free survival was significantly shorter (range, about 0.1-5 years) than for those with low/intermediate-risk FISH (including del13q, normal, and trisomy 12; range, about 1.5-22 years). Median overall survival also significantly differed, ranging from about 3-10 years for patients with high-risk FISH and from about 7.5-20.5 years for those with low/intermediate-risk FISH.
In multivariable analyses, the hazard ratio for high-risk FISH ranged from 1.3 to 4.7 for progression-free survival and from 0.9 to 8.2 for overall survival. In studies reporting the results of multivariable analysis, high-risk FISH remained an independent predictor of progression-free survival in 8 of 17 studies and of overall survival in 10 of 14 studies, including in 10 of 13 studies adjusting for the prognostic impact of IGHV.
In multivariable analyses, IGHV remained an independent predictor of progression-free survival in 15 of 18 studies, including 12 of 15 studies adjusting for the prognostic impact of FISH. IGHV remained an independent predictor of overall survival in 11 of 15 studies reporting the results of multivariable analysis, including 10 of 14 studies adjusting for the prognostic impact of FISH.
Patients with newly diagnosed chronic lymphocytic leukemia should standardly undergo immunoglobulin heavy-chain variable region gene (IGHV) mutation status and interphase fluorescence in situ hybridization (FISH) tests, based on the results of a meta-analysis published in Blood.
“This change will help define the minimal standard initial prognostic evaluation for patients with CLL and help facilitate use of the powerful, recently developed, integrated prognostic indices, all of which are dependent on these 2 variables,” wrote Dr. Sameer A. Parikh of Mayo Clinic, Rochester, Minn., and associates.
IGHV and FISH have prognostic value independent of clinical stage in patients with newly diagnosed and previously untreated CLL, they said (Blood. 2016;127[14]:1752-60). Better understanding of the patient’s risk of disease progression at diagnosis can guide counseling and follow-up intervals, and could potentially influence the decision to treat high-risk patients on early intervention protocols.
IGHV and FISH also appear to provide additional information on progression-free and overall survival.
The researchers cautioned, however, that the results of these tests should not be used to initiate CLL-specific therapy. Only patients who meet indications for therapy based on the 2008 International Workshop on Chronic Lymphocytic Leukemia guidelines should receive treatment.
Further, they noted, the median age of patients included in studies that they analyzed was 64 years; the median age of patients with CLL is 72 years. The prognostic abilities of IGHV mutation and FISH may differ in these older individuals with CLL.
The researchers analyzed 31 studies that met the criteria for inclusion – full-length publications that included at least 200 patients and reported on the prognostic value of IGHV and/or FISH for predicting progression-free or overall survival in patients with newly diagnosed CLL.
They found that the median progression-free survival (range, about 1-5 years) was significantly shorter for patients with unmutated IGHV genes, than was the median progression-free survival (range, about 9-19 years) for those with mutated IGHV genes. Similarly, the median overall survival was significantly shorter for patients with unmutated IGHV (range, about 3-10 years) than for those with mutated IGHV (range, about 18-26 years).
For patients with high-risk FISH (including del17p13 and del11q23), the median progression-free survival was significantly shorter (range, about 0.1-5 years) than for those with low/intermediate-risk FISH (including del13q, normal, and trisomy 12; range, about 1.5-22 years). Median overall survival also significantly differed, ranging from about 3-10 years for patients with high-risk FISH and from about 7.5-20.5 years for those with low/intermediate-risk FISH.
In multivariable analyses, the hazard ratio for high-risk FISH ranged from 1.3 to 4.7 for progression-free survival and from 0.9 to 8.2 for overall survival. In studies reporting the results of multivariable analysis, high-risk FISH remained an independent predictor of progression-free survival in 8 of 17 studies and of overall survival in 10 of 14 studies, including in 10 of 13 studies adjusting for the prognostic impact of IGHV.
In multivariable analyses, IGHV remained an independent predictor of progression-free survival in 15 of 18 studies, including 12 of 15 studies adjusting for the prognostic impact of FISH. IGHV remained an independent predictor of overall survival in 11 of 15 studies reporting the results of multivariable analysis, including 10 of 14 studies adjusting for the prognostic impact of FISH.
FROM BLOOD
