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Team identifies potential immunotherapy target for AML
New research could aid the development of immunotherapies tailored to patients with acute myeloid leukemia (AML) who are undergoing stem cell transplant (SCT).
Researchers found they could use genetic sequencing and computer software to identify minor histocompatibility antigens (mHAs) known to occur in AML.
The team used this method to predict novel graft-versus-leukemia (GVL) mHAs and demonstrated that one of these mHAs could be a “potentially useful” therapeutic target.
Ben Vincent, MD, of the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, and his colleagues reported these findings in Blood Advances.
In their retrospective study, the researchers tested whether their software could predict antigenic targets in 101 SCT donor-recipient pairs.
The researchers found they could correctly identify 14 of 18 mHAs known to occur in AML, but they were also able to predict 102 new GVL mHAs.
The researchers then confirmed one of these GVL mHAs, called UNC-GRK4-V, as a potential target for immunotherapy. The team observed immune responses to UNC-GRK4-V in four of nine AML patients who had undergone SCT.
Looking ahead, the researchers want to optimize their software to predict the most common AML-associated mHAs present in the U.S. population and confirm these predicted antigens as valid immunotherapy targets.
The team believes they could potentially use their predictions to engineer donor immune cells to specifically target the cancer cell antigens while preventing graft-versus-host disease.
“We’ve developed a software package that predicts leukemia-specific immune targets in any leukemia patient undergoing a stem cell transplant based on DNA and RNA sequencing and demonstrated that these data can lead to actual targets expressed on leukemia cells,” Dr. Vincent said.
“The next step of our work is to use that information for patient-specific therapies to try to improve cure rates without making graft-versus-host disease worse.”
The current research was supported by a National Cancer Institute grant, an ASCO Young Investigator Award, the North Carolina University Cancer Research Fund, and the Scott Neil Schwirck Fellowship.
New research could aid the development of immunotherapies tailored to patients with acute myeloid leukemia (AML) who are undergoing stem cell transplant (SCT).
Researchers found they could use genetic sequencing and computer software to identify minor histocompatibility antigens (mHAs) known to occur in AML.
The team used this method to predict novel graft-versus-leukemia (GVL) mHAs and demonstrated that one of these mHAs could be a “potentially useful” therapeutic target.
Ben Vincent, MD, of the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, and his colleagues reported these findings in Blood Advances.
In their retrospective study, the researchers tested whether their software could predict antigenic targets in 101 SCT donor-recipient pairs.
The researchers found they could correctly identify 14 of 18 mHAs known to occur in AML, but they were also able to predict 102 new GVL mHAs.
The researchers then confirmed one of these GVL mHAs, called UNC-GRK4-V, as a potential target for immunotherapy. The team observed immune responses to UNC-GRK4-V in four of nine AML patients who had undergone SCT.
Looking ahead, the researchers want to optimize their software to predict the most common AML-associated mHAs present in the U.S. population and confirm these predicted antigens as valid immunotherapy targets.
The team believes they could potentially use their predictions to engineer donor immune cells to specifically target the cancer cell antigens while preventing graft-versus-host disease.
“We’ve developed a software package that predicts leukemia-specific immune targets in any leukemia patient undergoing a stem cell transplant based on DNA and RNA sequencing and demonstrated that these data can lead to actual targets expressed on leukemia cells,” Dr. Vincent said.
“The next step of our work is to use that information for patient-specific therapies to try to improve cure rates without making graft-versus-host disease worse.”
The current research was supported by a National Cancer Institute grant, an ASCO Young Investigator Award, the North Carolina University Cancer Research Fund, and the Scott Neil Schwirck Fellowship.
New research could aid the development of immunotherapies tailored to patients with acute myeloid leukemia (AML) who are undergoing stem cell transplant (SCT).
Researchers found they could use genetic sequencing and computer software to identify minor histocompatibility antigens (mHAs) known to occur in AML.
The team used this method to predict novel graft-versus-leukemia (GVL) mHAs and demonstrated that one of these mHAs could be a “potentially useful” therapeutic target.
Ben Vincent, MD, of the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, and his colleagues reported these findings in Blood Advances.
In their retrospective study, the researchers tested whether their software could predict antigenic targets in 101 SCT donor-recipient pairs.
The researchers found they could correctly identify 14 of 18 mHAs known to occur in AML, but they were also able to predict 102 new GVL mHAs.
The researchers then confirmed one of these GVL mHAs, called UNC-GRK4-V, as a potential target for immunotherapy. The team observed immune responses to UNC-GRK4-V in four of nine AML patients who had undergone SCT.
Looking ahead, the researchers want to optimize their software to predict the most common AML-associated mHAs present in the U.S. population and confirm these predicted antigens as valid immunotherapy targets.
The team believes they could potentially use their predictions to engineer donor immune cells to specifically target the cancer cell antigens while preventing graft-versus-host disease.
“We’ve developed a software package that predicts leukemia-specific immune targets in any leukemia patient undergoing a stem cell transplant based on DNA and RNA sequencing and demonstrated that these data can lead to actual targets expressed on leukemia cells,” Dr. Vincent said.
“The next step of our work is to use that information for patient-specific therapies to try to improve cure rates without making graft-versus-host disease worse.”
The current research was supported by a National Cancer Institute grant, an ASCO Young Investigator Award, the North Carolina University Cancer Research Fund, and the Scott Neil Schwirck Fellowship.
New guidelines on antimicrobial prophylaxis
Experts have published updated guidelines on antimicrobial prophylaxis for adults with cancer-related immunosuppression.
The guidelines include antibacterial, antifungal, and antiviral prophylaxis recommendations, along with additional precautions, such as hand hygiene, that may reduce infection risk.
The guidelines were developed by the American Society of Clinical Oncology (ASCO) with the Infectious Diseases Society of America (IDSA) and published in the Journal of Clinical Oncology.
For the most part, the expert panel that created these guidelines endorsed the previous ASCO recommendations, published in 2013.
However, the panel considered six new studies and six new or updated meta-analyses to make modifications and add some new recommendations.
Recommendations
The ASCO/IDSA guidelines say health care providers should systematically assess the risk of febrile neutropenia, taking into account patient-, cancer-, and treatment-related factors.
Fluoroquinolone prophylaxis is recommended for patients at high risk of febrile neutropenia or profound, protracted neutropenia. This includes most patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) and patients undergoing hematopoietic stem cell transplant (HSCT) who are treated with myeloablative conditioning regimens.
Antifungal prophylaxis with an oral triazole or parenteral echinocandin is recommended for patients at risk of profound, protracted neutropenia, which includes HSCT recipients and most patients with AML/MDS.
However, neither antifungal nor antibiotic prophylaxis are routinely recommended for patients with solid tumors.
Prophylaxis with a nucleoside analog, such as acyclovir, is recommended in patients who are herpes simplex virus–seropositive and are undergoing allogeneic HSCT or leukemia induction.
Pneumocystis jirovecii prophylaxis, such as trimethoprim-sulfamethoxazole, is recommended for patients receiving chemotherapy regimens associated with a greater than 3.5% risk for pneumonia from P jirovecii.
Treatment with a nucleoside reverse transcription inhibitor, such as entecavir or tenofovir, is recommended for patients at high risk of hepatitis B virus reactivation.
Yearly influenza vaccination with an inactivated quadrivalent vaccine is recommended for all patients undergoing chemotherapy for malignancy as well as their family members, household contacts, and health care providers.
Health care workers should follow hand hygiene and respiratory hygiene/cough etiquette to reduce the risk of pathogen transmission, according to the guidelines.
The guidelines also note that outpatients who develop neutropenia following cancer therapy should avoid prolonged contact with environments that have high concentrations of airborne fungal spores.
The guidelines do not recommend interventions such as neutropenic diet, footwear exchange, nutritional supplements, and surgical masks. “Evidence of clinical benefit is lacking” for those interventions, the expert panel said.
Members of the expert panel disclosed potential conflicts of interest related to Merck, Chimerix, GlyPharma Therapeutic, Pfizer, Cidara Therapeutics, Celgene, Astellas Pharma, Gilead Sciences, and Allergan, among other entities.
Experts have published updated guidelines on antimicrobial prophylaxis for adults with cancer-related immunosuppression.
The guidelines include antibacterial, antifungal, and antiviral prophylaxis recommendations, along with additional precautions, such as hand hygiene, that may reduce infection risk.
The guidelines were developed by the American Society of Clinical Oncology (ASCO) with the Infectious Diseases Society of America (IDSA) and published in the Journal of Clinical Oncology.
For the most part, the expert panel that created these guidelines endorsed the previous ASCO recommendations, published in 2013.
However, the panel considered six new studies and six new or updated meta-analyses to make modifications and add some new recommendations.
Recommendations
The ASCO/IDSA guidelines say health care providers should systematically assess the risk of febrile neutropenia, taking into account patient-, cancer-, and treatment-related factors.
Fluoroquinolone prophylaxis is recommended for patients at high risk of febrile neutropenia or profound, protracted neutropenia. This includes most patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) and patients undergoing hematopoietic stem cell transplant (HSCT) who are treated with myeloablative conditioning regimens.
Antifungal prophylaxis with an oral triazole or parenteral echinocandin is recommended for patients at risk of profound, protracted neutropenia, which includes HSCT recipients and most patients with AML/MDS.
However, neither antifungal nor antibiotic prophylaxis are routinely recommended for patients with solid tumors.
Prophylaxis with a nucleoside analog, such as acyclovir, is recommended in patients who are herpes simplex virus–seropositive and are undergoing allogeneic HSCT or leukemia induction.
Pneumocystis jirovecii prophylaxis, such as trimethoprim-sulfamethoxazole, is recommended for patients receiving chemotherapy regimens associated with a greater than 3.5% risk for pneumonia from P jirovecii.
Treatment with a nucleoside reverse transcription inhibitor, such as entecavir or tenofovir, is recommended for patients at high risk of hepatitis B virus reactivation.
Yearly influenza vaccination with an inactivated quadrivalent vaccine is recommended for all patients undergoing chemotherapy for malignancy as well as their family members, household contacts, and health care providers.
Health care workers should follow hand hygiene and respiratory hygiene/cough etiquette to reduce the risk of pathogen transmission, according to the guidelines.
The guidelines also note that outpatients who develop neutropenia following cancer therapy should avoid prolonged contact with environments that have high concentrations of airborne fungal spores.
The guidelines do not recommend interventions such as neutropenic diet, footwear exchange, nutritional supplements, and surgical masks. “Evidence of clinical benefit is lacking” for those interventions, the expert panel said.
Members of the expert panel disclosed potential conflicts of interest related to Merck, Chimerix, GlyPharma Therapeutic, Pfizer, Cidara Therapeutics, Celgene, Astellas Pharma, Gilead Sciences, and Allergan, among other entities.
Experts have published updated guidelines on antimicrobial prophylaxis for adults with cancer-related immunosuppression.
The guidelines include antibacterial, antifungal, and antiviral prophylaxis recommendations, along with additional precautions, such as hand hygiene, that may reduce infection risk.
The guidelines were developed by the American Society of Clinical Oncology (ASCO) with the Infectious Diseases Society of America (IDSA) and published in the Journal of Clinical Oncology.
For the most part, the expert panel that created these guidelines endorsed the previous ASCO recommendations, published in 2013.
However, the panel considered six new studies and six new or updated meta-analyses to make modifications and add some new recommendations.
Recommendations
The ASCO/IDSA guidelines say health care providers should systematically assess the risk of febrile neutropenia, taking into account patient-, cancer-, and treatment-related factors.
Fluoroquinolone prophylaxis is recommended for patients at high risk of febrile neutropenia or profound, protracted neutropenia. This includes most patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) and patients undergoing hematopoietic stem cell transplant (HSCT) who are treated with myeloablative conditioning regimens.
Antifungal prophylaxis with an oral triazole or parenteral echinocandin is recommended for patients at risk of profound, protracted neutropenia, which includes HSCT recipients and most patients with AML/MDS.
However, neither antifungal nor antibiotic prophylaxis are routinely recommended for patients with solid tumors.
Prophylaxis with a nucleoside analog, such as acyclovir, is recommended in patients who are herpes simplex virus–seropositive and are undergoing allogeneic HSCT or leukemia induction.
Pneumocystis jirovecii prophylaxis, such as trimethoprim-sulfamethoxazole, is recommended for patients receiving chemotherapy regimens associated with a greater than 3.5% risk for pneumonia from P jirovecii.
Treatment with a nucleoside reverse transcription inhibitor, such as entecavir or tenofovir, is recommended for patients at high risk of hepatitis B virus reactivation.
Yearly influenza vaccination with an inactivated quadrivalent vaccine is recommended for all patients undergoing chemotherapy for malignancy as well as their family members, household contacts, and health care providers.
Health care workers should follow hand hygiene and respiratory hygiene/cough etiquette to reduce the risk of pathogen transmission, according to the guidelines.
The guidelines also note that outpatients who develop neutropenia following cancer therapy should avoid prolonged contact with environments that have high concentrations of airborne fungal spores.
The guidelines do not recommend interventions such as neutropenic diet, footwear exchange, nutritional supplements, and surgical masks. “Evidence of clinical benefit is lacking” for those interventions, the expert panel said.
Members of the expert panel disclosed potential conflicts of interest related to Merck, Chimerix, GlyPharma Therapeutic, Pfizer, Cidara Therapeutics, Celgene, Astellas Pharma, Gilead Sciences, and Allergan, among other entities.
First CAR T-cell therapy approved in Canada
Health Canada has authorized use of tisagenlecleucel (Kymriah™), making it the first chimeric antigen receptor (CAR) T-cell therapy to receive regulatory approval in Canada.
Tisagenlecleucel (formerly CTL019) is approved to treat patients ages 3 to 25 with B-cell acute lymphoblastic leukemia (ALL) who have relapsed after allogeneic stem cell transplant (SCT) or are otherwise ineligible for SCT, have experienced second or later relapse, or have refractory disease.
Tisagenlecleucel is also approved in Canada to treat adults who have received two or more lines of systemic therapy and have relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma, or DLBCL arising from follicular lymphoma.
Novartis, the company marketing tisagenlecleucel, said it is working with qualified treatment centers in Canada to prepare for the delivery of tisagenlecleucel. Certification and training are underway at these centers, and Novartis is enhancing manufacturing capacity to meet patient needs.
Tisagenlecleucel has been studied in a pair of phase 2 trials—ELIANA and JULIET.
JULIET trial
JULIET enrolled 165 adults with relapsed/refractory DLBCL, and 111 of them received a single infusion of tisagenlecleucel. Ninety-two percent of patients received bridging therapy, and 93% received lymphodepleting chemotherapy prior to tisagenlecleucel.
The overall response rate was 52%, and the complete response (CR) rate was 40%. The median duration of response was not reached with a median follow-up of 13.9 months. At last follow-up, none of the responders had gone on to SCT.
The 12-month overall survival (OS) rate was 49%, and the median OS was 11.7 months. The median OS was not reached for patients in CR.
Within 8 weeks of tisagenlecleucel infusion, 22% of patients had developed grade 3/4 cytokine release syndrome (CRS). Other adverse events (AEs) of interest included grade 3/4 neurologic events (12%), grade 3/4 cytopenias lasting more than 28 days (32%), grade 3/4 infections (20%), and grade 3/4 febrile neutropenia (15%).
These results were presented at the 23rd Annual Congress of the European Hematology Association in June (abstract S799).
ELIANA trial
ELIANA included 75 children and young adults with relapsed/refractory ALL. The patients’ median age was 11 (range, 3 to 23).
All patients received a single infusion of tisagenlecleucel, and 72 received lymphodepleting chemotherapy.
The median duration of follow-up was 13.1 months. The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CR with incomplete hematologic recovery (CRi) within 3 months.
The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi. All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.
Eight patients proceeded to SCT while in remission. At last follow-up, four were still in remission, and four had unknown disease status.
At 6 months, the event-free survival rate was 73%, and the OS rate was 90%. At 12 months, the rates were 50% and 76%, respectively.
Ninety-five percent of patients had AEs thought to be related to tisagenlecleucel. The incidence of treatment-related grade 3/4 AEs was 73%.
AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).
These results were published in The New England Journal of Medicine in February.
Health Canada has authorized use of tisagenlecleucel (Kymriah™), making it the first chimeric antigen receptor (CAR) T-cell therapy to receive regulatory approval in Canada.
Tisagenlecleucel (formerly CTL019) is approved to treat patients ages 3 to 25 with B-cell acute lymphoblastic leukemia (ALL) who have relapsed after allogeneic stem cell transplant (SCT) or are otherwise ineligible for SCT, have experienced second or later relapse, or have refractory disease.
Tisagenlecleucel is also approved in Canada to treat adults who have received two or more lines of systemic therapy and have relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma, or DLBCL arising from follicular lymphoma.
Novartis, the company marketing tisagenlecleucel, said it is working with qualified treatment centers in Canada to prepare for the delivery of tisagenlecleucel. Certification and training are underway at these centers, and Novartis is enhancing manufacturing capacity to meet patient needs.
Tisagenlecleucel has been studied in a pair of phase 2 trials—ELIANA and JULIET.
JULIET trial
JULIET enrolled 165 adults with relapsed/refractory DLBCL, and 111 of them received a single infusion of tisagenlecleucel. Ninety-two percent of patients received bridging therapy, and 93% received lymphodepleting chemotherapy prior to tisagenlecleucel.
The overall response rate was 52%, and the complete response (CR) rate was 40%. The median duration of response was not reached with a median follow-up of 13.9 months. At last follow-up, none of the responders had gone on to SCT.
The 12-month overall survival (OS) rate was 49%, and the median OS was 11.7 months. The median OS was not reached for patients in CR.
Within 8 weeks of tisagenlecleucel infusion, 22% of patients had developed grade 3/4 cytokine release syndrome (CRS). Other adverse events (AEs) of interest included grade 3/4 neurologic events (12%), grade 3/4 cytopenias lasting more than 28 days (32%), grade 3/4 infections (20%), and grade 3/4 febrile neutropenia (15%).
These results were presented at the 23rd Annual Congress of the European Hematology Association in June (abstract S799).
ELIANA trial
ELIANA included 75 children and young adults with relapsed/refractory ALL. The patients’ median age was 11 (range, 3 to 23).
All patients received a single infusion of tisagenlecleucel, and 72 received lymphodepleting chemotherapy.
The median duration of follow-up was 13.1 months. The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CR with incomplete hematologic recovery (CRi) within 3 months.
The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi. All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.
Eight patients proceeded to SCT while in remission. At last follow-up, four were still in remission, and four had unknown disease status.
At 6 months, the event-free survival rate was 73%, and the OS rate was 90%. At 12 months, the rates were 50% and 76%, respectively.
Ninety-five percent of patients had AEs thought to be related to tisagenlecleucel. The incidence of treatment-related grade 3/4 AEs was 73%.
AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).
These results were published in The New England Journal of Medicine in February.
Health Canada has authorized use of tisagenlecleucel (Kymriah™), making it the first chimeric antigen receptor (CAR) T-cell therapy to receive regulatory approval in Canada.
Tisagenlecleucel (formerly CTL019) is approved to treat patients ages 3 to 25 with B-cell acute lymphoblastic leukemia (ALL) who have relapsed after allogeneic stem cell transplant (SCT) or are otherwise ineligible for SCT, have experienced second or later relapse, or have refractory disease.
Tisagenlecleucel is also approved in Canada to treat adults who have received two or more lines of systemic therapy and have relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma, or DLBCL arising from follicular lymphoma.
Novartis, the company marketing tisagenlecleucel, said it is working with qualified treatment centers in Canada to prepare for the delivery of tisagenlecleucel. Certification and training are underway at these centers, and Novartis is enhancing manufacturing capacity to meet patient needs.
Tisagenlecleucel has been studied in a pair of phase 2 trials—ELIANA and JULIET.
JULIET trial
JULIET enrolled 165 adults with relapsed/refractory DLBCL, and 111 of them received a single infusion of tisagenlecleucel. Ninety-two percent of patients received bridging therapy, and 93% received lymphodepleting chemotherapy prior to tisagenlecleucel.
The overall response rate was 52%, and the complete response (CR) rate was 40%. The median duration of response was not reached with a median follow-up of 13.9 months. At last follow-up, none of the responders had gone on to SCT.
The 12-month overall survival (OS) rate was 49%, and the median OS was 11.7 months. The median OS was not reached for patients in CR.
Within 8 weeks of tisagenlecleucel infusion, 22% of patients had developed grade 3/4 cytokine release syndrome (CRS). Other adverse events (AEs) of interest included grade 3/4 neurologic events (12%), grade 3/4 cytopenias lasting more than 28 days (32%), grade 3/4 infections (20%), and grade 3/4 febrile neutropenia (15%).
These results were presented at the 23rd Annual Congress of the European Hematology Association in June (abstract S799).
ELIANA trial
ELIANA included 75 children and young adults with relapsed/refractory ALL. The patients’ median age was 11 (range, 3 to 23).
All patients received a single infusion of tisagenlecleucel, and 72 received lymphodepleting chemotherapy.
The median duration of follow-up was 13.1 months. The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CR with incomplete hematologic recovery (CRi) within 3 months.
The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi. All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.
Eight patients proceeded to SCT while in remission. At last follow-up, four were still in remission, and four had unknown disease status.
At 6 months, the event-free survival rate was 73%, and the OS rate was 90%. At 12 months, the rates were 50% and 76%, respectively.
Ninety-five percent of patients had AEs thought to be related to tisagenlecleucel. The incidence of treatment-related grade 3/4 AEs was 73%.
AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).
These results were published in The New England Journal of Medicine in February.
Ibrutinib maintains efficacy over time
Extended follow-up of the RESONATE-2 trial showed that first-line ibrutinib sustained efficacy in elderly patients with chronic lymphocytic leukemia (CLL).
Patients who received ibrutinib had a long-term progression-free survival benefit over those who received chlorambucil.
The depth of response to ibrutinib improved over time, which meant there was a substantial increase in the proportion of patients achieving complete response.
Additionally, rates of some serious adverse events associated with ibrutinib decreased over time.
Paul M. Barr, MD, of the University of Rochester in New York, and his colleagues reported these findings in Haematologica.
Previously reported results of the RESONATE-2 trial, which showed an 84% reduction in the risk of death for ibrutinib versus chlorambucil, led to the approval of ibrutinib for first-line CLL treatment, the authors said.
The study included 269 patients with untreated CLL or small lymphocytic lymphoma who had active disease and were at least 65 years of age. They were randomized to receive ibrutinib (n=136) or chlorambucil (n=133).
At a median follow-up of 29 months, 79% (107/136) of patients remained on ibrutinib.
There was an 88% reduction in the risk of progression or death for patients randomized to ibrutinib (P<0.0001).
The rate of complete response improved over time in ibrutinib-treated patients, from 7% at 12 months to 15% at 24 months and 18% at 36 months (maximum follow-up).
The overall response rate (ORR) with ibrutinib was 92%, with comparable findings in high-risk subgroups. The ORR was 100% in patients with del(11q) and 95% in those with unmutated IGHV.
Lymphadenopathy improved in most ibrutinib-treated patients, with complete resolution in 42%, compared to 7% of patients who received chlorambucil.
Splenomegaly improved by at least 50% in 95% of ibrutinib-treated patients and 52% in chlorambucil recipients, with complete resolution in 56% and 22%, respectively.
Adverse events of grade 3 or greater were generally seen more often in the first year of ibrutinib therapy and decreased over time.
The rate of grade 3 or higher neutropenia decreased from 8.1% in the first 12 months of treatment to 0% in the third year. The rate of grade 3 or higher anemia decreased from 5.9% to 1%. And the rate of grade 3 or higher thrombocytopenia decreased from 2.2% to 0%.
The rate of atrial fibrillation increased from 6% in the primary analysis to 10% in extended follow-up. However, investigators said ibrutinib dose reductions and discontinuations because of this adverse event were uncommon and less frequent with extended treatment.
“Atrial fibrillation therefore appears manageable and does not frequently necessitate ibrutinib discontinuation,” they concluded.
This study was supported by Pharmacyclics, an AbbVie company, and by grants from the National Institutes of Health and the MD Anderson Moon Shot Program in CLL. Pharmacyclics designed the study and performed analysis of the data. Several study authors reported funding from various companies, including Pharmacyclics.
Extended follow-up of the RESONATE-2 trial showed that first-line ibrutinib sustained efficacy in elderly patients with chronic lymphocytic leukemia (CLL).
Patients who received ibrutinib had a long-term progression-free survival benefit over those who received chlorambucil.
The depth of response to ibrutinib improved over time, which meant there was a substantial increase in the proportion of patients achieving complete response.
Additionally, rates of some serious adverse events associated with ibrutinib decreased over time.
Paul M. Barr, MD, of the University of Rochester in New York, and his colleagues reported these findings in Haematologica.
Previously reported results of the RESONATE-2 trial, which showed an 84% reduction in the risk of death for ibrutinib versus chlorambucil, led to the approval of ibrutinib for first-line CLL treatment, the authors said.
The study included 269 patients with untreated CLL or small lymphocytic lymphoma who had active disease and were at least 65 years of age. They were randomized to receive ibrutinib (n=136) or chlorambucil (n=133).
At a median follow-up of 29 months, 79% (107/136) of patients remained on ibrutinib.
There was an 88% reduction in the risk of progression or death for patients randomized to ibrutinib (P<0.0001).
The rate of complete response improved over time in ibrutinib-treated patients, from 7% at 12 months to 15% at 24 months and 18% at 36 months (maximum follow-up).
The overall response rate (ORR) with ibrutinib was 92%, with comparable findings in high-risk subgroups. The ORR was 100% in patients with del(11q) and 95% in those with unmutated IGHV.
Lymphadenopathy improved in most ibrutinib-treated patients, with complete resolution in 42%, compared to 7% of patients who received chlorambucil.
Splenomegaly improved by at least 50% in 95% of ibrutinib-treated patients and 52% in chlorambucil recipients, with complete resolution in 56% and 22%, respectively.
Adverse events of grade 3 or greater were generally seen more often in the first year of ibrutinib therapy and decreased over time.
The rate of grade 3 or higher neutropenia decreased from 8.1% in the first 12 months of treatment to 0% in the third year. The rate of grade 3 or higher anemia decreased from 5.9% to 1%. And the rate of grade 3 or higher thrombocytopenia decreased from 2.2% to 0%.
The rate of atrial fibrillation increased from 6% in the primary analysis to 10% in extended follow-up. However, investigators said ibrutinib dose reductions and discontinuations because of this adverse event were uncommon and less frequent with extended treatment.
“Atrial fibrillation therefore appears manageable and does not frequently necessitate ibrutinib discontinuation,” they concluded.
This study was supported by Pharmacyclics, an AbbVie company, and by grants from the National Institutes of Health and the MD Anderson Moon Shot Program in CLL. Pharmacyclics designed the study and performed analysis of the data. Several study authors reported funding from various companies, including Pharmacyclics.
Extended follow-up of the RESONATE-2 trial showed that first-line ibrutinib sustained efficacy in elderly patients with chronic lymphocytic leukemia (CLL).
Patients who received ibrutinib had a long-term progression-free survival benefit over those who received chlorambucil.
The depth of response to ibrutinib improved over time, which meant there was a substantial increase in the proportion of patients achieving complete response.
Additionally, rates of some serious adverse events associated with ibrutinib decreased over time.
Paul M. Barr, MD, of the University of Rochester in New York, and his colleagues reported these findings in Haematologica.
Previously reported results of the RESONATE-2 trial, which showed an 84% reduction in the risk of death for ibrutinib versus chlorambucil, led to the approval of ibrutinib for first-line CLL treatment, the authors said.
The study included 269 patients with untreated CLL or small lymphocytic lymphoma who had active disease and were at least 65 years of age. They were randomized to receive ibrutinib (n=136) or chlorambucil (n=133).
At a median follow-up of 29 months, 79% (107/136) of patients remained on ibrutinib.
There was an 88% reduction in the risk of progression or death for patients randomized to ibrutinib (P<0.0001).
The rate of complete response improved over time in ibrutinib-treated patients, from 7% at 12 months to 15% at 24 months and 18% at 36 months (maximum follow-up).
The overall response rate (ORR) with ibrutinib was 92%, with comparable findings in high-risk subgroups. The ORR was 100% in patients with del(11q) and 95% in those with unmutated IGHV.
Lymphadenopathy improved in most ibrutinib-treated patients, with complete resolution in 42%, compared to 7% of patients who received chlorambucil.
Splenomegaly improved by at least 50% in 95% of ibrutinib-treated patients and 52% in chlorambucil recipients, with complete resolution in 56% and 22%, respectively.
Adverse events of grade 3 or greater were generally seen more often in the first year of ibrutinib therapy and decreased over time.
The rate of grade 3 or higher neutropenia decreased from 8.1% in the first 12 months of treatment to 0% in the third year. The rate of grade 3 or higher anemia decreased from 5.9% to 1%. And the rate of grade 3 or higher thrombocytopenia decreased from 2.2% to 0%.
The rate of atrial fibrillation increased from 6% in the primary analysis to 10% in extended follow-up. However, investigators said ibrutinib dose reductions and discontinuations because of this adverse event were uncommon and less frequent with extended treatment.
“Atrial fibrillation therefore appears manageable and does not frequently necessitate ibrutinib discontinuation,” they concluded.
This study was supported by Pharmacyclics, an AbbVie company, and by grants from the National Institutes of Health and the MD Anderson Moon Shot Program in CLL. Pharmacyclics designed the study and performed analysis of the data. Several study authors reported funding from various companies, including Pharmacyclics.
Escalating MTX appears superior for T-ALL
Escalating methotrexate (MTX) may produce better outcomes than high-dose MTX in children and young adults with T-cell acute lymphoblastic leukemia (T-ALL), according to research published in the Journal of Clinical Oncology.
Researchers compared escalating and high-dose MTX given with the augmented Berlin-Frankfurt-Munster regimen in patients with T-ALL.
Disease-free survival (DFS) and overall survival (OS) rates were significantly higher among patients who received escalating MTX.
The improved survival outcomes in this trial, AALL0434, are the “opposite effect” of what was observed in a parallel trial, AALL0232. In that trial, high-dose MTX was superior to the escalating strategy in patients with B-cell acute lymphoblastic leukemia (B-ALL).
The parallel trial design was used because of the known differences between T-ALL and B-ALL in sensitivity to MTX and pegaspargase, according to investigator Stuart S. Winter, MD, of Children’s Minnesota Minneapolis Hospital, and his coauthors.
The AALL0434 study included 1,031 T-ALL patients between 1 and 31 years of age without CNS3 disease or testicular leukemia. They were randomized to post-induction therapy that included either escalating intravenous MTX or high-dose MTX.
The escalating regimen was superior to high-dose MTX, according to investigators.
The 5-year DFS rate was 91.5% with escalating MTX and 85.3% with high-dose MTX (P=0.005). The 5-year OS rate was 93.7% and 89.4%, respectively (P=0.036).
In contrast, the parallel AALL0232 study of B-ALL patients showed that high-dose MTX produced superior 5-year event-free survival and OS. This led Dr. Winter and his colleagues to speculate on how the findings could be reconciled.
Neither trial was a strict comparison of two different MTX schedules, due to differences in doses of pegaspargase, mercaptopurine, and vincristine between arms, as well as differences in the timing of cranial radiation therapy.
Of note, patients randomized to escalated MTX had two additional doses of pegaspargase. Enhanced asparagine depletion in that arm may have prevented relapse events, the investigators said.
They also said differences in adherence could have played a role, as the cost and time burden of the escalating MTX approach are “substantially less” than the high-dose approach.
The AALL0434 trial also included a second randomization to an addition of five, 6-day cycles of nelarabine versus no nelarabine. Results of that randomization, reported earlier this year, showed that nelarabine improved DFS.
AALL0434 was supported by grants from the National Institutes of Health and by St. Baldrick’s Foundation. Dr. Winter reported relationships with Amgen and Jazz Pharmaceuticals. His coauthors reported relationships with Novo Nordisk, Tandem, Pfizer, Novartis, and TypeZero Technologies, among others.
Escalating methotrexate (MTX) may produce better outcomes than high-dose MTX in children and young adults with T-cell acute lymphoblastic leukemia (T-ALL), according to research published in the Journal of Clinical Oncology.
Researchers compared escalating and high-dose MTX given with the augmented Berlin-Frankfurt-Munster regimen in patients with T-ALL.
Disease-free survival (DFS) and overall survival (OS) rates were significantly higher among patients who received escalating MTX.
The improved survival outcomes in this trial, AALL0434, are the “opposite effect” of what was observed in a parallel trial, AALL0232. In that trial, high-dose MTX was superior to the escalating strategy in patients with B-cell acute lymphoblastic leukemia (B-ALL).
The parallel trial design was used because of the known differences between T-ALL and B-ALL in sensitivity to MTX and pegaspargase, according to investigator Stuart S. Winter, MD, of Children’s Minnesota Minneapolis Hospital, and his coauthors.
The AALL0434 study included 1,031 T-ALL patients between 1 and 31 years of age without CNS3 disease or testicular leukemia. They were randomized to post-induction therapy that included either escalating intravenous MTX or high-dose MTX.
The escalating regimen was superior to high-dose MTX, according to investigators.
The 5-year DFS rate was 91.5% with escalating MTX and 85.3% with high-dose MTX (P=0.005). The 5-year OS rate was 93.7% and 89.4%, respectively (P=0.036).
In contrast, the parallel AALL0232 study of B-ALL patients showed that high-dose MTX produced superior 5-year event-free survival and OS. This led Dr. Winter and his colleagues to speculate on how the findings could be reconciled.
Neither trial was a strict comparison of two different MTX schedules, due to differences in doses of pegaspargase, mercaptopurine, and vincristine between arms, as well as differences in the timing of cranial radiation therapy.
Of note, patients randomized to escalated MTX had two additional doses of pegaspargase. Enhanced asparagine depletion in that arm may have prevented relapse events, the investigators said.
They also said differences in adherence could have played a role, as the cost and time burden of the escalating MTX approach are “substantially less” than the high-dose approach.
The AALL0434 trial also included a second randomization to an addition of five, 6-day cycles of nelarabine versus no nelarabine. Results of that randomization, reported earlier this year, showed that nelarabine improved DFS.
AALL0434 was supported by grants from the National Institutes of Health and by St. Baldrick’s Foundation. Dr. Winter reported relationships with Amgen and Jazz Pharmaceuticals. His coauthors reported relationships with Novo Nordisk, Tandem, Pfizer, Novartis, and TypeZero Technologies, among others.
Escalating methotrexate (MTX) may produce better outcomes than high-dose MTX in children and young adults with T-cell acute lymphoblastic leukemia (T-ALL), according to research published in the Journal of Clinical Oncology.
Researchers compared escalating and high-dose MTX given with the augmented Berlin-Frankfurt-Munster regimen in patients with T-ALL.
Disease-free survival (DFS) and overall survival (OS) rates were significantly higher among patients who received escalating MTX.
The improved survival outcomes in this trial, AALL0434, are the “opposite effect” of what was observed in a parallel trial, AALL0232. In that trial, high-dose MTX was superior to the escalating strategy in patients with B-cell acute lymphoblastic leukemia (B-ALL).
The parallel trial design was used because of the known differences between T-ALL and B-ALL in sensitivity to MTX and pegaspargase, according to investigator Stuart S. Winter, MD, of Children’s Minnesota Minneapolis Hospital, and his coauthors.
The AALL0434 study included 1,031 T-ALL patients between 1 and 31 years of age without CNS3 disease or testicular leukemia. They were randomized to post-induction therapy that included either escalating intravenous MTX or high-dose MTX.
The escalating regimen was superior to high-dose MTX, according to investigators.
The 5-year DFS rate was 91.5% with escalating MTX and 85.3% with high-dose MTX (P=0.005). The 5-year OS rate was 93.7% and 89.4%, respectively (P=0.036).
In contrast, the parallel AALL0232 study of B-ALL patients showed that high-dose MTX produced superior 5-year event-free survival and OS. This led Dr. Winter and his colleagues to speculate on how the findings could be reconciled.
Neither trial was a strict comparison of two different MTX schedules, due to differences in doses of pegaspargase, mercaptopurine, and vincristine between arms, as well as differences in the timing of cranial radiation therapy.
Of note, patients randomized to escalated MTX had two additional doses of pegaspargase. Enhanced asparagine depletion in that arm may have prevented relapse events, the investigators said.
They also said differences in adherence could have played a role, as the cost and time burden of the escalating MTX approach are “substantially less” than the high-dose approach.
The AALL0434 trial also included a second randomization to an addition of five, 6-day cycles of nelarabine versus no nelarabine. Results of that randomization, reported earlier this year, showed that nelarabine improved DFS.
AALL0434 was supported by grants from the National Institutes of Health and by St. Baldrick’s Foundation. Dr. Winter reported relationships with Amgen and Jazz Pharmaceuticals. His coauthors reported relationships with Novo Nordisk, Tandem, Pfizer, Novartis, and TypeZero Technologies, among others.
CAR T-cell therapy will soon be available in England, NHS says
The National Health Service (NHS) of England has announced that tisagenlecleucel (Kymriah®), a chimeric antigen receptor (CAR) T-cell therapy, will soon be available for certain leukemia patients.
Tisagenlecleucel will be made available through the Cancer Drugs Fund, and patients could potentially begin receiving the treatment within weeks.
NHS England struck a deal with Novartis to lower the price of tisagenlecleucel, which costs around £282,000 per patient at its full list price. The discount offered to the NHS is confidential.
Tisagenlecleucel was recently approved by the European Commission (EC) to treat patients up to 25 years of age who have B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post-transplant, or in second or later relapse.
The EC also approved tisagenlecleucel to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have received two or more lines of systemic therapy.
However, tisagenlecleucel will only be available for ALL patients in England, at least initially. A decision has not been made regarding funding for tisagenlecleucel in DLBCL, and Novartis previously decided to launch tisagenlecleucel in ALL first.
“It’s fantastic news for children and young people with this form of leukemia that CAR T-cell therapy will be made available on the NHS, making them the first in Europe to have routine access to this exciting new type of immunotherapy,” said Charles Swanton, Cancer Research UK’s chief clinician.
The first three NHS hospitals to go through the international accreditation process for the provision of tisagenlecleucel are in London, Manchester, and Newcastle. Subject to passing accreditation requirements, the first treatments could begin in a matter of weeks.
Another CAR T-cell therapy, axicabtagene ciloleucel (Yescarta®), has not fared as well as tisagenlecleucel. The National Institute for Health and Care Excellence (NICE) recently issued a draft guidance recommending against the use of axicabtagene ciloleucel in England.
Axicabtagene ciloleucel was approved by the EC to treat patients with relapsed/refractory DLBCL or primary mediastinal B-cell lymphoma who have received two or more lines of systemic therapy.
However, NICE said it isn’t clear how much of a benefit axicabtagene ciloleucel may provide over salvage chemotherapy. NICE also said the price of axicabtagene ciloleucel is too high for the therapy to be considered a cost-effective use of NHS resources, and axicabtagene ciloleucel does not meet the criteria for inclusion in the Cancer Drugs Fund.
The National Health Service (NHS) of England has announced that tisagenlecleucel (Kymriah®), a chimeric antigen receptor (CAR) T-cell therapy, will soon be available for certain leukemia patients.
Tisagenlecleucel will be made available through the Cancer Drugs Fund, and patients could potentially begin receiving the treatment within weeks.
NHS England struck a deal with Novartis to lower the price of tisagenlecleucel, which costs around £282,000 per patient at its full list price. The discount offered to the NHS is confidential.
Tisagenlecleucel was recently approved by the European Commission (EC) to treat patients up to 25 years of age who have B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post-transplant, or in second or later relapse.
The EC also approved tisagenlecleucel to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have received two or more lines of systemic therapy.
However, tisagenlecleucel will only be available for ALL patients in England, at least initially. A decision has not been made regarding funding for tisagenlecleucel in DLBCL, and Novartis previously decided to launch tisagenlecleucel in ALL first.
“It’s fantastic news for children and young people with this form of leukemia that CAR T-cell therapy will be made available on the NHS, making them the first in Europe to have routine access to this exciting new type of immunotherapy,” said Charles Swanton, Cancer Research UK’s chief clinician.
The first three NHS hospitals to go through the international accreditation process for the provision of tisagenlecleucel are in London, Manchester, and Newcastle. Subject to passing accreditation requirements, the first treatments could begin in a matter of weeks.
Another CAR T-cell therapy, axicabtagene ciloleucel (Yescarta®), has not fared as well as tisagenlecleucel. The National Institute for Health and Care Excellence (NICE) recently issued a draft guidance recommending against the use of axicabtagene ciloleucel in England.
Axicabtagene ciloleucel was approved by the EC to treat patients with relapsed/refractory DLBCL or primary mediastinal B-cell lymphoma who have received two or more lines of systemic therapy.
However, NICE said it isn’t clear how much of a benefit axicabtagene ciloleucel may provide over salvage chemotherapy. NICE also said the price of axicabtagene ciloleucel is too high for the therapy to be considered a cost-effective use of NHS resources, and axicabtagene ciloleucel does not meet the criteria for inclusion in the Cancer Drugs Fund.
The National Health Service (NHS) of England has announced that tisagenlecleucel (Kymriah®), a chimeric antigen receptor (CAR) T-cell therapy, will soon be available for certain leukemia patients.
Tisagenlecleucel will be made available through the Cancer Drugs Fund, and patients could potentially begin receiving the treatment within weeks.
NHS England struck a deal with Novartis to lower the price of tisagenlecleucel, which costs around £282,000 per patient at its full list price. The discount offered to the NHS is confidential.
Tisagenlecleucel was recently approved by the European Commission (EC) to treat patients up to 25 years of age who have B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post-transplant, or in second or later relapse.
The EC also approved tisagenlecleucel to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have received two or more lines of systemic therapy.
However, tisagenlecleucel will only be available for ALL patients in England, at least initially. A decision has not been made regarding funding for tisagenlecleucel in DLBCL, and Novartis previously decided to launch tisagenlecleucel in ALL first.
“It’s fantastic news for children and young people with this form of leukemia that CAR T-cell therapy will be made available on the NHS, making them the first in Europe to have routine access to this exciting new type of immunotherapy,” said Charles Swanton, Cancer Research UK’s chief clinician.
The first three NHS hospitals to go through the international accreditation process for the provision of tisagenlecleucel are in London, Manchester, and Newcastle. Subject to passing accreditation requirements, the first treatments could begin in a matter of weeks.
Another CAR T-cell therapy, axicabtagene ciloleucel (Yescarta®), has not fared as well as tisagenlecleucel. The National Institute for Health and Care Excellence (NICE) recently issued a draft guidance recommending against the use of axicabtagene ciloleucel in England.
Axicabtagene ciloleucel was approved by the EC to treat patients with relapsed/refractory DLBCL or primary mediastinal B-cell lymphoma who have received two or more lines of systemic therapy.
However, NICE said it isn’t clear how much of a benefit axicabtagene ciloleucel may provide over salvage chemotherapy. NICE also said the price of axicabtagene ciloleucel is too high for the therapy to be considered a cost-effective use of NHS resources, and axicabtagene ciloleucel does not meet the criteria for inclusion in the Cancer Drugs Fund.
Escalating methotrexate may improve survival in T-cell ALL
An escalating methotrexate strategy provided superior survival outcomes compared with high-dose methotrexate in a chemotherapy regimen for children and young adults with T-cell acute lymphoblastic leukemia (T-ALL), results of a large, randomized trial show.
There were also fewer relapses reported for escalating versus high-dose methotrexate in the study, which evaluated the effects of these two intensification strategies in patients receiving an augmented Berlin-Frankfurt-Muenster (ABFM) chemotherapy regimen.
These findings come from a report in the Journal of Clinical Oncology on the Children’s Oncology Group (COG) AALL0434 trial, which to the knowledge of the investigators is the largest T-ALL study ever conducted.
The improved survival outcomes in AALL0434 are the “opposite effect” of what was observed in a parallel trial, AALL0232, showing that high-dose methotrexate was superior to the escalating strategy in B-cell acute lymphoblastic leukemia (B-ALL), the authors reported.
The parallel trial design was in fact used because of the known differences between T-ALL and B-ALL in sensitivity to methotrexate and pegaspargase, according to investigator Stuart S. Winter, MD, of Children’s Minnesota Cancer and Blood Disorders Program, Minneapolis, and his coauthors.
“Although treatment intensification has improved survival for children with ALL, the best timing and sequence of key therapeutic interventions, such as asparaginase and methotrexate, which seem to be particularly important for T-ALL, remain unclear,” Dr. Winter and his colleagues said.
In the AALL0434 study, a total of 1,031 T-ALL patients between 1 and 31 years of age without CNS3 disease or testicular leukemia were randomized to postinduction therapy that included either the so-called Capizzi-style escalating intravenous methotrexate or high-dose methotrexate.
The escalating intravenous regimen was superior to high-dose methotrexate, according to investigators. Respectively, the 5-year rate of disease-free survival was 91.5% versus 85.3% (P = .005) and the 5-year rate of overall survival was 93.7% versus 89.4% (P = .036).
Relapses were observed in 32 patients receiving the escalating regimen, versus 59 for patients receiving high-dose methotrexate.
By contrast, the parallel AALL0232 study of B-ALL patients showed that high-dose methotrexate had superior 5-year event-free survival and overall survival, leading Dr. Winter and his colleagues to speculate on how the findings could be reconciled.
Neither trial was a strict comparison of two different methotrexate schedules, due to differences in doses of pegaspargase, 6-MP, and vincristine between arms, as well as differences in the timing of cranial radiation therapy.
Of note, patients randomized to escalated methotrexate had two additional doses of pegaspargase. As a result, enhanced asparagine depletion in that arm may have also prevented relapse events, the investigators said.
Differences in adherence could also have played a role, as the cost and time burden of the escalated approach are “substantially less” than the high-dose approach, they added.
The AALL0434 trial also included a second randomization to an addition of five, 6-day cycles of nelarabine versus no nelarabine. Results of that randomization, reported earlier this year, showed that nelarabine improved disease-free survival, including a 91% 4-year disease-free survival rate for patients receiving both nelarabine and escalating-dose methotrexate.
The study was supported by grants from the National Institutes of Health and by St. Baldrick’s Foundation. Dr. Winter reported relationships with Amgen and Jazz Pharmaceuticals. Study coauthors reported relationships with Novo Nordisk, Tandem, Pfizer, Novartis, and TypeZero Technologies, among others.
SOURCE: Winter SS et al. J Clin Oncol. 2018 Aug 23: doi: 10.1200/JCO.2018.77.7250.
An escalating methotrexate strategy provided superior survival outcomes compared with high-dose methotrexate in a chemotherapy regimen for children and young adults with T-cell acute lymphoblastic leukemia (T-ALL), results of a large, randomized trial show.
There were also fewer relapses reported for escalating versus high-dose methotrexate in the study, which evaluated the effects of these two intensification strategies in patients receiving an augmented Berlin-Frankfurt-Muenster (ABFM) chemotherapy regimen.
These findings come from a report in the Journal of Clinical Oncology on the Children’s Oncology Group (COG) AALL0434 trial, which to the knowledge of the investigators is the largest T-ALL study ever conducted.
The improved survival outcomes in AALL0434 are the “opposite effect” of what was observed in a parallel trial, AALL0232, showing that high-dose methotrexate was superior to the escalating strategy in B-cell acute lymphoblastic leukemia (B-ALL), the authors reported.
The parallel trial design was in fact used because of the known differences between T-ALL and B-ALL in sensitivity to methotrexate and pegaspargase, according to investigator Stuart S. Winter, MD, of Children’s Minnesota Cancer and Blood Disorders Program, Minneapolis, and his coauthors.
“Although treatment intensification has improved survival for children with ALL, the best timing and sequence of key therapeutic interventions, such as asparaginase and methotrexate, which seem to be particularly important for T-ALL, remain unclear,” Dr. Winter and his colleagues said.
In the AALL0434 study, a total of 1,031 T-ALL patients between 1 and 31 years of age without CNS3 disease or testicular leukemia were randomized to postinduction therapy that included either the so-called Capizzi-style escalating intravenous methotrexate or high-dose methotrexate.
The escalating intravenous regimen was superior to high-dose methotrexate, according to investigators. Respectively, the 5-year rate of disease-free survival was 91.5% versus 85.3% (P = .005) and the 5-year rate of overall survival was 93.7% versus 89.4% (P = .036).
Relapses were observed in 32 patients receiving the escalating regimen, versus 59 for patients receiving high-dose methotrexate.
By contrast, the parallel AALL0232 study of B-ALL patients showed that high-dose methotrexate had superior 5-year event-free survival and overall survival, leading Dr. Winter and his colleagues to speculate on how the findings could be reconciled.
Neither trial was a strict comparison of two different methotrexate schedules, due to differences in doses of pegaspargase, 6-MP, and vincristine between arms, as well as differences in the timing of cranial radiation therapy.
Of note, patients randomized to escalated methotrexate had two additional doses of pegaspargase. As a result, enhanced asparagine depletion in that arm may have also prevented relapse events, the investigators said.
Differences in adherence could also have played a role, as the cost and time burden of the escalated approach are “substantially less” than the high-dose approach, they added.
The AALL0434 trial also included a second randomization to an addition of five, 6-day cycles of nelarabine versus no nelarabine. Results of that randomization, reported earlier this year, showed that nelarabine improved disease-free survival, including a 91% 4-year disease-free survival rate for patients receiving both nelarabine and escalating-dose methotrexate.
The study was supported by grants from the National Institutes of Health and by St. Baldrick’s Foundation. Dr. Winter reported relationships with Amgen and Jazz Pharmaceuticals. Study coauthors reported relationships with Novo Nordisk, Tandem, Pfizer, Novartis, and TypeZero Technologies, among others.
SOURCE: Winter SS et al. J Clin Oncol. 2018 Aug 23: doi: 10.1200/JCO.2018.77.7250.
An escalating methotrexate strategy provided superior survival outcomes compared with high-dose methotrexate in a chemotherapy regimen for children and young adults with T-cell acute lymphoblastic leukemia (T-ALL), results of a large, randomized trial show.
There were also fewer relapses reported for escalating versus high-dose methotrexate in the study, which evaluated the effects of these two intensification strategies in patients receiving an augmented Berlin-Frankfurt-Muenster (ABFM) chemotherapy regimen.
These findings come from a report in the Journal of Clinical Oncology on the Children’s Oncology Group (COG) AALL0434 trial, which to the knowledge of the investigators is the largest T-ALL study ever conducted.
The improved survival outcomes in AALL0434 are the “opposite effect” of what was observed in a parallel trial, AALL0232, showing that high-dose methotrexate was superior to the escalating strategy in B-cell acute lymphoblastic leukemia (B-ALL), the authors reported.
The parallel trial design was in fact used because of the known differences between T-ALL and B-ALL in sensitivity to methotrexate and pegaspargase, according to investigator Stuart S. Winter, MD, of Children’s Minnesota Cancer and Blood Disorders Program, Minneapolis, and his coauthors.
“Although treatment intensification has improved survival for children with ALL, the best timing and sequence of key therapeutic interventions, such as asparaginase and methotrexate, which seem to be particularly important for T-ALL, remain unclear,” Dr. Winter and his colleagues said.
In the AALL0434 study, a total of 1,031 T-ALL patients between 1 and 31 years of age without CNS3 disease or testicular leukemia were randomized to postinduction therapy that included either the so-called Capizzi-style escalating intravenous methotrexate or high-dose methotrexate.
The escalating intravenous regimen was superior to high-dose methotrexate, according to investigators. Respectively, the 5-year rate of disease-free survival was 91.5% versus 85.3% (P = .005) and the 5-year rate of overall survival was 93.7% versus 89.4% (P = .036).
Relapses were observed in 32 patients receiving the escalating regimen, versus 59 for patients receiving high-dose methotrexate.
By contrast, the parallel AALL0232 study of B-ALL patients showed that high-dose methotrexate had superior 5-year event-free survival and overall survival, leading Dr. Winter and his colleagues to speculate on how the findings could be reconciled.
Neither trial was a strict comparison of two different methotrexate schedules, due to differences in doses of pegaspargase, 6-MP, and vincristine between arms, as well as differences in the timing of cranial radiation therapy.
Of note, patients randomized to escalated methotrexate had two additional doses of pegaspargase. As a result, enhanced asparagine depletion in that arm may have also prevented relapse events, the investigators said.
Differences in adherence could also have played a role, as the cost and time burden of the escalated approach are “substantially less” than the high-dose approach, they added.
The AALL0434 trial also included a second randomization to an addition of five, 6-day cycles of nelarabine versus no nelarabine. Results of that randomization, reported earlier this year, showed that nelarabine improved disease-free survival, including a 91% 4-year disease-free survival rate for patients receiving both nelarabine and escalating-dose methotrexate.
The study was supported by grants from the National Institutes of Health and by St. Baldrick’s Foundation. Dr. Winter reported relationships with Amgen and Jazz Pharmaceuticals. Study coauthors reported relationships with Novo Nordisk, Tandem, Pfizer, Novartis, and TypeZero Technologies, among others.
SOURCE: Winter SS et al. J Clin Oncol. 2018 Aug 23: doi: 10.1200/JCO.2018.77.7250.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: An (T-ALL).
Major finding: The 5-year disease-free survival rate was 91.5% versus 85.3% (P = .005) and overall survival was 93.7% versus 89.4% (P = .036), respectively, for the escalating and high-dose approaches.
Study details: Results after methotrexate randomization in 1,031 T-ALL patients without CNS3 disease or testicular leukemia in the Children’s Oncology Group (COG) AALL0434 trial.
Disclosures: The study was supported by grants from the National Institutes of Health and by St. Baldrick’s Foundation. The authors reported disclosures related to Amgen, Jazz Pharmaceuticals, Novo Nordisk, Tandem, Pfizer, Novartis, and TypeZero Technologies, among others.
Source: Winter SS et al. J Clin Oncol. 2018 Aug 23. doi: 10.1200/JCO.2018.77.7250.
Blinatumomab gains European approval in children
The a bispecific, CD19-directed, CD3 T-cell engager immunotherapy.
Blinatumomab is now approved as monotherapy for children aged 1 year or older who have relapsed/refractory, Philadelphia chromosome–negative, CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL). The patients must have received at least two prior therapies, or they must have relapsed after allogeneic hematopoietic stem cell transplant.
The European Commission’s (EC) new approval of blinatumomab extends to all countries in the European Union, as well as Norway, Iceland, and Liechtenstein.
In 2015, the EC approved blinatumomab to treat adults with Philadelphia chromosome–negative, relapsed/refractory B-cell precursor ALL.The EC’s approval of blinatumomab in pediatric patients is based on results from a phase 1/2 study published in the Journal of Clinical Oncology in 2016. The study included 93 pediatric patients with relapsed/refractory B-cell precursor ALL. Patients received blinatumomab as a continuous intravenous infusion – 49 patients in the phase 1 portion of the trial and 44 in phase 2. The patients were followed for 2 years.
There were four dose-limiting toxicities during the phase 1 portion of the trial, two of which were fatal. Three patients had grade 4 cytokine release syndrome (CRS), one had grade 5 cardiac failure (as well as grade 4 CRS), and one had grade 5 respiratory failure. Based on the dose-limiting toxicities, the maximum tolerated dose of blinatumomab was 15 mcg/m2 per day, but a stepwise dosage was recommended to reduce the risk of CRS.
The recommended dose was 5 mcg/m2 per day on days 1-7 and 15 mcg/m2 per day on days 8-28 for cycle 1, and 15 mcg/m2 per day on days 1-28 for subsequent cycles, according to the study results.Among the 70 patients who received the recommended dose of blinatumomab, 27 (39%) achieved a complete response within the first two cycles. A total of 14 of these patients (52%) achieved minimal residual disease negativity.
The a bispecific, CD19-directed, CD3 T-cell engager immunotherapy.
Blinatumomab is now approved as monotherapy for children aged 1 year or older who have relapsed/refractory, Philadelphia chromosome–negative, CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL). The patients must have received at least two prior therapies, or they must have relapsed after allogeneic hematopoietic stem cell transplant.
The European Commission’s (EC) new approval of blinatumomab extends to all countries in the European Union, as well as Norway, Iceland, and Liechtenstein.
In 2015, the EC approved blinatumomab to treat adults with Philadelphia chromosome–negative, relapsed/refractory B-cell precursor ALL.The EC’s approval of blinatumomab in pediatric patients is based on results from a phase 1/2 study published in the Journal of Clinical Oncology in 2016. The study included 93 pediatric patients with relapsed/refractory B-cell precursor ALL. Patients received blinatumomab as a continuous intravenous infusion – 49 patients in the phase 1 portion of the trial and 44 in phase 2. The patients were followed for 2 years.
There were four dose-limiting toxicities during the phase 1 portion of the trial, two of which were fatal. Three patients had grade 4 cytokine release syndrome (CRS), one had grade 5 cardiac failure (as well as grade 4 CRS), and one had grade 5 respiratory failure. Based on the dose-limiting toxicities, the maximum tolerated dose of blinatumomab was 15 mcg/m2 per day, but a stepwise dosage was recommended to reduce the risk of CRS.
The recommended dose was 5 mcg/m2 per day on days 1-7 and 15 mcg/m2 per day on days 8-28 for cycle 1, and 15 mcg/m2 per day on days 1-28 for subsequent cycles, according to the study results.Among the 70 patients who received the recommended dose of blinatumomab, 27 (39%) achieved a complete response within the first two cycles. A total of 14 of these patients (52%) achieved minimal residual disease negativity.
The a bispecific, CD19-directed, CD3 T-cell engager immunotherapy.
Blinatumomab is now approved as monotherapy for children aged 1 year or older who have relapsed/refractory, Philadelphia chromosome–negative, CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL). The patients must have received at least two prior therapies, or they must have relapsed after allogeneic hematopoietic stem cell transplant.
The European Commission’s (EC) new approval of blinatumomab extends to all countries in the European Union, as well as Norway, Iceland, and Liechtenstein.
In 2015, the EC approved blinatumomab to treat adults with Philadelphia chromosome–negative, relapsed/refractory B-cell precursor ALL.The EC’s approval of blinatumomab in pediatric patients is based on results from a phase 1/2 study published in the Journal of Clinical Oncology in 2016. The study included 93 pediatric patients with relapsed/refractory B-cell precursor ALL. Patients received blinatumomab as a continuous intravenous infusion – 49 patients in the phase 1 portion of the trial and 44 in phase 2. The patients were followed for 2 years.
There were four dose-limiting toxicities during the phase 1 portion of the trial, two of which were fatal. Three patients had grade 4 cytokine release syndrome (CRS), one had grade 5 cardiac failure (as well as grade 4 CRS), and one had grade 5 respiratory failure. Based on the dose-limiting toxicities, the maximum tolerated dose of blinatumomab was 15 mcg/m2 per day, but a stepwise dosage was recommended to reduce the risk of CRS.
The recommended dose was 5 mcg/m2 per day on days 1-7 and 15 mcg/m2 per day on days 8-28 for cycle 1, and 15 mcg/m2 per day on days 1-28 for subsequent cycles, according to the study results.Among the 70 patients who received the recommended dose of blinatumomab, 27 (39%) achieved a complete response within the first two cycles. A total of 14 of these patients (52%) achieved minimal residual disease negativity.
FDA fast-tracks CX-01 for newly diagnosed AML
The Food and Drug Administration has granted fast-track designation to CX-01 as a treatment for patients older than 60 years receiving induction therapy for newly diagnosed acute myeloid leukemia (AML).
CX-01 also has orphan drug designation from the FDA.
CX-01 is a polysaccharide derived from heparin thought to enhance chemotherapy by disrupting leukemia cell adhesion in bone marrow. Cantex Pharmaceuticals is conducting a randomized, phase 2b study to determine whether CX-01 can improve the efficacy of frontline chemotherapy in patients with AML.
This study builds upon results of a pilot study, which were published in Blood Advances (Blood Adv. 2018 Feb 27;2[4]:381-9). The pilot study enrolled 12 adults with newly diagnosed AML who received CX-01 as a continuous infusion for 7 days, along with standard induction chemotherapy (cytarabine and idarubicin).
A total of 11 patients achieved morphological complete remission after one cycle of induction. This included two patients who did not complete induction. All patients received subsequent therapy – consolidation, salvage, or transplant – on or off study.
At a median follow-up of 24 months, eight patients were still alive. Two patients died of transplant-related complications, one died of infectious complications, and one died of cerebral hemorrhage. The median disease-free survival was 14.8 months, and the median overall survival was not reached.
There were five serious adverse events in five patients; most were considered unrelated to CX-01, but a case of grade 4 sepsis was possibly related.
The FDA’s fast-track development program is designed to expedite clinical development and submission of applications for products with the potential to treat serious or life-threatening conditions and address unmet medical needs.
The Food and Drug Administration has granted fast-track designation to CX-01 as a treatment for patients older than 60 years receiving induction therapy for newly diagnosed acute myeloid leukemia (AML).
CX-01 also has orphan drug designation from the FDA.
CX-01 is a polysaccharide derived from heparin thought to enhance chemotherapy by disrupting leukemia cell adhesion in bone marrow. Cantex Pharmaceuticals is conducting a randomized, phase 2b study to determine whether CX-01 can improve the efficacy of frontline chemotherapy in patients with AML.
This study builds upon results of a pilot study, which were published in Blood Advances (Blood Adv. 2018 Feb 27;2[4]:381-9). The pilot study enrolled 12 adults with newly diagnosed AML who received CX-01 as a continuous infusion for 7 days, along with standard induction chemotherapy (cytarabine and idarubicin).
A total of 11 patients achieved morphological complete remission after one cycle of induction. This included two patients who did not complete induction. All patients received subsequent therapy – consolidation, salvage, or transplant – on or off study.
At a median follow-up of 24 months, eight patients were still alive. Two patients died of transplant-related complications, one died of infectious complications, and one died of cerebral hemorrhage. The median disease-free survival was 14.8 months, and the median overall survival was not reached.
There were five serious adverse events in five patients; most were considered unrelated to CX-01, but a case of grade 4 sepsis was possibly related.
The FDA’s fast-track development program is designed to expedite clinical development and submission of applications for products with the potential to treat serious or life-threatening conditions and address unmet medical needs.
The Food and Drug Administration has granted fast-track designation to CX-01 as a treatment for patients older than 60 years receiving induction therapy for newly diagnosed acute myeloid leukemia (AML).
CX-01 also has orphan drug designation from the FDA.
CX-01 is a polysaccharide derived from heparin thought to enhance chemotherapy by disrupting leukemia cell adhesion in bone marrow. Cantex Pharmaceuticals is conducting a randomized, phase 2b study to determine whether CX-01 can improve the efficacy of frontline chemotherapy in patients with AML.
This study builds upon results of a pilot study, which were published in Blood Advances (Blood Adv. 2018 Feb 27;2[4]:381-9). The pilot study enrolled 12 adults with newly diagnosed AML who received CX-01 as a continuous infusion for 7 days, along with standard induction chemotherapy (cytarabine and idarubicin).
A total of 11 patients achieved morphological complete remission after one cycle of induction. This included two patients who did not complete induction. All patients received subsequent therapy – consolidation, salvage, or transplant – on or off study.
At a median follow-up of 24 months, eight patients were still alive. Two patients died of transplant-related complications, one died of infectious complications, and one died of cerebral hemorrhage. The median disease-free survival was 14.8 months, and the median overall survival was not reached.
There were five serious adverse events in five patients; most were considered unrelated to CX-01, but a case of grade 4 sepsis was possibly related.
The FDA’s fast-track development program is designed to expedite clinical development and submission of applications for products with the potential to treat serious or life-threatening conditions and address unmet medical needs.
PLK1 inhibitor receives orphan designation for AML
The European Commission has granted orphan drug designation to onvansertib for the treatment of acute myeloid leukemia (AML).
Onvansertib (formerly PCM-075) is an oral adenosine triphosphate competitive inhibitor of the serine/threonine Polo-like kinase 1 (PLK1) enzyme, which is overexpressed in hematologic and solid tumor malignancies.
Trovagene, Inc., the company developing onvansertib, said the drug has a 24-hour half-life with reversible, on-target hematologic activity.
These factors, combined with an improved dose/scheduling protocol, could mean onvansertib will improve upon long-term outcomes observed in previous studies with a PLK inhibitor in AML.
This includes a phase 2 study in which AML patients who received a PLK inhibitor plus low-dose cytarabine (LDAC) had a higher response rate than patients who received LDAC alone—31% and 13.3%, respectively.
Trovagene said preclinical studies have shown that onvansertib synergizes with more than 10 drugs used to treat hematologic and solid tumor malignancies. This includes FLT3 and HDAC inhibitors, taxanes, and cytotoxins.
Trovagene is now conducting a phase 1b/2 trial of onvansertib in combination with standard care (LDAC or decitabine) in patients with AML (NCT03303339).
The company has already completed a phase 1 dose-escalation study of onvansertib in patients with advanced metastatic solid tumor malignancies. Results from this study were published in Investigational New Drugs.
About orphan designation
Orphan drug designation in Europe is available to companies developing products intended to treat a life-threatening or chronically debilitating condition that affects fewer than 5 in 10,000 people in the European Union (EU).
The designation allows for financial and regulatory incentives that include 10 years of marketing exclusivity in the EU after product approval, eligibility for conditional marketing authorization, protocol assistance from the European Medicines Agency at reduced fees during the product development phase, and direct access to centralized marketing authorization in the EU.
The European Commission has granted orphan drug designation to onvansertib for the treatment of acute myeloid leukemia (AML).
Onvansertib (formerly PCM-075) is an oral adenosine triphosphate competitive inhibitor of the serine/threonine Polo-like kinase 1 (PLK1) enzyme, which is overexpressed in hematologic and solid tumor malignancies.
Trovagene, Inc., the company developing onvansertib, said the drug has a 24-hour half-life with reversible, on-target hematologic activity.
These factors, combined with an improved dose/scheduling protocol, could mean onvansertib will improve upon long-term outcomes observed in previous studies with a PLK inhibitor in AML.
This includes a phase 2 study in which AML patients who received a PLK inhibitor plus low-dose cytarabine (LDAC) had a higher response rate than patients who received LDAC alone—31% and 13.3%, respectively.
Trovagene said preclinical studies have shown that onvansertib synergizes with more than 10 drugs used to treat hematologic and solid tumor malignancies. This includes FLT3 and HDAC inhibitors, taxanes, and cytotoxins.
Trovagene is now conducting a phase 1b/2 trial of onvansertib in combination with standard care (LDAC or decitabine) in patients with AML (NCT03303339).
The company has already completed a phase 1 dose-escalation study of onvansertib in patients with advanced metastatic solid tumor malignancies. Results from this study were published in Investigational New Drugs.
About orphan designation
Orphan drug designation in Europe is available to companies developing products intended to treat a life-threatening or chronically debilitating condition that affects fewer than 5 in 10,000 people in the European Union (EU).
The designation allows for financial and regulatory incentives that include 10 years of marketing exclusivity in the EU after product approval, eligibility for conditional marketing authorization, protocol assistance from the European Medicines Agency at reduced fees during the product development phase, and direct access to centralized marketing authorization in the EU.
The European Commission has granted orphan drug designation to onvansertib for the treatment of acute myeloid leukemia (AML).
Onvansertib (formerly PCM-075) is an oral adenosine triphosphate competitive inhibitor of the serine/threonine Polo-like kinase 1 (PLK1) enzyme, which is overexpressed in hematologic and solid tumor malignancies.
Trovagene, Inc., the company developing onvansertib, said the drug has a 24-hour half-life with reversible, on-target hematologic activity.
These factors, combined with an improved dose/scheduling protocol, could mean onvansertib will improve upon long-term outcomes observed in previous studies with a PLK inhibitor in AML.
This includes a phase 2 study in which AML patients who received a PLK inhibitor plus low-dose cytarabine (LDAC) had a higher response rate than patients who received LDAC alone—31% and 13.3%, respectively.
Trovagene said preclinical studies have shown that onvansertib synergizes with more than 10 drugs used to treat hematologic and solid tumor malignancies. This includes FLT3 and HDAC inhibitors, taxanes, and cytotoxins.
Trovagene is now conducting a phase 1b/2 trial of onvansertib in combination with standard care (LDAC or decitabine) in patients with AML (NCT03303339).
The company has already completed a phase 1 dose-escalation study of onvansertib in patients with advanced metastatic solid tumor malignancies. Results from this study were published in Investigational New Drugs.
About orphan designation
Orphan drug designation in Europe is available to companies developing products intended to treat a life-threatening or chronically debilitating condition that affects fewer than 5 in 10,000 people in the European Union (EU).
The designation allows for financial and regulatory incentives that include 10 years of marketing exclusivity in the EU after product approval, eligibility for conditional marketing authorization, protocol assistance from the European Medicines Agency at reduced fees during the product development phase, and direct access to centralized marketing authorization in the EU.