ALL

A contaminated hematopoietic stem cell (HSC) graft caused a clinically significant infection in a 15-year-old transplant recipient with B-cell acute lymphoblastic leukemia (B-ALL), according to a letter to the editor published in Infection Control & Hospital Epidemiology.

Strains of Staphylococcus aureus found in isolates from the HSC graft and the patient were confirmed to be identical using pulsed-field gel electrophoresis, the authors, led by Zachary I. Willis, MD, MPH, of the department of pediatrics at the University of North Carolina at Chapel Hill, said.

“While multiple reports have found that low-grade bacterial contamination of HSC products is rarely consequential, our patient’s experience demonstrated that clinically significant infections may occur,” Dr. Willis and his colleagues wrote in the case report.

When less virulent organisms are found in HSC grafts, close observation may be warranted, the investigators said; however, a more aggressive approach might be considered when more virulent organisms are found.

“In such a case, we suggest obtaining blood cultures and considering preemptive antibiotics as guided by the identity and susceptibility of the contaminating organism,” the investigators wrote.

Dr. Willis and his colleagues reported the case of a 15-year-old boy with hypodiploid B-ALL who achieved complete remission after treatment and then underwent a 10/10 HLA allele–matched unrelated donor hematopoietic cell transplant.

The patient developed a fever of 38.3º C with tachycardia but no other sepsis signs approximately 24 hours after the transplant. Soon afterward, the care team was informed that there was a single colony each of Micrococcus and S. aureus in the culture of the HSC product. Methicillin susceptibility was later confirmed. Antibiotic treatment was changed accordingly, and as of 117 days post transplant, the patient was “doing well with no evidence of further infectious complications,” the investigators said.

Bacterial contamination of HSC grafts is relatively common, with reported rates ranging from 1% to 45%. However, the clinical significance of the contamination has been unclear. Moreover, contamination is not an absolute contraindication to infusion, as options for the patient are limited after a myeloablative preparative regimen.

There are some previous case reports also identifying infections caused by contaminated grafts, but in those cases, the evidence linking the graft to the infection was based solely on finding identical species, while in the present report, the graft and patient isolates were confirmed to be identical using pulsed-field gel electrophoresis.

The investigators reported having no outside funding and no financial disclosures.

SOURCE: Willis Z et al, Infect Control Hosp Epidemiol. 2018 Jan 23. doi: 10.1017/ice.2017.285.

A contaminated hematopoietic stem cell (HSC) graft caused a clinically significant infection in a 15-year-old transplant recipient with B-cell acute lymphoblastic leukemia (B-ALL), according to a letter to the editor published in Infection Control & Hospital Epidemiology.

Strains of Staphylococcus aureus found in isolates from the HSC graft and the patient were confirmed to be identical using pulsed-field gel electrophoresis, the authors, led by Zachary I. Willis, MD, MPH, of the department of pediatrics at the University of North Carolina at Chapel Hill, said.

“While multiple reports have found that low-grade bacterial contamination of HSC products is rarely consequential, our patient’s experience demonstrated that clinically significant infections may occur,” Dr. Willis and his colleagues wrote in the case report.

When less virulent organisms are found in HSC grafts, close observation may be warranted, the investigators said; however, a more aggressive approach might be considered when more virulent organisms are found.

“In such a case, we suggest obtaining blood cultures and considering preemptive antibiotics as guided by the identity and susceptibility of the contaminating organism,” the investigators wrote.

Dr. Willis and his colleagues reported the case of a 15-year-old boy with hypodiploid B-ALL who achieved complete remission after treatment and then underwent a 10/10 HLA allele–matched unrelated donor hematopoietic cell transplant.

The patient developed a fever of 38.3º C with tachycardia but no other sepsis signs approximately 24 hours after the transplant. Soon afterward, the care team was informed that there was a single colony each of Micrococcus and S. aureus in the culture of the HSC product. Methicillin susceptibility was later confirmed. Antibiotic treatment was changed accordingly, and as of 117 days post transplant, the patient was “doing well with no evidence of further infectious complications,” the investigators said.

Bacterial contamination of HSC grafts is relatively common, with reported rates ranging from 1% to 45%. However, the clinical significance of the contamination has been unclear. Moreover, contamination is not an absolute contraindication to infusion, as options for the patient are limited after a myeloablative preparative regimen.

There are some previous case reports also identifying infections caused by contaminated grafts, but in those cases, the evidence linking the graft to the infection was based solely on finding identical species, while in the present report, the graft and patient isolates were confirmed to be identical using pulsed-field gel electrophoresis.

The investigators reported having no outside funding and no financial disclosures.

SOURCE: Willis Z et al, Infect Control Hosp Epidemiol. 2018 Jan 23. doi: 10.1017/ice.2017.285.

A contaminated hematopoietic stem cell (HSC) graft caused a clinically significant infection in a 15-year-old transplant recipient with B-cell acute lymphoblastic leukemia (B-ALL), according to a letter to the editor published in Infection Control & Hospital Epidemiology.

Strains of Staphylococcus aureus found in isolates from the HSC graft and the patient were confirmed to be identical using pulsed-field gel electrophoresis, the authors, led by Zachary I. Willis, MD, MPH, of the department of pediatrics at the University of North Carolina at Chapel Hill, said.

“While multiple reports have found that low-grade bacterial contamination of HSC products is rarely consequential, our patient’s experience demonstrated that clinically significant infections may occur,” Dr. Willis and his colleagues wrote in the case report.

When less virulent organisms are found in HSC grafts, close observation may be warranted, the investigators said; however, a more aggressive approach might be considered when more virulent organisms are found.

“In such a case, we suggest obtaining blood cultures and considering preemptive antibiotics as guided by the identity and susceptibility of the contaminating organism,” the investigators wrote.

Dr. Willis and his colleagues reported the case of a 15-year-old boy with hypodiploid B-ALL who achieved complete remission after treatment and then underwent a 10/10 HLA allele–matched unrelated donor hematopoietic cell transplant.

The patient developed a fever of 38.3º C with tachycardia but no other sepsis signs approximately 24 hours after the transplant. Soon afterward, the care team was informed that there was a single colony each of Micrococcus and S. aureus in the culture of the HSC product. Methicillin susceptibility was later confirmed. Antibiotic treatment was changed accordingly, and as of 117 days post transplant, the patient was “doing well with no evidence of further infectious complications,” the investigators said.

Bacterial contamination of HSC grafts is relatively common, with reported rates ranging from 1% to 45%. However, the clinical significance of the contamination has been unclear. Moreover, contamination is not an absolute contraindication to infusion, as options for the patient are limited after a myeloablative preparative regimen.

There are some previous case reports also identifying infections caused by contaminated grafts, but in those cases, the evidence linking the graft to the infection was based solely on finding identical species, while in the present report, the graft and patient isolates were confirmed to be identical using pulsed-field gel electrophoresis.

The investigators reported having no outside funding and no financial disclosures.

SOURCE: Willis Z et al, Infect Control Hosp Epidemiol. 2018 Jan 23. doi: 10.1017/ice.2017.285.

Micrograph showing ALL

A mutation that leads to relapse in patients with acute lymphoblastic leukemia (ALL) also causes a weakness that could be exploited to kill leukemia cells, according to research published in Nature.

Investigators found evidence to suggest that mutations in the NT5C2 gene make leukemic cells resistant to a common chemotherapy drug but vulnerable to a class of drugs called IMPDH inhibitors.

“Increased sensitivity to IMPDH inhibition shows proof of principle that the pathway for resistance provides a new therapeutic target,” said Adolfo Ferrando, MD, PhD, of Columbia University’s Herbert Irving Comprehensive Cancer Center in New York, New York.

Dr Ferrando’s lab had previously found that cancer cells from relapsed ALL patients frequently have mutations in NT5C2, which drives resistance to 6-mercaptopurine.

However, the investigators didn’t know how these mutations emerge as cancer recurs after remission.

In analyzing samples from ALL patients, the team found they could detect the NT5C2 mutation R367Q in cancer cells before patients were clinically diagnosed as relapsed. However, the mutation was not detectable in most cases at the time of diagnosis.

These findings suggest that cells with the R367Q mutation only multiply in response to treatment, and the mutation may help predict relapse.

“This seems to be a late mutation involved in disease progression,” Dr Ferrando said. “Our data support that it may not be present at diagnosis in many cases, and that, in cases where it may be present, it represents a very minor population.”

The investigators also found the R367Q mutation impaired leukemia cell growth and leukemia-initiating cell activity. This was “associated with excess export of purines to the extracellular space and depletion of the intracellular purine-nucleotide pool.”

These findings led the investigators to test mizoribine, an IMPDH inhibitor, in Nt5c2^+/R367Q mutant and Nt5c2^+/co-R367Q wild-type ALL lymphoblasts. The team found the mutant cells were significantly more sensitive to mizoribine.

In Nt5c2^+/R367Q leukemia-bearing mice, treatment with mizoribine produced a “marked” anti-leukemic response and significantly prolonged survival.

In immunodeficient mice transplanted with an NT5C2(R367Q) xenograft, mizoribine decreased tumor burden and tumor infiltration.

“IMPDH inhibitors could eventually emerge as relevant antileukemic drugs, but this would require additional preclinical work before clinical testing,” Dr Ferrando said.

Micrograph showing ALL

A mutation that leads to relapse in patients with acute lymphoblastic leukemia (ALL) also causes a weakness that could be exploited to kill leukemia cells, according to research published in Nature.

Investigators found evidence to suggest that mutations in the NT5C2 gene make leukemic cells resistant to a common chemotherapy drug but vulnerable to a class of drugs called IMPDH inhibitors.

“Increased sensitivity to IMPDH inhibition shows proof of principle that the pathway for resistance provides a new therapeutic target,” said Adolfo Ferrando, MD, PhD, of Columbia University’s Herbert Irving Comprehensive Cancer Center in New York, New York.

Dr Ferrando’s lab had previously found that cancer cells from relapsed ALL patients frequently have mutations in NT5C2, which drives resistance to 6-mercaptopurine.

However, the investigators didn’t know how these mutations emerge as cancer recurs after remission.

In analyzing samples from ALL patients, the team found they could detect the NT5C2 mutation R367Q in cancer cells before patients were clinically diagnosed as relapsed. However, the mutation was not detectable in most cases at the time of diagnosis.

These findings suggest that cells with the R367Q mutation only multiply in response to treatment, and the mutation may help predict relapse.

“This seems to be a late mutation involved in disease progression,” Dr Ferrando said. “Our data support that it may not be present at diagnosis in many cases, and that, in cases where it may be present, it represents a very minor population.”

The investigators also found the R367Q mutation impaired leukemia cell growth and leukemia-initiating cell activity. This was “associated with excess export of purines to the extracellular space and depletion of the intracellular purine-nucleotide pool.”

These findings led the investigators to test mizoribine, an IMPDH inhibitor, in Nt5c2^+/R367Q mutant and Nt5c2^+/co-R367Q wild-type ALL lymphoblasts. The team found the mutant cells were significantly more sensitive to mizoribine.

In Nt5c2^+/R367Q leukemia-bearing mice, treatment with mizoribine produced a “marked” anti-leukemic response and significantly prolonged survival.

In immunodeficient mice transplanted with an NT5C2(R367Q) xenograft, mizoribine decreased tumor burden and tumor infiltration.

“IMPDH inhibitors could eventually emerge as relevant antileukemic drugs, but this would require additional preclinical work before clinical testing,” Dr Ferrando said.

Micrograph showing ALL

A mutation that leads to relapse in patients with acute lymphoblastic leukemia (ALL) also causes a weakness that could be exploited to kill leukemia cells, according to research published in Nature.

Investigators found evidence to suggest that mutations in the NT5C2 gene make leukemic cells resistant to a common chemotherapy drug but vulnerable to a class of drugs called IMPDH inhibitors.

“Increased sensitivity to IMPDH inhibition shows proof of principle that the pathway for resistance provides a new therapeutic target,” said Adolfo Ferrando, MD, PhD, of Columbia University’s Herbert Irving Comprehensive Cancer Center in New York, New York.

Dr Ferrando’s lab had previously found that cancer cells from relapsed ALL patients frequently have mutations in NT5C2, which drives resistance to 6-mercaptopurine.

However, the investigators didn’t know how these mutations emerge as cancer recurs after remission.

In analyzing samples from ALL patients, the team found they could detect the NT5C2 mutation R367Q in cancer cells before patients were clinically diagnosed as relapsed. However, the mutation was not detectable in most cases at the time of diagnosis.

These findings suggest that cells with the R367Q mutation only multiply in response to treatment, and the mutation may help predict relapse.

“This seems to be a late mutation involved in disease progression,” Dr Ferrando said. “Our data support that it may not be present at diagnosis in many cases, and that, in cases where it may be present, it represents a very minor population.”

The investigators also found the R367Q mutation impaired leukemia cell growth and leukemia-initiating cell activity. This was “associated with excess export of purines to the extracellular space and depletion of the intracellular purine-nucleotide pool.”

These findings led the investigators to test mizoribine, an IMPDH inhibitor, in Nt5c2^+/R367Q mutant and Nt5c2^+/co-R367Q wild-type ALL lymphoblasts. The team found the mutant cells were significantly more sensitive to mizoribine.

In Nt5c2^+/R367Q leukemia-bearing mice, treatment with mizoribine produced a “marked” anti-leukemic response and significantly prolonged survival.

In immunodeficient mice transplanted with an NT5C2(R367Q) xenograft, mizoribine decreased tumor burden and tumor infiltration.

“IMPDH inhibitors could eventually emerge as relevant antileukemic drugs, but this would require additional preclinical work before clinical testing,” Dr Ferrando said.

Inotuzumab ozogamicin appeared active and safe when added to reduced-intensity chemotherapy for older patients with Philadelphia chromosome–negative acute lymphoblastic leukemia, according to the results of a single-arm phase 2 study.

After a median follow-up of 29 months, 2-year progression-free survival was 59% with a median of 25 months for 52 patients with newly diagnosed disease who were aged 60 years or older, Hagop Kantarjian, MD, and his associates reported online in the Lancet Oncology.

Nearly every patient experienced an overall response (98%). The treatment also appeared to be safe, Dr. Kantarjian and associates wrote.

They reported that no patient died within 4 weeks of treatment and that four patients experienced veno-occlusive disease. Common grade 3 or 4 side effects included thrombocytopenia (81%), consolidation chemotherapy (69%), hyperglycemia (54%), infections during induction (52%), hypokalemia (31%), increased aminotransferases (19%), hyperbilirubinemia (17%), and hemorrhage (15%). Six patients died from treatment-related side effects, five of whom died from sepsis and one of whom died as a result of veno-occlusive disease.

Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody that is bound to the toxin calicheamicin. It has shown “substantial improvements” for some patient subgroups when added to hyper-CVAD chemotherapy (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and high-dose cytarabine); however, older patients have yet to experience a similar benefit, Dr. Kantarjian and his associates said.

Both CVAD and inotuzumab ozogamicin have shown to be quite toxic for older patients. So – in order limit increased toxicity – Dr. Kantarjian and his associates lowered the intensity of hyper-CVAD. They accomplished this by reducing some aspects of the regimen by up to 50% and eliminating anthracyclines altogether. The researchers referred to this regimen as “mini–hyper-CVD.” The mini–hyper-CVD did not appear to impact activity.

“In our study, activity did not appear to be compromised by the use of lower-intensity chemotherapy in combination with a novel monoclonal antibody,” they wrote.

Dr. Kantarjian and his associates noted that, while they observed fewer deaths compared with previously published data, the number of deaths they did observe in patients who achieved a complete response was high.

They suggested that modifications to the regimen could further improve safety and that such modifications required further research.

For the time being, however, the researchers noted that this low-intensity regimen, in combination in inotuzumab ozogamicin, is highly effective and that these data now require prospective confirmation in a randomized, phase 3 setting.

The study was funded by the MD Anderson Cancer Center. Researchers reported that Pfizer provided inotuzumab ozogamicin free of charge and that Dr. Kantarjian and two other researchers received grants from Pfizer.

SOURCE: Kantarjian H et al. Lancet Oncol. 2018 Jan 15. doi: 10.1016/S1470-2945(18)30011-1.

Inotuzumab ozogamicin appeared active and safe when added to reduced-intensity chemotherapy for older patients with Philadelphia chromosome–negative acute lymphoblastic leukemia, according to the results of a single-arm phase 2 study.

After a median follow-up of 29 months, 2-year progression-free survival was 59% with a median of 25 months for 52 patients with newly diagnosed disease who were aged 60 years or older, Hagop Kantarjian, MD, and his associates reported online in the Lancet Oncology.

Nearly every patient experienced an overall response (98%). The treatment also appeared to be safe, Dr. Kantarjian and associates wrote.

They reported that no patient died within 4 weeks of treatment and that four patients experienced veno-occlusive disease. Common grade 3 or 4 side effects included thrombocytopenia (81%), consolidation chemotherapy (69%), hyperglycemia (54%), infections during induction (52%), hypokalemia (31%), increased aminotransferases (19%), hyperbilirubinemia (17%), and hemorrhage (15%). Six patients died from treatment-related side effects, five of whom died from sepsis and one of whom died as a result of veno-occlusive disease.

Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody that is bound to the toxin calicheamicin. It has shown “substantial improvements” for some patient subgroups when added to hyper-CVAD chemotherapy (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and high-dose cytarabine); however, older patients have yet to experience a similar benefit, Dr. Kantarjian and his associates said.

Both CVAD and inotuzumab ozogamicin have shown to be quite toxic for older patients. So – in order limit increased toxicity – Dr. Kantarjian and his associates lowered the intensity of hyper-CVAD. They accomplished this by reducing some aspects of the regimen by up to 50% and eliminating anthracyclines altogether. The researchers referred to this regimen as “mini–hyper-CVD.” The mini–hyper-CVD did not appear to impact activity.

“In our study, activity did not appear to be compromised by the use of lower-intensity chemotherapy in combination with a novel monoclonal antibody,” they wrote.

Dr. Kantarjian and his associates noted that, while they observed fewer deaths compared with previously published data, the number of deaths they did observe in patients who achieved a complete response was high.

They suggested that modifications to the regimen could further improve safety and that such modifications required further research.

For the time being, however, the researchers noted that this low-intensity regimen, in combination in inotuzumab ozogamicin, is highly effective and that these data now require prospective confirmation in a randomized, phase 3 setting.

The study was funded by the MD Anderson Cancer Center. Researchers reported that Pfizer provided inotuzumab ozogamicin free of charge and that Dr. Kantarjian and two other researchers received grants from Pfizer.

SOURCE: Kantarjian H et al. Lancet Oncol. 2018 Jan 15. doi: 10.1016/S1470-2945(18)30011-1.

Inotuzumab ozogamicin appeared active and safe when added to reduced-intensity chemotherapy for older patients with Philadelphia chromosome–negative acute lymphoblastic leukemia, according to the results of a single-arm phase 2 study.

After a median follow-up of 29 months, 2-year progression-free survival was 59% with a median of 25 months for 52 patients with newly diagnosed disease who were aged 60 years or older, Hagop Kantarjian, MD, and his associates reported online in the Lancet Oncology.

Nearly every patient experienced an overall response (98%). The treatment also appeared to be safe, Dr. Kantarjian and associates wrote.

They reported that no patient died within 4 weeks of treatment and that four patients experienced veno-occlusive disease. Common grade 3 or 4 side effects included thrombocytopenia (81%), consolidation chemotherapy (69%), hyperglycemia (54%), infections during induction (52%), hypokalemia (31%), increased aminotransferases (19%), hyperbilirubinemia (17%), and hemorrhage (15%). Six patients died from treatment-related side effects, five of whom died from sepsis and one of whom died as a result of veno-occlusive disease.

Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody that is bound to the toxin calicheamicin. It has shown “substantial improvements” for some patient subgroups when added to hyper-CVAD chemotherapy (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and high-dose cytarabine); however, older patients have yet to experience a similar benefit, Dr. Kantarjian and his associates said.

Both CVAD and inotuzumab ozogamicin have shown to be quite toxic for older patients. So – in order limit increased toxicity – Dr. Kantarjian and his associates lowered the intensity of hyper-CVAD. They accomplished this by reducing some aspects of the regimen by up to 50% and eliminating anthracyclines altogether. The researchers referred to this regimen as “mini–hyper-CVD.” The mini–hyper-CVD did not appear to impact activity.

“In our study, activity did not appear to be compromised by the use of lower-intensity chemotherapy in combination with a novel monoclonal antibody,” they wrote.

Dr. Kantarjian and his associates noted that, while they observed fewer deaths compared with previously published data, the number of deaths they did observe in patients who achieved a complete response was high.

They suggested that modifications to the regimen could further improve safety and that such modifications required further research.

For the time being, however, the researchers noted that this low-intensity regimen, in combination in inotuzumab ozogamicin, is highly effective and that these data now require prospective confirmation in a randomized, phase 3 setting.

The study was funded by the MD Anderson Cancer Center. Researchers reported that Pfizer provided inotuzumab ozogamicin free of charge and that Dr. Kantarjian and two other researchers received grants from Pfizer.

SOURCE: Kantarjian H et al. Lancet Oncol. 2018 Jan 15. doi: 10.1016/S1470-2945(18)30011-1.

Photo from Novartis

The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel (Kymriah, formerly CTL019) is getting fast-tracked in the United States (US) and European Union (EU).

The US Food and Drug Administration (FDA) has accepted for priority review the supplemental biologics license application (sBLA) for tisagenlecleucel for the treatment of adults with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who are ineligible for, or relapse after, autologous hematopoietic stem cell transplant (auto-HSCT).

Meanwhile, the European Medicines Agency (EMA) has granted accelerated assessment to the marketing authorization application (MAA) for tisagenlecleucel for the treatment of children and young adults with R/R B-cell acute lymphoblastic leukemia (ALL) and for adults with R/R DLBCL who are ineligible for auto-HSCT.

If the sBLA and MAA are approved, tisagenlecleucel will be the first CAR T-cell therapy available for 2 distinct indications in non-Hodgkin lymphoma and B-cell ALL.

Tisagenlecleucel became the first CAR T-cell therapy to receive regulatory approval when it was approved by the FDA in August 2017 for use in patients up to 25 years of age who have B-cell precursor ALL that is refractory or in second or later relapse.

Supporting data

The regulatory applications for tisagenlecleucel in the US and EU are supported by data from the Novartis-sponsored global clinical trial program in children and young adults with R/R B-cell ALL and adults with R/R DLBCL.

Results from the phase 2 JULIET trial served as the basis of the sBLA and MAA for tisagenlecleucel in adults with R/R DLCBL. Data from this trial were presented at the 2017 ASH Annual Meeting in December.

Results from the phase 2 ELIANA study were submitted as part of the MAA for tisagenlecleucel in children and young adults with R/R B-cell ALL. Data from this trial were presented at the 2017 EHA Congress last June.

About priority review, accelerated assessment

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The FDA’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The EMA grants accelerated assessment when a product is expected to be of major public health interest, particularly from the point of view of therapeutic innovation.

Accelerated assessment shortens the review period from 210 days to 150 days.

Photo from Novartis

The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel (Kymriah, formerly CTL019) is getting fast-tracked in the United States (US) and European Union (EU).

The US Food and Drug Administration (FDA) has accepted for priority review the supplemental biologics license application (sBLA) for tisagenlecleucel for the treatment of adults with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who are ineligible for, or relapse after, autologous hematopoietic stem cell transplant (auto-HSCT).

Meanwhile, the European Medicines Agency (EMA) has granted accelerated assessment to the marketing authorization application (MAA) for tisagenlecleucel for the treatment of children and young adults with R/R B-cell acute lymphoblastic leukemia (ALL) and for adults with R/R DLBCL who are ineligible for auto-HSCT.

If the sBLA and MAA are approved, tisagenlecleucel will be the first CAR T-cell therapy available for 2 distinct indications in non-Hodgkin lymphoma and B-cell ALL.

Tisagenlecleucel became the first CAR T-cell therapy to receive regulatory approval when it was approved by the FDA in August 2017 for use in patients up to 25 years of age who have B-cell precursor ALL that is refractory or in second or later relapse.

Supporting data

The regulatory applications for tisagenlecleucel in the US and EU are supported by data from the Novartis-sponsored global clinical trial program in children and young adults with R/R B-cell ALL and adults with R/R DLBCL.

Results from the phase 2 JULIET trial served as the basis of the sBLA and MAA for tisagenlecleucel in adults with R/R DLCBL. Data from this trial were presented at the 2017 ASH Annual Meeting in December.

Results from the phase 2 ELIANA study were submitted as part of the MAA for tisagenlecleucel in children and young adults with R/R B-cell ALL. Data from this trial were presented at the 2017 EHA Congress last June.

About priority review, accelerated assessment

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The FDA’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The EMA grants accelerated assessment when a product is expected to be of major public health interest, particularly from the point of view of therapeutic innovation.

Accelerated assessment shortens the review period from 210 days to 150 days.

Photo from Novartis

The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel (Kymriah, formerly CTL019) is getting fast-tracked in the United States (US) and European Union (EU).

The US Food and Drug Administration (FDA) has accepted for priority review the supplemental biologics license application (sBLA) for tisagenlecleucel for the treatment of adults with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who are ineligible for, or relapse after, autologous hematopoietic stem cell transplant (auto-HSCT).

Meanwhile, the European Medicines Agency (EMA) has granted accelerated assessment to the marketing authorization application (MAA) for tisagenlecleucel for the treatment of children and young adults with R/R B-cell acute lymphoblastic leukemia (ALL) and for adults with R/R DLBCL who are ineligible for auto-HSCT.

If the sBLA and MAA are approved, tisagenlecleucel will be the first CAR T-cell therapy available for 2 distinct indications in non-Hodgkin lymphoma and B-cell ALL.

Tisagenlecleucel became the first CAR T-cell therapy to receive regulatory approval when it was approved by the FDA in August 2017 for use in patients up to 25 years of age who have B-cell precursor ALL that is refractory or in second or later relapse.

Supporting data

The regulatory applications for tisagenlecleucel in the US and EU are supported by data from the Novartis-sponsored global clinical trial program in children and young adults with R/R B-cell ALL and adults with R/R DLBCL.

Results from the phase 2 JULIET trial served as the basis of the sBLA and MAA for tisagenlecleucel in adults with R/R DLCBL. Data from this trial were presented at the 2017 ASH Annual Meeting in December.

Results from the phase 2 ELIANA study were submitted as part of the MAA for tisagenlecleucel in children and young adults with R/R B-cell ALL. Data from this trial were presented at the 2017 EHA Congress last June.

About priority review, accelerated assessment

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The FDA’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The EMA grants accelerated assessment when a product is expected to be of major public health interest, particularly from the point of view of therapeutic innovation.

Accelerated assessment shortens the review period from 210 days to 150 days.

Pathogenic loss-of-function germline variants in the TP53 gene predispose children to acute lymphoblastic leukemia (ALL), and, later, to solid tumors that may be related to cancer therapy, according to results from a genetic sequencing study.

Researchers at St. Jude Children’s Hospital in Memphis have identified 49 unique variants of the gene among 3,801 children with newly diagnosed B-cell ALL; 22 variants were deemed pathogenic. Children with these variants were at a “dramatically higher risk” of secondary cancers, which occurred in 25% within 5 years of ALL treatment, compared with 0.7% among children without the pathogenic genetic signal, according to Maoxiang Qian, PhD, and colleagues. The report was published in the Journal of Clinical Oncology.

The increased risk of secondary cancers is probably related to a common characteristic of the pathogenic variants: the ablation of the p53-mediated DNA damage response. This increases the risk of the genotoxic therapy given during ALL treatment, according to the researchers.

“In fact, of the five patients with TP53 pathogenic variants who also had second cancers, two received irradiation therapy, including total body irradiation, and both subsequently developed solid tumors,” the researchers wrote. “The exact lifelong risk of second cancer in these patients is difficult to ascertain as many patients might have succumbed to relapsed ALL before they had the chance to develop second cancers.”

The research team conducted targeted sequencing of TP53 coding regions in 3,801 children who were enrolled in two trials sponsored by the Children’s Oncology Group (AALL0232 and P9900). They compared the results to TP53 mutations seen in almost 61,000 children enrolled in the Exome Aggregation Consortium (ExAC) cohort.

The researchers identified nine exonic nonsilent TP53 variants in the ALL cohort, all of which had an allele frequency of less than 0.5%. Of the variants, 22 were deemed pathogenic: Twelve showed a complete loss of transcriptional activity, three showed a partial loss of p53 function, and seven showed loss of the critical core DNA-binding domain in p53. The rest of the variants were deemed of unknown significance (VUS).

Pathogenic variants occurred in 26 children in the ALL cohort – significantly more often than in the control cohort (0.7% vs. 0.1%; odds ratio, 5.2). The VUS risk was not significantly elevated compared to controls, however.

Children with the pathogenic variants were significantly older at ALL diagnosis (15.5 vs. 6.6 years) and had significantly lower leukocyte count. Of the 26 with a pathogenic variant, 17 (65.4%) showed hypodiploidy in ALL blasts.

Pathogenic variants negatively affected ALL treatment outcomes, quadrupling the risk of lower event-free survival and lower overall survival (hazard ratio, 4.2 and 3.9, respectively) in both ALL cohorts.

Of the children with pathogenic variants, 14 experienced a pathological clinical event, including five ALL relapses and five second cancers, each accounting for 36% of all events.

“This pattern of events was dramatically different from that in patients with wild-type TP53 or VUS, for whom ALL relapse accounted for 75% of all events, with only 4% as second cancers,” the researchers wrote. “In fact, within hypodiploid ALL patients who experienced an event, the frequency of second cancer was significantly higher in those with TP53 pathogenic variants than in those without [50% vs. 5%], which additionally suggests that germline TP53 variation, instead of hypodiploid ALL, was the underlying cause of second cancers in these patients.”

The study was supported by grants from the National Institutes of Health and the American Lebanese Syrian Associated Charities. Dr. Qian reported having no financial disclosures. Other researchers reported funding from various pharmaceutical companies.

[email protected]

SOURCE: Qian et al. JCO 2018 Jan 4. doi: 10.1200/JCO.2017.75.5215

Pathogenic loss-of-function germline variants in the TP53 gene predispose children to acute lymphoblastic leukemia (ALL), and, later, to solid tumors that may be related to cancer therapy, according to results from a genetic sequencing study.

Researchers at St. Jude Children’s Hospital in Memphis have identified 49 unique variants of the gene among 3,801 children with newly diagnosed B-cell ALL; 22 variants were deemed pathogenic. Children with these variants were at a “dramatically higher risk” of secondary cancers, which occurred in 25% within 5 years of ALL treatment, compared with 0.7% among children without the pathogenic genetic signal, according to Maoxiang Qian, PhD, and colleagues. The report was published in the Journal of Clinical Oncology.

The increased risk of secondary cancers is probably related to a common characteristic of the pathogenic variants: the ablation of the p53-mediated DNA damage response. This increases the risk of the genotoxic therapy given during ALL treatment, according to the researchers.

“In fact, of the five patients with TP53 pathogenic variants who also had second cancers, two received irradiation therapy, including total body irradiation, and both subsequently developed solid tumors,” the researchers wrote. “The exact lifelong risk of second cancer in these patients is difficult to ascertain as many patients might have succumbed to relapsed ALL before they had the chance to develop second cancers.”

The research team conducted targeted sequencing of TP53 coding regions in 3,801 children who were enrolled in two trials sponsored by the Children’s Oncology Group (AALL0232 and P9900). They compared the results to TP53 mutations seen in almost 61,000 children enrolled in the Exome Aggregation Consortium (ExAC) cohort.

The researchers identified nine exonic nonsilent TP53 variants in the ALL cohort, all of which had an allele frequency of less than 0.5%. Of the variants, 22 were deemed pathogenic: Twelve showed a complete loss of transcriptional activity, three showed a partial loss of p53 function, and seven showed loss of the critical core DNA-binding domain in p53. The rest of the variants were deemed of unknown significance (VUS).

Pathogenic variants occurred in 26 children in the ALL cohort – significantly more often than in the control cohort (0.7% vs. 0.1%; odds ratio, 5.2). The VUS risk was not significantly elevated compared to controls, however.

Children with the pathogenic variants were significantly older at ALL diagnosis (15.5 vs. 6.6 years) and had significantly lower leukocyte count. Of the 26 with a pathogenic variant, 17 (65.4%) showed hypodiploidy in ALL blasts.

Pathogenic variants negatively affected ALL treatment outcomes, quadrupling the risk of lower event-free survival and lower overall survival (hazard ratio, 4.2 and 3.9, respectively) in both ALL cohorts.

Of the children with pathogenic variants, 14 experienced a pathological clinical event, including five ALL relapses and five second cancers, each accounting for 36% of all events.

“This pattern of events was dramatically different from that in patients with wild-type TP53 or VUS, for whom ALL relapse accounted for 75% of all events, with only 4% as second cancers,” the researchers wrote. “In fact, within hypodiploid ALL patients who experienced an event, the frequency of second cancer was significantly higher in those with TP53 pathogenic variants than in those without [50% vs. 5%], which additionally suggests that germline TP53 variation, instead of hypodiploid ALL, was the underlying cause of second cancers in these patients.”

The study was supported by grants from the National Institutes of Health and the American Lebanese Syrian Associated Charities. Dr. Qian reported having no financial disclosures. Other researchers reported funding from various pharmaceutical companies.

[email protected]

SOURCE: Qian et al. JCO 2018 Jan 4. doi: 10.1200/JCO.2017.75.5215

Pathogenic loss-of-function germline variants in the TP53 gene predispose children to acute lymphoblastic leukemia (ALL), and, later, to solid tumors that may be related to cancer therapy, according to results from a genetic sequencing study.

Researchers at St. Jude Children’s Hospital in Memphis have identified 49 unique variants of the gene among 3,801 children with newly diagnosed B-cell ALL; 22 variants were deemed pathogenic. Children with these variants were at a “dramatically higher risk” of secondary cancers, which occurred in 25% within 5 years of ALL treatment, compared with 0.7% among children without the pathogenic genetic signal, according to Maoxiang Qian, PhD, and colleagues. The report was published in the Journal of Clinical Oncology.

The increased risk of secondary cancers is probably related to a common characteristic of the pathogenic variants: the ablation of the p53-mediated DNA damage response. This increases the risk of the genotoxic therapy given during ALL treatment, according to the researchers.

“In fact, of the five patients with TP53 pathogenic variants who also had second cancers, two received irradiation therapy, including total body irradiation, and both subsequently developed solid tumors,” the researchers wrote. “The exact lifelong risk of second cancer in these patients is difficult to ascertain as many patients might have succumbed to relapsed ALL before they had the chance to develop second cancers.”

The research team conducted targeted sequencing of TP53 coding regions in 3,801 children who were enrolled in two trials sponsored by the Children’s Oncology Group (AALL0232 and P9900). They compared the results to TP53 mutations seen in almost 61,000 children enrolled in the Exome Aggregation Consortium (ExAC) cohort.

The researchers identified nine exonic nonsilent TP53 variants in the ALL cohort, all of which had an allele frequency of less than 0.5%. Of the variants, 22 were deemed pathogenic: Twelve showed a complete loss of transcriptional activity, three showed a partial loss of p53 function, and seven showed loss of the critical core DNA-binding domain in p53. The rest of the variants were deemed of unknown significance (VUS).

Pathogenic variants occurred in 26 children in the ALL cohort – significantly more often than in the control cohort (0.7% vs. 0.1%; odds ratio, 5.2). The VUS risk was not significantly elevated compared to controls, however.

Children with the pathogenic variants were significantly older at ALL diagnosis (15.5 vs. 6.6 years) and had significantly lower leukocyte count. Of the 26 with a pathogenic variant, 17 (65.4%) showed hypodiploidy in ALL blasts.

Pathogenic variants negatively affected ALL treatment outcomes, quadrupling the risk of lower event-free survival and lower overall survival (hazard ratio, 4.2 and 3.9, respectively) in both ALL cohorts.

Of the children with pathogenic variants, 14 experienced a pathological clinical event, including five ALL relapses and five second cancers, each accounting for 36% of all events.

“This pattern of events was dramatically different from that in patients with wild-type TP53 or VUS, for whom ALL relapse accounted for 75% of all events, with only 4% as second cancers,” the researchers wrote. “In fact, within hypodiploid ALL patients who experienced an event, the frequency of second cancer was significantly higher in those with TP53 pathogenic variants than in those without [50% vs. 5%], which additionally suggests that germline TP53 variation, instead of hypodiploid ALL, was the underlying cause of second cancers in these patients.”

The study was supported by grants from the National Institutes of Health and the American Lebanese Syrian Associated Charities. Dr. Qian reported having no financial disclosures. Other researchers reported funding from various pharmaceutical companies.

[email protected]

SOURCE: Qian et al. JCO 2018 Jan 4. doi: 10.1200/JCO.2017.75.5215

Photo by Rhoda Baer

A new report has revealed differences in survival among adolescents and young adults (AYAs) with hematologic malignancies.

The report includes information on AYAs—ages 15 to 39—living in Los Angeles County who were diagnosed with common cancers between 1988 and 2014.

The data showed differences in 5-year survival rates according to sex, race, age, and socioeconomic status (SES).

For example, lymphoma survival rates were lower for males, African Americans (AAs), older AYAs, and patients with low socioeconomic status (SES).

For AYAs with leukemias, there was no survival difference according to sex, but AAs had worse survival than patients of other races. And the impact of age and SES varied according to leukemia type.

“Cancer survival data are poorly understood for 15- to 39-year-olds,” noted Amie Hwang, PhD, of the University of Southern California Keck School of Medicine in Los Angeles.

That is why she and her colleagues created the report, “Cancer in Los Angeles County: Survival Among Adolescents and Young Adults 1988-2014.”

According to the authors, this is the first report to break down cancer survival rates for AYAs into segments on race/ethnicity, sex, age group, SES, and cancer stage.

Survival data for patients with hematologic malignancies were as follows.

Acute lymphoblastic leukemia

There were 1137 cases of acute lymphoblastic leukemia in the AYA population in Los Angeles County during the period studied. This included 752 males and 385 females.

Five-year survival was similar between males (43%) and females (41%).

Younger AYAs had better survival than older AYAs (48% for ages 15-24, 35% for ages 25-34, and 32% for ages 35-39).

Survival was highest among non-Latino whites (NLWs, 56%), followed by Asian/Pacific Islanders (APIs, 52%), patients of other/unknown races (51%), Latino whites (LWs, 38%), and AAs (29%).

Survival declined with SES (55% for high, 42% for middle, and 36% for low SES).

Acute myeloid leukemia

There were 1195 cases of acute myeloid leukemia—641 males and 554 females.

Five-year survival was similar for males (40%) and females (43%) as well as for the different age groups (45% for ages 15-24 vs 40% for the older age groups).

Survival was highest among NLWs (44%), followed by LWs (43%), APIs (40%), other/unknown (33%), and AAs (25%).

Survival declined somewhat with SES (49% for high, 39% for middle, and 41% for low SES).

Chronic myeloid leukemia

There were 655 cases of chronic myeloid leukemia—408 males and 247 females.

Five-year survival was similar for males (70%) and females (71%), but it was slightly higher for older AYAs (69% for ages 15-24, 68% for ages 25-34, and 76% for ages 35-39).

Survival was highest among patients in the “other/unknown” race category (76%), followed by LWs (73%), NLWs/APIs (both 72%), and AAs (57%).

Survival declined somewhat with SES (76% for high, 67% for middle, and 68% for low SES).

Hodgkin lymphoma

There were 2993 AYAs diagnosed with Hodgkin lymphoma—1553 males and 1440 females.

The 5-year survival rate was higher in females (93%) than males (86%) and in younger AYAs (93% for ages 15-24, 89% for ages 25-34, and 85% for ages 35-39).

Survival was highest among patients in the “other/unknown” race category (96%), followed by APIs/NLWs (both 91%), LWs (88%), and AAs (83%).

Survival declined with SES (95% for high, 89% for middle, and 83% for low SES).

And survival was lower for patients with advanced-stage disease (93% localized, 94% regional, and 83% distant).

Non-Hodkgin lymphoma

There were 4485 AYAs diagnosed with non-Hodgkin lymphoma during the study period­—3064 males and 1421 females.

The 5-year survival rate was higher in females (75%) than males (46%) and in younger AYAs (69% for ages 15-24, 51% for ages 25-34, and 52% for ages 35-39).

Survival was highest among patients in the “other/unknown” race category (88%), followed by APIs (68%), LWs/NLWs (both 53%), and AAs (50%).

Survival declined with SES (68% for high, 54% for middle, and 45% for low SES).

And survival was lower for patients with advanced-stage disease (61% localized, 66% regional, and 46% distant).

“Adolescents and young adults go to the doctor less often because they have this superhero mentality, like they’re invincible,” said author Dennis Deapen, DrPH, of the University of Southern California Keck School of Medicine.

“Once they do go to a health professional, their cancer diagnosis can be delayed because cancer isn’t the first concern doctors have for this age group. It comes as no surprise that patients diagnosed with late-stage cancer have reduced survival rates.”

Photo by Rhoda Baer

A new report has revealed differences in survival among adolescents and young adults (AYAs) with hematologic malignancies.

The report includes information on AYAs—ages 15 to 39—living in Los Angeles County who were diagnosed with common cancers between 1988 and 2014.

The data showed differences in 5-year survival rates according to sex, race, age, and socioeconomic status (SES).

For example, lymphoma survival rates were lower for males, African Americans (AAs), older AYAs, and patients with low socioeconomic status (SES).

For AYAs with leukemias, there was no survival difference according to sex, but AAs had worse survival than patients of other races. And the impact of age and SES varied according to leukemia type.

“Cancer survival data are poorly understood for 15- to 39-year-olds,” noted Amie Hwang, PhD, of the University of Southern California Keck School of Medicine in Los Angeles.

That is why she and her colleagues created the report, “Cancer in Los Angeles County: Survival Among Adolescents and Young Adults 1988-2014.”

According to the authors, this is the first report to break down cancer survival rates for AYAs into segments on race/ethnicity, sex, age group, SES, and cancer stage.

Survival data for patients with hematologic malignancies were as follows.

Acute lymphoblastic leukemia

There were 1137 cases of acute lymphoblastic leukemia in the AYA population in Los Angeles County during the period studied. This included 752 males and 385 females.

Five-year survival was similar between males (43%) and females (41%).

Younger AYAs had better survival than older AYAs (48% for ages 15-24, 35% for ages 25-34, and 32% for ages 35-39).

Survival was highest among non-Latino whites (NLWs, 56%), followed by Asian/Pacific Islanders (APIs, 52%), patients of other/unknown races (51%), Latino whites (LWs, 38%), and AAs (29%).

Survival declined with SES (55% for high, 42% for middle, and 36% for low SES).

Acute myeloid leukemia

There were 1195 cases of acute myeloid leukemia—641 males and 554 females.

Five-year survival was similar for males (40%) and females (43%) as well as for the different age groups (45% for ages 15-24 vs 40% for the older age groups).

Survival was highest among NLWs (44%), followed by LWs (43%), APIs (40%), other/unknown (33%), and AAs (25%).

Survival declined somewhat with SES (49% for high, 39% for middle, and 41% for low SES).

Chronic myeloid leukemia

There were 655 cases of chronic myeloid leukemia—408 males and 247 females.

Five-year survival was similar for males (70%) and females (71%), but it was slightly higher for older AYAs (69% for ages 15-24, 68% for ages 25-34, and 76% for ages 35-39).

Survival was highest among patients in the “other/unknown” race category (76%), followed by LWs (73%), NLWs/APIs (both 72%), and AAs (57%).

Survival declined somewhat with SES (76% for high, 67% for middle, and 68% for low SES).

Hodgkin lymphoma

There were 2993 AYAs diagnosed with Hodgkin lymphoma—1553 males and 1440 females.

The 5-year survival rate was higher in females (93%) than males (86%) and in younger AYAs (93% for ages 15-24, 89% for ages 25-34, and 85% for ages 35-39).

Survival was highest among patients in the “other/unknown” race category (96%), followed by APIs/NLWs (both 91%), LWs (88%), and AAs (83%).

Survival declined with SES (95% for high, 89% for middle, and 83% for low SES).

And survival was lower for patients with advanced-stage disease (93% localized, 94% regional, and 83% distant).

Non-Hodkgin lymphoma

There were 4485 AYAs diagnosed with non-Hodgkin lymphoma during the study period­—3064 males and 1421 females.

The 5-year survival rate was higher in females (75%) than males (46%) and in younger AYAs (69% for ages 15-24, 51% for ages 25-34, and 52% for ages 35-39).

Survival was highest among patients in the “other/unknown” race category (88%), followed by APIs (68%), LWs/NLWs (both 53%), and AAs (50%).

Survival declined with SES (68% for high, 54% for middle, and 45% for low SES).

And survival was lower for patients with advanced-stage disease (61% localized, 66% regional, and 46% distant).

“Adolescents and young adults go to the doctor less often because they have this superhero mentality, like they’re invincible,” said author Dennis Deapen, DrPH, of the University of Southern California Keck School of Medicine.

“Once they do go to a health professional, their cancer diagnosis can be delayed because cancer isn’t the first concern doctors have for this age group. It comes as no surprise that patients diagnosed with late-stage cancer have reduced survival rates.”

Photo by Rhoda Baer

A new report has revealed differences in survival among adolescents and young adults (AYAs) with hematologic malignancies.

The report includes information on AYAs—ages 15 to 39—living in Los Angeles County who were diagnosed with common cancers between 1988 and 2014.

The data showed differences in 5-year survival rates according to sex, race, age, and socioeconomic status (SES).

For example, lymphoma survival rates were lower for males, African Americans (AAs), older AYAs, and patients with low socioeconomic status (SES).

For AYAs with leukemias, there was no survival difference according to sex, but AAs had worse survival than patients of other races. And the impact of age and SES varied according to leukemia type.

“Cancer survival data are poorly understood for 15- to 39-year-olds,” noted Amie Hwang, PhD, of the University of Southern California Keck School of Medicine in Los Angeles.

That is why she and her colleagues created the report, “Cancer in Los Angeles County: Survival Among Adolescents and Young Adults 1988-2014.”

According to the authors, this is the first report to break down cancer survival rates for AYAs into segments on race/ethnicity, sex, age group, SES, and cancer stage.

Survival data for patients with hematologic malignancies were as follows.

Acute lymphoblastic leukemia

There were 1137 cases of acute lymphoblastic leukemia in the AYA population in Los Angeles County during the period studied. This included 752 males and 385 females.

Five-year survival was similar between males (43%) and females (41%).

Younger AYAs had better survival than older AYAs (48% for ages 15-24, 35% for ages 25-34, and 32% for ages 35-39).

Survival was highest among non-Latino whites (NLWs, 56%), followed by Asian/Pacific Islanders (APIs, 52%), patients of other/unknown races (51%), Latino whites (LWs, 38%), and AAs (29%).

Survival declined with SES (55% for high, 42% for middle, and 36% for low SES).

Acute myeloid leukemia

There were 1195 cases of acute myeloid leukemia—641 males and 554 females.

Five-year survival was similar for males (40%) and females (43%) as well as for the different age groups (45% for ages 15-24 vs 40% for the older age groups).

Survival was highest among NLWs (44%), followed by LWs (43%), APIs (40%), other/unknown (33%), and AAs (25%).

Survival declined somewhat with SES (49% for high, 39% for middle, and 41% for low SES).

Chronic myeloid leukemia

There were 655 cases of chronic myeloid leukemia—408 males and 247 females.

Five-year survival was similar for males (70%) and females (71%), but it was slightly higher for older AYAs (69% for ages 15-24, 68% for ages 25-34, and 76% for ages 35-39).

Survival was highest among patients in the “other/unknown” race category (76%), followed by LWs (73%), NLWs/APIs (both 72%), and AAs (57%).

Survival declined somewhat with SES (76% for high, 67% for middle, and 68% for low SES).

Hodgkin lymphoma

There were 2993 AYAs diagnosed with Hodgkin lymphoma—1553 males and 1440 females.

The 5-year survival rate was higher in females (93%) than males (86%) and in younger AYAs (93% for ages 15-24, 89% for ages 25-34, and 85% for ages 35-39).

Survival was highest among patients in the “other/unknown” race category (96%), followed by APIs/NLWs (both 91%), LWs (88%), and AAs (83%).

Survival declined with SES (95% for high, 89% for middle, and 83% for low SES).

And survival was lower for patients with advanced-stage disease (93% localized, 94% regional, and 83% distant).

Non-Hodkgin lymphoma

There were 4485 AYAs diagnosed with non-Hodgkin lymphoma during the study period­—3064 males and 1421 females.

The 5-year survival rate was higher in females (75%) than males (46%) and in younger AYAs (69% for ages 15-24, 51% for ages 25-34, and 52% for ages 35-39).

Survival was highest among patients in the “other/unknown” race category (88%), followed by APIs (68%), LWs/NLWs (both 53%), and AAs (50%).

Survival declined with SES (68% for high, 54% for middle, and 45% for low SES).

And survival was lower for patients with advanced-stage disease (61% localized, 66% regional, and 46% distant).

“Adolescents and young adults go to the doctor less often because they have this superhero mentality, like they’re invincible,” said author Dennis Deapen, DrPH, of the University of Southern California Keck School of Medicine.

“Once they do go to a health professional, their cancer diagnosis can be delayed because cancer isn’t the first concern doctors have for this age group. It comes as no surprise that patients diagnosed with late-stage cancer have reduced survival rates.”

Research Hospital

New research has revealed germline variations associated with high-risk acute lymphoblastic leukemia (ALL) in children.

Researchers sequenced the TP53 tumor suppressor gene in nearly 4000 children with ALL and identified 22 pathogenic germline variants.

These variants were associated with inferior survival and an increased risk of developing second malignancies.

Jun J. Yang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in the Journal of Clinical Oncology.

The researchers performed targeted sequencing of TP53 coding regions in 3801 children with ALL who were enrolled in 2 Children’s Oncology Group trials (AALL0232 and P9900).

The sequencing revealed 49 unique TP53 coding variants, which were found in 77 children. Twenty-two of the variants were pathogenic, and they were found in 26 children.

The researchers also analyzed data from 60,706 control subjects without ALL and found the 22 pathogenic variants were more likely to be found in the ALL patients than controls. The odds ratio was 5.2 (P<0.001).

Among the ALL patients, those who had the pathogenic variants were significantly older at diagnosis than those without the variants, with median ages of 15.5 years and 7.3 years, respectively (P<0.001).

The pathogenic variants were most common in patients with hypodiploid ALL. About 65% of patients who carried the pathogenic variants had hypodiploid ALL, as did 1.2% of children with wild-type genotype (P<0.001).

The pathogenic variants were associated with inferior event-free survival and overall survival as well. The hazard ratios were 4.2 (P<0.001) and 3.9 (P=0.001), respectively.

And the pathogenic variants were associated with a higher risk of second cancers. The 5-year cumulative incidence of second malignancies was 25.1% among patients with the pathogenic variants and 0.7% among patients without the variants (P<0.001).

“These germline variations are a double whammy for carriers,” Dr Yang said. “Not only is their risk of developing leukemia very high, they are also more likely to relapse or develop a second cancer.”

The association between the pathogenic variants and second cancers has prompted Dr Yang and his colleagues to explore ways to help patients manage their risk.

“Maybe these patients should avoid certain ALL therapies in order to reduce their risk of developing another cancer,” Dr Yang said. “I believe this finding may change treatment and follow-up for these high-risk patients.”

Dr Yang and his colleagues also noted that inherited variations in TP53 are a hallmark of Li-Fraumeni syndrome. And the syndrome might partially explain the high rate of second cancers in ALL patients with the pathogenic TP53 variants.

“The ALL treatment might have added to that risk,” Dr Yang said, “but we do not know for sure.”

Research Hospital

New research has revealed germline variations associated with high-risk acute lymphoblastic leukemia (ALL) in children.

Researchers sequenced the TP53 tumor suppressor gene in nearly 4000 children with ALL and identified 22 pathogenic germline variants.

These variants were associated with inferior survival and an increased risk of developing second malignancies.

Jun J. Yang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in the Journal of Clinical Oncology.

The researchers performed targeted sequencing of TP53 coding regions in 3801 children with ALL who were enrolled in 2 Children’s Oncology Group trials (AALL0232 and P9900).

The sequencing revealed 49 unique TP53 coding variants, which were found in 77 children. Twenty-two of the variants were pathogenic, and they were found in 26 children.

The researchers also analyzed data from 60,706 control subjects without ALL and found the 22 pathogenic variants were more likely to be found in the ALL patients than controls. The odds ratio was 5.2 (P<0.001).

Among the ALL patients, those who had the pathogenic variants were significantly older at diagnosis than those without the variants, with median ages of 15.5 years and 7.3 years, respectively (P<0.001).

The pathogenic variants were most common in patients with hypodiploid ALL. About 65% of patients who carried the pathogenic variants had hypodiploid ALL, as did 1.2% of children with wild-type genotype (P<0.001).

The pathogenic variants were associated with inferior event-free survival and overall survival as well. The hazard ratios were 4.2 (P<0.001) and 3.9 (P=0.001), respectively.

And the pathogenic variants were associated with a higher risk of second cancers. The 5-year cumulative incidence of second malignancies was 25.1% among patients with the pathogenic variants and 0.7% among patients without the variants (P<0.001).

“These germline variations are a double whammy for carriers,” Dr Yang said. “Not only is their risk of developing leukemia very high, they are also more likely to relapse or develop a second cancer.”

The association between the pathogenic variants and second cancers has prompted Dr Yang and his colleagues to explore ways to help patients manage their risk.

“Maybe these patients should avoid certain ALL therapies in order to reduce their risk of developing another cancer,” Dr Yang said. “I believe this finding may change treatment and follow-up for these high-risk patients.”

Dr Yang and his colleagues also noted that inherited variations in TP53 are a hallmark of Li-Fraumeni syndrome. And the syndrome might partially explain the high rate of second cancers in ALL patients with the pathogenic TP53 variants.

“The ALL treatment might have added to that risk,” Dr Yang said, “but we do not know for sure.”

Research Hospital

New research has revealed germline variations associated with high-risk acute lymphoblastic leukemia (ALL) in children.

Researchers sequenced the TP53 tumor suppressor gene in nearly 4000 children with ALL and identified 22 pathogenic germline variants.

These variants were associated with inferior survival and an increased risk of developing second malignancies.

Jun J. Yang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in the Journal of Clinical Oncology.

The researchers performed targeted sequencing of TP53 coding regions in 3801 children with ALL who were enrolled in 2 Children’s Oncology Group trials (AALL0232 and P9900).

The sequencing revealed 49 unique TP53 coding variants, which were found in 77 children. Twenty-two of the variants were pathogenic, and they were found in 26 children.

The researchers also analyzed data from 60,706 control subjects without ALL and found the 22 pathogenic variants were more likely to be found in the ALL patients than controls. The odds ratio was 5.2 (P<0.001).

Among the ALL patients, those who had the pathogenic variants were significantly older at diagnosis than those without the variants, with median ages of 15.5 years and 7.3 years, respectively (P<0.001).

The pathogenic variants were most common in patients with hypodiploid ALL. About 65% of patients who carried the pathogenic variants had hypodiploid ALL, as did 1.2% of children with wild-type genotype (P<0.001).

The pathogenic variants were associated with inferior event-free survival and overall survival as well. The hazard ratios were 4.2 (P<0.001) and 3.9 (P=0.001), respectively.

And the pathogenic variants were associated with a higher risk of second cancers. The 5-year cumulative incidence of second malignancies was 25.1% among patients with the pathogenic variants and 0.7% among patients without the variants (P<0.001).

“These germline variations are a double whammy for carriers,” Dr Yang said. “Not only is their risk of developing leukemia very high, they are also more likely to relapse or develop a second cancer.”

The association between the pathogenic variants and second cancers has prompted Dr Yang and his colleagues to explore ways to help patients manage their risk.

“Maybe these patients should avoid certain ALL therapies in order to reduce their risk of developing another cancer,” Dr Yang said. “I believe this finding may change treatment and follow-up for these high-risk patients.”

Dr Yang and his colleagues also noted that inherited variations in TP53 are a hallmark of Li-Fraumeni syndrome. And the syndrome might partially explain the high rate of second cancers in ALL patients with the pathogenic TP53 variants.

“The ALL treatment might have added to that risk,” Dr Yang said, “but we do not know for sure.”

© Todd Buchanan 2017

ATLANTA—A 2-drug combination has produced a high response rate in a small trial of patients with relapsed/refractory (R/R), Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).

The combination, inotuzumab ozogamicin and bosutinib, produced an overall response rate of 81% in this ongoing, phase 1/2 trial.

Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center in Houston, presented phase 1 results from the study at the 2017 ASH Annual Meeting (abstract 143*).

He reported results in 16 patients, 14 with R/R, Ph+ ALL and 2 with chronic myeloid leukemia in lymphoid blast phase.

The patients received inotuzumab ozogamicin at 0.8 mg/m² on day 1, 0.5 mg/m² on day 8, and 0.5 mg/m² on day 15 of cycle 1. Patients who achieved a response received inotuzumab ozogamicin at 1 mg/m² once every 4 weeks for subsequent cycles. Six cycles were planned.

Patients also received bosutinib at 300 mg, 400 mg, or 500 mg once a day for 4-week cycles. The median number of cycles was 2.5 (range, 1-8).

The maximum-tolerated dose has not been established, but there were 2 dose-limiting toxicities (DLTs). One DLT occurred with the 400 mg dose of bosutinib, and 1 occurred with the 500 mg dose. Both DLTs were grade 3 skin rash.

The investigators are continuing accrual with the 500 mg dose of bosutinib for the phase 2 portion of the trial, with 22 additional patients.

Response and survival

The overall response rate was 81% (n=13). This included a complete response (CR) in 8 patients, a CR with incomplete blood count recovery in 3 patients, and a CR with incomplete platelet recovery in 2 patients.

All responses occurred among the patients with ALL.

Twelve responders achieved complete cytogenetic remission, 11 achieved a major molecular response, 8 achieved a complete molecular response, and 9 were negative by flow cytometry.

The median duration of response was 8.8 months.

Of the 13 responders, 6 went on to receive an allogeneic stem cell transplant. Five of these patients are still alive, but 1 died from relapse.

The median overall survival was 10.7 months.

“These data suggest the tolerability and efficacy of inotuzumab ozogamicin and bosutinib in R/R Ph+ ALL,” Dr Jain said. “And we are looking forward to the next phase of this study.”

Dr Jain disclosed receiving research funding from Celgene, Verastem, BMS, Incyte, Pharmacyclics, ADC Therapeutics, Genentech, AbbVie, Pfizer, Astra Zeneca, Janssen, Cellectis, and Seattle Genetics. He disclosed membership on boards of directors/advisory committees for Verastem, Servier, Novimmune, Pharmacyclics, Novartis, ADC Therapeutics, AbbVie, Pfizer, Adaptive Biotechnologies, and Janssen.

*Data in the presentation differ from the abstract.

© Todd Buchanan 2017

ATLANTA—A 2-drug combination has produced a high response rate in a small trial of patients with relapsed/refractory (R/R), Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).

The combination, inotuzumab ozogamicin and bosutinib, produced an overall response rate of 81% in this ongoing, phase 1/2 trial.

Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center in Houston, presented phase 1 results from the study at the 2017 ASH Annual Meeting (abstract 143*).

He reported results in 16 patients, 14 with R/R, Ph+ ALL and 2 with chronic myeloid leukemia in lymphoid blast phase.

The patients received inotuzumab ozogamicin at 0.8 mg/m² on day 1, 0.5 mg/m² on day 8, and 0.5 mg/m² on day 15 of cycle 1. Patients who achieved a response received inotuzumab ozogamicin at 1 mg/m² once every 4 weeks for subsequent cycles. Six cycles were planned.

Patients also received bosutinib at 300 mg, 400 mg, or 500 mg once a day for 4-week cycles. The median number of cycles was 2.5 (range, 1-8).

The maximum-tolerated dose has not been established, but there were 2 dose-limiting toxicities (DLTs). One DLT occurred with the 400 mg dose of bosutinib, and 1 occurred with the 500 mg dose. Both DLTs were grade 3 skin rash.

The investigators are continuing accrual with the 500 mg dose of bosutinib for the phase 2 portion of the trial, with 22 additional patients.

Response and survival

The overall response rate was 81% (n=13). This included a complete response (CR) in 8 patients, a CR with incomplete blood count recovery in 3 patients, and a CR with incomplete platelet recovery in 2 patients.

All responses occurred among the patients with ALL.

Twelve responders achieved complete cytogenetic remission, 11 achieved a major molecular response, 8 achieved a complete molecular response, and 9 were negative by flow cytometry.

The median duration of response was 8.8 months.

Of the 13 responders, 6 went on to receive an allogeneic stem cell transplant. Five of these patients are still alive, but 1 died from relapse.

The median overall survival was 10.7 months.

“These data suggest the tolerability and efficacy of inotuzumab ozogamicin and bosutinib in R/R Ph+ ALL,” Dr Jain said. “And we are looking forward to the next phase of this study.”

Dr Jain disclosed receiving research funding from Celgene, Verastem, BMS, Incyte, Pharmacyclics, ADC Therapeutics, Genentech, AbbVie, Pfizer, Astra Zeneca, Janssen, Cellectis, and Seattle Genetics. He disclosed membership on boards of directors/advisory committees for Verastem, Servier, Novimmune, Pharmacyclics, Novartis, ADC Therapeutics, AbbVie, Pfizer, Adaptive Biotechnologies, and Janssen.

*Data in the presentation differ from the abstract.

© Todd Buchanan 2017

ATLANTA—A 2-drug combination has produced a high response rate in a small trial of patients with relapsed/refractory (R/R), Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).

The combination, inotuzumab ozogamicin and bosutinib, produced an overall response rate of 81% in this ongoing, phase 1/2 trial.

Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center in Houston, presented phase 1 results from the study at the 2017 ASH Annual Meeting (abstract 143*).

He reported results in 16 patients, 14 with R/R, Ph+ ALL and 2 with chronic myeloid leukemia in lymphoid blast phase.

The patients received inotuzumab ozogamicin at 0.8 mg/m² on day 1, 0.5 mg/m² on day 8, and 0.5 mg/m² on day 15 of cycle 1. Patients who achieved a response received inotuzumab ozogamicin at 1 mg/m² once every 4 weeks for subsequent cycles. Six cycles were planned.

Patients also received bosutinib at 300 mg, 400 mg, or 500 mg once a day for 4-week cycles. The median number of cycles was 2.5 (range, 1-8).

The maximum-tolerated dose has not been established, but there were 2 dose-limiting toxicities (DLTs). One DLT occurred with the 400 mg dose of bosutinib, and 1 occurred with the 500 mg dose. Both DLTs were grade 3 skin rash.

The investigators are continuing accrual with the 500 mg dose of bosutinib for the phase 2 portion of the trial, with 22 additional patients.

Response and survival

The overall response rate was 81% (n=13). This included a complete response (CR) in 8 patients, a CR with incomplete blood count recovery in 3 patients, and a CR with incomplete platelet recovery in 2 patients.

All responses occurred among the patients with ALL.

Twelve responders achieved complete cytogenetic remission, 11 achieved a major molecular response, 8 achieved a complete molecular response, and 9 were negative by flow cytometry.

The median duration of response was 8.8 months.

Of the 13 responders, 6 went on to receive an allogeneic stem cell transplant. Five of these patients are still alive, but 1 died from relapse.

The median overall survival was 10.7 months.

“These data suggest the tolerability and efficacy of inotuzumab ozogamicin and bosutinib in R/R Ph+ ALL,” Dr Jain said. “And we are looking forward to the next phase of this study.”

Dr Jain disclosed receiving research funding from Celgene, Verastem, BMS, Incyte, Pharmacyclics, ADC Therapeutics, Genentech, AbbVie, Pfizer, Astra Zeneca, Janssen, Cellectis, and Seattle Genetics. He disclosed membership on boards of directors/advisory committees for Verastem, Servier, Novimmune, Pharmacyclics, Novartis, ADC Therapeutics, AbbVie, Pfizer, Adaptive Biotechnologies, and Janssen.

*Data in the presentation differ from the abstract.

© Todd Buchanan 2017

ATLANTA—Results of a phase 2 trial suggest treatment with ponatinib and steroids is feasible for patients with acute lymphoblastic leukemia (ALL) who are elderly and/or unfit for intensive chemotherapy and stem cell transplant.

More than 90% of patients who received this combination had a complete hematologic response at 24 weeks, and the treatment was considered well-tolerated.

“Ponatinib plus steroids is safe and effective in this fragile patient population, which is in urgent need of better therapeutic regimens,” said Giovanni Martinelli, MD, of the University of Bologna in Italy.

Dr Martinelli presented these findings at the 2017 ASH Annual Meeting (abstract 99*).

The trial (GIMEMA LAL 1811) was designed to evaluate whether steroids and ponatinib would be safe and effective in patients with newly diagnosed, Philadelphia chromosome-positive ALL who were older than 60 or ineligible for intensive chemotherapy and stem cell transplant.

The study included 42 such patients. Their median age was 68 (range, 27-85). Nine patients were younger than 60 and unfit.

Sixty-two percent of patients had the p190 fusion transcript, 10% had p210, and 29% had p190/210 transcripts.

Patients received oral ponatinib (45 mg/day) for 8 consecutive 6-week courses. They also received steroids from day -14 to day 29 of course 1.

Patients received intrathecal methotrexate, cytarabine, and dexamethasone every 28 days for central nervous system (CNS) disease prophylaxis. If they were positive for CNS disease at diagnosis, patients received intrathecal therapy twice a week until complete remission.

The median follow-up was 17.2 months.

Results

Thirty-nine patients received steroid pretreatment, and 14 of them had a reduction in circulating blasts of 75% or more before starting ponatinib.

The study’s primary endpoint was complete hematologic response, which occurred in 95.2% of patients at 6 weeks and 90.5% at 24 weeks.

Based on test sensitivity of at least 10,000 ABL molecules, 60.6% of evaluable patients (20/33) had a complete molecular response at 24 weeks.

One patient with relapse had evidence of T315L mutations, which correlates with ponatinib resistance. No other mutations were detected in patients with relapse.

The overall survival rate was 97.6% at 6 months and 87.5% at 1 year.

“The fast and deep reduction of the disease burden in the majority of patients, the ability of ponatinib to prevent the emergence of clones harboring BCR-ABL mutations, and the synthetic lethality with steroids on the BCR-ABL, FLT3, HCK, CDK6, MCL1 pathway most likely explain the therapeutic effectiveness of this regimen,” Dr Martinelli said.

He also said steroids and ponatinib were well-tolerated, with 15 patients continuing treatment at 24 weeks.

Of 75 adverse events (AEs), 36 were related to ponatinib. There were 26 serious AEs, and 13 of them were related to ponatinib.

Serious cardiovascular AEs included arterial disorders (n=3), embolism (n=2), acute coronary syndrome (n=2), acute myocardial infarction (n=1), cardiac failure (n=1), pericardial effusion (n=1), and ischemia (n=1).

Ten deaths were reported. The causes were identified as progression (n=4), cardiovascular disease (n=3), toxicity (n=1), toxicity and progression (n=1), and unknown cause (n=1).

Dr Martinelli reported no disclosures.

*Data in the presentation differ from the abstract.

© Todd Buchanan 2017

ATLANTA—Results of a phase 2 trial suggest treatment with ponatinib and steroids is feasible for patients with acute lymphoblastic leukemia (ALL) who are elderly and/or unfit for intensive chemotherapy and stem cell transplant.

More than 90% of patients who received this combination had a complete hematologic response at 24 weeks, and the treatment was considered well-tolerated.

“Ponatinib plus steroids is safe and effective in this fragile patient population, which is in urgent need of better therapeutic regimens,” said Giovanni Martinelli, MD, of the University of Bologna in Italy.

Dr Martinelli presented these findings at the 2017 ASH Annual Meeting (abstract 99*).

The trial (GIMEMA LAL 1811) was designed to evaluate whether steroids and ponatinib would be safe and effective in patients with newly diagnosed, Philadelphia chromosome-positive ALL who were older than 60 or ineligible for intensive chemotherapy and stem cell transplant.

The study included 42 such patients. Their median age was 68 (range, 27-85). Nine patients were younger than 60 and unfit.

Sixty-two percent of patients had the p190 fusion transcript, 10% had p210, and 29% had p190/210 transcripts.

Patients received oral ponatinib (45 mg/day) for 8 consecutive 6-week courses. They also received steroids from day -14 to day 29 of course 1.

Patients received intrathecal methotrexate, cytarabine, and dexamethasone every 28 days for central nervous system (CNS) disease prophylaxis. If they were positive for CNS disease at diagnosis, patients received intrathecal therapy twice a week until complete remission.

The median follow-up was 17.2 months.

Results

Thirty-nine patients received steroid pretreatment, and 14 of them had a reduction in circulating blasts of 75% or more before starting ponatinib.

The study’s primary endpoint was complete hematologic response, which occurred in 95.2% of patients at 6 weeks and 90.5% at 24 weeks.

Based on test sensitivity of at least 10,000 ABL molecules, 60.6% of evaluable patients (20/33) had a complete molecular response at 24 weeks.

One patient with relapse had evidence of T315L mutations, which correlates with ponatinib resistance. No other mutations were detected in patients with relapse.

The overall survival rate was 97.6% at 6 months and 87.5% at 1 year.

“The fast and deep reduction of the disease burden in the majority of patients, the ability of ponatinib to prevent the emergence of clones harboring BCR-ABL mutations, and the synthetic lethality with steroids on the BCR-ABL, FLT3, HCK, CDK6, MCL1 pathway most likely explain the therapeutic effectiveness of this regimen,” Dr Martinelli said.

He also said steroids and ponatinib were well-tolerated, with 15 patients continuing treatment at 24 weeks.

Of 75 adverse events (AEs), 36 were related to ponatinib. There were 26 serious AEs, and 13 of them were related to ponatinib.

Serious cardiovascular AEs included arterial disorders (n=3), embolism (n=2), acute coronary syndrome (n=2), acute myocardial infarction (n=1), cardiac failure (n=1), pericardial effusion (n=1), and ischemia (n=1).

Ten deaths were reported. The causes were identified as progression (n=4), cardiovascular disease (n=3), toxicity (n=1), toxicity and progression (n=1), and unknown cause (n=1).

Dr Martinelli reported no disclosures.

*Data in the presentation differ from the abstract.

© Todd Buchanan 2017

ATLANTA—Results of a phase 2 trial suggest treatment with ponatinib and steroids is feasible for patients with acute lymphoblastic leukemia (ALL) who are elderly and/or unfit for intensive chemotherapy and stem cell transplant.

More than 90% of patients who received this combination had a complete hematologic response at 24 weeks, and the treatment was considered well-tolerated.

“Ponatinib plus steroids is safe and effective in this fragile patient population, which is in urgent need of better therapeutic regimens,” said Giovanni Martinelli, MD, of the University of Bologna in Italy.

Dr Martinelli presented these findings at the 2017 ASH Annual Meeting (abstract 99*).

The trial (GIMEMA LAL 1811) was designed to evaluate whether steroids and ponatinib would be safe and effective in patients with newly diagnosed, Philadelphia chromosome-positive ALL who were older than 60 or ineligible for intensive chemotherapy and stem cell transplant.

The study included 42 such patients. Their median age was 68 (range, 27-85). Nine patients were younger than 60 and unfit.

Sixty-two percent of patients had the p190 fusion transcript, 10% had p210, and 29% had p190/210 transcripts.

Patients received oral ponatinib (45 mg/day) for 8 consecutive 6-week courses. They also received steroids from day -14 to day 29 of course 1.

Patients received intrathecal methotrexate, cytarabine, and dexamethasone every 28 days for central nervous system (CNS) disease prophylaxis. If they were positive for CNS disease at diagnosis, patients received intrathecal therapy twice a week until complete remission.

The median follow-up was 17.2 months.

Results

Thirty-nine patients received steroid pretreatment, and 14 of them had a reduction in circulating blasts of 75% or more before starting ponatinib.

The study’s primary endpoint was complete hematologic response, which occurred in 95.2% of patients at 6 weeks and 90.5% at 24 weeks.

Based on test sensitivity of at least 10,000 ABL molecules, 60.6% of evaluable patients (20/33) had a complete molecular response at 24 weeks.

One patient with relapse had evidence of T315L mutations, which correlates with ponatinib resistance. No other mutations were detected in patients with relapse.

The overall survival rate was 97.6% at 6 months and 87.5% at 1 year.

“The fast and deep reduction of the disease burden in the majority of patients, the ability of ponatinib to prevent the emergence of clones harboring BCR-ABL mutations, and the synthetic lethality with steroids on the BCR-ABL, FLT3, HCK, CDK6, MCL1 pathway most likely explain the therapeutic effectiveness of this regimen,” Dr Martinelli said.

He also said steroids and ponatinib were well-tolerated, with 15 patients continuing treatment at 24 weeks.

Of 75 adverse events (AEs), 36 were related to ponatinib. There were 26 serious AEs, and 13 of them were related to ponatinib.

Serious cardiovascular AEs included arterial disorders (n=3), embolism (n=2), acute coronary syndrome (n=2), acute myocardial infarction (n=1), cardiac failure (n=1), pericardial effusion (n=1), and ischemia (n=1).

Ten deaths were reported. The causes were identified as progression (n=4), cardiovascular disease (n=3), toxicity (n=1), toxicity and progression (n=1), and unknown cause (n=1).

Dr Martinelli reported no disclosures.

*Data in the presentation differ from the abstract.

acute lymphoblastic leukemia

The European Commission (EC) has granted marketing authorization for a lyophilized formulation of pegaspargase (ONCASPAR).

The product is intended for use as a component of antineoplastic combination therapy in acute lymphoblastic leukemia patients of all ages.

The EC’s approval authorizes Shire to market lyophilized pegaspargase in the 28 member states of the European Union as well as Iceland, Liechtenstein, and Norway.

Lyophilized pegaspargase works the same way as the liquid formulation. By depleting serum L-asparagine levels and thereby interfering with protein synthesis, pegaspargase deprives lymphoblasts of L-asparagine, resulting in cell death.

The lyophilized formulation offers the same dosing regimen as liquid pegaspargase but also provides a shelf life of up to 24 months—3 times longer than that of the liquid formulation.

Shire expects lyophilized pegaspargase to be available in European markets beginning in the first half of 2018.

“With this lyophilized formulation, we aim to make pegylated asparaginase, part of the pediatric standard therapy in acute lymphoblastic leukemia, available to patients in countries where liquid ONCASPAR is not currently offered,” said Howard B. Mayer, MD, senior vice-president and ad-interim head of global research and development at Shire.

“Additionally, with extended shelf life up to 24 months, treatment centers will have flexibility in inventory management to help ensure continuous treatment supply for patients.”

acute lymphoblastic leukemia

The European Commission (EC) has granted marketing authorization for a lyophilized formulation of pegaspargase (ONCASPAR).

The product is intended for use as a component of antineoplastic combination therapy in acute lymphoblastic leukemia patients of all ages.

The EC’s approval authorizes Shire to market lyophilized pegaspargase in the 28 member states of the European Union as well as Iceland, Liechtenstein, and Norway.

Lyophilized pegaspargase works the same way as the liquid formulation. By depleting serum L-asparagine levels and thereby interfering with protein synthesis, pegaspargase deprives lymphoblasts of L-asparagine, resulting in cell death.

The lyophilized formulation offers the same dosing regimen as liquid pegaspargase but also provides a shelf life of up to 24 months—3 times longer than that of the liquid formulation.

Shire expects lyophilized pegaspargase to be available in European markets beginning in the first half of 2018.

“With this lyophilized formulation, we aim to make pegylated asparaginase, part of the pediatric standard therapy in acute lymphoblastic leukemia, available to patients in countries where liquid ONCASPAR is not currently offered,” said Howard B. Mayer, MD, senior vice-president and ad-interim head of global research and development at Shire.

“Additionally, with extended shelf life up to 24 months, treatment centers will have flexibility in inventory management to help ensure continuous treatment supply for patients.”

acute lymphoblastic leukemia

The European Commission (EC) has granted marketing authorization for a lyophilized formulation of pegaspargase (ONCASPAR).

The product is intended for use as a component of antineoplastic combination therapy in acute lymphoblastic leukemia patients of all ages.

The EC’s approval authorizes Shire to market lyophilized pegaspargase in the 28 member states of the European Union as well as Iceland, Liechtenstein, and Norway.

Lyophilized pegaspargase works the same way as the liquid formulation. By depleting serum L-asparagine levels and thereby interfering with protein synthesis, pegaspargase deprives lymphoblasts of L-asparagine, resulting in cell death.

The lyophilized formulation offers the same dosing regimen as liquid pegaspargase but also provides a shelf life of up to 24 months—3 times longer than that of the liquid formulation.

Shire expects lyophilized pegaspargase to be available in European markets beginning in the first half of 2018.

“With this lyophilized formulation, we aim to make pegylated asparaginase, part of the pediatric standard therapy in acute lymphoblastic leukemia, available to patients in countries where liquid ONCASPAR is not currently offered,” said Howard B. Mayer, MD, senior vice-president and ad-interim head of global research and development at Shire.

“Additionally, with extended shelf life up to 24 months, treatment centers will have flexibility in inventory management to help ensure continuous treatment supply for patients.”