Lymphoma & Plasma Cell Disorders

An artificial intelligence (AI) diagnostic system based on neural networks may assist in the diagnosis of COVID-19, according to a pilot study.

The system, called CXR-Net, was trained to differentiate SARS-CoV-2 chest x-rays (CXRs) from CXRs that are either normal or non–COVID-19 lung pathologies, explained Abdulah Haikal, an MD candidate at Wayne State University, Detroit.

Mr. Haikal described CXR-Net at the AACR Virtual Meeting: COVID-19 and Cancer (Abstract S11-04).

CXR-Net is a two-module pipeline, Mr. Haikal explained. Module I is based on Res-CR-Net, a type of neural network originally designed for the semantic segmentation of microscopy images, with the ability to retain the original resolution of the input images in the feature maps of all layers and in the final output.

Module II is a hybrid convolutional neural network in which the first convolutional layer with learned coefficients is replaced by a layer with fixed coefficients provided by the Wavelet Scattering Transform. Module II inputs patients’ CXRs and corresponding lung masks quantified by Module I, and generates as outputs a class assignment (COVID-19 or non–COVID-19) and high-resolution heat maps that detect the severe acute respiratory syndrome–-associated lung regions.

“The system is trained to differentiate COVID and non-COVID pathologies and produces a highly discriminative heat map to point to lung regions where COVID is suspected,” Mr. Haikal said. “The Wavelet Scattering Transform allows for fast determination of COVID versus non-COVID CXRs.”
 

Preliminary results and implications

CXR-Net was piloted on a small dataset of CXRs from non–COVID-19 and polymerase chain reaction–confirmed COVID-19 patients acquired at a single center in Detroit.

Upon fivefold cross validation of the training set with 2,265 images, 90% accuracy was observed when the training set was tested against the validation set. However, once 1,532 new images were introduced, a 76% accuracy rate was observed.

The F1 scores were 0.81 and 0.70 for the training and test sets, respectively.

“I’m really excited about this new approach, and I think AI will allow us to do more with less, which is exciting,” said Ross L. Levine, MD, of Memorial Sloan Kettering Cancer Center in New York, who led a discussion session with Mr. Haikal about CXR-Net.

One question raised during the discussion was whether the technology will help health care providers be more thoughtful about when and how they image COVID-19 patients.

“The more data you feed into the system, the stronger and more accurate it becomes,” Mr. Haikal said. “However, until we have data sharing from multiple centers, we won’t see improved accuracy results.”

Another question was whether this technology could be integrated with more clinical parameters.

“Some individuals are afraid that AI will replace the job of a professional, but it will only make it better for us,” Mr. Haikal said. “We don’t rely on current imaging techniques to make a definitive diagnosis, but rather have a specificity and sensitivity to establish a diagnosis, and AI can be used in the same way as a diagnostic tool.”

Mr. Haikal and Dr. Levine disclosed no conflicts of interest. No funding sources were reported in the presentation.

An artificial intelligence (AI) diagnostic system based on neural networks may assist in the diagnosis of COVID-19, according to a pilot study.

The system, called CXR-Net, was trained to differentiate SARS-CoV-2 chest x-rays (CXRs) from CXRs that are either normal or non–COVID-19 lung pathologies, explained Abdulah Haikal, an MD candidate at Wayne State University, Detroit.

Mr. Haikal described CXR-Net at the AACR Virtual Meeting: COVID-19 and Cancer (Abstract S11-04).

CXR-Net is a two-module pipeline, Mr. Haikal explained. Module I is based on Res-CR-Net, a type of neural network originally designed for the semantic segmentation of microscopy images, with the ability to retain the original resolution of the input images in the feature maps of all layers and in the final output.

Module II is a hybrid convolutional neural network in which the first convolutional layer with learned coefficients is replaced by a layer with fixed coefficients provided by the Wavelet Scattering Transform. Module II inputs patients’ CXRs and corresponding lung masks quantified by Module I, and generates as outputs a class assignment (COVID-19 or non–COVID-19) and high-resolution heat maps that detect the severe acute respiratory syndrome–-associated lung regions.

“The system is trained to differentiate COVID and non-COVID pathologies and produces a highly discriminative heat map to point to lung regions where COVID is suspected,” Mr. Haikal said. “The Wavelet Scattering Transform allows for fast determination of COVID versus non-COVID CXRs.”
 

Preliminary results and implications

CXR-Net was piloted on a small dataset of CXRs from non–COVID-19 and polymerase chain reaction–confirmed COVID-19 patients acquired at a single center in Detroit.

Upon fivefold cross validation of the training set with 2,265 images, 90% accuracy was observed when the training set was tested against the validation set. However, once 1,532 new images were introduced, a 76% accuracy rate was observed.

The F1 scores were 0.81 and 0.70 for the training and test sets, respectively.

“I’m really excited about this new approach, and I think AI will allow us to do more with less, which is exciting,” said Ross L. Levine, MD, of Memorial Sloan Kettering Cancer Center in New York, who led a discussion session with Mr. Haikal about CXR-Net.

One question raised during the discussion was whether the technology will help health care providers be more thoughtful about when and how they image COVID-19 patients.

“The more data you feed into the system, the stronger and more accurate it becomes,” Mr. Haikal said. “However, until we have data sharing from multiple centers, we won’t see improved accuracy results.”

Another question was whether this technology could be integrated with more clinical parameters.

“Some individuals are afraid that AI will replace the job of a professional, but it will only make it better for us,” Mr. Haikal said. “We don’t rely on current imaging techniques to make a definitive diagnosis, but rather have a specificity and sensitivity to establish a diagnosis, and AI can be used in the same way as a diagnostic tool.”

Mr. Haikal and Dr. Levine disclosed no conflicts of interest. No funding sources were reported in the presentation.

An artificial intelligence (AI) diagnostic system based on neural networks may assist in the diagnosis of COVID-19, according to a pilot study.

The system, called CXR-Net, was trained to differentiate SARS-CoV-2 chest x-rays (CXRs) from CXRs that are either normal or non–COVID-19 lung pathologies, explained Abdulah Haikal, an MD candidate at Wayne State University, Detroit.

Mr. Haikal described CXR-Net at the AACR Virtual Meeting: COVID-19 and Cancer (Abstract S11-04).

CXR-Net is a two-module pipeline, Mr. Haikal explained. Module I is based on Res-CR-Net, a type of neural network originally designed for the semantic segmentation of microscopy images, with the ability to retain the original resolution of the input images in the feature maps of all layers and in the final output.

Module II is a hybrid convolutional neural network in which the first convolutional layer with learned coefficients is replaced by a layer with fixed coefficients provided by the Wavelet Scattering Transform. Module II inputs patients’ CXRs and corresponding lung masks quantified by Module I, and generates as outputs a class assignment (COVID-19 or non–COVID-19) and high-resolution heat maps that detect the severe acute respiratory syndrome–-associated lung regions.

“The system is trained to differentiate COVID and non-COVID pathologies and produces a highly discriminative heat map to point to lung regions where COVID is suspected,” Mr. Haikal said. “The Wavelet Scattering Transform allows for fast determination of COVID versus non-COVID CXRs.”
 

Preliminary results and implications

CXR-Net was piloted on a small dataset of CXRs from non–COVID-19 and polymerase chain reaction–confirmed COVID-19 patients acquired at a single center in Detroit.

Upon fivefold cross validation of the training set with 2,265 images, 90% accuracy was observed when the training set was tested against the validation set. However, once 1,532 new images were introduced, a 76% accuracy rate was observed.

The F1 scores were 0.81 and 0.70 for the training and test sets, respectively.

“I’m really excited about this new approach, and I think AI will allow us to do more with less, which is exciting,” said Ross L. Levine, MD, of Memorial Sloan Kettering Cancer Center in New York, who led a discussion session with Mr. Haikal about CXR-Net.

One question raised during the discussion was whether the technology will help health care providers be more thoughtful about when and how they image COVID-19 patients.

“The more data you feed into the system, the stronger and more accurate it becomes,” Mr. Haikal said. “However, until we have data sharing from multiple centers, we won’t see improved accuracy results.”

Another question was whether this technology could be integrated with more clinical parameters.

“Some individuals are afraid that AI will replace the job of a professional, but it will only make it better for us,” Mr. Haikal said. “We don’t rely on current imaging techniques to make a definitive diagnosis, but rather have a specificity and sensitivity to establish a diagnosis, and AI can be used in the same way as a diagnostic tool.”

Mr. Haikal and Dr. Levine disclosed no conflicts of interest. No funding sources were reported in the presentation.

The Food and Drug Administration has approved lisocabtagene maraleucel (Breyanzi), a chimeric antigen receptor (CAR) T-cell product for the treatment of adults with certain types of relapsed or refractory large B-cell lymphoma who relapse or fail to respond to at least two systemic treatments.

The new approval comes with a risk evaluation and mitigation strategy (REMS) because of the risk for serious adverse events, including cytokine release syndrome (CRS).

The product, from Juno Therapeutics, a Bristol Myers Squibb company, is the third gene therapy to receive FDA approval for non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). DLBCL is the most common type of non-Hodgkin lymphoma in adults, accounting for about a third of the approximately 77,000 cases diagnosed each year in the United States.

The FDA previously granted Breyanzi orphan drug, regenerative medicine advanced therapy (RMAT), and breakthrough therapy designations. The product is the first therapy with an RMAT designation to be licensed by the agency.

The new approval is based on efficacy and safety demonstrated in a pivotal phase 1 trial of more than 250 adults with relapsed or refractory large B-cell lymphoma. The complete remission rate after treatment with Breyanzi was 54%. 

“Treatment with Breyanzi has the potential to cause severe side effects. The labeling carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T cells, causing high fever and flu-like symptoms and neurologic toxicities,” the FDA explained. “Both CRS and neurological events can be life-threatening.”

Other side effects, which typically present within 1-2 weeks after treatment, include hypersensitivity reactions, serious infections, low blood cell counts, and a weakened immune system, but some side effects may occur later.

The REMS requires special certification for facilities that dispense the product and “specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion – and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Breyanzi,” the FDA noted.

Breyanzi is not indicated for patients with primary central nervous system lymphoma, the FDA noted.

Facility certification involves training to recognize and manage the risks of CRS and neurologic toxicities.

A postmarketing study to further evaluate the long-term safety will also be required.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved lisocabtagene maraleucel (Breyanzi), a chimeric antigen receptor (CAR) T-cell product for the treatment of adults with certain types of relapsed or refractory large B-cell lymphoma who relapse or fail to respond to at least two systemic treatments.

The new approval comes with a risk evaluation and mitigation strategy (REMS) because of the risk for serious adverse events, including cytokine release syndrome (CRS).

The product, from Juno Therapeutics, a Bristol Myers Squibb company, is the third gene therapy to receive FDA approval for non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). DLBCL is the most common type of non-Hodgkin lymphoma in adults, accounting for about a third of the approximately 77,000 cases diagnosed each year in the United States.

The FDA previously granted Breyanzi orphan drug, regenerative medicine advanced therapy (RMAT), and breakthrough therapy designations. The product is the first therapy with an RMAT designation to be licensed by the agency.

The new approval is based on efficacy and safety demonstrated in a pivotal phase 1 trial of more than 250 adults with relapsed or refractory large B-cell lymphoma. The complete remission rate after treatment with Breyanzi was 54%. 

“Treatment with Breyanzi has the potential to cause severe side effects. The labeling carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T cells, causing high fever and flu-like symptoms and neurologic toxicities,” the FDA explained. “Both CRS and neurological events can be life-threatening.”

Other side effects, which typically present within 1-2 weeks after treatment, include hypersensitivity reactions, serious infections, low blood cell counts, and a weakened immune system, but some side effects may occur later.

The REMS requires special certification for facilities that dispense the product and “specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion – and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Breyanzi,” the FDA noted.

Breyanzi is not indicated for patients with primary central nervous system lymphoma, the FDA noted.

Facility certification involves training to recognize and manage the risks of CRS and neurologic toxicities.

A postmarketing study to further evaluate the long-term safety will also be required.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved lisocabtagene maraleucel (Breyanzi), a chimeric antigen receptor (CAR) T-cell product for the treatment of adults with certain types of relapsed or refractory large B-cell lymphoma who relapse or fail to respond to at least two systemic treatments.

The new approval comes with a risk evaluation and mitigation strategy (REMS) because of the risk for serious adverse events, including cytokine release syndrome (CRS).

The product, from Juno Therapeutics, a Bristol Myers Squibb company, is the third gene therapy to receive FDA approval for non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). DLBCL is the most common type of non-Hodgkin lymphoma in adults, accounting for about a third of the approximately 77,000 cases diagnosed each year in the United States.

The FDA previously granted Breyanzi orphan drug, regenerative medicine advanced therapy (RMAT), and breakthrough therapy designations. The product is the first therapy with an RMAT designation to be licensed by the agency.

The new approval is based on efficacy and safety demonstrated in a pivotal phase 1 trial of more than 250 adults with relapsed or refractory large B-cell lymphoma. The complete remission rate after treatment with Breyanzi was 54%. 

“Treatment with Breyanzi has the potential to cause severe side effects. The labeling carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T cells, causing high fever and flu-like symptoms and neurologic toxicities,” the FDA explained. “Both CRS and neurological events can be life-threatening.”

Other side effects, which typically present within 1-2 weeks after treatment, include hypersensitivity reactions, serious infections, low blood cell counts, and a weakened immune system, but some side effects may occur later.

The REMS requires special certification for facilities that dispense the product and “specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion – and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Breyanzi,” the FDA noted.

Breyanzi is not indicated for patients with primary central nervous system lymphoma, the FDA noted.

Facility certification involves training to recognize and manage the risks of CRS and neurologic toxicities.

A postmarketing study to further evaluate the long-term safety will also be required.

A version of this article first appeared on Medscape.com.

All patients receiving active cancer treatment should receive a COVID-19 vaccine and should be prioritized for vaccination, according to preliminary recommendations from the National Comprehensive Cancer Network (NCCN).

Vaccination timing considerations vary based on factors such as cancer and treatment type, and reasons for delaying vaccination in the general public also apply to cancer patients (recent COVID-19 exposure, for example).

In general, however, patients with cancer should be assigned to Centers for Disease Control and Prevention priority group 1 b/c and immunized when vaccination is available to them, the guidelines state. Exceptions to this recommendation include:

• Patients undergoing hematopoietic stem cell transplant or receiving engineered cellular therapy such as chimeric antigen receptor T-cell therapy. Vaccination should be delayed for at least 3 months in these patients to maximize vaccine efficacy. Caregivers of these patients, however, should be immunized when possible.
• Patients with hematologic malignancies who are receiving intensive cytotoxic chemotherapy, such as cytarabine- or anthracycline-based regimens for acute myeloid leukemia. Vaccination in these patients should be delayed until absolute neutrophil count recovery.
• Patients undergoing major surgery. Vaccination should occur at least a few days before or after surgery.
• Patients who have experienced a severe or immediate adverse reaction to any of the ingredients in the mRNA COVID-19 vaccines.

Conversely, vaccination should occur when available in patients with hematologic malignancies and marrow failure who are expected to have limited or no recovery, patients with hematologic malignancies who are on long-term maintenance therapy, and patients with solid tumors who are receiving cytotoxic chemotherapy, targeted therapy, checkpoint inhibitors and other immunotherapy, or radiotherapy.

Caregivers, household contacts, and other close contacts who are 16 years of age and older should be vaccinated whenever they are eligible.
 

Unique concerns in patients with cancer

The NCCN recommendations were developed to address the unique issues and concerns with respect to patients with cancer, who have an increased risk of severe illness from SARS-CoV-2 infection. But the guidelines come with a caveat: “[t]here are limited safety and efficacy data in these patients,” the NCCN emphasized in a press statement.

“Right now, there is urgent need and limited data,” Steven Pergam, MD, co-leader of the NCCN COVID-19 Vaccination Committee, said in the statement.

“Our number one goal is helping to get the vaccine to as many people as we can,” Dr. Pergam said. “That means following existing national and regional directions for prioritizing people who are more likely to face death or severe illness from COVID-19.”

Dr. Pergam, associate professor at Fred Hutchinson Cancer Research Center in Seattle, further explained that “people receiving active cancer treatment are at greater risk for worse outcomes from COVID-19, particularly if they are older and have additional comorbidities, like immunosuppression.”

NCCN’s recommendations couldn’t have come at a better time for patients with cancer, according to Nora Disis, MD, a professor at the University of Washington in Seattle.

“The NCCN’s recommendations to prioritize COVID vaccinations for cancer patients on active treatment is an important step forward in protecting our patients from the infection,” Dr. Disis said in an interview.

“Cancer patients may be at higher risk for the complications seen with infection. In addition, cancer is a disease of older people, and a good number of our patients have the comorbidities that would predict a poorer outcome if they should become sick,” Dr. Disis added. “With the correct treatment, many patients with cancer will be long-term survivors. It is important that they be protected from infection with COVID to realize their best outcome.”
 

Additional vaccine considerations

The NCCN recommendations also address several other issues of importance for cancer patients, including:

• Deprioritizing other vaccines. COVID-19 vaccines should take precedence over other vaccines because data on dual vaccination are lacking. The NCCN recommends waiting 14 days after COVID-19 vaccination to deliver other vaccines.
• Vaccinating clinical trial participants. Trial leads should be consulted to prevent protocol violations or exclusions.
• Decision-making in the setting of limited vaccine availability. The NCCN noted that decisions on allocation must be made in accordance with state and local vaccine guidance but suggests prioritizing appropriate patients on active treatment, those planning to start treatment, and those who have just completed treatment. Additional risk factors for these patients, as well as other factors associated with risk for adverse COVID-19 outcomes, should also be considered. These include advanced age, comorbidities, and adverse social and demographic factors such as poverty and limited health care access.
• The need for ongoing prevention measures. Vaccines have been shown to decrease the incidence of COVID-19 and related complications, but it remains unclear whether vaccines prevent infection and subsequent transmission. This means everyone should continue following prevention recommendations, such as wearing masks and avoiding crowds.

The NCCN stressed that these recommendations are “intended to be a living document that is constantly evolving – it will be updated rapidly whenever new data comes out, as well as any potential new vaccines that may get approved in the future.” The NCCN also noted that the advisory committee will meet regularly to refine the recommendations as needed.

Dr. Pergam disclosed relationships with Chimerix Inc., Merck & Co., Global Life Technologies Inc., and Sanofi-Aventis. Dr. Disis disclosed grants from Pfizer, Bavarian Nordisk, Janssen, and Precigen. She is the founder of EpiThany and editor-in-chief of JAMA Oncology.

[email protected]

All patients receiving active cancer treatment should receive a COVID-19 vaccine and should be prioritized for vaccination, according to preliminary recommendations from the National Comprehensive Cancer Network (NCCN).

Vaccination timing considerations vary based on factors such as cancer and treatment type, and reasons for delaying vaccination in the general public also apply to cancer patients (recent COVID-19 exposure, for example).

In general, however, patients with cancer should be assigned to Centers for Disease Control and Prevention priority group 1 b/c and immunized when vaccination is available to them, the guidelines state. Exceptions to this recommendation include:

• Patients undergoing hematopoietic stem cell transplant or receiving engineered cellular therapy such as chimeric antigen receptor T-cell therapy. Vaccination should be delayed for at least 3 months in these patients to maximize vaccine efficacy. Caregivers of these patients, however, should be immunized when possible.
• Patients with hematologic malignancies who are receiving intensive cytotoxic chemotherapy, such as cytarabine- or anthracycline-based regimens for acute myeloid leukemia. Vaccination in these patients should be delayed until absolute neutrophil count recovery.
• Patients undergoing major surgery. Vaccination should occur at least a few days before or after surgery.
• Patients who have experienced a severe or immediate adverse reaction to any of the ingredients in the mRNA COVID-19 vaccines.

Conversely, vaccination should occur when available in patients with hematologic malignancies and marrow failure who are expected to have limited or no recovery, patients with hematologic malignancies who are on long-term maintenance therapy, and patients with solid tumors who are receiving cytotoxic chemotherapy, targeted therapy, checkpoint inhibitors and other immunotherapy, or radiotherapy.

Caregivers, household contacts, and other close contacts who are 16 years of age and older should be vaccinated whenever they are eligible.
 

Unique concerns in patients with cancer

The NCCN recommendations were developed to address the unique issues and concerns with respect to patients with cancer, who have an increased risk of severe illness from SARS-CoV-2 infection. But the guidelines come with a caveat: “[t]here are limited safety and efficacy data in these patients,” the NCCN emphasized in a press statement.

“Right now, there is urgent need and limited data,” Steven Pergam, MD, co-leader of the NCCN COVID-19 Vaccination Committee, said in the statement.

“Our number one goal is helping to get the vaccine to as many people as we can,” Dr. Pergam said. “That means following existing national and regional directions for prioritizing people who are more likely to face death or severe illness from COVID-19.”

Dr. Pergam, associate professor at Fred Hutchinson Cancer Research Center in Seattle, further explained that “people receiving active cancer treatment are at greater risk for worse outcomes from COVID-19, particularly if they are older and have additional comorbidities, like immunosuppression.”

NCCN’s recommendations couldn’t have come at a better time for patients with cancer, according to Nora Disis, MD, a professor at the University of Washington in Seattle.

“The NCCN’s recommendations to prioritize COVID vaccinations for cancer patients on active treatment is an important step forward in protecting our patients from the infection,” Dr. Disis said in an interview.

“Cancer patients may be at higher risk for the complications seen with infection. In addition, cancer is a disease of older people, and a good number of our patients have the comorbidities that would predict a poorer outcome if they should become sick,” Dr. Disis added. “With the correct treatment, many patients with cancer will be long-term survivors. It is important that they be protected from infection with COVID to realize their best outcome.”
 

Additional vaccine considerations

The NCCN recommendations also address several other issues of importance for cancer patients, including:

• Deprioritizing other vaccines. COVID-19 vaccines should take precedence over other vaccines because data on dual vaccination are lacking. The NCCN recommends waiting 14 days after COVID-19 vaccination to deliver other vaccines.
• Vaccinating clinical trial participants. Trial leads should be consulted to prevent protocol violations or exclusions.
• Decision-making in the setting of limited vaccine availability. The NCCN noted that decisions on allocation must be made in accordance with state and local vaccine guidance but suggests prioritizing appropriate patients on active treatment, those planning to start treatment, and those who have just completed treatment. Additional risk factors for these patients, as well as other factors associated with risk for adverse COVID-19 outcomes, should also be considered. These include advanced age, comorbidities, and adverse social and demographic factors such as poverty and limited health care access.
• The need for ongoing prevention measures. Vaccines have been shown to decrease the incidence of COVID-19 and related complications, but it remains unclear whether vaccines prevent infection and subsequent transmission. This means everyone should continue following prevention recommendations, such as wearing masks and avoiding crowds.

The NCCN stressed that these recommendations are “intended to be a living document that is constantly evolving – it will be updated rapidly whenever new data comes out, as well as any potential new vaccines that may get approved in the future.” The NCCN also noted that the advisory committee will meet regularly to refine the recommendations as needed.

Dr. Pergam disclosed relationships with Chimerix Inc., Merck & Co., Global Life Technologies Inc., and Sanofi-Aventis. Dr. Disis disclosed grants from Pfizer, Bavarian Nordisk, Janssen, and Precigen. She is the founder of EpiThany and editor-in-chief of JAMA Oncology.

[email protected]

All patients receiving active cancer treatment should receive a COVID-19 vaccine and should be prioritized for vaccination, according to preliminary recommendations from the National Comprehensive Cancer Network (NCCN).

Vaccination timing considerations vary based on factors such as cancer and treatment type, and reasons for delaying vaccination in the general public also apply to cancer patients (recent COVID-19 exposure, for example).

In general, however, patients with cancer should be assigned to Centers for Disease Control and Prevention priority group 1 b/c and immunized when vaccination is available to them, the guidelines state. Exceptions to this recommendation include:

• Patients undergoing hematopoietic stem cell transplant or receiving engineered cellular therapy such as chimeric antigen receptor T-cell therapy. Vaccination should be delayed for at least 3 months in these patients to maximize vaccine efficacy. Caregivers of these patients, however, should be immunized when possible.
• Patients with hematologic malignancies who are receiving intensive cytotoxic chemotherapy, such as cytarabine- or anthracycline-based regimens for acute myeloid leukemia. Vaccination in these patients should be delayed until absolute neutrophil count recovery.
• Patients undergoing major surgery. Vaccination should occur at least a few days before or after surgery.
• Patients who have experienced a severe or immediate adverse reaction to any of the ingredients in the mRNA COVID-19 vaccines.

Conversely, vaccination should occur when available in patients with hematologic malignancies and marrow failure who are expected to have limited or no recovery, patients with hematologic malignancies who are on long-term maintenance therapy, and patients with solid tumors who are receiving cytotoxic chemotherapy, targeted therapy, checkpoint inhibitors and other immunotherapy, or radiotherapy.

Caregivers, household contacts, and other close contacts who are 16 years of age and older should be vaccinated whenever they are eligible.
 

Unique concerns in patients with cancer

The NCCN recommendations were developed to address the unique issues and concerns with respect to patients with cancer, who have an increased risk of severe illness from SARS-CoV-2 infection. But the guidelines come with a caveat: “[t]here are limited safety and efficacy data in these patients,” the NCCN emphasized in a press statement.

“Right now, there is urgent need and limited data,” Steven Pergam, MD, co-leader of the NCCN COVID-19 Vaccination Committee, said in the statement.

“Our number one goal is helping to get the vaccine to as many people as we can,” Dr. Pergam said. “That means following existing national and regional directions for prioritizing people who are more likely to face death or severe illness from COVID-19.”

Dr. Pergam, associate professor at Fred Hutchinson Cancer Research Center in Seattle, further explained that “people receiving active cancer treatment are at greater risk for worse outcomes from COVID-19, particularly if they are older and have additional comorbidities, like immunosuppression.”

NCCN’s recommendations couldn’t have come at a better time for patients with cancer, according to Nora Disis, MD, a professor at the University of Washington in Seattle.

“The NCCN’s recommendations to prioritize COVID vaccinations for cancer patients on active treatment is an important step forward in protecting our patients from the infection,” Dr. Disis said in an interview.

“Cancer patients may be at higher risk for the complications seen with infection. In addition, cancer is a disease of older people, and a good number of our patients have the comorbidities that would predict a poorer outcome if they should become sick,” Dr. Disis added. “With the correct treatment, many patients with cancer will be long-term survivors. It is important that they be protected from infection with COVID to realize their best outcome.”
 

Additional vaccine considerations

The NCCN recommendations also address several other issues of importance for cancer patients, including:

• Deprioritizing other vaccines. COVID-19 vaccines should take precedence over other vaccines because data on dual vaccination are lacking. The NCCN recommends waiting 14 days after COVID-19 vaccination to deliver other vaccines.
• Vaccinating clinical trial participants. Trial leads should be consulted to prevent protocol violations or exclusions.
• Decision-making in the setting of limited vaccine availability. The NCCN noted that decisions on allocation must be made in accordance with state and local vaccine guidance but suggests prioritizing appropriate patients on active treatment, those planning to start treatment, and those who have just completed treatment. Additional risk factors for these patients, as well as other factors associated with risk for adverse COVID-19 outcomes, should also be considered. These include advanced age, comorbidities, and adverse social and demographic factors such as poverty and limited health care access.
• The need for ongoing prevention measures. Vaccines have been shown to decrease the incidence of COVID-19 and related complications, but it remains unclear whether vaccines prevent infection and subsequent transmission. This means everyone should continue following prevention recommendations, such as wearing masks and avoiding crowds.

The NCCN stressed that these recommendations are “intended to be a living document that is constantly evolving – it will be updated rapidly whenever new data comes out, as well as any potential new vaccines that may get approved in the future.” The NCCN also noted that the advisory committee will meet regularly to refine the recommendations as needed.

Dr. Pergam disclosed relationships with Chimerix Inc., Merck & Co., Global Life Technologies Inc., and Sanofi-Aventis. Dr. Disis disclosed grants from Pfizer, Bavarian Nordisk, Janssen, and Precigen. She is the founder of EpiThany and editor-in-chief of JAMA Oncology.

[email protected]

A model that crunches data from routine blood tests can accurately identify cancer patients who will develop acute kidney injury (AKI) up to a month before it happens, according to a cohort study.

The algorithm spotted nearly 74% of the patients who went on to develop AKI within 30 days, providing a window for intervention and possibly prevention, according to investigators.

These results were reported at the AACR Virtual Special Conference: Artificial Intelligence, Diagnosis, and Imaging (abstract PR-11).

“Cancer patients are a high-risk population for AKI due to the nature of their treatment and illness,” said presenter Lauren A. Scanlon, PhD, a data scientist at The Christie NHS Foundation Trust in Huddersfield, England. “AKI causes a huge disruption in treatment and distress for the patient, so it would be amazing if we could, say, predict the AKI before it occurs and prevent it from even happening.”

U.K. health care providers are already using an algorithm to monitor patients’ creatinine levels, comparing new values against historic ones, Dr. Scanlon explained. When that algorithm detects AKI, it issues an alert that triggers implementation of an AKI care bundle, including measures such as fluid monitoring and medication review, within 24 hours.

Taking this concept further, Dr. Scanlon and colleagues developed a random forest model, a type of machine learning algorithm, that incorporates other markers from blood tests routinely obtained for all patients, with the aim of predicting AKI up to 30 days in advance.

“Using routinely collected blood test results will ensure that the model is applicable to all our patients and can be implemented in an automated manner,” Dr. Scanlon noted.

The investigators developed and trained the model using 597,403 blood test results from 48,865 patients undergoing cancer treatment between January 2017 and May 2020.

The model assigns patients to five categories of risk for AKI in the next 30 days: very low, low, medium, high, and very high.

“We wanted the model to output in this way so that it could be used by clinicians alongside their own insight and knowledge on a case-by-case basis,” Dr. Scanlon explained.

The investigators then prospectively validated the model and its risk categories in another 9,913 patients who underwent cancer treatment between June and August 2020.

Using a model threshold of medium risk or higher, the model correctly predicted AKI in 330 (73.8%) of the 447 patients in the validation cohort who ultimately developed AKI.

“This is pretty amazing and shows that this model really is working and can correctly detect these AKIs up to 30 days before they occur, giving a huge window to put in place preventive strategies,” Dr. Scanlon said.

Among the 154 patients in whom the model incorrectly predicted AKI, 9 patients had only a single follow-up blood test and 17 patients did not have any, leaving their actual outcomes unclear.

“Given that AKI detection uses blood tests, an AKI in these patients was never confirmed,” Dr. Scanlon noted. “So this could give a potential benefit of the model that we never intended: It could reduce undiagnosed AKI by flagging those who are at risk.”

“Our next steps are to test the model through a technology clinical trial to see if putting intervention strategies in place does prevent these AKIs from taking place,” Dr. Scanlon concluded. “We are also going to move to ongoing monitoring of the model performance.”

Dr. Scanlon disclosed no conflicts of interest. The study did not receive specific funding.

A model that crunches data from routine blood tests can accurately identify cancer patients who will develop acute kidney injury (AKI) up to a month before it happens, according to a cohort study.

The algorithm spotted nearly 74% of the patients who went on to develop AKI within 30 days, providing a window for intervention and possibly prevention, according to investigators.

These results were reported at the AACR Virtual Special Conference: Artificial Intelligence, Diagnosis, and Imaging (abstract PR-11).

“Cancer patients are a high-risk population for AKI due to the nature of their treatment and illness,” said presenter Lauren A. Scanlon, PhD, a data scientist at The Christie NHS Foundation Trust in Huddersfield, England. “AKI causes a huge disruption in treatment and distress for the patient, so it would be amazing if we could, say, predict the AKI before it occurs and prevent it from even happening.”

U.K. health care providers are already using an algorithm to monitor patients’ creatinine levels, comparing new values against historic ones, Dr. Scanlon explained. When that algorithm detects AKI, it issues an alert that triggers implementation of an AKI care bundle, including measures such as fluid monitoring and medication review, within 24 hours.

Taking this concept further, Dr. Scanlon and colleagues developed a random forest model, a type of machine learning algorithm, that incorporates other markers from blood tests routinely obtained for all patients, with the aim of predicting AKI up to 30 days in advance.

“Using routinely collected blood test results will ensure that the model is applicable to all our patients and can be implemented in an automated manner,” Dr. Scanlon noted.

The investigators developed and trained the model using 597,403 blood test results from 48,865 patients undergoing cancer treatment between January 2017 and May 2020.

The model assigns patients to five categories of risk for AKI in the next 30 days: very low, low, medium, high, and very high.

“We wanted the model to output in this way so that it could be used by clinicians alongside their own insight and knowledge on a case-by-case basis,” Dr. Scanlon explained.

The investigators then prospectively validated the model and its risk categories in another 9,913 patients who underwent cancer treatment between June and August 2020.

Using a model threshold of medium risk or higher, the model correctly predicted AKI in 330 (73.8%) of the 447 patients in the validation cohort who ultimately developed AKI.

“This is pretty amazing and shows that this model really is working and can correctly detect these AKIs up to 30 days before they occur, giving a huge window to put in place preventive strategies,” Dr. Scanlon said.

Among the 154 patients in whom the model incorrectly predicted AKI, 9 patients had only a single follow-up blood test and 17 patients did not have any, leaving their actual outcomes unclear.

“Given that AKI detection uses blood tests, an AKI in these patients was never confirmed,” Dr. Scanlon noted. “So this could give a potential benefit of the model that we never intended: It could reduce undiagnosed AKI by flagging those who are at risk.”

“Our next steps are to test the model through a technology clinical trial to see if putting intervention strategies in place does prevent these AKIs from taking place,” Dr. Scanlon concluded. “We are also going to move to ongoing monitoring of the model performance.”

Dr. Scanlon disclosed no conflicts of interest. The study did not receive specific funding.

A model that crunches data from routine blood tests can accurately identify cancer patients who will develop acute kidney injury (AKI) up to a month before it happens, according to a cohort study.

The algorithm spotted nearly 74% of the patients who went on to develop AKI within 30 days, providing a window for intervention and possibly prevention, according to investigators.

These results were reported at the AACR Virtual Special Conference: Artificial Intelligence, Diagnosis, and Imaging (abstract PR-11).

“Cancer patients are a high-risk population for AKI due to the nature of their treatment and illness,” said presenter Lauren A. Scanlon, PhD, a data scientist at The Christie NHS Foundation Trust in Huddersfield, England. “AKI causes a huge disruption in treatment and distress for the patient, so it would be amazing if we could, say, predict the AKI before it occurs and prevent it from even happening.”

U.K. health care providers are already using an algorithm to monitor patients’ creatinine levels, comparing new values against historic ones, Dr. Scanlon explained. When that algorithm detects AKI, it issues an alert that triggers implementation of an AKI care bundle, including measures such as fluid monitoring and medication review, within 24 hours.

Taking this concept further, Dr. Scanlon and colleagues developed a random forest model, a type of machine learning algorithm, that incorporates other markers from blood tests routinely obtained for all patients, with the aim of predicting AKI up to 30 days in advance.

“Using routinely collected blood test results will ensure that the model is applicable to all our patients and can be implemented in an automated manner,” Dr. Scanlon noted.

The investigators developed and trained the model using 597,403 blood test results from 48,865 patients undergoing cancer treatment between January 2017 and May 2020.

The model assigns patients to five categories of risk for AKI in the next 30 days: very low, low, medium, high, and very high.

“We wanted the model to output in this way so that it could be used by clinicians alongside their own insight and knowledge on a case-by-case basis,” Dr. Scanlon explained.

The investigators then prospectively validated the model and its risk categories in another 9,913 patients who underwent cancer treatment between June and August 2020.

Using a model threshold of medium risk or higher, the model correctly predicted AKI in 330 (73.8%) of the 447 patients in the validation cohort who ultimately developed AKI.

“This is pretty amazing and shows that this model really is working and can correctly detect these AKIs up to 30 days before they occur, giving a huge window to put in place preventive strategies,” Dr. Scanlon said.

Among the 154 patients in whom the model incorrectly predicted AKI, 9 patients had only a single follow-up blood test and 17 patients did not have any, leaving their actual outcomes unclear.

“Given that AKI detection uses blood tests, an AKI in these patients was never confirmed,” Dr. Scanlon noted. “So this could give a potential benefit of the model that we never intended: It could reduce undiagnosed AKI by flagging those who are at risk.”

“Our next steps are to test the model through a technology clinical trial to see if putting intervention strategies in place does prevent these AKIs from taking place,” Dr. Scanlon concluded. “We are also going to move to ongoing monitoring of the model performance.”

Dr. Scanlon disclosed no conflicts of interest. The study did not receive specific funding.

Earlier this week, Medscape spoke with Nora Disis, MD, about vaccinating cancer patients. Disis is a medical oncologist and director of both the Institute of Translational Health Sciences and the Cancer Vaccine Institute, the University of Washington, Seattle, Washington. As editor-in-chief of JAMA Oncology, she has watched COVID-19 developments in the oncology community over the past year.

Here are a few themes that Disis said oncologists should be aware of as vaccines eventually begin reaching cancer patients.

We should expect cancer patients to respond to vaccines. Historically, some believed that cancer patients would be unable to mount an immune response to vaccines. Data on other viral vaccines have shown otherwise. For example, there has been a long history of studies of flu vaccination in cancer patients, and in general, those vaccines confer protection. Likewise for pneumococcal vaccine, which, generally speaking, cancer patients should receive.

Special cases may include hematologic malignancies in which the immune system has been destroyed and profound immunosuppression occurs. Data on immunization during this immunosuppressed period are scarce, but what data are available suggest that once cancer patients are through this immunosuppressed period, they can be vaccinated successfully.

The type of vaccine will probably be important for cancer patients. Currently, there are 61 coronavirus vaccines in human clinical trials, and 17 have reached the final stages of testing. At least 85 preclinical vaccines are under active investigation in animals.

Both the Pfizer-BioNTech and Moderna COVID vaccines are mRNA type. There are many other types, including protein-based vaccines, viral vector vaccines based on adenoviruses, and inactivated or attenuated coronavirus vaccines.

The latter vaccines, particularly attenuated live virus vaccines, may not be a good choice for cancer patients. Especially in those with rapidly progressing disease or on chemotherapy, attenuated live viruses may cause a low-grade infection.

Incidentally, the technology used in the genetic, or mRNA, vaccines developed by both Pfizer-BioNTech and Moderna was initially developed for fighting cancer, and studies have shown that patients can generate immune responses to cancer-associated proteins with this type of vaccine.

These genetic vaccines could turn out to be the most effective for cancer patients, especially those with solid tumors.

Our understanding is very limited right now. Neither the Pfizer-BioNTech nor the Moderna early data discuss cancer patients. Two of the most important questions for cancer patients are dosing and booster scheduling. Potential defects in lymphocyte function among cancer patients may require unique initial dosing and booster schedules. In terms of timing, it is unclear how active therapy might affect a patient’s immune response to vaccination and whether vaccines should be timed with therapy cycles.

Vaccine access may depend on whether cancer patients are viewed as a vulnerable population. Those at higher risk for severe COVID-19 clearly have a greater need for vaccination. While there are data suggesting that cancer patients are at higher risk, they are a bit murky, in part because cancer patients are a heterogeneous group. For example, there are data suggesting that lung and blood cancer patients fare worse. There is also a suggestion that, like in the general population, COVID risk in cancer patients remains driven by comorbidities.

It is likely, then, that personalized risk factors such as type of cancer therapy, site of disease, and comorbidities will shape individual choices about vaccination among cancer patients.

A version of this article first appeared on Medscape.com.

Earlier this week, Medscape spoke with Nora Disis, MD, about vaccinating cancer patients. Disis is a medical oncologist and director of both the Institute of Translational Health Sciences and the Cancer Vaccine Institute, the University of Washington, Seattle, Washington. As editor-in-chief of JAMA Oncology, she has watched COVID-19 developments in the oncology community over the past year.

Here are a few themes that Disis said oncologists should be aware of as vaccines eventually begin reaching cancer patients.

We should expect cancer patients to respond to vaccines. Historically, some believed that cancer patients would be unable to mount an immune response to vaccines. Data on other viral vaccines have shown otherwise. For example, there has been a long history of studies of flu vaccination in cancer patients, and in general, those vaccines confer protection. Likewise for pneumococcal vaccine, which, generally speaking, cancer patients should receive.

Special cases may include hematologic malignancies in which the immune system has been destroyed and profound immunosuppression occurs. Data on immunization during this immunosuppressed period are scarce, but what data are available suggest that once cancer patients are through this immunosuppressed period, they can be vaccinated successfully.

The type of vaccine will probably be important for cancer patients. Currently, there are 61 coronavirus vaccines in human clinical trials, and 17 have reached the final stages of testing. At least 85 preclinical vaccines are under active investigation in animals.

Both the Pfizer-BioNTech and Moderna COVID vaccines are mRNA type. There are many other types, including protein-based vaccines, viral vector vaccines based on adenoviruses, and inactivated or attenuated coronavirus vaccines.

The latter vaccines, particularly attenuated live virus vaccines, may not be a good choice for cancer patients. Especially in those with rapidly progressing disease or on chemotherapy, attenuated live viruses may cause a low-grade infection.

Incidentally, the technology used in the genetic, or mRNA, vaccines developed by both Pfizer-BioNTech and Moderna was initially developed for fighting cancer, and studies have shown that patients can generate immune responses to cancer-associated proteins with this type of vaccine.

These genetic vaccines could turn out to be the most effective for cancer patients, especially those with solid tumors.

Our understanding is very limited right now. Neither the Pfizer-BioNTech nor the Moderna early data discuss cancer patients. Two of the most important questions for cancer patients are dosing and booster scheduling. Potential defects in lymphocyte function among cancer patients may require unique initial dosing and booster schedules. In terms of timing, it is unclear how active therapy might affect a patient’s immune response to vaccination and whether vaccines should be timed with therapy cycles.

Vaccine access may depend on whether cancer patients are viewed as a vulnerable population. Those at higher risk for severe COVID-19 clearly have a greater need for vaccination. While there are data suggesting that cancer patients are at higher risk, they are a bit murky, in part because cancer patients are a heterogeneous group. For example, there are data suggesting that lung and blood cancer patients fare worse. There is also a suggestion that, like in the general population, COVID risk in cancer patients remains driven by comorbidities.

It is likely, then, that personalized risk factors such as type of cancer therapy, site of disease, and comorbidities will shape individual choices about vaccination among cancer patients.

A version of this article first appeared on Medscape.com.

Earlier this week, Medscape spoke with Nora Disis, MD, about vaccinating cancer patients. Disis is a medical oncologist and director of both the Institute of Translational Health Sciences and the Cancer Vaccine Institute, the University of Washington, Seattle, Washington. As editor-in-chief of JAMA Oncology, she has watched COVID-19 developments in the oncology community over the past year.

Here are a few themes that Disis said oncologists should be aware of as vaccines eventually begin reaching cancer patients.

We should expect cancer patients to respond to vaccines. Historically, some believed that cancer patients would be unable to mount an immune response to vaccines. Data on other viral vaccines have shown otherwise. For example, there has been a long history of studies of flu vaccination in cancer patients, and in general, those vaccines confer protection. Likewise for pneumococcal vaccine, which, generally speaking, cancer patients should receive.

Special cases may include hematologic malignancies in which the immune system has been destroyed and profound immunosuppression occurs. Data on immunization during this immunosuppressed period are scarce, but what data are available suggest that once cancer patients are through this immunosuppressed period, they can be vaccinated successfully.

The type of vaccine will probably be important for cancer patients. Currently, there are 61 coronavirus vaccines in human clinical trials, and 17 have reached the final stages of testing. At least 85 preclinical vaccines are under active investigation in animals.

Both the Pfizer-BioNTech and Moderna COVID vaccines are mRNA type. There are many other types, including protein-based vaccines, viral vector vaccines based on adenoviruses, and inactivated or attenuated coronavirus vaccines.

The latter vaccines, particularly attenuated live virus vaccines, may not be a good choice for cancer patients. Especially in those with rapidly progressing disease or on chemotherapy, attenuated live viruses may cause a low-grade infection.

Incidentally, the technology used in the genetic, or mRNA, vaccines developed by both Pfizer-BioNTech and Moderna was initially developed for fighting cancer, and studies have shown that patients can generate immune responses to cancer-associated proteins with this type of vaccine.

These genetic vaccines could turn out to be the most effective for cancer patients, especially those with solid tumors.

Our understanding is very limited right now. Neither the Pfizer-BioNTech nor the Moderna early data discuss cancer patients. Two of the most important questions for cancer patients are dosing and booster scheduling. Potential defects in lymphocyte function among cancer patients may require unique initial dosing and booster schedules. In terms of timing, it is unclear how active therapy might affect a patient’s immune response to vaccination and whether vaccines should be timed with therapy cycles.

Vaccine access may depend on whether cancer patients are viewed as a vulnerable population. Those at higher risk for severe COVID-19 clearly have a greater need for vaccination. While there are data suggesting that cancer patients are at higher risk, they are a bit murky, in part because cancer patients are a heterogeneous group. For example, there are data suggesting that lung and blood cancer patients fare worse. There is also a suggestion that, like in the general population, COVID risk in cancer patients remains driven by comorbidities.

It is likely, then, that personalized risk factors such as type of cancer therapy, site of disease, and comorbidities will shape individual choices about vaccination among cancer patients.

A version of this article first appeared on Medscape.com.

Tending to patients who opt for outpatient autologous stem cell transplants is well tolerated by caregivers, so long as they have the resources and support necessary, according to a recent Italian report.

Investigators surveyed the primary caregivers – most often the spouse – of 25 multiple myeloma patients who, in consultation with their caregiver, opted for an outpatient procedure and 71 others who chose standard inpatient treatment, and compared the results. Outpatients were discharged a day after transplant with twice-weekly clinic visits until sustained hematologic recovery as reported in Clinical Lymphoma, Myeloma and Leukemia.

The teams used portions of the Caregiver Reaction Assessment survey that focused on self-reported sense of family support plus affect on daily activities and general health. Surveys were taken a week before transplant and 3 months afterwards.

Results did not differ significantly between outpatient and inpatient caregivers at either point, and there was no meaningful change in responses over time.

“The outpatient model neither improves nor impairs global caregivers’ burden, compared with” inpatient transplant. Outpatient caregivers “do not show that they suffer from a greater burden of responsibility as compared to those belonging to the inpatient’s arm,” said investigators led by Massimo Martino, MD, director of stem cell transplants at the Great Metropolitan Hospital in Reggio Calabria, Italy, where the patients were treated.

The relatively short-lasting neutropenia and the limited nonhematologic toxicity of high-dose melphalan make multiple myeloma good candidates for outpatient programs. Indeed, the incidence rate of mucositis, fever, chemotherapy-induced nausea and vomiting, and other adverse events did not differ between in and outpatients, which is in keeping with previous reports supporting the feasibility and safety of outpatient programs.

However, the burden on loved ones is considerable. At least during the aplastic phase, outpatient caregivers are on call around the clock and spend most of their time with the patient. Homes have to be kept meticulously clean, vital signs checked, medications administered, and ins and outs monitored, among other duties normally handled by inpatient staff.

The main limit of the study was that outpatients were a self-selected group. They and their caregivers may simply have had the resources and support needed for successful outpatient transplants, while other patients did not. As the investigators put it, “we cannot exclude the problem of residual confounding due to unmeasured variables” such as “factors underlying patients’ preference, which could potentially impact the study results.”

Administering the follow-up survey 3 months after transplant might also have missed the acute impact on outpatient caregivers. It’s been “reported that the quality of life of patients undergoing an” outpatient procedure decreases immediately post treatment but bounces back by 6 months. “The same result can probably be observed in caregivers,” the team said.

The outpatient and inpatient groups were comparable, with a majority of men and a mean age of about 60 years in both. The number of infused stem cells, engraftment kinetics, and hematopoietic cell transplantation–comorbidity index scores did not differ significantly between the two groups.

There was no funding for the work, and the investigators reported that they didn’t have any conflicts of interest.

[email protected]

SOURCE: Martino M et al. Clin Lymphoma Myeloma Leuk. 2020 Nov 19. doi: 10.1016/j.clml.2020.11.011.

Tending to patients who opt for outpatient autologous stem cell transplants is well tolerated by caregivers, so long as they have the resources and support necessary, according to a recent Italian report.

Investigators surveyed the primary caregivers – most often the spouse – of 25 multiple myeloma patients who, in consultation with their caregiver, opted for an outpatient procedure and 71 others who chose standard inpatient treatment, and compared the results. Outpatients were discharged a day after transplant with twice-weekly clinic visits until sustained hematologic recovery as reported in Clinical Lymphoma, Myeloma and Leukemia.

The teams used portions of the Caregiver Reaction Assessment survey that focused on self-reported sense of family support plus affect on daily activities and general health. Surveys were taken a week before transplant and 3 months afterwards.

Results did not differ significantly between outpatient and inpatient caregivers at either point, and there was no meaningful change in responses over time.

“The outpatient model neither improves nor impairs global caregivers’ burden, compared with” inpatient transplant. Outpatient caregivers “do not show that they suffer from a greater burden of responsibility as compared to those belonging to the inpatient’s arm,” said investigators led by Massimo Martino, MD, director of stem cell transplants at the Great Metropolitan Hospital in Reggio Calabria, Italy, where the patients were treated.

The relatively short-lasting neutropenia and the limited nonhematologic toxicity of high-dose melphalan make multiple myeloma good candidates for outpatient programs. Indeed, the incidence rate of mucositis, fever, chemotherapy-induced nausea and vomiting, and other adverse events did not differ between in and outpatients, which is in keeping with previous reports supporting the feasibility and safety of outpatient programs.

However, the burden on loved ones is considerable. At least during the aplastic phase, outpatient caregivers are on call around the clock and spend most of their time with the patient. Homes have to be kept meticulously clean, vital signs checked, medications administered, and ins and outs monitored, among other duties normally handled by inpatient staff.

The main limit of the study was that outpatients were a self-selected group. They and their caregivers may simply have had the resources and support needed for successful outpatient transplants, while other patients did not. As the investigators put it, “we cannot exclude the problem of residual confounding due to unmeasured variables” such as “factors underlying patients’ preference, which could potentially impact the study results.”

Administering the follow-up survey 3 months after transplant might also have missed the acute impact on outpatient caregivers. It’s been “reported that the quality of life of patients undergoing an” outpatient procedure decreases immediately post treatment but bounces back by 6 months. “The same result can probably be observed in caregivers,” the team said.

The outpatient and inpatient groups were comparable, with a majority of men and a mean age of about 60 years in both. The number of infused stem cells, engraftment kinetics, and hematopoietic cell transplantation–comorbidity index scores did not differ significantly between the two groups.

There was no funding for the work, and the investigators reported that they didn’t have any conflicts of interest.

[email protected]

SOURCE: Martino M et al. Clin Lymphoma Myeloma Leuk. 2020 Nov 19. doi: 10.1016/j.clml.2020.11.011.

Tending to patients who opt for outpatient autologous stem cell transplants is well tolerated by caregivers, so long as they have the resources and support necessary, according to a recent Italian report.

Investigators surveyed the primary caregivers – most often the spouse – of 25 multiple myeloma patients who, in consultation with their caregiver, opted for an outpatient procedure and 71 others who chose standard inpatient treatment, and compared the results. Outpatients were discharged a day after transplant with twice-weekly clinic visits until sustained hematologic recovery as reported in Clinical Lymphoma, Myeloma and Leukemia.

The teams used portions of the Caregiver Reaction Assessment survey that focused on self-reported sense of family support plus affect on daily activities and general health. Surveys were taken a week before transplant and 3 months afterwards.

Results did not differ significantly between outpatient and inpatient caregivers at either point, and there was no meaningful change in responses over time.

“The outpatient model neither improves nor impairs global caregivers’ burden, compared with” inpatient transplant. Outpatient caregivers “do not show that they suffer from a greater burden of responsibility as compared to those belonging to the inpatient’s arm,” said investigators led by Massimo Martino, MD, director of stem cell transplants at the Great Metropolitan Hospital in Reggio Calabria, Italy, where the patients were treated.

The relatively short-lasting neutropenia and the limited nonhematologic toxicity of high-dose melphalan make multiple myeloma good candidates for outpatient programs. Indeed, the incidence rate of mucositis, fever, chemotherapy-induced nausea and vomiting, and other adverse events did not differ between in and outpatients, which is in keeping with previous reports supporting the feasibility and safety of outpatient programs.

However, the burden on loved ones is considerable. At least during the aplastic phase, outpatient caregivers are on call around the clock and spend most of their time with the patient. Homes have to be kept meticulously clean, vital signs checked, medications administered, and ins and outs monitored, among other duties normally handled by inpatient staff.

The main limit of the study was that outpatients were a self-selected group. They and their caregivers may simply have had the resources and support needed for successful outpatient transplants, while other patients did not. As the investigators put it, “we cannot exclude the problem of residual confounding due to unmeasured variables” such as “factors underlying patients’ preference, which could potentially impact the study results.”

Administering the follow-up survey 3 months after transplant might also have missed the acute impact on outpatient caregivers. It’s been “reported that the quality of life of patients undergoing an” outpatient procedure decreases immediately post treatment but bounces back by 6 months. “The same result can probably be observed in caregivers,” the team said.

The outpatient and inpatient groups were comparable, with a majority of men and a mean age of about 60 years in both. The number of infused stem cells, engraftment kinetics, and hematopoietic cell transplantation–comorbidity index scores did not differ significantly between the two groups.

There was no funding for the work, and the investigators reported that they didn’t have any conflicts of interest.

[email protected]

SOURCE: Martino M et al. Clin Lymphoma Myeloma Leuk. 2020 Nov 19. doi: 10.1016/j.clml.2020.11.011.

The investigational drug asciminib (being developed by Novartis) may become the new kid on the block for the treatment of chronic phase chronic myeloid leukemia (CMP-CP) for patients who have relapsed on or are refractory to at least two prior tyrosine kinase inhibitors (TKIs).

New results from the ASCEMBL study (NCT03106779) show that patients who received asciminib, which works differently from currently approved therapies for CML-CP, achieved better responses, compared with bosutinib (Bosulif) as third-line therapy.

“The ASCEMBL study opens a new chapter for CML, proving comparatively superior efficacy and excellent safety for a new class of ABL inhibitors,” coinvestigator Michael J. Mauro, MD, from Memorial Sloan Kettering Cancer Center, New York, said in an interview.

The trial was presented as a late-breaking abstract at the annual meeting of the American Society of Hematology.

Asciminib is a first-of-a-kind STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor that works differently from currently approved TKIs, which are adenosine triphosphate (ATP)-–competitive ABL inhibitors.

Five TKIs have been approved by the Food and Drug Administration to treat CML: imatinib (Gleevec; generics), nilotinib (Tasigna), dasatinib (Sprycel), bosutinib, and ponatinib (Iclusig).

All of them inhibit BCR/ABL tyrosine kinase by binding to the ATP-binding pocket.

Most patients with TKI resistant disease develop mutations in the ATP-binding pocket, explained Michael Jay Styler, MD, associate professor at Fox Chase–Temple University Hospital bone marrow transplant program, Fox Chase Cancer Center, Philadelphia.

By inactivating the protein through binding outside the ATP site, asciminib is a novel BCR-ABL inhibitor and may be a superior alternative to further traditional TKIs. “This agent promises to be an important addition to our treatment armamentarium for CML,” Dr. Styler said in an interview.

Another expert agreed. “Although we have many excellent therapies for CML, having a new medication that targets BCR-ABL in a novel way is still welcome to help us better care for CML patients,” Gabriela S. Hobbs, MD, said in an interview. Dr. Hobbs is the clinical director of leukemia services at Boston’s Mass General Cancer Center.

Patients in this study had previously been receiving at least two different types of TKIs. “The responses looked very encouraging for this group of heavily pretreated patients. Although CML patients do very well on current therapies, those that don’t get a response with TKI remain a difficult clinical challenge,” Dr. Hobbs said.

“This is the first study comparing asciminib to a TKI directly (in this case bosutinib) and it showed safety as well as preliminary evidence of efficacy. I look forward to seeing additional studies with this promising drug and to have a new drug to add to the CML arsenal,” she added.
 

Identifying patients who will benefit from asciminib

Patients with CML are currently sequenced through more than one second-generation TKI, Dr. Mauro commented. “If imatinib and a second-generation TKI have not served a patient well, only bosutinib has been studied in the third line and comparatively in the ASCEMBL study.” Asciminib was shown to be superior and could offer a clear alternative to ponatinib, which would be the other choice and is typically given even later after sequencing all other available options.

Dr. Hobbs agreed. “This is a challenging group of patients to manage as their options are limited. Ponatinib is often the drug of choice in these scenarios, as well as bone marrow transplant.”

Asciminib is not approved yet, but both Dr. Mauro and Dr. Hobbs are hopeful it will be by early next year, and that initial approval is likely in patients with CML-CP after several (two or three) lines of therapy. They also agreed that it may be effective (alone or in combination) in treating patients with T315I-mutation CML, which is a particularly challenging disease.

Senior study author Andreas Hochhaus, MD, of the Klinik für Innere Medizin II in Jena, Germany, who presented the data at the meeting, noted new trials to test the efficacy of asciminib alone or in combination in earlier lines of therapy are ongoing and include the investigator-initiated FASCINATION study (first-line asciminib in combination) in Germany (NCT03906292).
 

ASCEMBL study details

ASCEMBL is a phase 3 study in which patients with CML who had received at least two previous TKIs were randomized to asciminib (n = 157) 40 mg twice daily or bosutinib (n = 76) 500 mg once daily. In a protocol amendment, patients with documented failure on bosutinib were allowed to switch to asciminib.

The main reason for discontinuing the last TKI therapy was lack of efficacy in approximately two-thirds of patients. More patients in the asciminib than the bosutinib group received two prior lines of therapy (52% vs. 40%); the others had received three or more prior lines of therapy.

Median follow-up for the data cutoff was 14.9 months.

Dr. Hochhaus reported that treatment discontinuation was lower in patients receiving asciminib than bosutinib (38% vs. 70%) and was mostly due to lack of efficacy (21% vs. 32%) or adverse events (5% vs. 21%).

The study met its primary endpoint: major molecular response (MMR) was approximately twice as high with asciminib than bosutinib at 24 weeks (25.5% vs. 13.2%; P = .029). Treatment effect for MMR was 12.2%. Median duration of exposure to asciminib was 43.4 weeks for asciminib and 29.2 weeks for bosutinib.

“Consistent treatment effect was seen across all subgroups of patients, and MMR rates were consistently high for patients on asciminib across all prior lines of therapy,” Dr. Hochhaus reported.

The probability of achieving MMR at 24 weeks was higher for patients receiving asciminib (25% vs. 11.9%) and started at week 12, he noted. Complete cytogenetic response was also higher for patients receiving asciminib (40.8% vs. 24.2%).

The occurrence of grade 3 or higher adverse events was lower with asciminib than bosutinib (51% vs. 61%). Thrombocytopenia and neutropenia were more common with asciminib and gastrointestinal events were more common with bosutinib. Arterial occlusion events were reported in five patients receiving asciminib and one patient receiving bosutinib. Most of these patients had prior exposure to imatinib, nilotinib, and/or dasatinib.

Dr. Mauro, a coinvestigator of the phase 3 study, also treated patients with the drug in the phase 1 study. “I feel asciminib has proven to be very well tolerated, with rare to absent cases of intolerance,” he said. Cardiovascular and cardiopulmonary adverse events are exceedingly rare as well.

Longer follow-up of the ASCEMBL study and continued follow-up of the myriad of groups from the phase 1 trial (T315I-positive patients treated with higher-dose asciminib, combination therapy with imatinib/nilotinib/dasatinib plus asciminib, and others) will be essential to settle any questions regarding selective adverse events of interest such as vascular occlusion, Dr. Mauro noted.

Dr. Hochhaus has reported receiving research funding from Novartis, Incyte, Pfizer, and Bristol-Myers Squibb. Dr. Hobbs has reported serving on advisory boards for Novartis. Dr. Mauro has reported financial relationships with Bristol-Myers Squibb, Novartis, Takeda, Pfizer, and Sun Pharma/SPARC.

A version of this article first appeared on Medscape.com.

The investigational drug asciminib (being developed by Novartis) may become the new kid on the block for the treatment of chronic phase chronic myeloid leukemia (CMP-CP) for patients who have relapsed on or are refractory to at least two prior tyrosine kinase inhibitors (TKIs).

New results from the ASCEMBL study (NCT03106779) show that patients who received asciminib, which works differently from currently approved therapies for CML-CP, achieved better responses, compared with bosutinib (Bosulif) as third-line therapy.

“The ASCEMBL study opens a new chapter for CML, proving comparatively superior efficacy and excellent safety for a new class of ABL inhibitors,” coinvestigator Michael J. Mauro, MD, from Memorial Sloan Kettering Cancer Center, New York, said in an interview.

The trial was presented as a late-breaking abstract at the annual meeting of the American Society of Hematology.

Asciminib is a first-of-a-kind STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor that works differently from currently approved TKIs, which are adenosine triphosphate (ATP)-–competitive ABL inhibitors.

Five TKIs have been approved by the Food and Drug Administration to treat CML: imatinib (Gleevec; generics), nilotinib (Tasigna), dasatinib (Sprycel), bosutinib, and ponatinib (Iclusig).

All of them inhibit BCR/ABL tyrosine kinase by binding to the ATP-binding pocket.

Most patients with TKI resistant disease develop mutations in the ATP-binding pocket, explained Michael Jay Styler, MD, associate professor at Fox Chase–Temple University Hospital bone marrow transplant program, Fox Chase Cancer Center, Philadelphia.

By inactivating the protein through binding outside the ATP site, asciminib is a novel BCR-ABL inhibitor and may be a superior alternative to further traditional TKIs. “This agent promises to be an important addition to our treatment armamentarium for CML,” Dr. Styler said in an interview.

Another expert agreed. “Although we have many excellent therapies for CML, having a new medication that targets BCR-ABL in a novel way is still welcome to help us better care for CML patients,” Gabriela S. Hobbs, MD, said in an interview. Dr. Hobbs is the clinical director of leukemia services at Boston’s Mass General Cancer Center.

Patients in this study had previously been receiving at least two different types of TKIs. “The responses looked very encouraging for this group of heavily pretreated patients. Although CML patients do very well on current therapies, those that don’t get a response with TKI remain a difficult clinical challenge,” Dr. Hobbs said.

“This is the first study comparing asciminib to a TKI directly (in this case bosutinib) and it showed safety as well as preliminary evidence of efficacy. I look forward to seeing additional studies with this promising drug and to have a new drug to add to the CML arsenal,” she added.
 

Identifying patients who will benefit from asciminib

Patients with CML are currently sequenced through more than one second-generation TKI, Dr. Mauro commented. “If imatinib and a second-generation TKI have not served a patient well, only bosutinib has been studied in the third line and comparatively in the ASCEMBL study.” Asciminib was shown to be superior and could offer a clear alternative to ponatinib, which would be the other choice and is typically given even later after sequencing all other available options.

Dr. Hobbs agreed. “This is a challenging group of patients to manage as their options are limited. Ponatinib is often the drug of choice in these scenarios, as well as bone marrow transplant.”

Asciminib is not approved yet, but both Dr. Mauro and Dr. Hobbs are hopeful it will be by early next year, and that initial approval is likely in patients with CML-CP after several (two or three) lines of therapy. They also agreed that it may be effective (alone or in combination) in treating patients with T315I-mutation CML, which is a particularly challenging disease.

Senior study author Andreas Hochhaus, MD, of the Klinik für Innere Medizin II in Jena, Germany, who presented the data at the meeting, noted new trials to test the efficacy of asciminib alone or in combination in earlier lines of therapy are ongoing and include the investigator-initiated FASCINATION study (first-line asciminib in combination) in Germany (NCT03906292).
 

ASCEMBL study details

ASCEMBL is a phase 3 study in which patients with CML who had received at least two previous TKIs were randomized to asciminib (n = 157) 40 mg twice daily or bosutinib (n = 76) 500 mg once daily. In a protocol amendment, patients with documented failure on bosutinib were allowed to switch to asciminib.

The main reason for discontinuing the last TKI therapy was lack of efficacy in approximately two-thirds of patients. More patients in the asciminib than the bosutinib group received two prior lines of therapy (52% vs. 40%); the others had received three or more prior lines of therapy.

Median follow-up for the data cutoff was 14.9 months.

Dr. Hochhaus reported that treatment discontinuation was lower in patients receiving asciminib than bosutinib (38% vs. 70%) and was mostly due to lack of efficacy (21% vs. 32%) or adverse events (5% vs. 21%).

The study met its primary endpoint: major molecular response (MMR) was approximately twice as high with asciminib than bosutinib at 24 weeks (25.5% vs. 13.2%; P = .029). Treatment effect for MMR was 12.2%. Median duration of exposure to asciminib was 43.4 weeks for asciminib and 29.2 weeks for bosutinib.

“Consistent treatment effect was seen across all subgroups of patients, and MMR rates were consistently high for patients on asciminib across all prior lines of therapy,” Dr. Hochhaus reported.

The probability of achieving MMR at 24 weeks was higher for patients receiving asciminib (25% vs. 11.9%) and started at week 12, he noted. Complete cytogenetic response was also higher for patients receiving asciminib (40.8% vs. 24.2%).

The occurrence of grade 3 or higher adverse events was lower with asciminib than bosutinib (51% vs. 61%). Thrombocytopenia and neutropenia were more common with asciminib and gastrointestinal events were more common with bosutinib. Arterial occlusion events were reported in five patients receiving asciminib and one patient receiving bosutinib. Most of these patients had prior exposure to imatinib, nilotinib, and/or dasatinib.

Dr. Mauro, a coinvestigator of the phase 3 study, also treated patients with the drug in the phase 1 study. “I feel asciminib has proven to be very well tolerated, with rare to absent cases of intolerance,” he said. Cardiovascular and cardiopulmonary adverse events are exceedingly rare as well.

Longer follow-up of the ASCEMBL study and continued follow-up of the myriad of groups from the phase 1 trial (T315I-positive patients treated with higher-dose asciminib, combination therapy with imatinib/nilotinib/dasatinib plus asciminib, and others) will be essential to settle any questions regarding selective adverse events of interest such as vascular occlusion, Dr. Mauro noted.

Dr. Hochhaus has reported receiving research funding from Novartis, Incyte, Pfizer, and Bristol-Myers Squibb. Dr. Hobbs has reported serving on advisory boards for Novartis. Dr. Mauro has reported financial relationships with Bristol-Myers Squibb, Novartis, Takeda, Pfizer, and Sun Pharma/SPARC.

A version of this article first appeared on Medscape.com.

The investigational drug asciminib (being developed by Novartis) may become the new kid on the block for the treatment of chronic phase chronic myeloid leukemia (CMP-CP) for patients who have relapsed on or are refractory to at least two prior tyrosine kinase inhibitors (TKIs).

New results from the ASCEMBL study (NCT03106779) show that patients who received asciminib, which works differently from currently approved therapies for CML-CP, achieved better responses, compared with bosutinib (Bosulif) as third-line therapy.

“The ASCEMBL study opens a new chapter for CML, proving comparatively superior efficacy and excellent safety for a new class of ABL inhibitors,” coinvestigator Michael J. Mauro, MD, from Memorial Sloan Kettering Cancer Center, New York, said in an interview.

The trial was presented as a late-breaking abstract at the annual meeting of the American Society of Hematology.

Asciminib is a first-of-a-kind STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor that works differently from currently approved TKIs, which are adenosine triphosphate (ATP)-–competitive ABL inhibitors.

Five TKIs have been approved by the Food and Drug Administration to treat CML: imatinib (Gleevec; generics), nilotinib (Tasigna), dasatinib (Sprycel), bosutinib, and ponatinib (Iclusig).

All of them inhibit BCR/ABL tyrosine kinase by binding to the ATP-binding pocket.

Most patients with TKI resistant disease develop mutations in the ATP-binding pocket, explained Michael Jay Styler, MD, associate professor at Fox Chase–Temple University Hospital bone marrow transplant program, Fox Chase Cancer Center, Philadelphia.

By inactivating the protein through binding outside the ATP site, asciminib is a novel BCR-ABL inhibitor and may be a superior alternative to further traditional TKIs. “This agent promises to be an important addition to our treatment armamentarium for CML,” Dr. Styler said in an interview.

Another expert agreed. “Although we have many excellent therapies for CML, having a new medication that targets BCR-ABL in a novel way is still welcome to help us better care for CML patients,” Gabriela S. Hobbs, MD, said in an interview. Dr. Hobbs is the clinical director of leukemia services at Boston’s Mass General Cancer Center.

Patients in this study had previously been receiving at least two different types of TKIs. “The responses looked very encouraging for this group of heavily pretreated patients. Although CML patients do very well on current therapies, those that don’t get a response with TKI remain a difficult clinical challenge,” Dr. Hobbs said.

“This is the first study comparing asciminib to a TKI directly (in this case bosutinib) and it showed safety as well as preliminary evidence of efficacy. I look forward to seeing additional studies with this promising drug and to have a new drug to add to the CML arsenal,” she added.
 

Identifying patients who will benefit from asciminib

Patients with CML are currently sequenced through more than one second-generation TKI, Dr. Mauro commented. “If imatinib and a second-generation TKI have not served a patient well, only bosutinib has been studied in the third line and comparatively in the ASCEMBL study.” Asciminib was shown to be superior and could offer a clear alternative to ponatinib, which would be the other choice and is typically given even later after sequencing all other available options.

Dr. Hobbs agreed. “This is a challenging group of patients to manage as their options are limited. Ponatinib is often the drug of choice in these scenarios, as well as bone marrow transplant.”

Asciminib is not approved yet, but both Dr. Mauro and Dr. Hobbs are hopeful it will be by early next year, and that initial approval is likely in patients with CML-CP after several (two or three) lines of therapy. They also agreed that it may be effective (alone or in combination) in treating patients with T315I-mutation CML, which is a particularly challenging disease.

Senior study author Andreas Hochhaus, MD, of the Klinik für Innere Medizin II in Jena, Germany, who presented the data at the meeting, noted new trials to test the efficacy of asciminib alone or in combination in earlier lines of therapy are ongoing and include the investigator-initiated FASCINATION study (first-line asciminib in combination) in Germany (NCT03906292).
 

ASCEMBL study details

ASCEMBL is a phase 3 study in which patients with CML who had received at least two previous TKIs were randomized to asciminib (n = 157) 40 mg twice daily or bosutinib (n = 76) 500 mg once daily. In a protocol amendment, patients with documented failure on bosutinib were allowed to switch to asciminib.

The main reason for discontinuing the last TKI therapy was lack of efficacy in approximately two-thirds of patients. More patients in the asciminib than the bosutinib group received two prior lines of therapy (52% vs. 40%); the others had received three or more prior lines of therapy.

Median follow-up for the data cutoff was 14.9 months.

Dr. Hochhaus reported that treatment discontinuation was lower in patients receiving asciminib than bosutinib (38% vs. 70%) and was mostly due to lack of efficacy (21% vs. 32%) or adverse events (5% vs. 21%).

The study met its primary endpoint: major molecular response (MMR) was approximately twice as high with asciminib than bosutinib at 24 weeks (25.5% vs. 13.2%; P = .029). Treatment effect for MMR was 12.2%. Median duration of exposure to asciminib was 43.4 weeks for asciminib and 29.2 weeks for bosutinib.

“Consistent treatment effect was seen across all subgroups of patients, and MMR rates were consistently high for patients on asciminib across all prior lines of therapy,” Dr. Hochhaus reported.

The probability of achieving MMR at 24 weeks was higher for patients receiving asciminib (25% vs. 11.9%) and started at week 12, he noted. Complete cytogenetic response was also higher for patients receiving asciminib (40.8% vs. 24.2%).

The occurrence of grade 3 or higher adverse events was lower with asciminib than bosutinib (51% vs. 61%). Thrombocytopenia and neutropenia were more common with asciminib and gastrointestinal events were more common with bosutinib. Arterial occlusion events were reported in five patients receiving asciminib and one patient receiving bosutinib. Most of these patients had prior exposure to imatinib, nilotinib, and/or dasatinib.

Dr. Mauro, a coinvestigator of the phase 3 study, also treated patients with the drug in the phase 1 study. “I feel asciminib has proven to be very well tolerated, with rare to absent cases of intolerance,” he said. Cardiovascular and cardiopulmonary adverse events are exceedingly rare as well.

Longer follow-up of the ASCEMBL study and continued follow-up of the myriad of groups from the phase 1 trial (T315I-positive patients treated with higher-dose asciminib, combination therapy with imatinib/nilotinib/dasatinib plus asciminib, and others) will be essential to settle any questions regarding selective adverse events of interest such as vascular occlusion, Dr. Mauro noted.

Dr. Hochhaus has reported receiving research funding from Novartis, Incyte, Pfizer, and Bristol-Myers Squibb. Dr. Hobbs has reported serving on advisory boards for Novartis. Dr. Mauro has reported financial relationships with Bristol-Myers Squibb, Novartis, Takeda, Pfizer, and Sun Pharma/SPARC.

A version of this article first appeared on Medscape.com.

A newly devised, validated prognostic tool – the Burkitt Lymphoma International Prognostic Index – can consistently identify low-risk patients who might benefit from treatment de-escalation, and high-risk patients who are unlikely to be cured with current therapies and may require novel approaches, investigators said.

In a cohort of patients treated at international sites, patients with a low-risk score on the BL-IPI had a 3-year progression-free survival (PFS) rate of 96%, and 3-year overall survival rate (OS) of 99%. In contrast, the 3-year PFS rate for patients in the high-risk category was 63%, and the 3-year OS rate was 64%, reported Adam J Olszewski, MD, from the Lifespan Cancer Institute at Rhode Island Hospital and The Miriam Hospital, both in Providence.

“The Burkitt Lymphoma International Prognostic Index – or the ‘BLI-PI’ [‘blippy’] as it was inevitably called – is a novel prognostic index that is specific to Burkitt lymphoma. It has been validated with sufficient calibration and discrimination in external data sets to allow for simple stratification and comparison of risk distribution in geographically diverse cohorts,” he said in an oral abstract presented virtually during the annual meeting of the American Society of Hematology.
 

Inconsistent criteria

There is a need for a Burkitt-specific index, he said, because of significant differences in age, stage at presentation, and abnormal lactate dehydrogenase (LDH) levels between patients with Burkitt and those with diffuse large B-cell lymphoma (DLBCL), and because historical definitions of “low-risk” Burkitt lymphoma have been inconsistent, with less than 10% of patients falling into this group, leaving the remainder in a undifferentiated “high-risk” category.

“Burkitt lymphoma is considered highly curable, but current therapy requires administration of dose-intense chemoimmunotherapy for which there are many chemotherapy backbone regimens developed across the world, and used mostly locally. These are often studied in phase 2 studies with limited sample sizes, which makes it difficult to compare populations across trials,” Dr. Olszewski said.

A validated prognostic index can help clinicians and researchers compare cohorts and can be used to help design future trials, he added.

To devise the BL-IPI, the investigators first selected a retrospective cohort of 570 adults with Burkitt lymphoma treated at 30 U.S. centers for whom data on outcomes were available.

They determined the best prognostic cutoffs for age, LDH, hemoglobin and albumin levels, and identified independent risk factors using stepwise selection in Cox regression and lasso regression analysis, a machine learning approach. The variables included age; sex; HIV-positivity status; loss of MYC rearrangement; performance status; stage; nodal involvement; marrow involvement; central nervous system involvement; and LDH, hemoglobin, and albumin levels.

For validation, they pooled data from European, Canadian, Australian, and U.K. studies to identify 457 patients for whom retrospective treatment and outcomes data were available.

The derivation and validation cohorts were similar in most respects, expect for a higher proportion of patients with Eastern Cooperative Oncology Group performance status scores of 2 or higher in the validation cohort (22% vs. 35%), and a higher proportion of patients with CNS involvement in the U.S.-based derivation cohort (19% vs. 10%, respectively).

Therapy also differed markedly between the U.S. and international cohorts, with about 30% each of U.S. patients receiving either the CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine) regimen, DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) regimen, or hCVAD/MA (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) regimen, and the remaining 10% receiving other, unspecified therapy.

In contrast, 65% of the patients in the international (validation) cohort received CODOX-M/IVAC, 10% and 9%, respectively, received DA-EPOCH-R and hCVAD/MA, and 16% receiving other regimens.

Rituximab was administered to 91% of U.S. and 95% of international patients.
 

Higher survival rates outside US

Both PFS and OS were higher in the international versus U.S. cohort. At a median follow-up of 45 months, the PFS rate in the United States was 65%, and the OS rate was 70%.

In the international cohort, after a median follow-up of 52 months, the PFS rate was 75%, and the OS rate was 76%, the investigators found.

Reasons for the differences may be because of differences in treatment regimens, socioeconomic and racial disparities in the United States versus other countries, or to decentralized Burkitt lymphoma therapy in the United States, Dr. Olszewski said.

In univariate analysis, factors significantly predictive of worse PFS included age 40 years or older, ECOG performance status 2 or greater, stage 3 or 4 disease, marrow involvement, CNS involvement, LDH more than three times the upper limit of normal, and hemoglobin <11.5 g/dL (P < .001 for all preceding), as well as albumin <3.5 g/dL (P = .001).

“However, the multivariable analysis was more complicated, because many of these factors were overlapping, and most patients with high LDH also had advanced disease, and this group also encompassed patients who had bone marrow and CNS involvement,” he said.

Using the two types of regression analysis mentioned before, investigators identified ECOG performance status 2 or greater (P = .001), age 40 and older (P = .005), LDH greater than three times the upper limit of normal (P < .001) and CNS involvement (P = .002) as significant predictors for worse outcomes in multivariable analysis, and were included in the final model.

“We initially had five groups according to the number of these factors, but we observed that the survival curves for patients with two, three, or four factors were overlapping, and not significantly different, so ultimately we had three risk groups. In the derivation (U.S.) cohort, patients in the low-risk group, with no risk factors, a 3-year PFS of 92%, compared with 72% for patients with one risk factor (intermediate risk), and 53% for patients with two to four risk factors (high risk).

Respective hazard ratios for worse PFS in the low-, intermediate-, and high-risk groups were 1 (reference), 4.15 (95% confidence interval, 1.99-8.68), and 8.83 (95% CI, 4.32-18.03).

Respective HR for worse OS was 1, 7.06 (95% CI, 2.55-19.53), and 15.12 (95% CI, 5.58-40.99).

There were no significant differences in either PFS or OS when either LDH or stage was added into the model.

The BL-IPI was prognostic for PFS and OS in all subgroups, including HIV-positive or -negative patients, those with MYC rearrangements, stage 1 or 2 versus stage 3 or 4, or those treated with rituximab versus those who were not.

As noted before, 3-year PFS rates in the validation cohort for low, intermediate, high-risk groups were 96%, 82%, and 63% respectively, and 3-year OS rates were 99%, 85%, and 64%.
 

Why the CNS discrepancy?

In the question and answer session following the presentation, comoderator Christopher J. Melani, MD, from the Lymphoid Malignancies Branch at the National Cancer Institute in Bethesda, Md., said that “it was interesting to see the difference between CNS involvement in both the U.S. and the international cohort,” and asked whether Dr. Olszweski could elaborate on whether baseline CNS involvement was assessed by contrast-enhanced MRI of flow cytometry studies of cerebrospinal fluid.

“Could some of these differences between the U.S. and the international cohort be from the baseline assessment differing between the two?” he asked.

Dr. Olszewski replied that the retrospective nature of the data precluded capturing those data, but added that “I do suspect there may be some differences in the way that central nervous system is staged in different countries. In the United States the use of flow cytometry is more commonly employed, but we don’t know how it is used internationally. We do not know how often this is staged radiographically.”

Asked by others who viewed the presentation whether extranodal disease or peripheral blood involvement were prognostic in the final model, Dr. Olszewski replied that “one has to understand that, when one constructs a prognostic index, there is a balance between trying to input as much information as possible and to create something that is useful, clinically meaningful, and accurate.”

He said that, despite trying different models with different factors, “we couldn’t get the discrimination to be much better than the basic model that we ultimately created, so we favored using a more parsimonious model.”

No study funding source was reported. Dr. Olszewski reported research funding from Spectrum Pharmaceuticals, Genentech, TG Therapeutics, and Adaptive Biotechnologies. Dr. Melani reported having no relevant conflicts of interest.

SOURCE: Olszewski AJ et al. ASH 2020, Abstract 705.

A newly devised, validated prognostic tool – the Burkitt Lymphoma International Prognostic Index – can consistently identify low-risk patients who might benefit from treatment de-escalation, and high-risk patients who are unlikely to be cured with current therapies and may require novel approaches, investigators said.

In a cohort of patients treated at international sites, patients with a low-risk score on the BL-IPI had a 3-year progression-free survival (PFS) rate of 96%, and 3-year overall survival rate (OS) of 99%. In contrast, the 3-year PFS rate for patients in the high-risk category was 63%, and the 3-year OS rate was 64%, reported Adam J Olszewski, MD, from the Lifespan Cancer Institute at Rhode Island Hospital and The Miriam Hospital, both in Providence.

“The Burkitt Lymphoma International Prognostic Index – or the ‘BLI-PI’ [‘blippy’] as it was inevitably called – is a novel prognostic index that is specific to Burkitt lymphoma. It has been validated with sufficient calibration and discrimination in external data sets to allow for simple stratification and comparison of risk distribution in geographically diverse cohorts,” he said in an oral abstract presented virtually during the annual meeting of the American Society of Hematology.
 

Inconsistent criteria

There is a need for a Burkitt-specific index, he said, because of significant differences in age, stage at presentation, and abnormal lactate dehydrogenase (LDH) levels between patients with Burkitt and those with diffuse large B-cell lymphoma (DLBCL), and because historical definitions of “low-risk” Burkitt lymphoma have been inconsistent, with less than 10% of patients falling into this group, leaving the remainder in a undifferentiated “high-risk” category.

“Burkitt lymphoma is considered highly curable, but current therapy requires administration of dose-intense chemoimmunotherapy for which there are many chemotherapy backbone regimens developed across the world, and used mostly locally. These are often studied in phase 2 studies with limited sample sizes, which makes it difficult to compare populations across trials,” Dr. Olszewski said.

A validated prognostic index can help clinicians and researchers compare cohorts and can be used to help design future trials, he added.

To devise the BL-IPI, the investigators first selected a retrospective cohort of 570 adults with Burkitt lymphoma treated at 30 U.S. centers for whom data on outcomes were available.

They determined the best prognostic cutoffs for age, LDH, hemoglobin and albumin levels, and identified independent risk factors using stepwise selection in Cox regression and lasso regression analysis, a machine learning approach. The variables included age; sex; HIV-positivity status; loss of MYC rearrangement; performance status; stage; nodal involvement; marrow involvement; central nervous system involvement; and LDH, hemoglobin, and albumin levels.

For validation, they pooled data from European, Canadian, Australian, and U.K. studies to identify 457 patients for whom retrospective treatment and outcomes data were available.

The derivation and validation cohorts were similar in most respects, expect for a higher proportion of patients with Eastern Cooperative Oncology Group performance status scores of 2 or higher in the validation cohort (22% vs. 35%), and a higher proportion of patients with CNS involvement in the U.S.-based derivation cohort (19% vs. 10%, respectively).

Therapy also differed markedly between the U.S. and international cohorts, with about 30% each of U.S. patients receiving either the CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine) regimen, DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) regimen, or hCVAD/MA (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) regimen, and the remaining 10% receiving other, unspecified therapy.

In contrast, 65% of the patients in the international (validation) cohort received CODOX-M/IVAC, 10% and 9%, respectively, received DA-EPOCH-R and hCVAD/MA, and 16% receiving other regimens.

Rituximab was administered to 91% of U.S. and 95% of international patients.
 

Higher survival rates outside US

Both PFS and OS were higher in the international versus U.S. cohort. At a median follow-up of 45 months, the PFS rate in the United States was 65%, and the OS rate was 70%.

In the international cohort, after a median follow-up of 52 months, the PFS rate was 75%, and the OS rate was 76%, the investigators found.

Reasons for the differences may be because of differences in treatment regimens, socioeconomic and racial disparities in the United States versus other countries, or to decentralized Burkitt lymphoma therapy in the United States, Dr. Olszewski said.

In univariate analysis, factors significantly predictive of worse PFS included age 40 years or older, ECOG performance status 2 or greater, stage 3 or 4 disease, marrow involvement, CNS involvement, LDH more than three times the upper limit of normal, and hemoglobin <11.5 g/dL (P < .001 for all preceding), as well as albumin <3.5 g/dL (P = .001).

“However, the multivariable analysis was more complicated, because many of these factors were overlapping, and most patients with high LDH also had advanced disease, and this group also encompassed patients who had bone marrow and CNS involvement,” he said.

Using the two types of regression analysis mentioned before, investigators identified ECOG performance status 2 or greater (P = .001), age 40 and older (P = .005), LDH greater than three times the upper limit of normal (P < .001) and CNS involvement (P = .002) as significant predictors for worse outcomes in multivariable analysis, and were included in the final model.

“We initially had five groups according to the number of these factors, but we observed that the survival curves for patients with two, three, or four factors were overlapping, and not significantly different, so ultimately we had three risk groups. In the derivation (U.S.) cohort, patients in the low-risk group, with no risk factors, a 3-year PFS of 92%, compared with 72% for patients with one risk factor (intermediate risk), and 53% for patients with two to four risk factors (high risk).

Respective hazard ratios for worse PFS in the low-, intermediate-, and high-risk groups were 1 (reference), 4.15 (95% confidence interval, 1.99-8.68), and 8.83 (95% CI, 4.32-18.03).

Respective HR for worse OS was 1, 7.06 (95% CI, 2.55-19.53), and 15.12 (95% CI, 5.58-40.99).

There were no significant differences in either PFS or OS when either LDH or stage was added into the model.

The BL-IPI was prognostic for PFS and OS in all subgroups, including HIV-positive or -negative patients, those with MYC rearrangements, stage 1 or 2 versus stage 3 or 4, or those treated with rituximab versus those who were not.

As noted before, 3-year PFS rates in the validation cohort for low, intermediate, high-risk groups were 96%, 82%, and 63% respectively, and 3-year OS rates were 99%, 85%, and 64%.
 

Why the CNS discrepancy?

In the question and answer session following the presentation, comoderator Christopher J. Melani, MD, from the Lymphoid Malignancies Branch at the National Cancer Institute in Bethesda, Md., said that “it was interesting to see the difference between CNS involvement in both the U.S. and the international cohort,” and asked whether Dr. Olszweski could elaborate on whether baseline CNS involvement was assessed by contrast-enhanced MRI of flow cytometry studies of cerebrospinal fluid.

“Could some of these differences between the U.S. and the international cohort be from the baseline assessment differing between the two?” he asked.

Dr. Olszewski replied that the retrospective nature of the data precluded capturing those data, but added that “I do suspect there may be some differences in the way that central nervous system is staged in different countries. In the United States the use of flow cytometry is more commonly employed, but we don’t know how it is used internationally. We do not know how often this is staged radiographically.”

Asked by others who viewed the presentation whether extranodal disease or peripheral blood involvement were prognostic in the final model, Dr. Olszewski replied that “one has to understand that, when one constructs a prognostic index, there is a balance between trying to input as much information as possible and to create something that is useful, clinically meaningful, and accurate.”

He said that, despite trying different models with different factors, “we couldn’t get the discrimination to be much better than the basic model that we ultimately created, so we favored using a more parsimonious model.”

No study funding source was reported. Dr. Olszewski reported research funding from Spectrum Pharmaceuticals, Genentech, TG Therapeutics, and Adaptive Biotechnologies. Dr. Melani reported having no relevant conflicts of interest.

SOURCE: Olszewski AJ et al. ASH 2020, Abstract 705.

A newly devised, validated prognostic tool – the Burkitt Lymphoma International Prognostic Index – can consistently identify low-risk patients who might benefit from treatment de-escalation, and high-risk patients who are unlikely to be cured with current therapies and may require novel approaches, investigators said.

In a cohort of patients treated at international sites, patients with a low-risk score on the BL-IPI had a 3-year progression-free survival (PFS) rate of 96%, and 3-year overall survival rate (OS) of 99%. In contrast, the 3-year PFS rate for patients in the high-risk category was 63%, and the 3-year OS rate was 64%, reported Adam J Olszewski, MD, from the Lifespan Cancer Institute at Rhode Island Hospital and The Miriam Hospital, both in Providence.

“The Burkitt Lymphoma International Prognostic Index – or the ‘BLI-PI’ [‘blippy’] as it was inevitably called – is a novel prognostic index that is specific to Burkitt lymphoma. It has been validated with sufficient calibration and discrimination in external data sets to allow for simple stratification and comparison of risk distribution in geographically diverse cohorts,” he said in an oral abstract presented virtually during the annual meeting of the American Society of Hematology.
 

Inconsistent criteria

There is a need for a Burkitt-specific index, he said, because of significant differences in age, stage at presentation, and abnormal lactate dehydrogenase (LDH) levels between patients with Burkitt and those with diffuse large B-cell lymphoma (DLBCL), and because historical definitions of “low-risk” Burkitt lymphoma have been inconsistent, with less than 10% of patients falling into this group, leaving the remainder in a undifferentiated “high-risk” category.

“Burkitt lymphoma is considered highly curable, but current therapy requires administration of dose-intense chemoimmunotherapy for which there are many chemotherapy backbone regimens developed across the world, and used mostly locally. These are often studied in phase 2 studies with limited sample sizes, which makes it difficult to compare populations across trials,” Dr. Olszewski said.

A validated prognostic index can help clinicians and researchers compare cohorts and can be used to help design future trials, he added.

To devise the BL-IPI, the investigators first selected a retrospective cohort of 570 adults with Burkitt lymphoma treated at 30 U.S. centers for whom data on outcomes were available.

They determined the best prognostic cutoffs for age, LDH, hemoglobin and albumin levels, and identified independent risk factors using stepwise selection in Cox regression and lasso regression analysis, a machine learning approach. The variables included age; sex; HIV-positivity status; loss of MYC rearrangement; performance status; stage; nodal involvement; marrow involvement; central nervous system involvement; and LDH, hemoglobin, and albumin levels.

For validation, they pooled data from European, Canadian, Australian, and U.K. studies to identify 457 patients for whom retrospective treatment and outcomes data were available.

The derivation and validation cohorts were similar in most respects, expect for a higher proportion of patients with Eastern Cooperative Oncology Group performance status scores of 2 or higher in the validation cohort (22% vs. 35%), and a higher proportion of patients with CNS involvement in the U.S.-based derivation cohort (19% vs. 10%, respectively).

Therapy also differed markedly between the U.S. and international cohorts, with about 30% each of U.S. patients receiving either the CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine) regimen, DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) regimen, or hCVAD/MA (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) regimen, and the remaining 10% receiving other, unspecified therapy.

In contrast, 65% of the patients in the international (validation) cohort received CODOX-M/IVAC, 10% and 9%, respectively, received DA-EPOCH-R and hCVAD/MA, and 16% receiving other regimens.

Rituximab was administered to 91% of U.S. and 95% of international patients.
 

Higher survival rates outside US

Both PFS and OS were higher in the international versus U.S. cohort. At a median follow-up of 45 months, the PFS rate in the United States was 65%, and the OS rate was 70%.

In the international cohort, after a median follow-up of 52 months, the PFS rate was 75%, and the OS rate was 76%, the investigators found.

Reasons for the differences may be because of differences in treatment regimens, socioeconomic and racial disparities in the United States versus other countries, or to decentralized Burkitt lymphoma therapy in the United States, Dr. Olszewski said.

In univariate analysis, factors significantly predictive of worse PFS included age 40 years or older, ECOG performance status 2 or greater, stage 3 or 4 disease, marrow involvement, CNS involvement, LDH more than three times the upper limit of normal, and hemoglobin <11.5 g/dL (P < .001 for all preceding), as well as albumin <3.5 g/dL (P = .001).

“However, the multivariable analysis was more complicated, because many of these factors were overlapping, and most patients with high LDH also had advanced disease, and this group also encompassed patients who had bone marrow and CNS involvement,” he said.

Using the two types of regression analysis mentioned before, investigators identified ECOG performance status 2 or greater (P = .001), age 40 and older (P = .005), LDH greater than three times the upper limit of normal (P < .001) and CNS involvement (P = .002) as significant predictors for worse outcomes in multivariable analysis, and were included in the final model.

“We initially had five groups according to the number of these factors, but we observed that the survival curves for patients with two, three, or four factors were overlapping, and not significantly different, so ultimately we had three risk groups. In the derivation (U.S.) cohort, patients in the low-risk group, with no risk factors, a 3-year PFS of 92%, compared with 72% for patients with one risk factor (intermediate risk), and 53% for patients with two to four risk factors (high risk).

Respective hazard ratios for worse PFS in the low-, intermediate-, and high-risk groups were 1 (reference), 4.15 (95% confidence interval, 1.99-8.68), and 8.83 (95% CI, 4.32-18.03).

Respective HR for worse OS was 1, 7.06 (95% CI, 2.55-19.53), and 15.12 (95% CI, 5.58-40.99).

There were no significant differences in either PFS or OS when either LDH or stage was added into the model.

The BL-IPI was prognostic for PFS and OS in all subgroups, including HIV-positive or -negative patients, those with MYC rearrangements, stage 1 or 2 versus stage 3 or 4, or those treated with rituximab versus those who were not.

As noted before, 3-year PFS rates in the validation cohort for low, intermediate, high-risk groups were 96%, 82%, and 63% respectively, and 3-year OS rates were 99%, 85%, and 64%.
 

Why the CNS discrepancy?

In the question and answer session following the presentation, comoderator Christopher J. Melani, MD, from the Lymphoid Malignancies Branch at the National Cancer Institute in Bethesda, Md., said that “it was interesting to see the difference between CNS involvement in both the U.S. and the international cohort,” and asked whether Dr. Olszweski could elaborate on whether baseline CNS involvement was assessed by contrast-enhanced MRI of flow cytometry studies of cerebrospinal fluid.

“Could some of these differences between the U.S. and the international cohort be from the baseline assessment differing between the two?” he asked.

Dr. Olszewski replied that the retrospective nature of the data precluded capturing those data, but added that “I do suspect there may be some differences in the way that central nervous system is staged in different countries. In the United States the use of flow cytometry is more commonly employed, but we don’t know how it is used internationally. We do not know how often this is staged radiographically.”

Asked by others who viewed the presentation whether extranodal disease or peripheral blood involvement were prognostic in the final model, Dr. Olszewski replied that “one has to understand that, when one constructs a prognostic index, there is a balance between trying to input as much information as possible and to create something that is useful, clinically meaningful, and accurate.”

He said that, despite trying different models with different factors, “we couldn’t get the discrimination to be much better than the basic model that we ultimately created, so we favored using a more parsimonious model.”

No study funding source was reported. Dr. Olszewski reported research funding from Spectrum Pharmaceuticals, Genentech, TG Therapeutics, and Adaptive Biotechnologies. Dr. Melani reported having no relevant conflicts of interest.

SOURCE: Olszewski AJ et al. ASH 2020, Abstract 705.

An investigational chimeric antigen receptor T-cell (CAR T-cell) construct targeting two antigens on multiple myeloma cells showed promise in a first-in-humans trial, investigators said.

Among 16 patients with relapsed/refractory, heavily pretreated multiple myeloma who received the dual-targeting construct GC012F, the overall response rate was 93.8%, and all of six patients who received the cells at the highest of three dose levels had stringent complete responses (sCR) and were negative for minimal residual disease (MRD) at 6 months follow-up, reported Weijun Fu, MD, PhD, from Shanghai (China) Changzheng Hospital in an oral abstract presented during the virtual American Society of Hematology annual meeting.

GC012F is a novel CAR-T cell platform targeting both the B-cell maturation antigen (BCMA), which is universally expressed on malignant plasma cells, and CD19, which is expressed on both multiple myeloma cells and progenitors, Dr. Fu said.

“Targeting CD19 can trigger elimination of malignant cells by CAR T. Our preclinical work demonstrated more effective elimination of multiple myeloma clone-forming cells by BCMA and CD19 dual CAR T, so targeting both BCMA and CD19 antigens could improve efficacy and reduce relapse,” he said.

The construct is created using the FasTCAR platform that, according to manufacturer Gracell Biotechnologies (Shanghai), allows for cell culturing and expansion within 24-36 hours, rather than 2-3 weeks required for other CAR T-cell products.
 

Investigator-initiated trial

In a phase 1 investigator-initiated trial, 16 patients with a median age of 56 (range 27-71) years were enrolled. The patients all had relapsed or refractory multiple myeloma according to 2016 International Myeloma Working Group criteria, with a life expectancy of at least 3 months and adequate organ function.

The median time since diagnosis was 3 years (range 1-10). All but one of the 16 patients had high-risk disease, 3 had double-hit disease (the presence of two deletions, gain of function, or p53 mutation), and 5 patients had one or more extramedullary plasmacytomas. Four of the patients had received therapy with an anti-CD38 monoclonal antibody.

Following lymphodepletion with fludarabine and cyclophosphamide, the patients received the CAR T cells in a single infusion at dose levels of either 1, 2, or 3 times 10⁵ cells/kg.

As of the cutoff date in July 2020, 15 of the 16 patients had a clinical response, including 9 with a CR or sCR, and 6 with a very good partial response (VGPR). As noted before, all of the six patients treated at the highest dose level had a sCR. At the median follow-up of 7.3 months, the median duration of response had not been reached.

Among all patients evaluable for response at month 1 (14 patients), 11 were MRD negative by flow cytometry. At month 3 all 11 evaluable patients were MRD negative, and all of 10 patients evaluable at 6 months were also MRD negative.

As with other CAR T-cell constructs, all patients developed the cytokine-release syndrome (CRS), with grade 1 or 2 severity in 14 patients, and grade 3 in 2 patients. The median time to onset of CRS was 6 days (range 2-10), and the median duration was 4 days (range 1-8 days).

No cases of immune effector cell–associated neurotoxicity syndrome (ICANS) were observed.

One patient treated at the middle dose level presented with fever and died shortly after day 78 of an unknown cause during the COVID-19 pandemic. Two patients died of extramedullary disease; each had achieved MRD negativity.

Investigators continue to follow the patients and are enrolling new patients in the ongoing study.
 

‘Interesting approach’

Sandy W. Wong, MD, from the Helen Diller Family Comprehensive Cancer Center at the University of California San Francisco, who was not involved in the study, said in an interview that the dual-targeted approach is interesting, in light of a case report presented at ASH 2020 of a patient with multiple myeloma who had a partial response to CAR T-cell therapy with a different construct and who developed a subsequent biallelic loss of BCMA that resulted in resistance to CAR T-cell therapy.

“This raises the idea that, if we perhaps had a dual-targeted CAR T, perhaps we will prolong progression-free survival, in order to avoid antigen escape. So I do think the concept is very interesting and does deserve further study,” she said.

CD19 is thought to be expressed on myeloma stem cells, “so the question is: Are patients not being cured because there is a reservoir of myeloma cells, and targeting CD19 is thought to get at this putative myeloma stem cell? but that remains to be seen,” she added.

Dr. Wong comoderated the session where Dr. Fu presented the data.

The study was supported by participating medical centers and Gracell Biotechnologies. Dr. Fu and Dr. Wong reported no relevant conflicts of interest to disclose.

SOURCE: Jiang H et al. ASH 2020, Abstract 178.

An investigational chimeric antigen receptor T-cell (CAR T-cell) construct targeting two antigens on multiple myeloma cells showed promise in a first-in-humans trial, investigators said.

Among 16 patients with relapsed/refractory, heavily pretreated multiple myeloma who received the dual-targeting construct GC012F, the overall response rate was 93.8%, and all of six patients who received the cells at the highest of three dose levels had stringent complete responses (sCR) and were negative for minimal residual disease (MRD) at 6 months follow-up, reported Weijun Fu, MD, PhD, from Shanghai (China) Changzheng Hospital in an oral abstract presented during the virtual American Society of Hematology annual meeting.

GC012F is a novel CAR-T cell platform targeting both the B-cell maturation antigen (BCMA), which is universally expressed on malignant plasma cells, and CD19, which is expressed on both multiple myeloma cells and progenitors, Dr. Fu said.

“Targeting CD19 can trigger elimination of malignant cells by CAR T. Our preclinical work demonstrated more effective elimination of multiple myeloma clone-forming cells by BCMA and CD19 dual CAR T, so targeting both BCMA and CD19 antigens could improve efficacy and reduce relapse,” he said.

The construct is created using the FasTCAR platform that, according to manufacturer Gracell Biotechnologies (Shanghai), allows for cell culturing and expansion within 24-36 hours, rather than 2-3 weeks required for other CAR T-cell products.
 

Investigator-initiated trial

In a phase 1 investigator-initiated trial, 16 patients with a median age of 56 (range 27-71) years were enrolled. The patients all had relapsed or refractory multiple myeloma according to 2016 International Myeloma Working Group criteria, with a life expectancy of at least 3 months and adequate organ function.

The median time since diagnosis was 3 years (range 1-10). All but one of the 16 patients had high-risk disease, 3 had double-hit disease (the presence of two deletions, gain of function, or p53 mutation), and 5 patients had one or more extramedullary plasmacytomas. Four of the patients had received therapy with an anti-CD38 monoclonal antibody.

Following lymphodepletion with fludarabine and cyclophosphamide, the patients received the CAR T cells in a single infusion at dose levels of either 1, 2, or 3 times 10⁵ cells/kg.

As of the cutoff date in July 2020, 15 of the 16 patients had a clinical response, including 9 with a CR or sCR, and 6 with a very good partial response (VGPR). As noted before, all of the six patients treated at the highest dose level had a sCR. At the median follow-up of 7.3 months, the median duration of response had not been reached.

Among all patients evaluable for response at month 1 (14 patients), 11 were MRD negative by flow cytometry. At month 3 all 11 evaluable patients were MRD negative, and all of 10 patients evaluable at 6 months were also MRD negative.

As with other CAR T-cell constructs, all patients developed the cytokine-release syndrome (CRS), with grade 1 or 2 severity in 14 patients, and grade 3 in 2 patients. The median time to onset of CRS was 6 days (range 2-10), and the median duration was 4 days (range 1-8 days).

No cases of immune effector cell–associated neurotoxicity syndrome (ICANS) were observed.

One patient treated at the middle dose level presented with fever and died shortly after day 78 of an unknown cause during the COVID-19 pandemic. Two patients died of extramedullary disease; each had achieved MRD negativity.

Investigators continue to follow the patients and are enrolling new patients in the ongoing study.
 

‘Interesting approach’

Sandy W. Wong, MD, from the Helen Diller Family Comprehensive Cancer Center at the University of California San Francisco, who was not involved in the study, said in an interview that the dual-targeted approach is interesting, in light of a case report presented at ASH 2020 of a patient with multiple myeloma who had a partial response to CAR T-cell therapy with a different construct and who developed a subsequent biallelic loss of BCMA that resulted in resistance to CAR T-cell therapy.

“This raises the idea that, if we perhaps had a dual-targeted CAR T, perhaps we will prolong progression-free survival, in order to avoid antigen escape. So I do think the concept is very interesting and does deserve further study,” she said.

CD19 is thought to be expressed on myeloma stem cells, “so the question is: Are patients not being cured because there is a reservoir of myeloma cells, and targeting CD19 is thought to get at this putative myeloma stem cell? but that remains to be seen,” she added.

Dr. Wong comoderated the session where Dr. Fu presented the data.

The study was supported by participating medical centers and Gracell Biotechnologies. Dr. Fu and Dr. Wong reported no relevant conflicts of interest to disclose.

SOURCE: Jiang H et al. ASH 2020, Abstract 178.

An investigational chimeric antigen receptor T-cell (CAR T-cell) construct targeting two antigens on multiple myeloma cells showed promise in a first-in-humans trial, investigators said.

Among 16 patients with relapsed/refractory, heavily pretreated multiple myeloma who received the dual-targeting construct GC012F, the overall response rate was 93.8%, and all of six patients who received the cells at the highest of three dose levels had stringent complete responses (sCR) and were negative for minimal residual disease (MRD) at 6 months follow-up, reported Weijun Fu, MD, PhD, from Shanghai (China) Changzheng Hospital in an oral abstract presented during the virtual American Society of Hematology annual meeting.

GC012F is a novel CAR-T cell platform targeting both the B-cell maturation antigen (BCMA), which is universally expressed on malignant plasma cells, and CD19, which is expressed on both multiple myeloma cells and progenitors, Dr. Fu said.

“Targeting CD19 can trigger elimination of malignant cells by CAR T. Our preclinical work demonstrated more effective elimination of multiple myeloma clone-forming cells by BCMA and CD19 dual CAR T, so targeting both BCMA and CD19 antigens could improve efficacy and reduce relapse,” he said.

The construct is created using the FasTCAR platform that, according to manufacturer Gracell Biotechnologies (Shanghai), allows for cell culturing and expansion within 24-36 hours, rather than 2-3 weeks required for other CAR T-cell products.
 

Investigator-initiated trial

In a phase 1 investigator-initiated trial, 16 patients with a median age of 56 (range 27-71) years were enrolled. The patients all had relapsed or refractory multiple myeloma according to 2016 International Myeloma Working Group criteria, with a life expectancy of at least 3 months and adequate organ function.

The median time since diagnosis was 3 years (range 1-10). All but one of the 16 patients had high-risk disease, 3 had double-hit disease (the presence of two deletions, gain of function, or p53 mutation), and 5 patients had one or more extramedullary plasmacytomas. Four of the patients had received therapy with an anti-CD38 monoclonal antibody.

Following lymphodepletion with fludarabine and cyclophosphamide, the patients received the CAR T cells in a single infusion at dose levels of either 1, 2, or 3 times 10⁵ cells/kg.

As of the cutoff date in July 2020, 15 of the 16 patients had a clinical response, including 9 with a CR or sCR, and 6 with a very good partial response (VGPR). As noted before, all of the six patients treated at the highest dose level had a sCR. At the median follow-up of 7.3 months, the median duration of response had not been reached.

Among all patients evaluable for response at month 1 (14 patients), 11 were MRD negative by flow cytometry. At month 3 all 11 evaluable patients were MRD negative, and all of 10 patients evaluable at 6 months were also MRD negative.

As with other CAR T-cell constructs, all patients developed the cytokine-release syndrome (CRS), with grade 1 or 2 severity in 14 patients, and grade 3 in 2 patients. The median time to onset of CRS was 6 days (range 2-10), and the median duration was 4 days (range 1-8 days).

No cases of immune effector cell–associated neurotoxicity syndrome (ICANS) were observed.

One patient treated at the middle dose level presented with fever and died shortly after day 78 of an unknown cause during the COVID-19 pandemic. Two patients died of extramedullary disease; each had achieved MRD negativity.

Investigators continue to follow the patients and are enrolling new patients in the ongoing study.
 

‘Interesting approach’

Sandy W. Wong, MD, from the Helen Diller Family Comprehensive Cancer Center at the University of California San Francisco, who was not involved in the study, said in an interview that the dual-targeted approach is interesting, in light of a case report presented at ASH 2020 of a patient with multiple myeloma who had a partial response to CAR T-cell therapy with a different construct and who developed a subsequent biallelic loss of BCMA that resulted in resistance to CAR T-cell therapy.

“This raises the idea that, if we perhaps had a dual-targeted CAR T, perhaps we will prolong progression-free survival, in order to avoid antigen escape. So I do think the concept is very interesting and does deserve further study,” she said.

CD19 is thought to be expressed on myeloma stem cells, “so the question is: Are patients not being cured because there is a reservoir of myeloma cells, and targeting CD19 is thought to get at this putative myeloma stem cell? but that remains to be seen,” she added.

Dr. Wong comoderated the session where Dr. Fu presented the data.

The study was supported by participating medical centers and Gracell Biotechnologies. Dr. Fu and Dr. Wong reported no relevant conflicts of interest to disclose.

SOURCE: Jiang H et al. ASH 2020, Abstract 178.

A phase 1 first-in-human study demonstrated synthetic T-cell receptor and antigen receptor (STAR) technical feasibility, clinical safety and efficacy in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), according to senior study author Peihua Lu, MD, Beijing Lu Daopei Institute of Hematology, Beijing, China. STAR T cells were found to be superior to conventional chimeric antigen receptor (CAR) T cells with respect to signaling capacity, cytokine production and antitumor potency in an animal model study, according to Dr. Lu’s presentation at the annual meeting of the American Society of Hematology.
 

Remission can be improved

While CAR T-cell therapy has demonstrated high response rates in patients with B-cell malignancies, remission durability and safety can be improved, Dr Lu said. Her team developed STAR, a novel double-chain chimeric receptor consisting of two protein modules, each containing an antibody light or heavy chain variable region, the T cell receptor (TCR) alpha or beta chain constant region fused to the OX-40 costimulatory domain. The 2 modules are linked by a self-cleaving Furin-p2A sequence that allows the modules to be proteolytically separated and reconstituted. In preclinical in vitro research, STAR-T-cells showed a much faster and stronger cell activation, compared with CAR T cells and superior target cell–killing ability, and higher levels of interferon-y after coculture with the CD19+ Raji cell. In a murine in vivo study, STAR-T cells had higher antileukemia activity, compared with CAR-T cells, and significantly inhibited tumor cell growth, Dr. Lu stated. All animals were sustainably tumor free 5 days after STAR-T cell injection.

The first-in-human study included 18 CD19+ relapsed/refractory B-cell ALL (median age 22.5 years) patients, with a median bone marrow blast level pre–CAR T of 15.3%.

The manufacture success rate was 100% and took about 9 days (7-13). Transduction efficacy was 57.4% (41.0%-78.2%). Subjects received a conditioning regimen of intravenous fludarabine (25mg/m² per day) and cyclophosphamide (250mg/m² per day) for 3 days followed by a single STAR T-cell infusion. Patients were given the option, after they achieved complete remission (CR), of proceeding to consolidation allogeneic hematopoietic stem cell transplantation (allo-HSCT).
 

100% MRD negative

On day 14 following transplant, 18/18 had achieved minimal residual disease–negative complete response/CRi (with incomplete hematologic recovery). One patient relapsed after allogeneic transplant, becoming minimal residual disease positive on day 28. After a median follow-up of 105 days, 11/18 bridged into allo-HSCT without relapse. Among the seven patients who did not undergo allo-HSCT, one relapsed on day 58 and died on day 63. The patient had CNS leukemia and 87% bone marrow blasts before receiving STAR T. The others, Dr. Lu said, remain in CR.

Mild cytokine release syndrome (CRS) occurred in only 10 patients (55.6%), with grade 1 CRS in 8 patients and grade 2 in 2 patients. Grade 3 neurotoxicity occurred in two patients.

Reporting cellular kinetics of STAR T cells in peripheral blood by fluorescence-activated cell sorting (FACS)/quantitative PCR showed the highest STAR-T proliferation ratio (STAR/CD3) of 88.1%. Median peak level was 4.9 x 10⁴ copies number/mcg genomic DNA. The peak time was day 8.5 and the longest detection time was 6 months after STAR T infusion (STAR T ratio, 0.46%-1.85%). High in vivo proliferation and persistence was observed regardless of infusion dose.
 

STAR holds promise

Dr. Lu concluded: “The phase 1 first-in-human study demonstrated technical feasibility, clinical safety and efficacy of STAR T in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia.” She noted also that long-term observation of these patients and studies of larger patient cohorts are warranted to evaluate a beneficial advantage of the STAR T over the conventional CAR T product.

Asked about future directions in the discussion period, Dr. Lu responded that “this product holds great promise, No. 1 because it is actually between a T-cell receptor and a CAR T, and so clearly has fewer side effects. It potentially can recognize and target the tumor intracellular antigen better than a conventional CAR T. It is easier to construct – and holds great promise for treating solid tumors.”

Dr. Lu reported that she had no relevant disclosures.

SOURCE: Lu P et al. ASH 2020, Abstract 270.

A phase 1 first-in-human study demonstrated synthetic T-cell receptor and antigen receptor (STAR) technical feasibility, clinical safety and efficacy in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), according to senior study author Peihua Lu, MD, Beijing Lu Daopei Institute of Hematology, Beijing, China. STAR T cells were found to be superior to conventional chimeric antigen receptor (CAR) T cells with respect to signaling capacity, cytokine production and antitumor potency in an animal model study, according to Dr. Lu’s presentation at the annual meeting of the American Society of Hematology.
 

Remission can be improved

While CAR T-cell therapy has demonstrated high response rates in patients with B-cell malignancies, remission durability and safety can be improved, Dr Lu said. Her team developed STAR, a novel double-chain chimeric receptor consisting of two protein modules, each containing an antibody light or heavy chain variable region, the T cell receptor (TCR) alpha or beta chain constant region fused to the OX-40 costimulatory domain. The 2 modules are linked by a self-cleaving Furin-p2A sequence that allows the modules to be proteolytically separated and reconstituted. In preclinical in vitro research, STAR-T-cells showed a much faster and stronger cell activation, compared with CAR T cells and superior target cell–killing ability, and higher levels of interferon-y after coculture with the CD19+ Raji cell. In a murine in vivo study, STAR-T cells had higher antileukemia activity, compared with CAR-T cells, and significantly inhibited tumor cell growth, Dr. Lu stated. All animals were sustainably tumor free 5 days after STAR-T cell injection.

The first-in-human study included 18 CD19+ relapsed/refractory B-cell ALL (median age 22.5 years) patients, with a median bone marrow blast level pre–CAR T of 15.3%.

The manufacture success rate was 100% and took about 9 days (7-13). Transduction efficacy was 57.4% (41.0%-78.2%). Subjects received a conditioning regimen of intravenous fludarabine (25mg/m² per day) and cyclophosphamide (250mg/m² per day) for 3 days followed by a single STAR T-cell infusion. Patients were given the option, after they achieved complete remission (CR), of proceeding to consolidation allogeneic hematopoietic stem cell transplantation (allo-HSCT).
 

100% MRD negative

On day 14 following transplant, 18/18 had achieved minimal residual disease–negative complete response/CRi (with incomplete hematologic recovery). One patient relapsed after allogeneic transplant, becoming minimal residual disease positive on day 28. After a median follow-up of 105 days, 11/18 bridged into allo-HSCT without relapse. Among the seven patients who did not undergo allo-HSCT, one relapsed on day 58 and died on day 63. The patient had CNS leukemia and 87% bone marrow blasts before receiving STAR T. The others, Dr. Lu said, remain in CR.

Mild cytokine release syndrome (CRS) occurred in only 10 patients (55.6%), with grade 1 CRS in 8 patients and grade 2 in 2 patients. Grade 3 neurotoxicity occurred in two patients.

Reporting cellular kinetics of STAR T cells in peripheral blood by fluorescence-activated cell sorting (FACS)/quantitative PCR showed the highest STAR-T proliferation ratio (STAR/CD3) of 88.1%. Median peak level was 4.9 x 10⁴ copies number/mcg genomic DNA. The peak time was day 8.5 and the longest detection time was 6 months after STAR T infusion (STAR T ratio, 0.46%-1.85%). High in vivo proliferation and persistence was observed regardless of infusion dose.
 

STAR holds promise

Dr. Lu concluded: “The phase 1 first-in-human study demonstrated technical feasibility, clinical safety and efficacy of STAR T in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia.” She noted also that long-term observation of these patients and studies of larger patient cohorts are warranted to evaluate a beneficial advantage of the STAR T over the conventional CAR T product.

Asked about future directions in the discussion period, Dr. Lu responded that “this product holds great promise, No. 1 because it is actually between a T-cell receptor and a CAR T, and so clearly has fewer side effects. It potentially can recognize and target the tumor intracellular antigen better than a conventional CAR T. It is easier to construct – and holds great promise for treating solid tumors.”

Dr. Lu reported that she had no relevant disclosures.

SOURCE: Lu P et al. ASH 2020, Abstract 270.

A phase 1 first-in-human study demonstrated synthetic T-cell receptor and antigen receptor (STAR) technical feasibility, clinical safety and efficacy in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), according to senior study author Peihua Lu, MD, Beijing Lu Daopei Institute of Hematology, Beijing, China. STAR T cells were found to be superior to conventional chimeric antigen receptor (CAR) T cells with respect to signaling capacity, cytokine production and antitumor potency in an animal model study, according to Dr. Lu’s presentation at the annual meeting of the American Society of Hematology.
 

Remission can be improved

While CAR T-cell therapy has demonstrated high response rates in patients with B-cell malignancies, remission durability and safety can be improved, Dr Lu said. Her team developed STAR, a novel double-chain chimeric receptor consisting of two protein modules, each containing an antibody light or heavy chain variable region, the T cell receptor (TCR) alpha or beta chain constant region fused to the OX-40 costimulatory domain. The 2 modules are linked by a self-cleaving Furin-p2A sequence that allows the modules to be proteolytically separated and reconstituted. In preclinical in vitro research, STAR-T-cells showed a much faster and stronger cell activation, compared with CAR T cells and superior target cell–killing ability, and higher levels of interferon-y after coculture with the CD19+ Raji cell. In a murine in vivo study, STAR-T cells had higher antileukemia activity, compared with CAR-T cells, and significantly inhibited tumor cell growth, Dr. Lu stated. All animals were sustainably tumor free 5 days after STAR-T cell injection.

The first-in-human study included 18 CD19+ relapsed/refractory B-cell ALL (median age 22.5 years) patients, with a median bone marrow blast level pre–CAR T of 15.3%.

The manufacture success rate was 100% and took about 9 days (7-13). Transduction efficacy was 57.4% (41.0%-78.2%). Subjects received a conditioning regimen of intravenous fludarabine (25mg/m² per day) and cyclophosphamide (250mg/m² per day) for 3 days followed by a single STAR T-cell infusion. Patients were given the option, after they achieved complete remission (CR), of proceeding to consolidation allogeneic hematopoietic stem cell transplantation (allo-HSCT).
 

100% MRD negative

On day 14 following transplant, 18/18 had achieved minimal residual disease–negative complete response/CRi (with incomplete hematologic recovery). One patient relapsed after allogeneic transplant, becoming minimal residual disease positive on day 28. After a median follow-up of 105 days, 11/18 bridged into allo-HSCT without relapse. Among the seven patients who did not undergo allo-HSCT, one relapsed on day 58 and died on day 63. The patient had CNS leukemia and 87% bone marrow blasts before receiving STAR T. The others, Dr. Lu said, remain in CR.

Mild cytokine release syndrome (CRS) occurred in only 10 patients (55.6%), with grade 1 CRS in 8 patients and grade 2 in 2 patients. Grade 3 neurotoxicity occurred in two patients.

Reporting cellular kinetics of STAR T cells in peripheral blood by fluorescence-activated cell sorting (FACS)/quantitative PCR showed the highest STAR-T proliferation ratio (STAR/CD3) of 88.1%. Median peak level was 4.9 x 10⁴ copies number/mcg genomic DNA. The peak time was day 8.5 and the longest detection time was 6 months after STAR T infusion (STAR T ratio, 0.46%-1.85%). High in vivo proliferation and persistence was observed regardless of infusion dose.
 

STAR holds promise

Dr. Lu concluded: “The phase 1 first-in-human study demonstrated technical feasibility, clinical safety and efficacy of STAR T in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia.” She noted also that long-term observation of these patients and studies of larger patient cohorts are warranted to evaluate a beneficial advantage of the STAR T over the conventional CAR T product.

Asked about future directions in the discussion period, Dr. Lu responded that “this product holds great promise, No. 1 because it is actually between a T-cell receptor and a CAR T, and so clearly has fewer side effects. It potentially can recognize and target the tumor intracellular antigen better than a conventional CAR T. It is easier to construct – and holds great promise for treating solid tumors.”

Dr. Lu reported that she had no relevant disclosures.

SOURCE: Lu P et al. ASH 2020, Abstract 270.