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Immunotherapy for ALL: Roles emerge in R/R disease, MRD+ disease
“Most of the emerging therapies in ALL are immunotherapies that have really made an impact in the relapsed and refractory setting,” he said during a presentation at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress. “Another very exciting development is that these immunotherapies are now demonstrating efficacy and increased tolerability over chemotherapy in the minimal residual disease (MRD)-positive setting up front.”
Dr. Brown, director of the pediatric leukemia program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, focused on blinatumomab, inotuzumab, and chimeric antigen receptor (CAR) T-cell therapy for ALL, and explained the rationale for their use.
Why immunotherapy?
“It turns out that in normal B cell development there are a number of proteins that are expressed on the surface of B cells and these same proteins are expressed on the surface of many B-cell malignancies,” he said, noting that ALL is “probably the least differentiated of the B-lineage malignancies,” but the vast majority of ALL cases will express CD19 and CD22, and – in adults more often than pediatric patients – CD20.
These antigens make good targets for ALL therapy because they aren’t expressed on bone marrow stem cells or other tissues in the body.
“They really are specific for B cells,” he said, explaining that inotuzumab, a CD22 antibody drug conjugate (ADC), and blinatumomab, a bi-specific T cell-engaging antibody (BiTE) that targets CD19, are antibody-based immunotherapies, whereas CAR T-cell therapies are a separate category that can be single- or multi-antigen targeted.
Inotuzumab, blinatumomab, and CAR T cells
Inotuzumab targets the CD22 immunotoxin antigen via a T-cell independent process and is delivered as a once-weekly 1-hour infusion. It is approved for adult relapsed/refractory B-ALL. Blinatumomab binds CD19 on the surface of the tumor cells and CD3 on the surface of any T cell in the vicinity of the tumor cell.
“The recognition that blinatumomab allows between the tumor cell and the T cell is independent of the specificity of the T-cell receptor. It also does not require [major histocompatibility complex] class 1 or peptide antigens on the surface of the T cell,” he said, adding that it does, however, rely on a functional endogenous cytotoxic T-cell response, unlike inotuzumab. “It’s also very difficult technically to give because it’s given as a 28-day continuous IV infusion with bag changes required every 4-7 days.”
Blinatumomab is approved for adult and pediatric Philadelphia chromosome-negative relapsed/refractory B-cell precursor ALL and MRD-positive B-cell precursor ALL.
CAR T-cell therapy, an autologous immunotherapy, is “really kind of the pinnacle of technological advances in immunotherapy in that it combine three different modalities into one: cellular therapy, gene therapy, and immunotherapy,” he said, noting that the process of genetically engineering T cells to express a CAR is complex and costly and access is limited, but expanding with about 90 centers in the U.S. now providing CAR T-cell therapy.
Response rates with each of these therapies represent a paradigm shift in the relapsed/refractory ALL setting, Dr. Brown said.
Studies have shown complete remission (CR) and minimum residual disease (MRD)-negative CR rates of 81% and 78%, respectively, with inotuzumab, and 43% and 33%, respectively, with blinatumomab.
“This depth of remission was really not seen with prior salvage therapies,” he noted, but added that neither has shown significant durable improvement in overall survival (OS) rates.
CAR T-cell therapy, however, has the highest response rates, with tisagenlecleucel – which targets CD19 and was the first CAR T-cell therapy approved for refractory or second or greater relapse in patients up to age 26 years – showing 81% CR and MRD-negative CR rates and providing a durable survival advantage without subsequent therapy in 40-50% of patients.
“So CAR T cells can represent definitive therapy in a subset of patients,” Dr. Brown said. “One thing we’re struggling with is to be able to predict which patients those are, and there are some emerging biomarkers that may help us with that, but as of now it’s very difficult to predict which patients, when you’re treating them, are going to be in [that group].”
Toxicities and limitations
Cytokine release syndrome and neurotoxicity are the primary toxicities associated with both blinatumomab and tisagenlecleucel. Hepatotoxicity is a major concern with inotuzumab.
“This is particularly important because that hepatotoxicity appears to be primarily a problem in patients who receive inotuzumab either after or prior to hematopoietic stem cell transplant, and since this therapy does not represent definitive therapy and often is really a bridge to transplant, this ... can be a significant limitation to this product,” Dr. Brown said.
A limitation of CAR T cells is failure to manufacture the product, which occurs most often in very young and heavily pretreated patients in whom it can be difficult to obtain enough functional T cells to create the product. Failure to engraft or lack of persistence of the CAR T cells can also occur.
Endogenous or CAR T-cell exhaustion is another potential limitation with blinatumomab and CAR T-cell therapy, and antigen escape can occur with both therapies, as well.
Strategies are being investigated to overcome treatment challenges, Dr. Brown noted.
Examples include efforts to develop universal “off-the-shelf” allogeneic CAR T-cell products to address failure to manufacture, working on more co-stimulatory domains that may be more effective to promote engraftment and persistence, adding immune checkpoint inhibitors to therapy to combat endogenous or CAR T-cell exhaustion, and developing multi-antigen targeted approaches to overcome antigen escape, he said.
NCCN Treatment Guidelines
Based on the currently available data, the NCCN has included these immunotherapies in guidelines for both adolescent and young adult (AYA)/adult ALL and for pediatric ALL.
Each of the treatments is listed as an option to consider in both Philadelphia chromosome-positive and -negative AYA and adult patients under age 65 years. Additionally, blinatumomab is listed as an option for up-front treatment of MRD-positive Philadelphia chromosome-negative AYA patients and older patients.
Pediatric guidelines include blinatumomab and tisagenlecleucel as options for patients with MRD-positive disease after induction and for first relapse, and they include all three therapies as options in patients with multiple relapses or refractory disease, said Dr. Brown who chairs the NCCN Clinical Practice Guidelines panel for adult and pediatric ALL.
Treatment decision making
Asked by session moderator Ranjana H. Advani, MD, how to decide between the available immunotherapies, Dr. Brown said there is no one-size-fits-all answer.
“Is it availability, insurance coverage, the patient fits better with one therapy,” asked Dr. Advani, the Saul Rosenberg Professor of Lymphoma and the Physician Leader of the Lymphoma Clinical Care Program of Stanford Cancer Institute, Palo Alto, Calif.
“All of the above,” Dr. Brown said. “In 2020 with all these options available, we are a little bit spoiled for choice ... but every patient is an individual case and the risk -benefit ratios of all these therapies differ.”
An exception is that CAR T-cell therapy is a clear stand-out for the patient who isn’t transplant eligible, he noted, adding that CAR T cells “probably give that patient the best chance of survival.”
In a patient who could potentially go to transplant, selection is a bit more challenging, but given the risks associated with inotuzumab, blinatumomab is generally the preferred non-CAR T option, he said.
“It’s a complicated question, and the answer ... is [that it is] an individualized patient-by-patient decision,” he added.
Dr. Brown reported consulting, advisory board, or expert witness activity for Novartis Pharmaceuticals Corporation and Takeda Pharmaceuticals North America Inc.
“Most of the emerging therapies in ALL are immunotherapies that have really made an impact in the relapsed and refractory setting,” he said during a presentation at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress. “Another very exciting development is that these immunotherapies are now demonstrating efficacy and increased tolerability over chemotherapy in the minimal residual disease (MRD)-positive setting up front.”
Dr. Brown, director of the pediatric leukemia program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, focused on blinatumomab, inotuzumab, and chimeric antigen receptor (CAR) T-cell therapy for ALL, and explained the rationale for their use.
Why immunotherapy?
“It turns out that in normal B cell development there are a number of proteins that are expressed on the surface of B cells and these same proteins are expressed on the surface of many B-cell malignancies,” he said, noting that ALL is “probably the least differentiated of the B-lineage malignancies,” but the vast majority of ALL cases will express CD19 and CD22, and – in adults more often than pediatric patients – CD20.
These antigens make good targets for ALL therapy because they aren’t expressed on bone marrow stem cells or other tissues in the body.
“They really are specific for B cells,” he said, explaining that inotuzumab, a CD22 antibody drug conjugate (ADC), and blinatumomab, a bi-specific T cell-engaging antibody (BiTE) that targets CD19, are antibody-based immunotherapies, whereas CAR T-cell therapies are a separate category that can be single- or multi-antigen targeted.
Inotuzumab, blinatumomab, and CAR T cells
Inotuzumab targets the CD22 immunotoxin antigen via a T-cell independent process and is delivered as a once-weekly 1-hour infusion. It is approved for adult relapsed/refractory B-ALL. Blinatumomab binds CD19 on the surface of the tumor cells and CD3 on the surface of any T cell in the vicinity of the tumor cell.
“The recognition that blinatumomab allows between the tumor cell and the T cell is independent of the specificity of the T-cell receptor. It also does not require [major histocompatibility complex] class 1 or peptide antigens on the surface of the T cell,” he said, adding that it does, however, rely on a functional endogenous cytotoxic T-cell response, unlike inotuzumab. “It’s also very difficult technically to give because it’s given as a 28-day continuous IV infusion with bag changes required every 4-7 days.”
Blinatumomab is approved for adult and pediatric Philadelphia chromosome-negative relapsed/refractory B-cell precursor ALL and MRD-positive B-cell precursor ALL.
CAR T-cell therapy, an autologous immunotherapy, is “really kind of the pinnacle of technological advances in immunotherapy in that it combine three different modalities into one: cellular therapy, gene therapy, and immunotherapy,” he said, noting that the process of genetically engineering T cells to express a CAR is complex and costly and access is limited, but expanding with about 90 centers in the U.S. now providing CAR T-cell therapy.
Response rates with each of these therapies represent a paradigm shift in the relapsed/refractory ALL setting, Dr. Brown said.
Studies have shown complete remission (CR) and minimum residual disease (MRD)-negative CR rates of 81% and 78%, respectively, with inotuzumab, and 43% and 33%, respectively, with blinatumomab.
“This depth of remission was really not seen with prior salvage therapies,” he noted, but added that neither has shown significant durable improvement in overall survival (OS) rates.
CAR T-cell therapy, however, has the highest response rates, with tisagenlecleucel – which targets CD19 and was the first CAR T-cell therapy approved for refractory or second or greater relapse in patients up to age 26 years – showing 81% CR and MRD-negative CR rates and providing a durable survival advantage without subsequent therapy in 40-50% of patients.
“So CAR T cells can represent definitive therapy in a subset of patients,” Dr. Brown said. “One thing we’re struggling with is to be able to predict which patients those are, and there are some emerging biomarkers that may help us with that, but as of now it’s very difficult to predict which patients, when you’re treating them, are going to be in [that group].”
Toxicities and limitations
Cytokine release syndrome and neurotoxicity are the primary toxicities associated with both blinatumomab and tisagenlecleucel. Hepatotoxicity is a major concern with inotuzumab.
“This is particularly important because that hepatotoxicity appears to be primarily a problem in patients who receive inotuzumab either after or prior to hematopoietic stem cell transplant, and since this therapy does not represent definitive therapy and often is really a bridge to transplant, this ... can be a significant limitation to this product,” Dr. Brown said.
A limitation of CAR T cells is failure to manufacture the product, which occurs most often in very young and heavily pretreated patients in whom it can be difficult to obtain enough functional T cells to create the product. Failure to engraft or lack of persistence of the CAR T cells can also occur.
Endogenous or CAR T-cell exhaustion is another potential limitation with blinatumomab and CAR T-cell therapy, and antigen escape can occur with both therapies, as well.
Strategies are being investigated to overcome treatment challenges, Dr. Brown noted.
Examples include efforts to develop universal “off-the-shelf” allogeneic CAR T-cell products to address failure to manufacture, working on more co-stimulatory domains that may be more effective to promote engraftment and persistence, adding immune checkpoint inhibitors to therapy to combat endogenous or CAR T-cell exhaustion, and developing multi-antigen targeted approaches to overcome antigen escape, he said.
NCCN Treatment Guidelines
Based on the currently available data, the NCCN has included these immunotherapies in guidelines for both adolescent and young adult (AYA)/adult ALL and for pediatric ALL.
Each of the treatments is listed as an option to consider in both Philadelphia chromosome-positive and -negative AYA and adult patients under age 65 years. Additionally, blinatumomab is listed as an option for up-front treatment of MRD-positive Philadelphia chromosome-negative AYA patients and older patients.
Pediatric guidelines include blinatumomab and tisagenlecleucel as options for patients with MRD-positive disease after induction and for first relapse, and they include all three therapies as options in patients with multiple relapses or refractory disease, said Dr. Brown who chairs the NCCN Clinical Practice Guidelines panel for adult and pediatric ALL.
Treatment decision making
Asked by session moderator Ranjana H. Advani, MD, how to decide between the available immunotherapies, Dr. Brown said there is no one-size-fits-all answer.
“Is it availability, insurance coverage, the patient fits better with one therapy,” asked Dr. Advani, the Saul Rosenberg Professor of Lymphoma and the Physician Leader of the Lymphoma Clinical Care Program of Stanford Cancer Institute, Palo Alto, Calif.
“All of the above,” Dr. Brown said. “In 2020 with all these options available, we are a little bit spoiled for choice ... but every patient is an individual case and the risk -benefit ratios of all these therapies differ.”
An exception is that CAR T-cell therapy is a clear stand-out for the patient who isn’t transplant eligible, he noted, adding that CAR T cells “probably give that patient the best chance of survival.”
In a patient who could potentially go to transplant, selection is a bit more challenging, but given the risks associated with inotuzumab, blinatumomab is generally the preferred non-CAR T option, he said.
“It’s a complicated question, and the answer ... is [that it is] an individualized patient-by-patient decision,” he added.
Dr. Brown reported consulting, advisory board, or expert witness activity for Novartis Pharmaceuticals Corporation and Takeda Pharmaceuticals North America Inc.
“Most of the emerging therapies in ALL are immunotherapies that have really made an impact in the relapsed and refractory setting,” he said during a presentation at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress. “Another very exciting development is that these immunotherapies are now demonstrating efficacy and increased tolerability over chemotherapy in the minimal residual disease (MRD)-positive setting up front.”
Dr. Brown, director of the pediatric leukemia program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, focused on blinatumomab, inotuzumab, and chimeric antigen receptor (CAR) T-cell therapy for ALL, and explained the rationale for their use.
Why immunotherapy?
“It turns out that in normal B cell development there are a number of proteins that are expressed on the surface of B cells and these same proteins are expressed on the surface of many B-cell malignancies,” he said, noting that ALL is “probably the least differentiated of the B-lineage malignancies,” but the vast majority of ALL cases will express CD19 and CD22, and – in adults more often than pediatric patients – CD20.
These antigens make good targets for ALL therapy because they aren’t expressed on bone marrow stem cells or other tissues in the body.
“They really are specific for B cells,” he said, explaining that inotuzumab, a CD22 antibody drug conjugate (ADC), and blinatumomab, a bi-specific T cell-engaging antibody (BiTE) that targets CD19, are antibody-based immunotherapies, whereas CAR T-cell therapies are a separate category that can be single- or multi-antigen targeted.
Inotuzumab, blinatumomab, and CAR T cells
Inotuzumab targets the CD22 immunotoxin antigen via a T-cell independent process and is delivered as a once-weekly 1-hour infusion. It is approved for adult relapsed/refractory B-ALL. Blinatumomab binds CD19 on the surface of the tumor cells and CD3 on the surface of any T cell in the vicinity of the tumor cell.
“The recognition that blinatumomab allows between the tumor cell and the T cell is independent of the specificity of the T-cell receptor. It also does not require [major histocompatibility complex] class 1 or peptide antigens on the surface of the T cell,” he said, adding that it does, however, rely on a functional endogenous cytotoxic T-cell response, unlike inotuzumab. “It’s also very difficult technically to give because it’s given as a 28-day continuous IV infusion with bag changes required every 4-7 days.”
Blinatumomab is approved for adult and pediatric Philadelphia chromosome-negative relapsed/refractory B-cell precursor ALL and MRD-positive B-cell precursor ALL.
CAR T-cell therapy, an autologous immunotherapy, is “really kind of the pinnacle of technological advances in immunotherapy in that it combine three different modalities into one: cellular therapy, gene therapy, and immunotherapy,” he said, noting that the process of genetically engineering T cells to express a CAR is complex and costly and access is limited, but expanding with about 90 centers in the U.S. now providing CAR T-cell therapy.
Response rates with each of these therapies represent a paradigm shift in the relapsed/refractory ALL setting, Dr. Brown said.
Studies have shown complete remission (CR) and minimum residual disease (MRD)-negative CR rates of 81% and 78%, respectively, with inotuzumab, and 43% and 33%, respectively, with blinatumomab.
“This depth of remission was really not seen with prior salvage therapies,” he noted, but added that neither has shown significant durable improvement in overall survival (OS) rates.
CAR T-cell therapy, however, has the highest response rates, with tisagenlecleucel – which targets CD19 and was the first CAR T-cell therapy approved for refractory or second or greater relapse in patients up to age 26 years – showing 81% CR and MRD-negative CR rates and providing a durable survival advantage without subsequent therapy in 40-50% of patients.
“So CAR T cells can represent definitive therapy in a subset of patients,” Dr. Brown said. “One thing we’re struggling with is to be able to predict which patients those are, and there are some emerging biomarkers that may help us with that, but as of now it’s very difficult to predict which patients, when you’re treating them, are going to be in [that group].”
Toxicities and limitations
Cytokine release syndrome and neurotoxicity are the primary toxicities associated with both blinatumomab and tisagenlecleucel. Hepatotoxicity is a major concern with inotuzumab.
“This is particularly important because that hepatotoxicity appears to be primarily a problem in patients who receive inotuzumab either after or prior to hematopoietic stem cell transplant, and since this therapy does not represent definitive therapy and often is really a bridge to transplant, this ... can be a significant limitation to this product,” Dr. Brown said.
A limitation of CAR T cells is failure to manufacture the product, which occurs most often in very young and heavily pretreated patients in whom it can be difficult to obtain enough functional T cells to create the product. Failure to engraft or lack of persistence of the CAR T cells can also occur.
Endogenous or CAR T-cell exhaustion is another potential limitation with blinatumomab and CAR T-cell therapy, and antigen escape can occur with both therapies, as well.
Strategies are being investigated to overcome treatment challenges, Dr. Brown noted.
Examples include efforts to develop universal “off-the-shelf” allogeneic CAR T-cell products to address failure to manufacture, working on more co-stimulatory domains that may be more effective to promote engraftment and persistence, adding immune checkpoint inhibitors to therapy to combat endogenous or CAR T-cell exhaustion, and developing multi-antigen targeted approaches to overcome antigen escape, he said.
NCCN Treatment Guidelines
Based on the currently available data, the NCCN has included these immunotherapies in guidelines for both adolescent and young adult (AYA)/adult ALL and for pediatric ALL.
Each of the treatments is listed as an option to consider in both Philadelphia chromosome-positive and -negative AYA and adult patients under age 65 years. Additionally, blinatumomab is listed as an option for up-front treatment of MRD-positive Philadelphia chromosome-negative AYA patients and older patients.
Pediatric guidelines include blinatumomab and tisagenlecleucel as options for patients with MRD-positive disease after induction and for first relapse, and they include all three therapies as options in patients with multiple relapses or refractory disease, said Dr. Brown who chairs the NCCN Clinical Practice Guidelines panel for adult and pediatric ALL.
Treatment decision making
Asked by session moderator Ranjana H. Advani, MD, how to decide between the available immunotherapies, Dr. Brown said there is no one-size-fits-all answer.
“Is it availability, insurance coverage, the patient fits better with one therapy,” asked Dr. Advani, the Saul Rosenberg Professor of Lymphoma and the Physician Leader of the Lymphoma Clinical Care Program of Stanford Cancer Institute, Palo Alto, Calif.
“All of the above,” Dr. Brown said. “In 2020 with all these options available, we are a little bit spoiled for choice ... but every patient is an individual case and the risk -benefit ratios of all these therapies differ.”
An exception is that CAR T-cell therapy is a clear stand-out for the patient who isn’t transplant eligible, he noted, adding that CAR T cells “probably give that patient the best chance of survival.”
In a patient who could potentially go to transplant, selection is a bit more challenging, but given the risks associated with inotuzumab, blinatumomab is generally the preferred non-CAR T option, he said.
“It’s a complicated question, and the answer ... is [that it is] an individualized patient-by-patient decision,” he added.
Dr. Brown reported consulting, advisory board, or expert witness activity for Novartis Pharmaceuticals Corporation and Takeda Pharmaceuticals North America Inc.
FROM NCCN HEMATOLOGIC MALIGNANCIES
CAR T for all R/R DLBCL patients: The jury is still out
Is it time to consider chimeric antigen receptor (CAR) T-cell therapy for all relapsed/refractory diffuse large B-cell lymphoma patients? Maybe not, according to Andrew Zelenetz, MD, PhD.
CAR T-cell therapy has demonstrated activity in relapsed/refractory non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), transformed indolent NHL, and mantle cell lymphoma, and can provide durable complete responses in a portion of patients with chemorefractory disease, Dr. Zelenetz, chair of the National Comprehensive Cancer Network Lymphoma Guidelines Panel and a specialist in lymphoma at Memorial Sloan Kettering Cancer Center in New York, said at the NCCN Hematologic Malignancies Annual Congress.
In chemosensitive patients, however, its role requires further examination, especially given findings from a recent analysis of patients from the Center for International Blood & Marrow Transplant Research (CIBMTR) registry showing comparable outcomes with high-dose chemotherapy and autologous stem cell rescue for patients with a positron emission testing–positive partial response (PR) after second-line chemotherapy, he said.
Of 249 patients who underwent a first autologous transplant for DLBCL between 2003 and 2018, received front-line rituximab chemotherapy, and had PET– or computed tomography–positive disease prior to transplant, 182 had early chemotherapy failure (within 12 months) and 67 had late chemotherapy failure (at 12 months or later) after therapy, according to findings from the study as reported at ASCO 2020.
The adjusted nonrelapse mortality rates in the early- and late-failure patients, respectively, were not significantly different at 7% and 3% at 1 year, and at 10% and 8% at 5 years. The corresponding progression/relapse rates were 41% and 35% at 1 year and 48% and 57% at 5 years; these were also not significantly different.
The adjusted progression-free survival (PFS) and overall survival (OS) in the groups at 5 years also did not differ significantly (PFS of 41% in both the early- and late-failure groups, and OS of 51% and 63%, respectively).
These outcomes are comparable to those seen with CAR T-cell therapy in refractory DLBCL patients in trials of CAR T-cell products, including the ZUMA-1 study of axicabtagene cyloleucel (Yescarta), which, in a 2019 update, showed survival plateaus of about 40% vs. the 5%-10% expected rate based on pre-CAR-T outcomes data; the JULIET trial of tisagenlecleucel (Kymriah), which showed survival plateaus in the range of 30%-35%; and the recently published TRANSCEND study of the investigational modified CAR-T product, lisocabtagene maraleucel, which also showed survival plateaus “in the range of 40%.”
“So all three agents are showing that CAR T cells represent a new treatment for diffuse large B-cell lymphoma in the relapsed/refractory setting,” Dr. Zelenetz said. “And as a result, [CAR T-cell therapy has] been included in the NCCN guidelines for transformed follicular lymphoma, for transformed marginal zone lymphoma, and for diffuse large B-cell lymphoma, as well as for refractory large B-cell lymphoma.
“But are CAR T cells absolutely required? Generally what we consider these days is that if you’re not in a PET-negative CR prior to high-dose therapy stem cell rescue, you should go on to CAR T cells,” Dr. Zelenetz said.
The analysis based on the CIBMTR registry data, however, suggests there may be other alternatives.
“The bottom line is that nonrelapse mortality was very low. Progression occurred in about half of the patients, but if we look at the overall and progression-free survival curves, there’s a plateau at around 45%,” Dr. Zelenetz said, explaining that the results are “very similar to the results that we’re getting in third-line treatment with CAR T cells, and this is a very similar population [of] PET-positive patients after second-line chemotherapy.”
CAR T-cell therapy can provide a durable CR in a portion of chemorefractory patients, and although there is room for improvement, “this represents a major step forward for these patients,” he said.
However, it’s not clear that CAR T cells are clearly superior to high-dose therapy and stem cell rescue for chemosensitive patients, he added, noting that “additional randomized trials are needed to answer this question, and they are ongoing as we speak.”
Dr. Zelenetz reported clinical research support or data safety monitoring board activity for BeiGene, Genentech, Juno Therapeutics, and MEI Pharma, and scientific advisory board, consulting, or expert witness activity for Celgene Corporation, Curries, Genentech, Gilead Sciences, Janssen Pharmaceutical Products, and several other pharmaceutical and biotechnology companies.
Is it time to consider chimeric antigen receptor (CAR) T-cell therapy for all relapsed/refractory diffuse large B-cell lymphoma patients? Maybe not, according to Andrew Zelenetz, MD, PhD.
CAR T-cell therapy has demonstrated activity in relapsed/refractory non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), transformed indolent NHL, and mantle cell lymphoma, and can provide durable complete responses in a portion of patients with chemorefractory disease, Dr. Zelenetz, chair of the National Comprehensive Cancer Network Lymphoma Guidelines Panel and a specialist in lymphoma at Memorial Sloan Kettering Cancer Center in New York, said at the NCCN Hematologic Malignancies Annual Congress.
In chemosensitive patients, however, its role requires further examination, especially given findings from a recent analysis of patients from the Center for International Blood & Marrow Transplant Research (CIBMTR) registry showing comparable outcomes with high-dose chemotherapy and autologous stem cell rescue for patients with a positron emission testing–positive partial response (PR) after second-line chemotherapy, he said.
Of 249 patients who underwent a first autologous transplant for DLBCL between 2003 and 2018, received front-line rituximab chemotherapy, and had PET– or computed tomography–positive disease prior to transplant, 182 had early chemotherapy failure (within 12 months) and 67 had late chemotherapy failure (at 12 months or later) after therapy, according to findings from the study as reported at ASCO 2020.
The adjusted nonrelapse mortality rates in the early- and late-failure patients, respectively, were not significantly different at 7% and 3% at 1 year, and at 10% and 8% at 5 years. The corresponding progression/relapse rates were 41% and 35% at 1 year and 48% and 57% at 5 years; these were also not significantly different.
The adjusted progression-free survival (PFS) and overall survival (OS) in the groups at 5 years also did not differ significantly (PFS of 41% in both the early- and late-failure groups, and OS of 51% and 63%, respectively).
These outcomes are comparable to those seen with CAR T-cell therapy in refractory DLBCL patients in trials of CAR T-cell products, including the ZUMA-1 study of axicabtagene cyloleucel (Yescarta), which, in a 2019 update, showed survival plateaus of about 40% vs. the 5%-10% expected rate based on pre-CAR-T outcomes data; the JULIET trial of tisagenlecleucel (Kymriah), which showed survival plateaus in the range of 30%-35%; and the recently published TRANSCEND study of the investigational modified CAR-T product, lisocabtagene maraleucel, which also showed survival plateaus “in the range of 40%.”
“So all three agents are showing that CAR T cells represent a new treatment for diffuse large B-cell lymphoma in the relapsed/refractory setting,” Dr. Zelenetz said. “And as a result, [CAR T-cell therapy has] been included in the NCCN guidelines for transformed follicular lymphoma, for transformed marginal zone lymphoma, and for diffuse large B-cell lymphoma, as well as for refractory large B-cell lymphoma.
“But are CAR T cells absolutely required? Generally what we consider these days is that if you’re not in a PET-negative CR prior to high-dose therapy stem cell rescue, you should go on to CAR T cells,” Dr. Zelenetz said.
The analysis based on the CIBMTR registry data, however, suggests there may be other alternatives.
“The bottom line is that nonrelapse mortality was very low. Progression occurred in about half of the patients, but if we look at the overall and progression-free survival curves, there’s a plateau at around 45%,” Dr. Zelenetz said, explaining that the results are “very similar to the results that we’re getting in third-line treatment with CAR T cells, and this is a very similar population [of] PET-positive patients after second-line chemotherapy.”
CAR T-cell therapy can provide a durable CR in a portion of chemorefractory patients, and although there is room for improvement, “this represents a major step forward for these patients,” he said.
However, it’s not clear that CAR T cells are clearly superior to high-dose therapy and stem cell rescue for chemosensitive patients, he added, noting that “additional randomized trials are needed to answer this question, and they are ongoing as we speak.”
Dr. Zelenetz reported clinical research support or data safety monitoring board activity for BeiGene, Genentech, Juno Therapeutics, and MEI Pharma, and scientific advisory board, consulting, or expert witness activity for Celgene Corporation, Curries, Genentech, Gilead Sciences, Janssen Pharmaceutical Products, and several other pharmaceutical and biotechnology companies.
Is it time to consider chimeric antigen receptor (CAR) T-cell therapy for all relapsed/refractory diffuse large B-cell lymphoma patients? Maybe not, according to Andrew Zelenetz, MD, PhD.
CAR T-cell therapy has demonstrated activity in relapsed/refractory non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), transformed indolent NHL, and mantle cell lymphoma, and can provide durable complete responses in a portion of patients with chemorefractory disease, Dr. Zelenetz, chair of the National Comprehensive Cancer Network Lymphoma Guidelines Panel and a specialist in lymphoma at Memorial Sloan Kettering Cancer Center in New York, said at the NCCN Hematologic Malignancies Annual Congress.
In chemosensitive patients, however, its role requires further examination, especially given findings from a recent analysis of patients from the Center for International Blood & Marrow Transplant Research (CIBMTR) registry showing comparable outcomes with high-dose chemotherapy and autologous stem cell rescue for patients with a positron emission testing–positive partial response (PR) after second-line chemotherapy, he said.
Of 249 patients who underwent a first autologous transplant for DLBCL between 2003 and 2018, received front-line rituximab chemotherapy, and had PET– or computed tomography–positive disease prior to transplant, 182 had early chemotherapy failure (within 12 months) and 67 had late chemotherapy failure (at 12 months or later) after therapy, according to findings from the study as reported at ASCO 2020.
The adjusted nonrelapse mortality rates in the early- and late-failure patients, respectively, were not significantly different at 7% and 3% at 1 year, and at 10% and 8% at 5 years. The corresponding progression/relapse rates were 41% and 35% at 1 year and 48% and 57% at 5 years; these were also not significantly different.
The adjusted progression-free survival (PFS) and overall survival (OS) in the groups at 5 years also did not differ significantly (PFS of 41% in both the early- and late-failure groups, and OS of 51% and 63%, respectively).
These outcomes are comparable to those seen with CAR T-cell therapy in refractory DLBCL patients in trials of CAR T-cell products, including the ZUMA-1 study of axicabtagene cyloleucel (Yescarta), which, in a 2019 update, showed survival plateaus of about 40% vs. the 5%-10% expected rate based on pre-CAR-T outcomes data; the JULIET trial of tisagenlecleucel (Kymriah), which showed survival plateaus in the range of 30%-35%; and the recently published TRANSCEND study of the investigational modified CAR-T product, lisocabtagene maraleucel, which also showed survival plateaus “in the range of 40%.”
“So all three agents are showing that CAR T cells represent a new treatment for diffuse large B-cell lymphoma in the relapsed/refractory setting,” Dr. Zelenetz said. “And as a result, [CAR T-cell therapy has] been included in the NCCN guidelines for transformed follicular lymphoma, for transformed marginal zone lymphoma, and for diffuse large B-cell lymphoma, as well as for refractory large B-cell lymphoma.
“But are CAR T cells absolutely required? Generally what we consider these days is that if you’re not in a PET-negative CR prior to high-dose therapy stem cell rescue, you should go on to CAR T cells,” Dr. Zelenetz said.
The analysis based on the CIBMTR registry data, however, suggests there may be other alternatives.
“The bottom line is that nonrelapse mortality was very low. Progression occurred in about half of the patients, but if we look at the overall and progression-free survival curves, there’s a plateau at around 45%,” Dr. Zelenetz said, explaining that the results are “very similar to the results that we’re getting in third-line treatment with CAR T cells, and this is a very similar population [of] PET-positive patients after second-line chemotherapy.”
CAR T-cell therapy can provide a durable CR in a portion of chemorefractory patients, and although there is room for improvement, “this represents a major step forward for these patients,” he said.
However, it’s not clear that CAR T cells are clearly superior to high-dose therapy and stem cell rescue for chemosensitive patients, he added, noting that “additional randomized trials are needed to answer this question, and they are ongoing as we speak.”
Dr. Zelenetz reported clinical research support or data safety monitoring board activity for BeiGene, Genentech, Juno Therapeutics, and MEI Pharma, and scientific advisory board, consulting, or expert witness activity for Celgene Corporation, Curries, Genentech, Gilead Sciences, Janssen Pharmaceutical Products, and several other pharmaceutical and biotechnology companies.
FROM NCCN HEMATOLOGIC MALIGNANCIES