Erilyn Riley

Hand washing

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.

Hand washing

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.

Hand washing

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.

Neil P. Shah, MD, PhD

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.

Neil P. Shah, MD, PhD

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.

Neil P. Shah, MD, PhD

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.

Preparing for transplant

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.

Preparing for transplant

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.

Preparing for transplant

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.

The ASCO 2012 Annual Meeting
Credit: ASCO/Scott Morgan

CHICAGO—A new monoclonal antibody, blinatumomab, achieves an “exceptionally high complete remission rate” as a single agent in acute lymphoblastic leukemia (ALL), according to investigators.

They reported that about 70% of adult patients with relapsed/refractory B-precursor ALL achieved a hematologic complete remission (CR).

Max Topp, MD, of the Wuerzburg University Medical Center in Germany, presented the findings as abstract 6500 at the 2012 ASCO Annual Meeting held here recently.

Outcomes are poor for adult patients with relapsed/refractory ALL following frontline therapy. Several clinical trials have shown that most patients fail to achieve CR. Response rates are typically 20% to 30%.

“Treatment-related mortality is high, CR is not durable, and overall survival is dismal at a median of 4-6 months after relapse,” Dr Topp said. “[A]llogeneic stem cell transplant (alloSCT) is only really available to patients who reach a CR, and few patients make it to SCT.”

After alloSCT, the overall survival rate at 1 year is about 20%, regardless of CR status. “There is a need for something completely different,” Dr Topp said.

Enter blinatumomab. Blinatumomab is a bispecific T-cell engaging antibody that directs cytotoxic T cells to CD19-expressing target cells.

Dr Topp and colleagues designed an open-label, multicenter, exploratory phase 2 study and enrolled 36 relapsed/refractory ALL patients. The patients were a median age of 31 years and had a high blast count. Some 40% had relapsed after alloSCT.

Patients received blinatumomab by continuous intravenous infusion for 4 weeks, with 2 weeks off, for up to 5 cycles. The investigators determined the safest dose to be 5 µg/m²/day in week 1, followed by 15 µg/m²/day for the remaining treatment. Twenty-three patients entered the extension phase at this dose.

Of the 36 patients enrolled, 26 (72%) achieved a hematologic CR, as did 17 of 23 patients (74%) in the extension phase.

The duration of hematologic CR was 8.9 months after a median observation time of 4.5 months.

Median overall survival was 9 months after a median follow-up of 10.7 months. This compares favorably with historical data, Dr Topp pointed out.

“Most importantly,” he added, “almost every patient who achieved CR had a molecular remission. Only 2 out of 26 patients didn’t reach this endpoint.”

He noted that 13 patients who reached CR had an alloSCT.

Early on, several patients developed cytokine release syndrome. So the researchers developed a prevention strategy of giving corticosteroids upfront. As a result, there were no cases of cytokine release syndrome in the extension phase.

The most common adverse events in the safest dosing schedule were pyrexia and headache. There were few grade 3 events, and all adverse events were reversible.

Dr Topp said the data support further investigation of blinatumomab in adult patients with relapsed/refractory ALL.

He noted that a global phase 2 study in this setting has already been initiated in the United States and Europe.

The ASCO 2012 Annual Meeting
Credit: ASCO/Scott Morgan

CHICAGO—A new monoclonal antibody, blinatumomab, achieves an “exceptionally high complete remission rate” as a single agent in acute lymphoblastic leukemia (ALL), according to investigators.

They reported that about 70% of adult patients with relapsed/refractory B-precursor ALL achieved a hematologic complete remission (CR).

Max Topp, MD, of the Wuerzburg University Medical Center in Germany, presented the findings as abstract 6500 at the 2012 ASCO Annual Meeting held here recently.

Outcomes are poor for adult patients with relapsed/refractory ALL following frontline therapy. Several clinical trials have shown that most patients fail to achieve CR. Response rates are typically 20% to 30%.

“Treatment-related mortality is high, CR is not durable, and overall survival is dismal at a median of 4-6 months after relapse,” Dr Topp said. “[A]llogeneic stem cell transplant (alloSCT) is only really available to patients who reach a CR, and few patients make it to SCT.”

After alloSCT, the overall survival rate at 1 year is about 20%, regardless of CR status. “There is a need for something completely different,” Dr Topp said.

Enter blinatumomab. Blinatumomab is a bispecific T-cell engaging antibody that directs cytotoxic T cells to CD19-expressing target cells.

Dr Topp and colleagues designed an open-label, multicenter, exploratory phase 2 study and enrolled 36 relapsed/refractory ALL patients. The patients were a median age of 31 years and had a high blast count. Some 40% had relapsed after alloSCT.

Patients received blinatumomab by continuous intravenous infusion for 4 weeks, with 2 weeks off, for up to 5 cycles. The investigators determined the safest dose to be 5 µg/m²/day in week 1, followed by 15 µg/m²/day for the remaining treatment. Twenty-three patients entered the extension phase at this dose.

Of the 36 patients enrolled, 26 (72%) achieved a hematologic CR, as did 17 of 23 patients (74%) in the extension phase.

The duration of hematologic CR was 8.9 months after a median observation time of 4.5 months.

Median overall survival was 9 months after a median follow-up of 10.7 months. This compares favorably with historical data, Dr Topp pointed out.

“Most importantly,” he added, “almost every patient who achieved CR had a molecular remission. Only 2 out of 26 patients didn’t reach this endpoint.”

He noted that 13 patients who reached CR had an alloSCT.

Early on, several patients developed cytokine release syndrome. So the researchers developed a prevention strategy of giving corticosteroids upfront. As a result, there were no cases of cytokine release syndrome in the extension phase.

The most common adverse events in the safest dosing schedule were pyrexia and headache. There were few grade 3 events, and all adverse events were reversible.

Dr Topp said the data support further investigation of blinatumomab in adult patients with relapsed/refractory ALL.

He noted that a global phase 2 study in this setting has already been initiated in the United States and Europe.

The ASCO 2012 Annual Meeting
Credit: ASCO/Scott Morgan

CHICAGO—A new monoclonal antibody, blinatumomab, achieves an “exceptionally high complete remission rate” as a single agent in acute lymphoblastic leukemia (ALL), according to investigators.

They reported that about 70% of adult patients with relapsed/refractory B-precursor ALL achieved a hematologic complete remission (CR).

Max Topp, MD, of the Wuerzburg University Medical Center in Germany, presented the findings as abstract 6500 at the 2012 ASCO Annual Meeting held here recently.

Outcomes are poor for adult patients with relapsed/refractory ALL following frontline therapy. Several clinical trials have shown that most patients fail to achieve CR. Response rates are typically 20% to 30%.

“Treatment-related mortality is high, CR is not durable, and overall survival is dismal at a median of 4-6 months after relapse,” Dr Topp said. “[A]llogeneic stem cell transplant (alloSCT) is only really available to patients who reach a CR, and few patients make it to SCT.”

After alloSCT, the overall survival rate at 1 year is about 20%, regardless of CR status. “There is a need for something completely different,” Dr Topp said.

Enter blinatumomab. Blinatumomab is a bispecific T-cell engaging antibody that directs cytotoxic T cells to CD19-expressing target cells.

Dr Topp and colleagues designed an open-label, multicenter, exploratory phase 2 study and enrolled 36 relapsed/refractory ALL patients. The patients were a median age of 31 years and had a high blast count. Some 40% had relapsed after alloSCT.

Patients received blinatumomab by continuous intravenous infusion for 4 weeks, with 2 weeks off, for up to 5 cycles. The investigators determined the safest dose to be 5 µg/m²/day in week 1, followed by 15 µg/m²/day for the remaining treatment. Twenty-three patients entered the extension phase at this dose.

Of the 36 patients enrolled, 26 (72%) achieved a hematologic CR, as did 17 of 23 patients (74%) in the extension phase.

The duration of hematologic CR was 8.9 months after a median observation time of 4.5 months.

Median overall survival was 9 months after a median follow-up of 10.7 months. This compares favorably with historical data, Dr Topp pointed out.

“Most importantly,” he added, “almost every patient who achieved CR had a molecular remission. Only 2 out of 26 patients didn’t reach this endpoint.”

He noted that 13 patients who reached CR had an alloSCT.

Early on, several patients developed cytokine release syndrome. So the researchers developed a prevention strategy of giving corticosteroids upfront. As a result, there were no cases of cytokine release syndrome in the extension phase.

The most common adverse events in the safest dosing schedule were pyrexia and headache. There were few grade 3 events, and all adverse events were reversible.

Dr Topp said the data support further investigation of blinatumomab in adult patients with relapsed/refractory ALL.

He noted that a global phase 2 study in this setting has already been initiated in the United States and Europe.

Inside the San Diego
Convention Center, site of
the 53rd ASH Annual Meeting
Photo courtesy of ASH

SAN DIEGO—Impressive results have been achieved with pomalidomide and low-dose dexamethasone (loDex) in relapsed and refractory patients with multiple myeloma (MM), according to study investigators.

The combination achieved a 34% response rate, including a complete response of 1% and very good partial response of 10% in this population of MM patients refractory to lenalidomide, bortezomib, or both.

Paul Richardson, MD, of Dana-Farber Cancer Institute, reported the results of the phase 1/2 study, known as MM-002, at the 53rd ASH Annual Meeting (abstract 634).

The phase 1 portion of the trial had been reported previously. It established a maximum-tolerated dose of 4 mg daily of pomalidomide.

Dr Richardson called pomalidomide “arguably the most potent of all the IMiDs.” It has significant antimyeloma activity in vitro, promising activity as a single agent in patients with relapsed/refractory MM and efficacy when combined with loDex in patients previously treated with lenalidomide and/or bortezomib.

Dr Richardson pointed out that the investigators defined relapsed and refractory disease rigorously.

“Patients had to have progressed during or 60 days from last treatment, and this had to be confirmed with source documentation prior to study entry,” he said.

In addition, patients had to have measurable levels of M-paraprotein in serum or urine. They must have had 2 or more prior therapies that included 2 or more cycles of lenalidomide and 2 or more cycles of bortezomib, either separately or in combination.

Two hundred twenty-one patients were randomized, 108 to pomalidomide alone and 113 to pomalidomide plus loDex. The pomalidomide regimen was 4 mg daily for 3 weeks with 1 week off. The loDex consisted of 40 mg per week.

Patients were a median age of 63 years. Seventy-eight percent were refractory to lenalidomide, 71% to bortezomib, and 60% to both agents. They had a median of 5 prior therapies, range 2-13.

One hundred ninety-one patients were evaluable for response. They had a median number of 5 cycles of therapy (range, 1-17) and a median duration of 5 months of treatment.

The combination arm had a 34% overall response rate, including partial response or better, compared to 13% in the pomalidomide-alone arm.

Forty-five percent in the combination arm achieved a minor response, compared to 29% in the pomalidomide-alone arm.

And 81% of the patients overall achieved stable disease or better. Responses were rapid and appeared durable, Dr Richardson said.

“What was particularly reassuring and encouraging as well,” he said, “is to see a very similar rate of response for those patients who were refractory to lenalidomide and bortezomib together.” The overall response rate in those patients was 30%.

The median progression-free survival for patients on the combination was 4.7 months. For those on pomalidomide alone, it was 2.7 months.

And the median overall survival on the combination arm was 16.9 months. For those on pomalidomide alone, it was 14 months.

Patients who were refractory to both lenalidomide and bortezomib achieved progression-free survival approaching 4 months with the drug combination and 2 months for pomalidomide alone.

Neutropenia was the dominant grade 3-4 hematologic side effect, followed by thrombocytopenia and anemia. Dose reduction was required in a minority of patients.

The nonhematologic side effects were quite uncommon and included pneumonia and fatigue. No grade 3-4 peripheral neuropathy was reported.

The rate of thromboembolism was less than 5% in either arm. Anticoagulation with low-dose aspirin was required, however.

The investigators concluded that pomalidomide and loDex are synergistic in terms of response rate, and they were impressed that the consistent and durable responses occurred regardless of prior therapy or refractoriness.

On this basis, pomalidomide plus loDex is being investigated in phase 3 trials and as part of combination treatments, including bortezomib.

Inside the San Diego
Convention Center, site of
the 53rd ASH Annual Meeting
Photo courtesy of ASH

SAN DIEGO—Impressive results have been achieved with pomalidomide and low-dose dexamethasone (loDex) in relapsed and refractory patients with multiple myeloma (MM), according to study investigators.

The combination achieved a 34% response rate, including a complete response of 1% and very good partial response of 10% in this population of MM patients refractory to lenalidomide, bortezomib, or both.

Paul Richardson, MD, of Dana-Farber Cancer Institute, reported the results of the phase 1/2 study, known as MM-002, at the 53rd ASH Annual Meeting (abstract 634).

The phase 1 portion of the trial had been reported previously. It established a maximum-tolerated dose of 4 mg daily of pomalidomide.

Dr Richardson called pomalidomide “arguably the most potent of all the IMiDs.” It has significant antimyeloma activity in vitro, promising activity as a single agent in patients with relapsed/refractory MM and efficacy when combined with loDex in patients previously treated with lenalidomide and/or bortezomib.

Dr Richardson pointed out that the investigators defined relapsed and refractory disease rigorously.

“Patients had to have progressed during or 60 days from last treatment, and this had to be confirmed with source documentation prior to study entry,” he said.

In addition, patients had to have measurable levels of M-paraprotein in serum or urine. They must have had 2 or more prior therapies that included 2 or more cycles of lenalidomide and 2 or more cycles of bortezomib, either separately or in combination.

Two hundred twenty-one patients were randomized, 108 to pomalidomide alone and 113 to pomalidomide plus loDex. The pomalidomide regimen was 4 mg daily for 3 weeks with 1 week off. The loDex consisted of 40 mg per week.

Patients were a median age of 63 years. Seventy-eight percent were refractory to lenalidomide, 71% to bortezomib, and 60% to both agents. They had a median of 5 prior therapies, range 2-13.

One hundred ninety-one patients were evaluable for response. They had a median number of 5 cycles of therapy (range, 1-17) and a median duration of 5 months of treatment.

The combination arm had a 34% overall response rate, including partial response or better, compared to 13% in the pomalidomide-alone arm.

Forty-five percent in the combination arm achieved a minor response, compared to 29% in the pomalidomide-alone arm.

And 81% of the patients overall achieved stable disease or better. Responses were rapid and appeared durable, Dr Richardson said.

“What was particularly reassuring and encouraging as well,” he said, “is to see a very similar rate of response for those patients who were refractory to lenalidomide and bortezomib together.” The overall response rate in those patients was 30%.

The median progression-free survival for patients on the combination was 4.7 months. For those on pomalidomide alone, it was 2.7 months.

And the median overall survival on the combination arm was 16.9 months. For those on pomalidomide alone, it was 14 months.

Patients who were refractory to both lenalidomide and bortezomib achieved progression-free survival approaching 4 months with the drug combination and 2 months for pomalidomide alone.

Neutropenia was the dominant grade 3-4 hematologic side effect, followed by thrombocytopenia and anemia. Dose reduction was required in a minority of patients.

The nonhematologic side effects were quite uncommon and included pneumonia and fatigue. No grade 3-4 peripheral neuropathy was reported.

The rate of thromboembolism was less than 5% in either arm. Anticoagulation with low-dose aspirin was required, however.

The investigators concluded that pomalidomide and loDex are synergistic in terms of response rate, and they were impressed that the consistent and durable responses occurred regardless of prior therapy or refractoriness.

On this basis, pomalidomide plus loDex is being investigated in phase 3 trials and as part of combination treatments, including bortezomib.

Inside the San Diego
Convention Center, site of
the 53rd ASH Annual Meeting
Photo courtesy of ASH

SAN DIEGO—Impressive results have been achieved with pomalidomide and low-dose dexamethasone (loDex) in relapsed and refractory patients with multiple myeloma (MM), according to study investigators.

The combination achieved a 34% response rate, including a complete response of 1% and very good partial response of 10% in this population of MM patients refractory to lenalidomide, bortezomib, or both.

Paul Richardson, MD, of Dana-Farber Cancer Institute, reported the results of the phase 1/2 study, known as MM-002, at the 53rd ASH Annual Meeting (abstract 634).

The phase 1 portion of the trial had been reported previously. It established a maximum-tolerated dose of 4 mg daily of pomalidomide.

Dr Richardson called pomalidomide “arguably the most potent of all the IMiDs.” It has significant antimyeloma activity in vitro, promising activity as a single agent in patients with relapsed/refractory MM and efficacy when combined with loDex in patients previously treated with lenalidomide and/or bortezomib.

Dr Richardson pointed out that the investigators defined relapsed and refractory disease rigorously.

“Patients had to have progressed during or 60 days from last treatment, and this had to be confirmed with source documentation prior to study entry,” he said.

In addition, patients had to have measurable levels of M-paraprotein in serum or urine. They must have had 2 or more prior therapies that included 2 or more cycles of lenalidomide and 2 or more cycles of bortezomib, either separately or in combination.

Two hundred twenty-one patients were randomized, 108 to pomalidomide alone and 113 to pomalidomide plus loDex. The pomalidomide regimen was 4 mg daily for 3 weeks with 1 week off. The loDex consisted of 40 mg per week.

Patients were a median age of 63 years. Seventy-eight percent were refractory to lenalidomide, 71% to bortezomib, and 60% to both agents. They had a median of 5 prior therapies, range 2-13.

One hundred ninety-one patients were evaluable for response. They had a median number of 5 cycles of therapy (range, 1-17) and a median duration of 5 months of treatment.

The combination arm had a 34% overall response rate, including partial response or better, compared to 13% in the pomalidomide-alone arm.

Forty-five percent in the combination arm achieved a minor response, compared to 29% in the pomalidomide-alone arm.

And 81% of the patients overall achieved stable disease or better. Responses were rapid and appeared durable, Dr Richardson said.

“What was particularly reassuring and encouraging as well,” he said, “is to see a very similar rate of response for those patients who were refractory to lenalidomide and bortezomib together.” The overall response rate in those patients was 30%.

The median progression-free survival for patients on the combination was 4.7 months. For those on pomalidomide alone, it was 2.7 months.

And the median overall survival on the combination arm was 16.9 months. For those on pomalidomide alone, it was 14 months.

Patients who were refractory to both lenalidomide and bortezomib achieved progression-free survival approaching 4 months with the drug combination and 2 months for pomalidomide alone.

Neutropenia was the dominant grade 3-4 hematologic side effect, followed by thrombocytopenia and anemia. Dose reduction was required in a minority of patients.

The nonhematologic side effects were quite uncommon and included pneumonia and fatigue. No grade 3-4 peripheral neuropathy was reported.

The rate of thromboembolism was less than 5% in either arm. Anticoagulation with low-dose aspirin was required, however.

The investigators concluded that pomalidomide and loDex are synergistic in terms of response rate, and they were impressed that the consistent and durable responses occurred regardless of prior therapy or refractoriness.

On this basis, pomalidomide plus loDex is being investigated in phase 3 trials and as part of combination treatments, including bortezomib.

Gene therapy with a lentiviral vector expressing a chimeric antigen receptor with specificity for CD19 (CART19) has induced complete remission in 3 patients with chronic lymphocytic leukemia (CLL), according to research published simultaneously in the August 10 issues of The New England Journal of Medicine and Science Translational Medicine.

The research team, from the University of Pennsylvania, reported that the reinfused, modified T cells expanded to more than 1000 times the initial engraftment level. The patients’ remission was ongoing at 10 months after treatment.

The investigators believe the big difference between this genetically modified T cell and previous ones that had disappointing clinical activity is the addition of the CD137 (4-1BB) costimulatory signaling domain that significantly increases antitumor activity.

The team, led by Carl June, MD, described in the NEJM article the T-cell treatment of one of the patients with advanced, p53-deficient CLL.

A half year prior to enrolling in the trial, the 64-year-old patient’s T cells were collected and frozen. Before reinfusing the T cells into the patient, the investigators thawed the cells and transduced them with lentivirus expressing CD19-specific chimeric antigen receptor.

Four days prior to reinfusion, the patient received chemotherapy with pentostatin and cyclophosphamide to deplete his lymphocytes. After 3 days of chemotherapy, his bone marrow was hypercellular with approximately 40% involvement by CLL.

After 4 days of chemotherapy, the patient received an infusion of T cells, of which 5% were transduced, totaling 1.42 x 10⁷ transduced cells, split into 3 consecutive daily infusions.

Two weeks after the infusion, the patient experienced chills, fever, and fatigue, which intensified over the subsequent days. He was diagnosed with tumor lysis syndrome on day 22 after infusion. On day 23 after the CART19-cell infusion, the patient had no evidence of CLL in the bone marrow, and by day 28, his adenopathy was not palpable.

In addition to tumor lysis syndrome, the only other grade 3/4 toxicity observed was lymphopenia.

The investigators did not expect that such a low dose of chimeric antigen receptor T cells would result in a clinically evident antitumor response. The dose was several orders of magnitude lower than that used in previous studies of modified T cells.

They speculated that the course of chemotherapy administered to the patient prior to the CART19-cell infusion may have been responsible for the increased engraftment and for “potentiating the ability of chimeric antigen receptor T cells to kill stressed tumor cells that would otherwise survive the chemotherapy.”

The researchers conclude that continued study of CD19-redirected T cells is warranted and plan to test the approach in other CD19-positive tumors, including non-Hodgkin lymphoma and acute lymphocytic leukemia.

Gene therapy with a lentiviral vector expressing a chimeric antigen receptor with specificity for CD19 (CART19) has induced complete remission in 3 patients with chronic lymphocytic leukemia (CLL), according to research published simultaneously in the August 10 issues of The New England Journal of Medicine and Science Translational Medicine.

The research team, from the University of Pennsylvania, reported that the reinfused, modified T cells expanded to more than 1000 times the initial engraftment level. The patients’ remission was ongoing at 10 months after treatment.

The investigators believe the big difference between this genetically modified T cell and previous ones that had disappointing clinical activity is the addition of the CD137 (4-1BB) costimulatory signaling domain that significantly increases antitumor activity.

The team, led by Carl June, MD, described in the NEJM article the T-cell treatment of one of the patients with advanced, p53-deficient CLL.

A half year prior to enrolling in the trial, the 64-year-old patient’s T cells were collected and frozen. Before reinfusing the T cells into the patient, the investigators thawed the cells and transduced them with lentivirus expressing CD19-specific chimeric antigen receptor.

Four days prior to reinfusion, the patient received chemotherapy with pentostatin and cyclophosphamide to deplete his lymphocytes. After 3 days of chemotherapy, his bone marrow was hypercellular with approximately 40% involvement by CLL.

After 4 days of chemotherapy, the patient received an infusion of T cells, of which 5% were transduced, totaling 1.42 x 10⁷ transduced cells, split into 3 consecutive daily infusions.

Two weeks after the infusion, the patient experienced chills, fever, and fatigue, which intensified over the subsequent days. He was diagnosed with tumor lysis syndrome on day 22 after infusion. On day 23 after the CART19-cell infusion, the patient had no evidence of CLL in the bone marrow, and by day 28, his adenopathy was not palpable.

In addition to tumor lysis syndrome, the only other grade 3/4 toxicity observed was lymphopenia.

The investigators did not expect that such a low dose of chimeric antigen receptor T cells would result in a clinically evident antitumor response. The dose was several orders of magnitude lower than that used in previous studies of modified T cells.

They speculated that the course of chemotherapy administered to the patient prior to the CART19-cell infusion may have been responsible for the increased engraftment and for “potentiating the ability of chimeric antigen receptor T cells to kill stressed tumor cells that would otherwise survive the chemotherapy.”

The researchers conclude that continued study of CD19-redirected T cells is warranted and plan to test the approach in other CD19-positive tumors, including non-Hodgkin lymphoma and acute lymphocytic leukemia.

Gene therapy with a lentiviral vector expressing a chimeric antigen receptor with specificity for CD19 (CART19) has induced complete remission in 3 patients with chronic lymphocytic leukemia (CLL), according to research published simultaneously in the August 10 issues of The New England Journal of Medicine and Science Translational Medicine.

The research team, from the University of Pennsylvania, reported that the reinfused, modified T cells expanded to more than 1000 times the initial engraftment level. The patients’ remission was ongoing at 10 months after treatment.

The investigators believe the big difference between this genetically modified T cell and previous ones that had disappointing clinical activity is the addition of the CD137 (4-1BB) costimulatory signaling domain that significantly increases antitumor activity.

The team, led by Carl June, MD, described in the NEJM article the T-cell treatment of one of the patients with advanced, p53-deficient CLL.

A half year prior to enrolling in the trial, the 64-year-old patient’s T cells were collected and frozen. Before reinfusing the T cells into the patient, the investigators thawed the cells and transduced them with lentivirus expressing CD19-specific chimeric antigen receptor.

Four days prior to reinfusion, the patient received chemotherapy with pentostatin and cyclophosphamide to deplete his lymphocytes. After 3 days of chemotherapy, his bone marrow was hypercellular with approximately 40% involvement by CLL.

After 4 days of chemotherapy, the patient received an infusion of T cells, of which 5% were transduced, totaling 1.42 x 10⁷ transduced cells, split into 3 consecutive daily infusions.

Two weeks after the infusion, the patient experienced chills, fever, and fatigue, which intensified over the subsequent days. He was diagnosed with tumor lysis syndrome on day 22 after infusion. On day 23 after the CART19-cell infusion, the patient had no evidence of CLL in the bone marrow, and by day 28, his adenopathy was not palpable.

In addition to tumor lysis syndrome, the only other grade 3/4 toxicity observed was lymphopenia.

The investigators did not expect that such a low dose of chimeric antigen receptor T cells would result in a clinically evident antitumor response. The dose was several orders of magnitude lower than that used in previous studies of modified T cells.

They speculated that the course of chemotherapy administered to the patient prior to the CART19-cell infusion may have been responsible for the increased engraftment and for “potentiating the ability of chimeric antigen receptor T cells to kill stressed tumor cells that would otherwise survive the chemotherapy.”

The researchers conclude that continued study of CD19-redirected T cells is warranted and plan to test the approach in other CD19-positive tumors, including non-Hodgkin lymphoma and acute lymphocytic leukemia.