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Armored CAR T cells next on the production line
NEW YORK—Chimeric antigen receptor (CAR) T cells have “remarkable” activity, according to a speaker at the NCCN 9th Annual Congress: Hematologic Malignancies.
“[T]his chimera binds like an antibody, but it acts like a T cell, so it combines the best of both worlds,” said Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York.
He then traced the evolution of CAR T-cell design, discussed clinical trials using CD19-targed T cells, and described how investigators are working at building a better T cell.
Researchers found that T-cell activation and proliferation require signaling through a costimulatory receptor, such as CD28, 4-1BB, or OX-40. Without costimulation, the T cell becomes unresponsive or undergoes apoptosis.
So based on this observation, Dr Park said, several research groups created second- and third-generation CARs to incorporate the costimulatory signal.
The first generation was typically fused to the CD8 domain. Second-generation CARs include a costimulatory signaling domain, such as CD28, 4-1BB, or OX40. And the third generation contains signaling domains from 2 costimulatory receptors, CD28 with 4-1BB and CD28 with OX40.
The built-in costimulatory signal proved superior to the first-generation CAR T cells.
In NOD/SCID mice inoculated with NALM-6 lymphoma cells, Dr Park said, about 50% more were “cured,” in terms of survival, using a CD80 costimulatory ligand with CD19-targeted T cells compared to those without the ligand.
Clinical trials
Clinical trials using second-generation CD19-targeted T cells in relapsed B-cell acute lymphoblastic leukemia (ALL) at MSKCC produced an overall complete response (CR) rate of 88% in a median of 22.1 days. And 72% of the CRs were minimal residual disease (MRD) negative.
So the CAR T cells produce a “very rapid and deep remission,” Dr Park said.
CAR T-cell therapy, however, comes with adverse events, most notably, cytokine release syndrome (CRS), which results from T-cell activation. CRS causes fevers, hypotension, and neurologic toxicities including mental status changes, obtundation, and seizures.
“CRS is not unique to CAR T-cell therapy,” Dr Park said. “Any therapy that activates T cells can have this type of side effect.”
Dr Park noted that CRS is associated with disease burden at the time of treatment. “The larger the disease burden pre T-cell therapy,” he said, “the more likely [patients are] to develop CRS.”
In the MSKCC trial, no patient with very low disease burden—5% blasts in the bone marrow—developed CRS.
However, there is also a correlation between tumor burden and T-cell expansion, he added. T cells expand much better with a larger disease burden, because there is a greater antigen load.
The investigators found that serum C-reactive protein can serve as a surrogate marker for the severity of CRS. Patients with levels above 20 mg/dL are more likely to experience CRS.
And Dr Park pointed out that CRS symptoms respond pretty rapidly to steroids or interleukin-6 receptor blockade.
CAR T-cell therapy has also been used to treat chronic lymphocytic leukemia, but with much more modest response rates than in ALL. Both University of Pennsylvania and MSKCC trials in CLL have produced overall response rates around 40%.
Building a better T cell
Dr Park described efforts underway to develop the fourth-generation “armored” CAR T cells to overcome the hostile tumor microenvironment, which contains multiple inhibitory factors designed to suppress effector T cells.
Armored T cells can actually secrete some of the inflammatory cytokines to change the tumor microenvironment and overcome the inhibitory effect.
Dr Park described a potential scenario: The armored CAR T cells secrete IL-12, enhance the central memory phenotype, enhance cytotoxicity, enhance persistence, modify the endogenous immune system and T-cell activation, and reactivate tumor-infiltrating lymphocytes.
He said future studies will focus on translation of these armored CAR T cells to the clinical setting in both hematologic and solid tumor malignancies. 
NEW YORK—Chimeric antigen receptor (CAR) T cells have “remarkable” activity, according to a speaker at the NCCN 9th Annual Congress: Hematologic Malignancies.
“[T]his chimera binds like an antibody, but it acts like a T cell, so it combines the best of both worlds,” said Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York.
He then traced the evolution of CAR T-cell design, discussed clinical trials using CD19-targed T cells, and described how investigators are working at building a better T cell.
Researchers found that T-cell activation and proliferation require signaling through a costimulatory receptor, such as CD28, 4-1BB, or OX-40. Without costimulation, the T cell becomes unresponsive or undergoes apoptosis.
So based on this observation, Dr Park said, several research groups created second- and third-generation CARs to incorporate the costimulatory signal.
The first generation was typically fused to the CD8 domain. Second-generation CARs include a costimulatory signaling domain, such as CD28, 4-1BB, or OX40. And the third generation contains signaling domains from 2 costimulatory receptors, CD28 with 4-1BB and CD28 with OX40.
The built-in costimulatory signal proved superior to the first-generation CAR T cells.
In NOD/SCID mice inoculated with NALM-6 lymphoma cells, Dr Park said, about 50% more were “cured,” in terms of survival, using a CD80 costimulatory ligand with CD19-targeted T cells compared to those without the ligand.
Clinical trials
Clinical trials using second-generation CD19-targeted T cells in relapsed B-cell acute lymphoblastic leukemia (ALL) at MSKCC produced an overall complete response (CR) rate of 88% in a median of 22.1 days. And 72% of the CRs were minimal residual disease (MRD) negative.
So the CAR T cells produce a “very rapid and deep remission,” Dr Park said.
CAR T-cell therapy, however, comes with adverse events, most notably, cytokine release syndrome (CRS), which results from T-cell activation. CRS causes fevers, hypotension, and neurologic toxicities including mental status changes, obtundation, and seizures.
“CRS is not unique to CAR T-cell therapy,” Dr Park said. “Any therapy that activates T cells can have this type of side effect.”
Dr Park noted that CRS is associated with disease burden at the time of treatment. “The larger the disease burden pre T-cell therapy,” he said, “the more likely [patients are] to develop CRS.”
In the MSKCC trial, no patient with very low disease burden—5% blasts in the bone marrow—developed CRS.
However, there is also a correlation between tumor burden and T-cell expansion, he added. T cells expand much better with a larger disease burden, because there is a greater antigen load.
The investigators found that serum C-reactive protein can serve as a surrogate marker for the severity of CRS. Patients with levels above 20 mg/dL are more likely to experience CRS.
And Dr Park pointed out that CRS symptoms respond pretty rapidly to steroids or interleukin-6 receptor blockade.
CAR T-cell therapy has also been used to treat chronic lymphocytic leukemia, but with much more modest response rates than in ALL. Both University of Pennsylvania and MSKCC trials in CLL have produced overall response rates around 40%.
Building a better T cell
Dr Park described efforts underway to develop the fourth-generation “armored” CAR T cells to overcome the hostile tumor microenvironment, which contains multiple inhibitory factors designed to suppress effector T cells.
Armored T cells can actually secrete some of the inflammatory cytokines to change the tumor microenvironment and overcome the inhibitory effect.
Dr Park described a potential scenario: The armored CAR T cells secrete IL-12, enhance the central memory phenotype, enhance cytotoxicity, enhance persistence, modify the endogenous immune system and T-cell activation, and reactivate tumor-infiltrating lymphocytes.
He said future studies will focus on translation of these armored CAR T cells to the clinical setting in both hematologic and solid tumor malignancies.
NEW YORK—Chimeric antigen receptor (CAR) T cells have “remarkable” activity, according to a speaker at the NCCN 9th Annual Congress: Hematologic Malignancies.
“[T]his chimera binds like an antibody, but it acts like a T cell, so it combines the best of both worlds,” said Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York.
He then traced the evolution of CAR T-cell design, discussed clinical trials using CD19-targed T cells, and described how investigators are working at building a better T cell.
Researchers found that T-cell activation and proliferation require signaling through a costimulatory receptor, such as CD28, 4-1BB, or OX-40. Without costimulation, the T cell becomes unresponsive or undergoes apoptosis.
So based on this observation, Dr Park said, several research groups created second- and third-generation CARs to incorporate the costimulatory signal.
The first generation was typically fused to the CD8 domain. Second-generation CARs include a costimulatory signaling domain, such as CD28, 4-1BB, or OX40. And the third generation contains signaling domains from 2 costimulatory receptors, CD28 with 4-1BB and CD28 with OX40.
The built-in costimulatory signal proved superior to the first-generation CAR T cells.
In NOD/SCID mice inoculated with NALM-6 lymphoma cells, Dr Park said, about 50% more were “cured,” in terms of survival, using a CD80 costimulatory ligand with CD19-targeted T cells compared to those without the ligand.
Clinical trials
Clinical trials using second-generation CD19-targeted T cells in relapsed B-cell acute lymphoblastic leukemia (ALL) at MSKCC produced an overall complete response (CR) rate of 88% in a median of 22.1 days. And 72% of the CRs were minimal residual disease (MRD) negative.
So the CAR T cells produce a “very rapid and deep remission,” Dr Park said.
CAR T-cell therapy, however, comes with adverse events, most notably, cytokine release syndrome (CRS), which results from T-cell activation. CRS causes fevers, hypotension, and neurologic toxicities including mental status changes, obtundation, and seizures.
“CRS is not unique to CAR T-cell therapy,” Dr Park said. “Any therapy that activates T cells can have this type of side effect.”
Dr Park noted that CRS is associated with disease burden at the time of treatment. “The larger the disease burden pre T-cell therapy,” he said, “the more likely [patients are] to develop CRS.”
In the MSKCC trial, no patient with very low disease burden—5% blasts in the bone marrow—developed CRS.
However, there is also a correlation between tumor burden and T-cell expansion, he added. T cells expand much better with a larger disease burden, because there is a greater antigen load.
The investigators found that serum C-reactive protein can serve as a surrogate marker for the severity of CRS. Patients with levels above 20 mg/dL are more likely to experience CRS.
And Dr Park pointed out that CRS symptoms respond pretty rapidly to steroids or interleukin-6 receptor blockade.
CAR T-cell therapy has also been used to treat chronic lymphocytic leukemia, but with much more modest response rates than in ALL. Both University of Pennsylvania and MSKCC trials in CLL have produced overall response rates around 40%.
Building a better T cell
Dr Park described efforts underway to develop the fourth-generation “armored” CAR T cells to overcome the hostile tumor microenvironment, which contains multiple inhibitory factors designed to suppress effector T cells.
Armored T cells can actually secrete some of the inflammatory cytokines to change the tumor microenvironment and overcome the inhibitory effect.
Dr Park described a potential scenario: The armored CAR T cells secrete IL-12, enhance the central memory phenotype, enhance cytotoxicity, enhance persistence, modify the endogenous immune system and T-cell activation, and reactivate tumor-infiltrating lymphocytes.
He said future studies will focus on translation of these armored CAR T cells to the clinical setting in both hematologic and solid tumor malignancies.
Preventing cancer-related infection
Credit: CDC/Kimberly Smith
and Christine Ford
NEW YORK—Hand washing is still the single most effective method to prevent the transmission of infection, but additional measures can reduce the risk of cancer-related infections, according to a speaker at the NCCN 9th Annual Congress: Hematologic Malignancies.
In her presentation, Laura Zitella, RN, of the Stanford Cancer Institute in California, discussed current recommendations for pharmacologic and non-pharmacologic infection prophylaxis.
She noted that NCCN Guidelines on the Prevention and Treatment of Cancer-Related Infections state that the highest risk of infection is in patients undergoing allogeneic hematopoietic stem cell transplant (HSCT), acute leukemia patients undergoing induction or consolidation therapy, patients receiving alemtuzumab therapy, patients with graft-vs-host disease (GVHD) treated with high-dose steroids, and patients with neutropenia anticipated to last greater than 10 days.
Antibiotic prophylaxis
Prior to 2005, Zitella said, no survival benefit was observed for antibiotic prophylaxis. All of this changed with the results of a meta-analysis. The analysis included 95 randomized, controlled trials and 9283 patients, the majority having acute leukemia or undergoing HSCT.
For the first time, antibiotic prophylaxis was shown to confer a survival benefit. In neutropenic patients, prophylaxis reduced overall mortality by 33% and infection-related mortality by 42%, compared with placebo or no treatment.
Prophylaxis is not recommended for low-risk neutropenic patients, Zitella said, because it is not proven to decrease morality.
And the drugs of choice are levofloxacin (500-750 mg PO daily) or ciprofloxacin (500-750 mg PO twice daily).
Colony-stimulating factors
Consensus guidelines for the use of colony-stimulating factors (CSFs) are a compilation of ASCO, EORTC, ESMO, and NCCN guidelines.
CSFs may be used prophylactically to prevent chemotherapy-induced neutropenia, febrile neutropenia, and infection. They reduce the duration of hospitalization, the duration of parenteral antibiotics, and have shown a survival benefit.
CSFs are recommended if the risk of febrile neutropenia is 20% or greater. CSFs are not routinely recommended for patients undergoing radiation treatment, acute myeloid leukemia induction, or patients with Hodgkin lymphoma.
Antifungal prophylaxis
Zitella noted that fluconazole is the best-studied antifungal prophylaxis and is recommended as the primary prophylaxis for HSCT patients.
In double-blind, placebo-controlled trials, fluconazole reduced mucosal candidiasis and invasive Candida infections in patients undergoing HSCT. And it improved survival at day 110 after transplant.
Posaconazole prophylaxis has proven effective in patients with acute myeloid leukemia or myelodysplastic syndromes undergoing intensive chemotherapy. The drug reduced invasive fungal infections, including aspergillosis, and improved survival.
For patients with GVHD on immunosuppressive therapy, posaconazole and fluconazole prophylaxis were equivalent in preventing invasive fungal infections. However, posaconazole reduced the incidence of invasive aspergillosis and fungal-related mortality.
The NCCN guidelines, Zitella said, spell out which antifungal agents should be used for each disease or therapeutic intervention.
Antiviral prophylaxis
HSV and VZV
Patients requiring antiviral prophylaxis for herpes simplex virus (HSV) and varicella zoster virus (VZV) should be seropositive and have acute leukemia, GVHD treated with steroids, prior HSV reactivation under treatment, or have undergone HSCT.
Zitella pointed out that patients treated with proteasome inhibitors, such as bortezomib, alemtuzumab, or purine analaogs, such as fludarabine, are more at risk and should also receive antiviral prophylaxis.
Recommended drugs include valacyclovir, acyclovir, or famciclovir.
CMV
Cytomegalovirus-positive (CMV+) patients at high risk include those who have received an allogeneic HSCT or treatment with alemtuzumab.
Zitella explained that for these patients, prophylaxis is uncommon, and a pre-emptive strategy should be used, including testing 3 to 6 months after transplant or in the setting of GVHD and 2 months after alemtuzumab therapy.
CMV viremia should be treated with valganciclovir, ganciclovir, foscarnet, or cidofovir.
HBV
Zitella noted that 30% of the world population has been infected with hepatitis B virus (HBV), and reactivation during cancer treatment can lead to fulminant hepatitis and death.
NCCN recommends that patients undergoing immunosuppressive therapy, allogeneic HSCT candidates, patients receiving anti-CD20 monoclonal antibodies, those treated with alemtuzumab, and patients receiving systemic therapy who have an obvious risk factor for HBV infection should be tested.
Entecavir, tenofovir, adefovir, telbivudine, or lamivudine may be used to prevent HBV reactivation.
Pneumocystis pneumonia prophylaxis
Patients undergoing allogeneic HSCT, patients with acute lymphoblastic leukemia, those treated with alemtuzumab, and those with a CD4 count below 200 cells/mcL should receive pneumocystis pneumonia prophylaxis.
Trimethorpim/sulfamethoxazole is the drug of choice. Atovaquone, dapsone, and inhaled or IV pentamidine are alternatives.
Vaccines
Zitella pointed out that recommended vaccines include influenza, pneumococcal, and tetanus, diphtheria, and acellular pertussis.
She cautioned that live attenuated vaccines should not be given to cancer patients. Other vaccines to avoid include smallpox; measles, mumps, and rubella; varicella zoster; rotavirus; yellow fever; oral typhoid; BCG; and oral polio vaccine.
Neutropenic precautions
Low microbial diets are a hot topic among patients undergoing cancer treatment, Zitella said. Fresh fruits and vegetables used to be restricted, but no studies show that dietary restrictions decrease the risk of infection.
Zitella stressed, however, that standard food safety recommendations of the USDA/FDA should be followed.
She also noted that HEPA filtration is protective against molds in high-risk patients, antiseptic bathing has contradictory evidence, the benefit of laminar airflow is unclear, and protective isolation has not been proven to reduce the risk of infection.
Credit: CDC/Kimberly Smith
and Christine Ford
NEW YORK—Hand washing is still the single most effective method to prevent the transmission of infection, but additional measures can reduce the risk of cancer-related infections, according to a speaker at the NCCN 9th Annual Congress: Hematologic Malignancies.
In her presentation, Laura Zitella, RN, of the Stanford Cancer Institute in California, discussed current recommendations for pharmacologic and non-pharmacologic infection prophylaxis.
She noted that NCCN Guidelines on the Prevention and Treatment of Cancer-Related Infections state that the highest risk of infection is in patients undergoing allogeneic hematopoietic stem cell transplant (HSCT), acute leukemia patients undergoing induction or consolidation therapy, patients receiving alemtuzumab therapy, patients with graft-vs-host disease (GVHD) treated with high-dose steroids, and patients with neutropenia anticipated to last greater than 10 days.
Antibiotic prophylaxis
Prior to 2005, Zitella said, no survival benefit was observed for antibiotic prophylaxis. All of this changed with the results of a meta-analysis. The analysis included 95 randomized, controlled trials and 9283 patients, the majority having acute leukemia or undergoing HSCT.
For the first time, antibiotic prophylaxis was shown to confer a survival benefit. In neutropenic patients, prophylaxis reduced overall mortality by 33% and infection-related mortality by 42%, compared with placebo or no treatment.
Prophylaxis is not recommended for low-risk neutropenic patients, Zitella said, because it is not proven to decrease morality.
And the drugs of choice are levofloxacin (500-750 mg PO daily) or ciprofloxacin (500-750 mg PO twice daily).
Colony-stimulating factors
Consensus guidelines for the use of colony-stimulating factors (CSFs) are a compilation of ASCO, EORTC, ESMO, and NCCN guidelines.
CSFs may be used prophylactically to prevent chemotherapy-induced neutropenia, febrile neutropenia, and infection. They reduce the duration of hospitalization, the duration of parenteral antibiotics, and have shown a survival benefit.
CSFs are recommended if the risk of febrile neutropenia is 20% or greater. CSFs are not routinely recommended for patients undergoing radiation treatment, acute myeloid leukemia induction, or patients with Hodgkin lymphoma.
Antifungal prophylaxis
Zitella noted that fluconazole is the best-studied antifungal prophylaxis and is recommended as the primary prophylaxis for HSCT patients.
In double-blind, placebo-controlled trials, fluconazole reduced mucosal candidiasis and invasive Candida infections in patients undergoing HSCT. And it improved survival at day 110 after transplant.
Posaconazole prophylaxis has proven effective in patients with acute myeloid leukemia or myelodysplastic syndromes undergoing intensive chemotherapy. The drug reduced invasive fungal infections, including aspergillosis, and improved survival.
For patients with GVHD on immunosuppressive therapy, posaconazole and fluconazole prophylaxis were equivalent in preventing invasive fungal infections. However, posaconazole reduced the incidence of invasive aspergillosis and fungal-related mortality.
The NCCN guidelines, Zitella said, spell out which antifungal agents should be used for each disease or therapeutic intervention.
Antiviral prophylaxis
HSV and VZV
Patients requiring antiviral prophylaxis for herpes simplex virus (HSV) and varicella zoster virus (VZV) should be seropositive and have acute leukemia, GVHD treated with steroids, prior HSV reactivation under treatment, or have undergone HSCT.
Zitella pointed out that patients treated with proteasome inhibitors, such as bortezomib, alemtuzumab, or purine analaogs, such as fludarabine, are more at risk and should also receive antiviral prophylaxis.
Recommended drugs include valacyclovir, acyclovir, or famciclovir.
CMV
Cytomegalovirus-positive (CMV+) patients at high risk include those who have received an allogeneic HSCT or treatment with alemtuzumab.
Zitella explained that for these patients, prophylaxis is uncommon, and a pre-emptive strategy should be used, including testing 3 to 6 months after transplant or in the setting of GVHD and 2 months after alemtuzumab therapy.
CMV viremia should be treated with valganciclovir, ganciclovir, foscarnet, or cidofovir.
HBV
Zitella noted that 30% of the world population has been infected with hepatitis B virus (HBV), and reactivation during cancer treatment can lead to fulminant hepatitis and death.
NCCN recommends that patients undergoing immunosuppressive therapy, allogeneic HSCT candidates, patients receiving anti-CD20 monoclonal antibodies, those treated with alemtuzumab, and patients receiving systemic therapy who have an obvious risk factor for HBV infection should be tested.
Entecavir, tenofovir, adefovir, telbivudine, or lamivudine may be used to prevent HBV reactivation.
Pneumocystis pneumonia prophylaxis
Patients undergoing allogeneic HSCT, patients with acute lymphoblastic leukemia, those treated with alemtuzumab, and those with a CD4 count below 200 cells/mcL should receive pneumocystis pneumonia prophylaxis.
Trimethorpim/sulfamethoxazole is the drug of choice. Atovaquone, dapsone, and inhaled or IV pentamidine are alternatives.
Vaccines
Zitella pointed out that recommended vaccines include influenza, pneumococcal, and tetanus, diphtheria, and acellular pertussis.
She cautioned that live attenuated vaccines should not be given to cancer patients. Other vaccines to avoid include smallpox; measles, mumps, and rubella; varicella zoster; rotavirus; yellow fever; oral typhoid; BCG; and oral polio vaccine.
Neutropenic precautions
Low microbial diets are a hot topic among patients undergoing cancer treatment, Zitella said. Fresh fruits and vegetables used to be restricted, but no studies show that dietary restrictions decrease the risk of infection.
Zitella stressed, however, that standard food safety recommendations of the USDA/FDA should be followed.
She also noted that HEPA filtration is protective against molds in high-risk patients, antiseptic bathing has contradictory evidence, the benefit of laminar airflow is unclear, and protective isolation has not been proven to reduce the risk of infection.
Credit: CDC/Kimberly Smith
and Christine Ford
NEW YORK—Hand washing is still the single most effective method to prevent the transmission of infection, but additional measures can reduce the risk of cancer-related infections, according to a speaker at the NCCN 9th Annual Congress: Hematologic Malignancies.
In her presentation, Laura Zitella, RN, of the Stanford Cancer Institute in California, discussed current recommendations for pharmacologic and non-pharmacologic infection prophylaxis.
She noted that NCCN Guidelines on the Prevention and Treatment of Cancer-Related Infections state that the highest risk of infection is in patients undergoing allogeneic hematopoietic stem cell transplant (HSCT), acute leukemia patients undergoing induction or consolidation therapy, patients receiving alemtuzumab therapy, patients with graft-vs-host disease (GVHD) treated with high-dose steroids, and patients with neutropenia anticipated to last greater than 10 days.
Antibiotic prophylaxis
Prior to 2005, Zitella said, no survival benefit was observed for antibiotic prophylaxis. All of this changed with the results of a meta-analysis. The analysis included 95 randomized, controlled trials and 9283 patients, the majority having acute leukemia or undergoing HSCT.
For the first time, antibiotic prophylaxis was shown to confer a survival benefit. In neutropenic patients, prophylaxis reduced overall mortality by 33% and infection-related mortality by 42%, compared with placebo or no treatment.
Prophylaxis is not recommended for low-risk neutropenic patients, Zitella said, because it is not proven to decrease morality.
And the drugs of choice are levofloxacin (500-750 mg PO daily) or ciprofloxacin (500-750 mg PO twice daily).
Colony-stimulating factors
Consensus guidelines for the use of colony-stimulating factors (CSFs) are a compilation of ASCO, EORTC, ESMO, and NCCN guidelines.
CSFs may be used prophylactically to prevent chemotherapy-induced neutropenia, febrile neutropenia, and infection. They reduce the duration of hospitalization, the duration of parenteral antibiotics, and have shown a survival benefit.
CSFs are recommended if the risk of febrile neutropenia is 20% or greater. CSFs are not routinely recommended for patients undergoing radiation treatment, acute myeloid leukemia induction, or patients with Hodgkin lymphoma.
Antifungal prophylaxis
Zitella noted that fluconazole is the best-studied antifungal prophylaxis and is recommended as the primary prophylaxis for HSCT patients.
In double-blind, placebo-controlled trials, fluconazole reduced mucosal candidiasis and invasive Candida infections in patients undergoing HSCT. And it improved survival at day 110 after transplant.
Posaconazole prophylaxis has proven effective in patients with acute myeloid leukemia or myelodysplastic syndromes undergoing intensive chemotherapy. The drug reduced invasive fungal infections, including aspergillosis, and improved survival.
For patients with GVHD on immunosuppressive therapy, posaconazole and fluconazole prophylaxis were equivalent in preventing invasive fungal infections. However, posaconazole reduced the incidence of invasive aspergillosis and fungal-related mortality.
The NCCN guidelines, Zitella said, spell out which antifungal agents should be used for each disease or therapeutic intervention.
Antiviral prophylaxis
HSV and VZV
Patients requiring antiviral prophylaxis for herpes simplex virus (HSV) and varicella zoster virus (VZV) should be seropositive and have acute leukemia, GVHD treated with steroids, prior HSV reactivation under treatment, or have undergone HSCT.
Zitella pointed out that patients treated with proteasome inhibitors, such as bortezomib, alemtuzumab, or purine analaogs, such as fludarabine, are more at risk and should also receive antiviral prophylaxis.
Recommended drugs include valacyclovir, acyclovir, or famciclovir.
CMV
Cytomegalovirus-positive (CMV+) patients at high risk include those who have received an allogeneic HSCT or treatment with alemtuzumab.
Zitella explained that for these patients, prophylaxis is uncommon, and a pre-emptive strategy should be used, including testing 3 to 6 months after transplant or in the setting of GVHD and 2 months after alemtuzumab therapy.
CMV viremia should be treated with valganciclovir, ganciclovir, foscarnet, or cidofovir.
HBV
Zitella noted that 30% of the world population has been infected with hepatitis B virus (HBV), and reactivation during cancer treatment can lead to fulminant hepatitis and death.
NCCN recommends that patients undergoing immunosuppressive therapy, allogeneic HSCT candidates, patients receiving anti-CD20 monoclonal antibodies, those treated with alemtuzumab, and patients receiving systemic therapy who have an obvious risk factor for HBV infection should be tested.
Entecavir, tenofovir, adefovir, telbivudine, or lamivudine may be used to prevent HBV reactivation.
Pneumocystis pneumonia prophylaxis
Patients undergoing allogeneic HSCT, patients with acute lymphoblastic leukemia, those treated with alemtuzumab, and those with a CD4 count below 200 cells/mcL should receive pneumocystis pneumonia prophylaxis.
Trimethorpim/sulfamethoxazole is the drug of choice. Atovaquone, dapsone, and inhaled or IV pentamidine are alternatives.
Vaccines
Zitella pointed out that recommended vaccines include influenza, pneumococcal, and tetanus, diphtheria, and acellular pertussis.
She cautioned that live attenuated vaccines should not be given to cancer patients. Other vaccines to avoid include smallpox; measles, mumps, and rubella; varicella zoster; rotavirus; yellow fever; oral typhoid; BCG; and oral polio vaccine.
Neutropenic precautions
Low microbial diets are a hot topic among patients undergoing cancer treatment, Zitella said. Fresh fruits and vegetables used to be restricted, but no studies show that dietary restrictions decrease the risk of infection.
Zitella stressed, however, that standard food safety recommendations of the USDA/FDA should be followed.
She also noted that HEPA filtration is protective against molds in high-risk patients, antiseptic bathing has contradictory evidence, the benefit of laminar airflow is unclear, and protective isolation has not been proven to reduce the risk of infection.
Speaker offers alternatives for sustainable TKI use in CML
NEW YORK—If any oncology drugs warrant a high price, BCR-ABL tyrosine kinase inhibitors (TKIs) could make a strong case, according to a speaker at the NCCN 9th Annual Congress: Hematologic Malignancies.
TKIs have revolutionized the therapeutic landscape in chronic myeloid leukemia (CML), said Neil P. Shah, MD, PhD, of the UCSF
Helen Diller Family Comprehensive Cancer Center in San Francisco.
Five-year overall survival is 93% in CML patients treated with imatinib. And 80,000 people are estimated to be living with CML in 2014, a number that is expected to double by 2035.
Yet the increase in life expectancy places a burden on the healthcare system, Dr Shah said, particularly since the price of BCR-ABL TKIs has risen dramatically.
A year of imatinib therapy circa 2001 cost approximately $30,000, and by 2013, approximately $92,000. Second-generation (2G) TKIs cost even more, at about $115,000 annually, and the third-generation TKI ponatinib costs about $138,000 annually.
Confounding the financial picture will be the advent of generic imatinib, which will be available in the US in early 2016.
Generic imatinib will, presumably, be less expensive than the brand-name drug. However, it is not clear whether it will be as effective or what impact it will have on the 2G and 3G TKIs.
With all that in mind, Dr Shah provided some options for maximizing therapeutic outcomes in a fiscally responsible manner.
He based his potential solutions on evidence-based premises. First, imatinib is a highly active therapy for many chronic-phase CML patients. The 8-year update of the IRIS study shows that 53% of patients sustain complete cytogenetic remission (CCyR) with imatinib.
Second, patients who are likely to do well on TKI therapy can be identified early based on their BCR-ABL PCR levels after 3 months of therapy.
This important 3-month milestone has been incorporated into the NCCN guidelines. Patients who achieve BCR-ABL/ABL levels of 10% or less have a significantly better overall survival than those who have levels greater than 10%.
Third, the ENESTnd and DASISION studies demonstrated that nilotinib and dasatinib elicit achievement of important treatment milestones (PCR<10% at 3 months and CCyR after 12 months) in a significantly higher proportion of patients than imatinib. But to date, neither agent has produced a significant improvement in overall survival.
And fourth, while nilotinib and dasatinib have an undisputable clinical benefit over imatinib in terms of transformation to accelerated phase/blast crisis (AP/BC), these agents cost between $23,000 and $31,000 more than imatinib for an annual course of treatment.
Dr Shah calculated that to achieve approximately 10 fewer AP/BC transformations over 5 years, approximately 300 patients would need to be treated at an additional cost of $37.5 million. This equates to $3.75 million in additional costs for 1 transformation event spared over 5 years.
“We do have to keep in mind transformation events are not cheap,” he said. “So when these happen, patients need to be hospitalized for chemotherapy, typically, or they have to go to allogeneic stem cell transplantation.”
So Dr Shah proffered 3 potential approaches for fiscally sustainable TKI use.
The first approach would be to initiate imatinib in most, if not all, chronic-phase CML patients. If they achieve BCR-ABL levels <10% at 3 months or partial CyR after 12 months, then continue imatinib. If not, switch to a 2G TKI.
Dr Shah noted that 40% to 60% of patients will have a deep, durable response to imatinib.
The second approach would be to initiate 2G TKIs in newly diagnosed patients. And when they achieve CCyR or major molecular response (MMR), enroll them in a clinical trial.
These trials could investigate a switch to imatinib, use of a lower dose of the 2G TKI, a switch to interferon-alfa, the addition of a CYP3A4 inhibitor (such as grapefruit) and a lower dose, or another investigational option.
And the third approach would be to initiate imatinib or an approved 2G TKI in newly diagnosed patients. When they achieve targeted molecular remission, enroll them in a treatment-discontinuation trial.
Dr Shah pointed out that in the STIM study, 61% of patients remained in complete molecular remission 60 months after discontinuing imatinib, and 40% experienced treatment-free survival.
Taking into account the cost of imatinib and the number of months without treatment, STIM investigators estimated the savings to be €4,587,500, or approximately $6 to $7 million.
Patients who relapsed 6 to 9 months after discontinuing imatinib tended to respond well to a rechallenge with imatinib. But Dr Shah cautioned that, at present, discontinuation should only be performed in the context of a clinical trial.
NEW YORK—If any oncology drugs warrant a high price, BCR-ABL tyrosine kinase inhibitors (TKIs) could make a strong case, according to a speaker at the NCCN 9th Annual Congress: Hematologic Malignancies.
TKIs have revolutionized the therapeutic landscape in chronic myeloid leukemia (CML), said Neil P. Shah, MD, PhD, of the UCSF
Helen Diller Family Comprehensive Cancer Center in San Francisco.
Five-year overall survival is 93% in CML patients treated with imatinib. And 80,000 people are estimated to be living with CML in 2014, a number that is expected to double by 2035.
Yet the increase in life expectancy places a burden on the healthcare system, Dr Shah said, particularly since the price of BCR-ABL TKIs has risen dramatically.
A year of imatinib therapy circa 2001 cost approximately $30,000, and by 2013, approximately $92,000. Second-generation (2G) TKIs cost even more, at about $115,000 annually, and the third-generation TKI ponatinib costs about $138,000 annually.
Confounding the financial picture will be the advent of generic imatinib, which will be available in the US in early 2016.
Generic imatinib will, presumably, be less expensive than the brand-name drug. However, it is not clear whether it will be as effective or what impact it will have on the 2G and 3G TKIs.
With all that in mind, Dr Shah provided some options for maximizing therapeutic outcomes in a fiscally responsible manner.
He based his potential solutions on evidence-based premises. First, imatinib is a highly active therapy for many chronic-phase CML patients. The 8-year update of the IRIS study shows that 53% of patients sustain complete cytogenetic remission (CCyR) with imatinib.
Second, patients who are likely to do well on TKI therapy can be identified early based on their BCR-ABL PCR levels after 3 months of therapy.
This important 3-month milestone has been incorporated into the NCCN guidelines. Patients who achieve BCR-ABL/ABL levels of 10% or less have a significantly better overall survival than those who have levels greater than 10%.
Third, the ENESTnd and DASISION studies demonstrated that nilotinib and dasatinib elicit achievement of important treatment milestones (PCR<10% at 3 months and CCyR after 12 months) in a significantly higher proportion of patients than imatinib. But to date, neither agent has produced a significant improvement in overall survival.
And fourth, while nilotinib and dasatinib have an undisputable clinical benefit over imatinib in terms of transformation to accelerated phase/blast crisis (AP/BC), these agents cost between $23,000 and $31,000 more than imatinib for an annual course of treatment.
Dr Shah calculated that to achieve approximately 10 fewer AP/BC transformations over 5 years, approximately 300 patients would need to be treated at an additional cost of $37.5 million. This equates to $3.75 million in additional costs for 1 transformation event spared over 5 years.
“We do have to keep in mind transformation events are not cheap,” he said. “So when these happen, patients need to be hospitalized for chemotherapy, typically, or they have to go to allogeneic stem cell transplantation.”
So Dr Shah proffered 3 potential approaches for fiscally sustainable TKI use.
The first approach would be to initiate imatinib in most, if not all, chronic-phase CML patients. If they achieve BCR-ABL levels <10% at 3 months or partial CyR after 12 months, then continue imatinib. If not, switch to a 2G TKI.
Dr Shah noted that 40% to 60% of patients will have a deep, durable response to imatinib.
The second approach would be to initiate 2G TKIs in newly diagnosed patients. And when they achieve CCyR or major molecular response (MMR), enroll them in a clinical trial.
These trials could investigate a switch to imatinib, use of a lower dose of the 2G TKI, a switch to interferon-alfa, the addition of a CYP3A4 inhibitor (such as grapefruit) and a lower dose, or another investigational option.
And the third approach would be to initiate imatinib or an approved 2G TKI in newly diagnosed patients. When they achieve targeted molecular remission, enroll them in a treatment-discontinuation trial.
Dr Shah pointed out that in the STIM study, 61% of patients remained in complete molecular remission 60 months after discontinuing imatinib, and 40% experienced treatment-free survival.
Taking into account the cost of imatinib and the number of months without treatment, STIM investigators estimated the savings to be €4,587,500, or approximately $6 to $7 million.
Patients who relapsed 6 to 9 months after discontinuing imatinib tended to respond well to a rechallenge with imatinib. But Dr Shah cautioned that, at present, discontinuation should only be performed in the context of a clinical trial.
NEW YORK—If any oncology drugs warrant a high price, BCR-ABL tyrosine kinase inhibitors (TKIs) could make a strong case, according to a speaker at the NCCN 9th Annual Congress: Hematologic Malignancies.
TKIs have revolutionized the therapeutic landscape in chronic myeloid leukemia (CML), said Neil P. Shah, MD, PhD, of the UCSF
Helen Diller Family Comprehensive Cancer Center in San Francisco.
Five-year overall survival is 93% in CML patients treated with imatinib. And 80,000 people are estimated to be living with CML in 2014, a number that is expected to double by 2035.
Yet the increase in life expectancy places a burden on the healthcare system, Dr Shah said, particularly since the price of BCR-ABL TKIs has risen dramatically.
A year of imatinib therapy circa 2001 cost approximately $30,000, and by 2013, approximately $92,000. Second-generation (2G) TKIs cost even more, at about $115,000 annually, and the third-generation TKI ponatinib costs about $138,000 annually.
Confounding the financial picture will be the advent of generic imatinib, which will be available in the US in early 2016.
Generic imatinib will, presumably, be less expensive than the brand-name drug. However, it is not clear whether it will be as effective or what impact it will have on the 2G and 3G TKIs.
With all that in mind, Dr Shah provided some options for maximizing therapeutic outcomes in a fiscally responsible manner.
He based his potential solutions on evidence-based premises. First, imatinib is a highly active therapy for many chronic-phase CML patients. The 8-year update of the IRIS study shows that 53% of patients sustain complete cytogenetic remission (CCyR) with imatinib.
Second, patients who are likely to do well on TKI therapy can be identified early based on their BCR-ABL PCR levels after 3 months of therapy.
This important 3-month milestone has been incorporated into the NCCN guidelines. Patients who achieve BCR-ABL/ABL levels of 10% or less have a significantly better overall survival than those who have levels greater than 10%.
Third, the ENESTnd and DASISION studies demonstrated that nilotinib and dasatinib elicit achievement of important treatment milestones (PCR<10% at 3 months and CCyR after 12 months) in a significantly higher proportion of patients than imatinib. But to date, neither agent has produced a significant improvement in overall survival.
And fourth, while nilotinib and dasatinib have an undisputable clinical benefit over imatinib in terms of transformation to accelerated phase/blast crisis (AP/BC), these agents cost between $23,000 and $31,000 more than imatinib for an annual course of treatment.
Dr Shah calculated that to achieve approximately 10 fewer AP/BC transformations over 5 years, approximately 300 patients would need to be treated at an additional cost of $37.5 million. This equates to $3.75 million in additional costs for 1 transformation event spared over 5 years.
“We do have to keep in mind transformation events are not cheap,” he said. “So when these happen, patients need to be hospitalized for chemotherapy, typically, or they have to go to allogeneic stem cell transplantation.”
So Dr Shah proffered 3 potential approaches for fiscally sustainable TKI use.
The first approach would be to initiate imatinib in most, if not all, chronic-phase CML patients. If they achieve BCR-ABL levels <10% at 3 months or partial CyR after 12 months, then continue imatinib. If not, switch to a 2G TKI.
Dr Shah noted that 40% to 60% of patients will have a deep, durable response to imatinib.
The second approach would be to initiate 2G TKIs in newly diagnosed patients. And when they achieve CCyR or major molecular response (MMR), enroll them in a clinical trial.
These trials could investigate a switch to imatinib, use of a lower dose of the 2G TKI, a switch to interferon-alfa, the addition of a CYP3A4 inhibitor (such as grapefruit) and a lower dose, or another investigational option.
And the third approach would be to initiate imatinib or an approved 2G TKI in newly diagnosed patients. When they achieve targeted molecular remission, enroll them in a treatment-discontinuation trial.
Dr Shah pointed out that in the STIM study, 61% of patients remained in complete molecular remission 60 months after discontinuing imatinib, and 40% experienced treatment-free survival.
Taking into account the cost of imatinib and the number of months without treatment, STIM investigators estimated the savings to be €4,587,500, or approximately $6 to $7 million.
Patients who relapsed 6 to 9 months after discontinuing imatinib tended to respond well to a rechallenge with imatinib. But Dr Shah cautioned that, at present, discontinuation should only be performed in the context of a clinical trial.
Split decision on role of upfront transplant in MM
Credit: Chad McNeeley
NEW YORK—A debate on the pros and cons of upfront transplant in symptomatic multiple myeloma (MM) yielded a split decision from the audience during the NCCN 9th Annual Congress: Hematologic Malignancies.
Sergio Giralt, MD, of Memorial Sloan Kettering Cancer Center in New York, argued for upfront transplant, pointing out that long-term MM survivors have transplant as upfront therapy.
Kenneth Anderson, MD, of Dana Farber/Brigham and Women’s Cancer Center in Boston, took the stance that, in the past 10 years, there has been a
revolution in novel therapies that has significantly improved survival in MM.
For upfront transplant
Dr Giralt cited the 36-month follow-up of the E4A03 landmark analysis of patients who went off therapy after 4 cycles of lenalidomide/dexamethasone to pursue early stem cell transplant and those who continued treatment until disease progression.
Regardless of whether the patients were younger than 65 years or between 65 and 70, the patients who had an early transplant had superior progression-free survival (PFS) and overall survival (OS) compared to those who did not.
Dr Giralt added that bortezomib should be a component of induction therapy prior to autologous stem cell transplant (ASCT). Even though there is no survival benefit with bortezomib-based regimens, he said, there is significant improvement in PFS, as shown in a meta-analysis of phase 3 European studies.
The E4A03 landmark study also determined that the more intense the treatment, the better the outcome. So patients with double ASCT had a significantly longer PFS than patients who only had a single transplant.
This held true for OS as well, and included patients with 17p deletion and/or t(4;14) who failed to achieve complete remission after bortezomib-based induction regimens.
An analysis of 27,987 MM patients with a median age of 68 years (range, 19 to 90) revealed that of the patients who survived 10 years or more, 16.5% had ASCT as part of their initial therapy.
Dr Giralt concluded that the preponderance of evidence supports high-dose melphalan and ASCT as upfront consolidation therapy for MM. And until results of randomized trials investigating combination therapies are reported, melphalan consolidation should be considered the standard of care for all eligible patients with MM.
Against upfront transplant
Dr Anderson countered with data showing limited or no improvement in survival with ASCT, including evidence from studies by Attal, Fermand, Blade, Child, and Barlogie.
ASCT confers only modest PFS advantage, he said, showing results of the Barlogie study in which patients undergoing ASCT had a 25-month PFS, compared with a 21-month PFS with VBMCP (vincristine, carmustine, melphalan, cyclophosphamide, and prednisone).
“In the last 10 to 15 years, there has been a revolution in myeloma,” Dr Anderson said. “We have a lot of novel agents here today, and we have even more coming. It’s a hugely exciting time.”
Dr Anderson pointed out that since the introduction of novel agents, survival has improved between 2006 and 2010, compared to the period between 2001 and 2005, and particularly in patients older than 65 years (P=0.001).
Transplant has also changed, he said. Novel therapies have been integrated into the transplant paradigm, either before, as induction and consolidation therapy, or after, as maintenance. He indicated that this begs the question as to whether we really need the transplant component.
There has also been unprecedented use of triplets in combination therapy, Dr Anderson said, resulting in overall response rates upwards of 90%. For example, carfilzomib in combination with lenalidomide and dexamethasone prompted an overall response rate of 94%, with a stringent complete response (CR), CR, and near CR of 53%.
“It’s a new day in myeloma,” he said. “It’s taken us a long time, but we’re worrying about minimal residual disease (MRD) now. We’re worried about getting to the endpoint of 1 myeloma cell in 1 million normal cells.”
The point is, he added, that with novel therapies, such as carfilzomib, lenalidomide, and dexamethasone, patients who achieve a complete response can become MRD negative, suggesting an unprecedented extent of response without transplant.
MRD negativity may also be accomplished with oral agents, such as ixazomib. The depth of response with ixazomib increases over the course of treatment, with 27% achieving stringent CR or CR with a median duration of response of 13.8 months, and 82% of patients attaining MRD-negative status.
“In the absence of transplant,” Dr Anderson said, “this is an unprecedented response.”
Dr Anderson also pointed out that in the era of novel agents, there is no difference in outcome between early or delayed transplant. The 4-year OS in transplant-eligible patients who received initial therapy with lenalidomide was 80%, regardless of the timing of ASCT.
And in one trial, patients who received a delayed transplant fared better in OS than those transplanted early.
Dr Anderson said there is a parallel, international phase 3 study underway (IFM/DFCI2009) that will provide an answer to the debate on upfront transplant in the not-too-distant future.
Credit: Chad McNeeley
NEW YORK—A debate on the pros and cons of upfront transplant in symptomatic multiple myeloma (MM) yielded a split decision from the audience during the NCCN 9th Annual Congress: Hematologic Malignancies.
Sergio Giralt, MD, of Memorial Sloan Kettering Cancer Center in New York, argued for upfront transplant, pointing out that long-term MM survivors have transplant as upfront therapy.
Kenneth Anderson, MD, of Dana Farber/Brigham and Women’s Cancer Center in Boston, took the stance that, in the past 10 years, there has been a
revolution in novel therapies that has significantly improved survival in MM.
For upfront transplant
Dr Giralt cited the 36-month follow-up of the E4A03 landmark analysis of patients who went off therapy after 4 cycles of lenalidomide/dexamethasone to pursue early stem cell transplant and those who continued treatment until disease progression.
Regardless of whether the patients were younger than 65 years or between 65 and 70, the patients who had an early transplant had superior progression-free survival (PFS) and overall survival (OS) compared to those who did not.
Dr Giralt added that bortezomib should be a component of induction therapy prior to autologous stem cell transplant (ASCT). Even though there is no survival benefit with bortezomib-based regimens, he said, there is significant improvement in PFS, as shown in a meta-analysis of phase 3 European studies.
The E4A03 landmark study also determined that the more intense the treatment, the better the outcome. So patients with double ASCT had a significantly longer PFS than patients who only had a single transplant.
This held true for OS as well, and included patients with 17p deletion and/or t(4;14) who failed to achieve complete remission after bortezomib-based induction regimens.
An analysis of 27,987 MM patients with a median age of 68 years (range, 19 to 90) revealed that of the patients who survived 10 years or more, 16.5% had ASCT as part of their initial therapy.
Dr Giralt concluded that the preponderance of evidence supports high-dose melphalan and ASCT as upfront consolidation therapy for MM. And until results of randomized trials investigating combination therapies are reported, melphalan consolidation should be considered the standard of care for all eligible patients with MM.
Against upfront transplant
Dr Anderson countered with data showing limited or no improvement in survival with ASCT, including evidence from studies by Attal, Fermand, Blade, Child, and Barlogie.
ASCT confers only modest PFS advantage, he said, showing results of the Barlogie study in which patients undergoing ASCT had a 25-month PFS, compared with a 21-month PFS with VBMCP (vincristine, carmustine, melphalan, cyclophosphamide, and prednisone).
“In the last 10 to 15 years, there has been a revolution in myeloma,” Dr Anderson said. “We have a lot of novel agents here today, and we have even more coming. It’s a hugely exciting time.”
Dr Anderson pointed out that since the introduction of novel agents, survival has improved between 2006 and 2010, compared to the period between 2001 and 2005, and particularly in patients older than 65 years (P=0.001).
Transplant has also changed, he said. Novel therapies have been integrated into the transplant paradigm, either before, as induction and consolidation therapy, or after, as maintenance. He indicated that this begs the question as to whether we really need the transplant component.
There has also been unprecedented use of triplets in combination therapy, Dr Anderson said, resulting in overall response rates upwards of 90%. For example, carfilzomib in combination with lenalidomide and dexamethasone prompted an overall response rate of 94%, with a stringent complete response (CR), CR, and near CR of 53%.
“It’s a new day in myeloma,” he said. “It’s taken us a long time, but we’re worrying about minimal residual disease (MRD) now. We’re worried about getting to the endpoint of 1 myeloma cell in 1 million normal cells.”
The point is, he added, that with novel therapies, such as carfilzomib, lenalidomide, and dexamethasone, patients who achieve a complete response can become MRD negative, suggesting an unprecedented extent of response without transplant.
MRD negativity may also be accomplished with oral agents, such as ixazomib. The depth of response with ixazomib increases over the course of treatment, with 27% achieving stringent CR or CR with a median duration of response of 13.8 months, and 82% of patients attaining MRD-negative status.
“In the absence of transplant,” Dr Anderson said, “this is an unprecedented response.”
Dr Anderson also pointed out that in the era of novel agents, there is no difference in outcome between early or delayed transplant. The 4-year OS in transplant-eligible patients who received initial therapy with lenalidomide was 80%, regardless of the timing of ASCT.
And in one trial, patients who received a delayed transplant fared better in OS than those transplanted early.
Dr Anderson said there is a parallel, international phase 3 study underway (IFM/DFCI2009) that will provide an answer to the debate on upfront transplant in the not-too-distant future.
Credit: Chad McNeeley
NEW YORK—A debate on the pros and cons of upfront transplant in symptomatic multiple myeloma (MM) yielded a split decision from the audience during the NCCN 9th Annual Congress: Hematologic Malignancies.
Sergio Giralt, MD, of Memorial Sloan Kettering Cancer Center in New York, argued for upfront transplant, pointing out that long-term MM survivors have transplant as upfront therapy.
Kenneth Anderson, MD, of Dana Farber/Brigham and Women’s Cancer Center in Boston, took the stance that, in the past 10 years, there has been a
revolution in novel therapies that has significantly improved survival in MM.
For upfront transplant
Dr Giralt cited the 36-month follow-up of the E4A03 landmark analysis of patients who went off therapy after 4 cycles of lenalidomide/dexamethasone to pursue early stem cell transplant and those who continued treatment until disease progression.
Regardless of whether the patients were younger than 65 years or between 65 and 70, the patients who had an early transplant had superior progression-free survival (PFS) and overall survival (OS) compared to those who did not.
Dr Giralt added that bortezomib should be a component of induction therapy prior to autologous stem cell transplant (ASCT). Even though there is no survival benefit with bortezomib-based regimens, he said, there is significant improvement in PFS, as shown in a meta-analysis of phase 3 European studies.
The E4A03 landmark study also determined that the more intense the treatment, the better the outcome. So patients with double ASCT had a significantly longer PFS than patients who only had a single transplant.
This held true for OS as well, and included patients with 17p deletion and/or t(4;14) who failed to achieve complete remission after bortezomib-based induction regimens.
An analysis of 27,987 MM patients with a median age of 68 years (range, 19 to 90) revealed that of the patients who survived 10 years or more, 16.5% had ASCT as part of their initial therapy.
Dr Giralt concluded that the preponderance of evidence supports high-dose melphalan and ASCT as upfront consolidation therapy for MM. And until results of randomized trials investigating combination therapies are reported, melphalan consolidation should be considered the standard of care for all eligible patients with MM.
Against upfront transplant
Dr Anderson countered with data showing limited or no improvement in survival with ASCT, including evidence from studies by Attal, Fermand, Blade, Child, and Barlogie.
ASCT confers only modest PFS advantage, he said, showing results of the Barlogie study in which patients undergoing ASCT had a 25-month PFS, compared with a 21-month PFS with VBMCP (vincristine, carmustine, melphalan, cyclophosphamide, and prednisone).
“In the last 10 to 15 years, there has been a revolution in myeloma,” Dr Anderson said. “We have a lot of novel agents here today, and we have even more coming. It’s a hugely exciting time.”
Dr Anderson pointed out that since the introduction of novel agents, survival has improved between 2006 and 2010, compared to the period between 2001 and 2005, and particularly in patients older than 65 years (P=0.001).
Transplant has also changed, he said. Novel therapies have been integrated into the transplant paradigm, either before, as induction and consolidation therapy, or after, as maintenance. He indicated that this begs the question as to whether we really need the transplant component.
There has also been unprecedented use of triplets in combination therapy, Dr Anderson said, resulting in overall response rates upwards of 90%. For example, carfilzomib in combination with lenalidomide and dexamethasone prompted an overall response rate of 94%, with a stringent complete response (CR), CR, and near CR of 53%.
“It’s a new day in myeloma,” he said. “It’s taken us a long time, but we’re worrying about minimal residual disease (MRD) now. We’re worried about getting to the endpoint of 1 myeloma cell in 1 million normal cells.”
The point is, he added, that with novel therapies, such as carfilzomib, lenalidomide, and dexamethasone, patients who achieve a complete response can become MRD negative, suggesting an unprecedented extent of response without transplant.
MRD negativity may also be accomplished with oral agents, such as ixazomib. The depth of response with ixazomib increases over the course of treatment, with 27% achieving stringent CR or CR with a median duration of response of 13.8 months, and 82% of patients attaining MRD-negative status.
“In the absence of transplant,” Dr Anderson said, “this is an unprecedented response.”
Dr Anderson also pointed out that in the era of novel agents, there is no difference in outcome between early or delayed transplant. The 4-year OS in transplant-eligible patients who received initial therapy with lenalidomide was 80%, regardless of the timing of ASCT.
And in one trial, patients who received a delayed transplant fared better in OS than those transplanted early.
Dr Anderson said there is a parallel, international phase 3 study underway (IFM/DFCI2009) that will provide an answer to the debate on upfront transplant in the not-too-distant future.