Leukemia, Myelodysplasia, Transplantation

For patients with myelodysplastic syndrome, gene sequencing of bone marrow samples early after bone marrow transplant with curative intent may provide important prognostic information.

Among 86 patients with myelodysplastic syndrome (MDS), higher maximum variant allele frequency of residual disease–associated mutations at 30 days posttransplantation was significantly associated with disease progression and lower rates of progression-free survival (PFS) at 1 year, reported Eric J. Duncavage, MD, from Washington University in St. Louis, and his colleagues.

“Although this exploratory study has limitations, our results suggest that sequencing-based detection of tumor cells and measurable residual disease after allogeneic hematopoietic stem cell transplantation has prognostic significance for patients with MDS,” they wrote in the New England Journal of Medicine.

Risk of progression was significantly higher among patients who had undergone reduced-intensity conditioning prior to hematopoietic stem cell transplants (HSCT) than among patients who had undergone myeloablative conditioning regimens.

To get a better handle on the significance of molecular predictors of disease progression after HSCT, the authors used enhanced exome sequencing to evaluate paired samples of bone marrow and control DNA from normal skin, and error-corrected sequencing to identify somatic single-nucleotide variant mutations in posttransplant samples.

They detected at least one validated somatic mutation in the pretransplant samples from 86 of 90 patients. Of the 86 patients, 32 had at least one mutation with a maximum variant allele frequency of at least 0.5% detected 30 days after transplantation. The frequency is equivalent to 1 heterozygous mutant cell per 100 cells, the authors explained.

Patients who experienced disease progression had mutations with a median maximum variant allele frequency of 0.9%, compared with 0% for patients who did not have progression (P less than .001).

In all, 53.1% of patients with one or more mutations with a variant allele frequency of at least 0.5% at 30 days had disease progression within a year, compared with 13% of patients who did not have the mutations, even after adjustment for the type of conditioning regimen. The hazard ratio (HR) for disease progression in the patients with mutations was 3.86 (P less than .001).

The association between the presence of one or more mutations with a variant allele frequency of at least 0.5% with increased risk of disease progression was also seen at 100 days, even after adjustment for conditioning regimen (66.7% vs. 0%; HR, 6.52; P less than .001). In multivariable analysis controlling for prognostic scores, maximum variant allele frequency at 30 days, TP53 mutation status and conditioning regimen, the presence of a mutation with at least 0.5% variant allele frequency was associated with a more than fourfold risk of progression, including when the revised International Prognostic Scoring System score and conditioning regimen were considered as covariates. (HR, 4.48; P less than .001),

A separate multivariable analysis of PFS controlling for maximum variant allele frequency at day 30, conditioning regimen, age at transplantation, and type of MDS showed that mutations were associated with a more than twofold risk of progression or death (HR, 2.39; P = .002).

This analysis also showed that secondary acute myeloid leukemia was associated with worse PFS, compared with primary MDS (HR, 2.24; P = .001).

The investigators acknowledged that the high-coverage exome sequencing technique used for the study is not routinely available in the clinic. To control for this, they also looked at their data using a subset of genes that are usually included in gene sequencing panels for MDS and AML.

“Although we identified fewer patients with mutations with the use of this approach than with enhanced exome sequencing, the prognostic value of detection of measurable residual disease was still highly clinically significant,” they wrote.

The study was supported by grants from the Leukemia and Lymphoma Society, Edward P. Evans Foundation, National Cancer Institute, National Institutes of Health, Gabrielle’s Angel Foundation, and the Lottie Caroline Hardy Trust. Dr. Duncavage disclosed personal fees from AbbVie and Cofactor Genomics. The majority of coauthors reported nothing to disclose.

SOURCE: Duncavage EJ et al. N Engl J Med 2018;379:1028-41.

For patients with myelodysplastic syndrome, gene sequencing of bone marrow samples early after bone marrow transplant with curative intent may provide important prognostic information.

Among 86 patients with myelodysplastic syndrome (MDS), higher maximum variant allele frequency of residual disease–associated mutations at 30 days posttransplantation was significantly associated with disease progression and lower rates of progression-free survival (PFS) at 1 year, reported Eric J. Duncavage, MD, from Washington University in St. Louis, and his colleagues.

“Although this exploratory study has limitations, our results suggest that sequencing-based detection of tumor cells and measurable residual disease after allogeneic hematopoietic stem cell transplantation has prognostic significance for patients with MDS,” they wrote in the New England Journal of Medicine.

Risk of progression was significantly higher among patients who had undergone reduced-intensity conditioning prior to hematopoietic stem cell transplants (HSCT) than among patients who had undergone myeloablative conditioning regimens.

To get a better handle on the significance of molecular predictors of disease progression after HSCT, the authors used enhanced exome sequencing to evaluate paired samples of bone marrow and control DNA from normal skin, and error-corrected sequencing to identify somatic single-nucleotide variant mutations in posttransplant samples.

They detected at least one validated somatic mutation in the pretransplant samples from 86 of 90 patients. Of the 86 patients, 32 had at least one mutation with a maximum variant allele frequency of at least 0.5% detected 30 days after transplantation. The frequency is equivalent to 1 heterozygous mutant cell per 100 cells, the authors explained.

Patients who experienced disease progression had mutations with a median maximum variant allele frequency of 0.9%, compared with 0% for patients who did not have progression (P less than .001).

In all, 53.1% of patients with one or more mutations with a variant allele frequency of at least 0.5% at 30 days had disease progression within a year, compared with 13% of patients who did not have the mutations, even after adjustment for the type of conditioning regimen. The hazard ratio (HR) for disease progression in the patients with mutations was 3.86 (P less than .001).

The association between the presence of one or more mutations with a variant allele frequency of at least 0.5% with increased risk of disease progression was also seen at 100 days, even after adjustment for conditioning regimen (66.7% vs. 0%; HR, 6.52; P less than .001). In multivariable analysis controlling for prognostic scores, maximum variant allele frequency at 30 days, TP53 mutation status and conditioning regimen, the presence of a mutation with at least 0.5% variant allele frequency was associated with a more than fourfold risk of progression, including when the revised International Prognostic Scoring System score and conditioning regimen were considered as covariates. (HR, 4.48; P less than .001),

A separate multivariable analysis of PFS controlling for maximum variant allele frequency at day 30, conditioning regimen, age at transplantation, and type of MDS showed that mutations were associated with a more than twofold risk of progression or death (HR, 2.39; P = .002).

This analysis also showed that secondary acute myeloid leukemia was associated with worse PFS, compared with primary MDS (HR, 2.24; P = .001).

The investigators acknowledged that the high-coverage exome sequencing technique used for the study is not routinely available in the clinic. To control for this, they also looked at their data using a subset of genes that are usually included in gene sequencing panels for MDS and AML.

“Although we identified fewer patients with mutations with the use of this approach than with enhanced exome sequencing, the prognostic value of detection of measurable residual disease was still highly clinically significant,” they wrote.

The study was supported by grants from the Leukemia and Lymphoma Society, Edward P. Evans Foundation, National Cancer Institute, National Institutes of Health, Gabrielle’s Angel Foundation, and the Lottie Caroline Hardy Trust. Dr. Duncavage disclosed personal fees from AbbVie and Cofactor Genomics. The majority of coauthors reported nothing to disclose.

SOURCE: Duncavage EJ et al. N Engl J Med 2018;379:1028-41.

For patients with myelodysplastic syndrome, gene sequencing of bone marrow samples early after bone marrow transplant with curative intent may provide important prognostic information.

Among 86 patients with myelodysplastic syndrome (MDS), higher maximum variant allele frequency of residual disease–associated mutations at 30 days posttransplantation was significantly associated with disease progression and lower rates of progression-free survival (PFS) at 1 year, reported Eric J. Duncavage, MD, from Washington University in St. Louis, and his colleagues.

“Although this exploratory study has limitations, our results suggest that sequencing-based detection of tumor cells and measurable residual disease after allogeneic hematopoietic stem cell transplantation has prognostic significance for patients with MDS,” they wrote in the New England Journal of Medicine.

Risk of progression was significantly higher among patients who had undergone reduced-intensity conditioning prior to hematopoietic stem cell transplants (HSCT) than among patients who had undergone myeloablative conditioning regimens.

To get a better handle on the significance of molecular predictors of disease progression after HSCT, the authors used enhanced exome sequencing to evaluate paired samples of bone marrow and control DNA from normal skin, and error-corrected sequencing to identify somatic single-nucleotide variant mutations in posttransplant samples.

They detected at least one validated somatic mutation in the pretransplant samples from 86 of 90 patients. Of the 86 patients, 32 had at least one mutation with a maximum variant allele frequency of at least 0.5% detected 30 days after transplantation. The frequency is equivalent to 1 heterozygous mutant cell per 100 cells, the authors explained.

Patients who experienced disease progression had mutations with a median maximum variant allele frequency of 0.9%, compared with 0% for patients who did not have progression (P less than .001).

In all, 53.1% of patients with one or more mutations with a variant allele frequency of at least 0.5% at 30 days had disease progression within a year, compared with 13% of patients who did not have the mutations, even after adjustment for the type of conditioning regimen. The hazard ratio (HR) for disease progression in the patients with mutations was 3.86 (P less than .001).

The association between the presence of one or more mutations with a variant allele frequency of at least 0.5% with increased risk of disease progression was also seen at 100 days, even after adjustment for conditioning regimen (66.7% vs. 0%; HR, 6.52; P less than .001). In multivariable analysis controlling for prognostic scores, maximum variant allele frequency at 30 days, TP53 mutation status and conditioning regimen, the presence of a mutation with at least 0.5% variant allele frequency was associated with a more than fourfold risk of progression, including when the revised International Prognostic Scoring System score and conditioning regimen were considered as covariates. (HR, 4.48; P less than .001),

A separate multivariable analysis of PFS controlling for maximum variant allele frequency at day 30, conditioning regimen, age at transplantation, and type of MDS showed that mutations were associated with a more than twofold risk of progression or death (HR, 2.39; P = .002).

This analysis also showed that secondary acute myeloid leukemia was associated with worse PFS, compared with primary MDS (HR, 2.24; P = .001).

The investigators acknowledged that the high-coverage exome sequencing technique used for the study is not routinely available in the clinic. To control for this, they also looked at their data using a subset of genes that are usually included in gene sequencing panels for MDS and AML.

“Although we identified fewer patients with mutations with the use of this approach than with enhanced exome sequencing, the prognostic value of detection of measurable residual disease was still highly clinically significant,” they wrote.

The study was supported by grants from the Leukemia and Lymphoma Society, Edward P. Evans Foundation, National Cancer Institute, National Institutes of Health, Gabrielle’s Angel Foundation, and the Lottie Caroline Hardy Trust. Dr. Duncavage disclosed personal fees from AbbVie and Cofactor Genomics. The majority of coauthors reported nothing to disclose.

SOURCE: Duncavage EJ et al. N Engl J Med 2018;379:1028-41.

Researchers believe they have identified cells that are responsible for relapse of acute myeloid leukemia (AML).

These “leukemic-regenerating cells” (LRCs), which are distinct from leukemic stem cells (LSCs), seem to arise in response to chemotherapy.

Experiments in mouse models of AML suggested that targeting LRCs could reduce the risk of relapse, and analyses of AML patient samples suggested LRCs might be used to predict relapse.

Allison Boyd, PhD, of McMaster University in Hamilton, Ont., and her colleagues reported these findings in Cancer Cell.

The researchers evaluated the leukemic populations that persist after chemotherapy by analyzing AML patient samples and xenograft AML models. The team found that LSCs were depleted by chemotherapy, and a different cell population, LRCs, appeared to arise in response to treatment.

LRCs are “molecularly distinct from therapy-naive LSCs,” the researchers said. In fact, the team identified 19 genes that are preferentially expressed by LRCs and could be treated with drugs.

One of these genes is DRD2, and the researchers found they could target LRCs using a small-molecule antagonist of DRD2.
 

Targeting LRCs

Dr. Boyd and her colleagues compared the effects of treatment with a DRD2 antagonist in AML xenografts populated with therapy-naive LSCs and AML xenografts that harbored LRCs following exposure to cytarabine.

The researchers said DRD2 antagonist therapy “moderately” affected AML progenitors in the LSC model but “had profound effects on regenerating LRCs.”

Treatment with the DRD2 antagonist also improved the efficacy of chemotherapy.

In xenografts derived from one AML patient, treatment with cytarabine alone left 50% of mice with residual disease. However, the addition of the DRD2 antagonist enabled 100% of the mice to achieve disease-free status.

In xenografts derived from a patient with more aggressive AML, all recipient mice had residual disease after receiving cytarabine. Treatment with the DRD2 antagonist slowed leukemic regrowth and nearly doubled the time to relapse.

Targeting LRCs also reduced disease regeneration potential in samples from other AML patients.

“This is a major clinical opportunity because this type of leukemia is very diverse and responds differently across patients,” Dr. Boyd said. “It has been a challenge in a clinical setting to find a commonality for therapeutic targeting across the wide array of patients, and these regenerative cells provide that similarity.”
 

Predicting relapse

Dr. Boyd and her colleagues also analyzed bone marrow samples collected from AML patients approximately 3 weeks after they completed standard induction chemotherapy.

The team found that progenitor activity was enriched among residual leukemic cells. However, patient cells lacked gene expression signatures related to therapy-naive LSCs.

“Instead, these highly regenerative AML cells preferentially expressed our LRC signature,” the researchers said.

The team also found evidence to suggest that LRC molecular profiles arise temporarily after chemotherapy. The LRC signature was not observed at diagnosis or once AML was reestablished at relapse.

“We think there are opportunities here because now we have a window where we can kick the cancer while it’s down,” Dr. Boyd said.

She and her colleagues also found the LRC signature might be useful for predicting relapse in AML patients.

The team assessed expression of SLC2A2, an LRC marker that has overlapping expression with DRD2, in seven patients who were in remission after induction.

Chemotherapy increased expression of SLC2A2 only in the four patients who had residual disease – not in the three patients who remained in disease-free remission for at least 5 years. “These results suggest that LRC populations represent reservoirs of residual disease, and LRC marker expression levels can be linked to clinical outcomes of AML relapse,” the researchers said.

This study was supported by the Canadian Cancer Society, the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research, and other organizations.

[email protected]

SOURCE: Boyd AL et al. Cancer Cell. 2018 Sep 10. doi: 10.1016/j.ccell.2018.08.007.

Researchers believe they have identified cells that are responsible for relapse of acute myeloid leukemia (AML).

These “leukemic-regenerating cells” (LRCs), which are distinct from leukemic stem cells (LSCs), seem to arise in response to chemotherapy.

Experiments in mouse models of AML suggested that targeting LRCs could reduce the risk of relapse, and analyses of AML patient samples suggested LRCs might be used to predict relapse.

Allison Boyd, PhD, of McMaster University in Hamilton, Ont., and her colleagues reported these findings in Cancer Cell.

The researchers evaluated the leukemic populations that persist after chemotherapy by analyzing AML patient samples and xenograft AML models. The team found that LSCs were depleted by chemotherapy, and a different cell population, LRCs, appeared to arise in response to treatment.

LRCs are “molecularly distinct from therapy-naive LSCs,” the researchers said. In fact, the team identified 19 genes that are preferentially expressed by LRCs and could be treated with drugs.

One of these genes is DRD2, and the researchers found they could target LRCs using a small-molecule antagonist of DRD2.
 

Targeting LRCs

Dr. Boyd and her colleagues compared the effects of treatment with a DRD2 antagonist in AML xenografts populated with therapy-naive LSCs and AML xenografts that harbored LRCs following exposure to cytarabine.

The researchers said DRD2 antagonist therapy “moderately” affected AML progenitors in the LSC model but “had profound effects on regenerating LRCs.”

Treatment with the DRD2 antagonist also improved the efficacy of chemotherapy.

In xenografts derived from one AML patient, treatment with cytarabine alone left 50% of mice with residual disease. However, the addition of the DRD2 antagonist enabled 100% of the mice to achieve disease-free status.

In xenografts derived from a patient with more aggressive AML, all recipient mice had residual disease after receiving cytarabine. Treatment with the DRD2 antagonist slowed leukemic regrowth and nearly doubled the time to relapse.

Targeting LRCs also reduced disease regeneration potential in samples from other AML patients.

“This is a major clinical opportunity because this type of leukemia is very diverse and responds differently across patients,” Dr. Boyd said. “It has been a challenge in a clinical setting to find a commonality for therapeutic targeting across the wide array of patients, and these regenerative cells provide that similarity.”
 

Predicting relapse

Dr. Boyd and her colleagues also analyzed bone marrow samples collected from AML patients approximately 3 weeks after they completed standard induction chemotherapy.

The team found that progenitor activity was enriched among residual leukemic cells. However, patient cells lacked gene expression signatures related to therapy-naive LSCs.

“Instead, these highly regenerative AML cells preferentially expressed our LRC signature,” the researchers said.

The team also found evidence to suggest that LRC molecular profiles arise temporarily after chemotherapy. The LRC signature was not observed at diagnosis or once AML was reestablished at relapse.

“We think there are opportunities here because now we have a window where we can kick the cancer while it’s down,” Dr. Boyd said.

She and her colleagues also found the LRC signature might be useful for predicting relapse in AML patients.

The team assessed expression of SLC2A2, an LRC marker that has overlapping expression with DRD2, in seven patients who were in remission after induction.

Chemotherapy increased expression of SLC2A2 only in the four patients who had residual disease – not in the three patients who remained in disease-free remission for at least 5 years. “These results suggest that LRC populations represent reservoirs of residual disease, and LRC marker expression levels can be linked to clinical outcomes of AML relapse,” the researchers said.

This study was supported by the Canadian Cancer Society, the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research, and other organizations.

[email protected]

SOURCE: Boyd AL et al. Cancer Cell. 2018 Sep 10. doi: 10.1016/j.ccell.2018.08.007.

Researchers believe they have identified cells that are responsible for relapse of acute myeloid leukemia (AML).

These “leukemic-regenerating cells” (LRCs), which are distinct from leukemic stem cells (LSCs), seem to arise in response to chemotherapy.

Experiments in mouse models of AML suggested that targeting LRCs could reduce the risk of relapse, and analyses of AML patient samples suggested LRCs might be used to predict relapse.

Allison Boyd, PhD, of McMaster University in Hamilton, Ont., and her colleagues reported these findings in Cancer Cell.

The researchers evaluated the leukemic populations that persist after chemotherapy by analyzing AML patient samples and xenograft AML models. The team found that LSCs were depleted by chemotherapy, and a different cell population, LRCs, appeared to arise in response to treatment.

LRCs are “molecularly distinct from therapy-naive LSCs,” the researchers said. In fact, the team identified 19 genes that are preferentially expressed by LRCs and could be treated with drugs.

One of these genes is DRD2, and the researchers found they could target LRCs using a small-molecule antagonist of DRD2.
 

Targeting LRCs

Dr. Boyd and her colleagues compared the effects of treatment with a DRD2 antagonist in AML xenografts populated with therapy-naive LSCs and AML xenografts that harbored LRCs following exposure to cytarabine.

The researchers said DRD2 antagonist therapy “moderately” affected AML progenitors in the LSC model but “had profound effects on regenerating LRCs.”

Treatment with the DRD2 antagonist also improved the efficacy of chemotherapy.

In xenografts derived from one AML patient, treatment with cytarabine alone left 50% of mice with residual disease. However, the addition of the DRD2 antagonist enabled 100% of the mice to achieve disease-free status.

In xenografts derived from a patient with more aggressive AML, all recipient mice had residual disease after receiving cytarabine. Treatment with the DRD2 antagonist slowed leukemic regrowth and nearly doubled the time to relapse.

Targeting LRCs also reduced disease regeneration potential in samples from other AML patients.

“This is a major clinical opportunity because this type of leukemia is very diverse and responds differently across patients,” Dr. Boyd said. “It has been a challenge in a clinical setting to find a commonality for therapeutic targeting across the wide array of patients, and these regenerative cells provide that similarity.”
 

Predicting relapse

Dr. Boyd and her colleagues also analyzed bone marrow samples collected from AML patients approximately 3 weeks after they completed standard induction chemotherapy.

The team found that progenitor activity was enriched among residual leukemic cells. However, patient cells lacked gene expression signatures related to therapy-naive LSCs.

“Instead, these highly regenerative AML cells preferentially expressed our LRC signature,” the researchers said.

The team also found evidence to suggest that LRC molecular profiles arise temporarily after chemotherapy. The LRC signature was not observed at diagnosis or once AML was reestablished at relapse.

“We think there are opportunities here because now we have a window where we can kick the cancer while it’s down,” Dr. Boyd said.

She and her colleagues also found the LRC signature might be useful for predicting relapse in AML patients.

The team assessed expression of SLC2A2, an LRC marker that has overlapping expression with DRD2, in seven patients who were in remission after induction.

Chemotherapy increased expression of SLC2A2 only in the four patients who had residual disease – not in the three patients who remained in disease-free remission for at least 5 years. “These results suggest that LRC populations represent reservoirs of residual disease, and LRC marker expression levels can be linked to clinical outcomes of AML relapse,” the researchers said.

This study was supported by the Canadian Cancer Society, the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research, and other organizations.

[email protected]

SOURCE: Boyd AL et al. Cancer Cell. 2018 Sep 10. doi: 10.1016/j.ccell.2018.08.007.

The Food and Drug Administration has expanded the label for venetoclax tablets (Venclexta) to include data on minimal residual disease.

The drug’s prescribing information will now include details on minimal residual disease (MRD) negativity in previously treated patients with chronic lymphocytic leukemia (CLL) who received venetoclax in combination with rituximab in the phase 3 MURANO trial.

The combination of venetoclax and rituximab was approved by the FDA in June 2018 for the treatment of patients with CLL or small lymphocytic lymphoma, with or without 17p deletion, who received at least one prior therapy.

The MURANO trial (NCT02005471), which supported the FDA approval, included 389 patients with relapsed or refractory CLL. They were randomized to receive venetoclax plus rituximab or bendamustine plus rituximab (N Engl J Med. 2018; 378:1107-20).

Researchers evaluated MRD in patients who achieved a partial response or better. MRD was assessed using allele-specific oligonucleotide polymerase chain reaction; the definition of MRD negativity was less than one CLL cell per 10,000 lymphocytes.

The researchers assessed MRD in the peripheral blood after about 9 months on therapy (3 months after the last dose of rituximab). At that time, 53% (103/194) of patients in the venetoclax-rituximab arm were MRD negative, as were 12% (23/195) of patients in the bendamustine-rituximab arm.

The researchers also assessed MRD in the peripheral blood of patients with a complete response or complete response with incomplete marrow recovery. MRD negativity was achieved by 3% (6/194) of these patients in the venetoclax-rituximab arm and 2% (3/195) in the bendamustine-rituximab arm.

Venetoclax is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the United States and by AbbVie outside of the United States.

[email protected]

The Food and Drug Administration has expanded the label for venetoclax tablets (Venclexta) to include data on minimal residual disease.

The drug’s prescribing information will now include details on minimal residual disease (MRD) negativity in previously treated patients with chronic lymphocytic leukemia (CLL) who received venetoclax in combination with rituximab in the phase 3 MURANO trial.

The combination of venetoclax and rituximab was approved by the FDA in June 2018 for the treatment of patients with CLL or small lymphocytic lymphoma, with or without 17p deletion, who received at least one prior therapy.

The MURANO trial (NCT02005471), which supported the FDA approval, included 389 patients with relapsed or refractory CLL. They were randomized to receive venetoclax plus rituximab or bendamustine plus rituximab (N Engl J Med. 2018; 378:1107-20).

Researchers evaluated MRD in patients who achieved a partial response or better. MRD was assessed using allele-specific oligonucleotide polymerase chain reaction; the definition of MRD negativity was less than one CLL cell per 10,000 lymphocytes.

The researchers assessed MRD in the peripheral blood after about 9 months on therapy (3 months after the last dose of rituximab). At that time, 53% (103/194) of patients in the venetoclax-rituximab arm were MRD negative, as were 12% (23/195) of patients in the bendamustine-rituximab arm.

The researchers also assessed MRD in the peripheral blood of patients with a complete response or complete response with incomplete marrow recovery. MRD negativity was achieved by 3% (6/194) of these patients in the venetoclax-rituximab arm and 2% (3/195) in the bendamustine-rituximab arm.

Venetoclax is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the United States and by AbbVie outside of the United States.

[email protected]

The Food and Drug Administration has expanded the label for venetoclax tablets (Venclexta) to include data on minimal residual disease.

The drug’s prescribing information will now include details on minimal residual disease (MRD) negativity in previously treated patients with chronic lymphocytic leukemia (CLL) who received venetoclax in combination with rituximab in the phase 3 MURANO trial.

The combination of venetoclax and rituximab was approved by the FDA in June 2018 for the treatment of patients with CLL or small lymphocytic lymphoma, with or without 17p deletion, who received at least one prior therapy.

The MURANO trial (NCT02005471), which supported the FDA approval, included 389 patients with relapsed or refractory CLL. They were randomized to receive venetoclax plus rituximab or bendamustine plus rituximab (N Engl J Med. 2018; 378:1107-20).

Researchers evaluated MRD in patients who achieved a partial response or better. MRD was assessed using allele-specific oligonucleotide polymerase chain reaction; the definition of MRD negativity was less than one CLL cell per 10,000 lymphocytes.

The researchers assessed MRD in the peripheral blood after about 9 months on therapy (3 months after the last dose of rituximab). At that time, 53% (103/194) of patients in the venetoclax-rituximab arm were MRD negative, as were 12% (23/195) of patients in the bendamustine-rituximab arm.

The researchers also assessed MRD in the peripheral blood of patients with a complete response or complete response with incomplete marrow recovery. MRD negativity was achieved by 3% (6/194) of these patients in the venetoclax-rituximab arm and 2% (3/195) in the bendamustine-rituximab arm.

Venetoclax is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the United States and by AbbVie outside of the United States.

[email protected]

Photo by Nina Matthews

A nationwide cohort study suggests an association between a woman’s use of hormonal contraceptives and leukemia in her offspring.

Children of mothers who used hormonal contraception, either during pregnancy or in the 3 months beforehand, had a 1.5-fold greater risk of leukemia, when compared to children of mothers who had never used hormonal contraception.

This increased risk translated to one additional case of leukemia per about 50,000 children exposed to hormonal contraceptives.

The increased risk appeared limited to non-lymphoid leukemia.

Marie Hargreave, PhD, of the Danish Cancer Society Research Center in Copenhagen, Denmark, and her colleagues reported these findings in The Lancet Oncology.

The study included 1,185,157 children born between 1996 and 2014 and followed for a median of 9.3 years. Data on these children were collected from the Danish Medical Birth Registry and the Danish Cancer Registry.

The researchers looked at redeemed prescriptions from the Danish National Prescription Registry to determine the mothers’ contraceptive use and divided the women into three categories:

• Mothers who had never used hormonal contraceptives
• Those with previous hormonal contraceptive use, defined as greater than 3 months before the start of pregnancy
• Mothers with recent contraceptive use, defined as during or within 3 months of pregnancy.

Results

There were 606 children diagnosed with leukemia in the study cohort—465 with lymphoid leukemia and 141 with non-lymphoid leukemia.

Overall, children born to mothers with previous or recent use of hormonal contraceptives had a significantly increased risk of developing any leukemia. The hazard ratios (HRs) were as follows:

• Previous use of hormonal contraceptives—HR=1.25 (P=0.039)
• Recent use—HR=1.46 (P=0.011)
• Use within 3 months of pregnancy—HR=1.42 (P=0.025)
• Use during pregnancy—HR=1.78 (P=0.070).

The risk of lymphoid leukemia did not increase significantly with maternal use of hormonal contraceptives. The HRs were as follows:

• Previous use of hormonal contraceptives—HR=1.23 (P=0.089)
• Recent use—HR=1.27 (P=0.167)
• Use within 3 months of pregnancy—HR=1.28 (P=0.173)
• Use during pregnancy—HR=1.22 (P=0.635).

However, the risk of non-lymphoid leukemia was significantly increased in children born to mothers with recent hormonal contraceptive use. The HRs were as follows:

• Previous use of hormonal contraceptives—HR=1.33 (P=0.232)
• Recent use—HR=2.17 (P=0.008)
• Use within 3 months of pregnancy—HR=1.95 (P=0.033)
• Use during pregnancy—HR=3.87 (P=0.006).

The association between recent contraceptive use and any leukemia was strongest in children ages 6 to 10 years. The researchers said this was not surprising because the incidence of non-lymphoid leukemia increases after the age of 6.

The researchers estimated that a mother’s recent use of hormonal contraceptives would have resulted in about one additional case of leukemia per 47,170 children; in other words, 25 additional cases of leukemia over the study period.

This low risk of leukemia “is not a major concern with regard to the safety of hormonal contraceptives,” the researchers said.

However, the findings do suggest the intrauterine hormonal environment affects leukemia development in children, and this should be explored in future research.

This study was supported by the Danish Cancer Research Foundation and other foundations. One author reported grants from the sponsoring foundations, and another author reported speaking fees from Jazz Pharmaceuticals and Shire Pharmaceuticals.

Photo by Nina Matthews

A nationwide cohort study suggests an association between a woman’s use of hormonal contraceptives and leukemia in her offspring.

Children of mothers who used hormonal contraception, either during pregnancy or in the 3 months beforehand, had a 1.5-fold greater risk of leukemia, when compared to children of mothers who had never used hormonal contraception.

This increased risk translated to one additional case of leukemia per about 50,000 children exposed to hormonal contraceptives.

The increased risk appeared limited to non-lymphoid leukemia.

Marie Hargreave, PhD, of the Danish Cancer Society Research Center in Copenhagen, Denmark, and her colleagues reported these findings in The Lancet Oncology.

The study included 1,185,157 children born between 1996 and 2014 and followed for a median of 9.3 years. Data on these children were collected from the Danish Medical Birth Registry and the Danish Cancer Registry.

The researchers looked at redeemed prescriptions from the Danish National Prescription Registry to determine the mothers’ contraceptive use and divided the women into three categories:

• Mothers who had never used hormonal contraceptives
• Those with previous hormonal contraceptive use, defined as greater than 3 months before the start of pregnancy
• Mothers with recent contraceptive use, defined as during or within 3 months of pregnancy.

Results

There were 606 children diagnosed with leukemia in the study cohort—465 with lymphoid leukemia and 141 with non-lymphoid leukemia.

Overall, children born to mothers with previous or recent use of hormonal contraceptives had a significantly increased risk of developing any leukemia. The hazard ratios (HRs) were as follows:

• Previous use of hormonal contraceptives—HR=1.25 (P=0.039)
• Recent use—HR=1.46 (P=0.011)
• Use within 3 months of pregnancy—HR=1.42 (P=0.025)
• Use during pregnancy—HR=1.78 (P=0.070).

The risk of lymphoid leukemia did not increase significantly with maternal use of hormonal contraceptives. The HRs were as follows:

• Previous use of hormonal contraceptives—HR=1.23 (P=0.089)
• Recent use—HR=1.27 (P=0.167)
• Use within 3 months of pregnancy—HR=1.28 (P=0.173)
• Use during pregnancy—HR=1.22 (P=0.635).

However, the risk of non-lymphoid leukemia was significantly increased in children born to mothers with recent hormonal contraceptive use. The HRs were as follows:

• Previous use of hormonal contraceptives—HR=1.33 (P=0.232)
• Recent use—HR=2.17 (P=0.008)
• Use within 3 months of pregnancy—HR=1.95 (P=0.033)
• Use during pregnancy—HR=3.87 (P=0.006).

The association between recent contraceptive use and any leukemia was strongest in children ages 6 to 10 years. The researchers said this was not surprising because the incidence of non-lymphoid leukemia increases after the age of 6.

The researchers estimated that a mother’s recent use of hormonal contraceptives would have resulted in about one additional case of leukemia per 47,170 children; in other words, 25 additional cases of leukemia over the study period.

This low risk of leukemia “is not a major concern with regard to the safety of hormonal contraceptives,” the researchers said.

However, the findings do suggest the intrauterine hormonal environment affects leukemia development in children, and this should be explored in future research.

This study was supported by the Danish Cancer Research Foundation and other foundations. One author reported grants from the sponsoring foundations, and another author reported speaking fees from Jazz Pharmaceuticals and Shire Pharmaceuticals.

Photo by Nina Matthews

A nationwide cohort study suggests an association between a woman’s use of hormonal contraceptives and leukemia in her offspring.

Children of mothers who used hormonal contraception, either during pregnancy or in the 3 months beforehand, had a 1.5-fold greater risk of leukemia, when compared to children of mothers who had never used hormonal contraception.

This increased risk translated to one additional case of leukemia per about 50,000 children exposed to hormonal contraceptives.

The increased risk appeared limited to non-lymphoid leukemia.

Marie Hargreave, PhD, of the Danish Cancer Society Research Center in Copenhagen, Denmark, and her colleagues reported these findings in The Lancet Oncology.

The study included 1,185,157 children born between 1996 and 2014 and followed for a median of 9.3 years. Data on these children were collected from the Danish Medical Birth Registry and the Danish Cancer Registry.

The researchers looked at redeemed prescriptions from the Danish National Prescription Registry to determine the mothers’ contraceptive use and divided the women into three categories:

• Mothers who had never used hormonal contraceptives
• Those with previous hormonal contraceptive use, defined as greater than 3 months before the start of pregnancy
• Mothers with recent contraceptive use, defined as during or within 3 months of pregnancy.

Results

There were 606 children diagnosed with leukemia in the study cohort—465 with lymphoid leukemia and 141 with non-lymphoid leukemia.

Overall, children born to mothers with previous or recent use of hormonal contraceptives had a significantly increased risk of developing any leukemia. The hazard ratios (HRs) were as follows:

• Previous use of hormonal contraceptives—HR=1.25 (P=0.039)
• Recent use—HR=1.46 (P=0.011)
• Use within 3 months of pregnancy—HR=1.42 (P=0.025)
• Use during pregnancy—HR=1.78 (P=0.070).

The risk of lymphoid leukemia did not increase significantly with maternal use of hormonal contraceptives. The HRs were as follows:

• Previous use of hormonal contraceptives—HR=1.23 (P=0.089)
• Recent use—HR=1.27 (P=0.167)
• Use within 3 months of pregnancy—HR=1.28 (P=0.173)
• Use during pregnancy—HR=1.22 (P=0.635).

However, the risk of non-lymphoid leukemia was significantly increased in children born to mothers with recent hormonal contraceptive use. The HRs were as follows:

• Previous use of hormonal contraceptives—HR=1.33 (P=0.232)
• Recent use—HR=2.17 (P=0.008)
• Use within 3 months of pregnancy—HR=1.95 (P=0.033)
• Use during pregnancy—HR=3.87 (P=0.006).

The association between recent contraceptive use and any leukemia was strongest in children ages 6 to 10 years. The researchers said this was not surprising because the incidence of non-lymphoid leukemia increases after the age of 6.

The researchers estimated that a mother’s recent use of hormonal contraceptives would have resulted in about one additional case of leukemia per 47,170 children; in other words, 25 additional cases of leukemia over the study period.

This low risk of leukemia “is not a major concern with regard to the safety of hormonal contraceptives,” the researchers said.

However, the findings do suggest the intrauterine hormonal environment affects leukemia development in children, and this should be explored in future research.

This study was supported by the Danish Cancer Research Foundation and other foundations. One author reported grants from the sponsoring foundations, and another author reported speaking fees from Jazz Pharmaceuticals and Shire Pharmaceuticals.

©Raimond Spekking

In a prospective study, Hispanic pediatric patients with acute lymphoblastic leukemia (ALL) had a risk of methotrexate-induced neurotoxicity that was more than twice the risk observed in non-Hispanic white patients.

However, there was no significant difference in methotrexate neurotoxicity between non-Hispanic black patients and non-Hispanic white patients.

There were no cases of neurotoxicity among patients of other races/ethnicities.

Michael E. Scheurer, PhD, of Baylor College of Medicine in Houston, Texas, and his colleagues conducted this study and detailed the results in Clinical Cancer Research.

The study included 280 patients with newly diagnosed ALL. Most patients (85.7%) had B-ALL, 10.7% had T-ALL, and 3.6% had lymphoblastic lymphoma.

Nearly half of the patients (48.2%) were Hispanic, 36.2% were non-Hispanic white, 8.3% were non-Hispanic black, and 7.3% were non-Hispanic “other.”

The patients, who had a mean age of 8.4 years at diagnosis, were treated with modern ALL protocols and were followed from diagnosis to the start of maintenance/continuation therapy.

Methotrexate neurotoxicity was seen in 39 patients at the time of the analysis. Of those patients, 29 (74.4%) were Hispanic.

Compared with non-Hispanic whites, Hispanics had a high risk of methotrexate neurotoxicity, even after the researchers accounted for age, sex, ALL risk stratification, and other factors. The adjusted hazard ratio (HR) was 2.43 (P=0.036).

“We had observed that our Hispanic patients tended to experience neurotoxicity more often than other groups, but we were surprised to see the magnitude of the difference,” Dr. Scheurer said.

There was no significant difference in methotrexate neurotoxicity between non-Hispanic black patients and non-Hispanic white patients. The adjusted HR for non-Hispanic black patients was 1.23 (P=0.80).

Patients in the “other” racial/ethnic group did not experience any neurotoxic events.

All nine patients who experienced a second neurotoxic event were Hispanic.

Patients who had neurotoxicity received an average of 2.25 fewer doses of intrathecal methotrexate (P<0.01) and 1.81 fewer doses of intravenous methotrexate (P=0.084) than patients without neurotoxicity.

About three-quarters (74.4%) of patients experiencing methotrexate neurotoxicity received leucovorin rescue, according to the investigators, who noted that leucovorin may interact with methotrexate and reduce its efficacy.

Relapse occurred in 15.4% (6/39) of patients with neurotoxicity and 2.1% (13/241) of patients with no neurotoxicity (P=0.0038).

The investigators said these findings add to the growing body of evidence that Hispanics and other minority pediatric patients with ALL experience “significant disparities” in treatment outcomes.

It remains unclear why Hispanic patients would have a higher risk of methotrexate neurotoxicity, and that must be explored in future studies, the investigators said.

The team is currently investigating whether biomarkers could be used to identify patients at risk of methotrexate neurotoxicity.

“Biomarkers may someday allow us to identify patients upfront, before even beginning therapy, who might be at risk for such outcomes,” Dr. Scheurer said. “If we can identify these at-risk patients, we can potentially employ strategies to either fully prevent or mitigate these toxicities.”

This research was supported by the National Institutes of Health and Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium, a St. Baldrick’s Foundation Consortium Research Grant. The researchers said they had no potential conflicts of interest.

©Raimond Spekking

In a prospective study, Hispanic pediatric patients with acute lymphoblastic leukemia (ALL) had a risk of methotrexate-induced neurotoxicity that was more than twice the risk observed in non-Hispanic white patients.

However, there was no significant difference in methotrexate neurotoxicity between non-Hispanic black patients and non-Hispanic white patients.

There were no cases of neurotoxicity among patients of other races/ethnicities.

Michael E. Scheurer, PhD, of Baylor College of Medicine in Houston, Texas, and his colleagues conducted this study and detailed the results in Clinical Cancer Research.

The study included 280 patients with newly diagnosed ALL. Most patients (85.7%) had B-ALL, 10.7% had T-ALL, and 3.6% had lymphoblastic lymphoma.

Nearly half of the patients (48.2%) were Hispanic, 36.2% were non-Hispanic white, 8.3% were non-Hispanic black, and 7.3% were non-Hispanic “other.”

The patients, who had a mean age of 8.4 years at diagnosis, were treated with modern ALL protocols and were followed from diagnosis to the start of maintenance/continuation therapy.

Methotrexate neurotoxicity was seen in 39 patients at the time of the analysis. Of those patients, 29 (74.4%) were Hispanic.

Compared with non-Hispanic whites, Hispanics had a high risk of methotrexate neurotoxicity, even after the researchers accounted for age, sex, ALL risk stratification, and other factors. The adjusted hazard ratio (HR) was 2.43 (P=0.036).

“We had observed that our Hispanic patients tended to experience neurotoxicity more often than other groups, but we were surprised to see the magnitude of the difference,” Dr. Scheurer said.

There was no significant difference in methotrexate neurotoxicity between non-Hispanic black patients and non-Hispanic white patients. The adjusted HR for non-Hispanic black patients was 1.23 (P=0.80).

Patients in the “other” racial/ethnic group did not experience any neurotoxic events.

All nine patients who experienced a second neurotoxic event were Hispanic.

Patients who had neurotoxicity received an average of 2.25 fewer doses of intrathecal methotrexate (P<0.01) and 1.81 fewer doses of intravenous methotrexate (P=0.084) than patients without neurotoxicity.

About three-quarters (74.4%) of patients experiencing methotrexate neurotoxicity received leucovorin rescue, according to the investigators, who noted that leucovorin may interact with methotrexate and reduce its efficacy.

Relapse occurred in 15.4% (6/39) of patients with neurotoxicity and 2.1% (13/241) of patients with no neurotoxicity (P=0.0038).

The investigators said these findings add to the growing body of evidence that Hispanics and other minority pediatric patients with ALL experience “significant disparities” in treatment outcomes.

It remains unclear why Hispanic patients would have a higher risk of methotrexate neurotoxicity, and that must be explored in future studies, the investigators said.

The team is currently investigating whether biomarkers could be used to identify patients at risk of methotrexate neurotoxicity.

“Biomarkers may someday allow us to identify patients upfront, before even beginning therapy, who might be at risk for such outcomes,” Dr. Scheurer said. “If we can identify these at-risk patients, we can potentially employ strategies to either fully prevent or mitigate these toxicities.”

This research was supported by the National Institutes of Health and Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium, a St. Baldrick’s Foundation Consortium Research Grant. The researchers said they had no potential conflicts of interest.

©Raimond Spekking

In a prospective study, Hispanic pediatric patients with acute lymphoblastic leukemia (ALL) had a risk of methotrexate-induced neurotoxicity that was more than twice the risk observed in non-Hispanic white patients.

However, there was no significant difference in methotrexate neurotoxicity between non-Hispanic black patients and non-Hispanic white patients.

There were no cases of neurotoxicity among patients of other races/ethnicities.

Michael E. Scheurer, PhD, of Baylor College of Medicine in Houston, Texas, and his colleagues conducted this study and detailed the results in Clinical Cancer Research.

The study included 280 patients with newly diagnosed ALL. Most patients (85.7%) had B-ALL, 10.7% had T-ALL, and 3.6% had lymphoblastic lymphoma.

Nearly half of the patients (48.2%) were Hispanic, 36.2% were non-Hispanic white, 8.3% were non-Hispanic black, and 7.3% were non-Hispanic “other.”

The patients, who had a mean age of 8.4 years at diagnosis, were treated with modern ALL protocols and were followed from diagnosis to the start of maintenance/continuation therapy.

Methotrexate neurotoxicity was seen in 39 patients at the time of the analysis. Of those patients, 29 (74.4%) were Hispanic.

Compared with non-Hispanic whites, Hispanics had a high risk of methotrexate neurotoxicity, even after the researchers accounted for age, sex, ALL risk stratification, and other factors. The adjusted hazard ratio (HR) was 2.43 (P=0.036).

“We had observed that our Hispanic patients tended to experience neurotoxicity more often than other groups, but we were surprised to see the magnitude of the difference,” Dr. Scheurer said.

There was no significant difference in methotrexate neurotoxicity between non-Hispanic black patients and non-Hispanic white patients. The adjusted HR for non-Hispanic black patients was 1.23 (P=0.80).

Patients in the “other” racial/ethnic group did not experience any neurotoxic events.

All nine patients who experienced a second neurotoxic event were Hispanic.

Patients who had neurotoxicity received an average of 2.25 fewer doses of intrathecal methotrexate (P<0.01) and 1.81 fewer doses of intravenous methotrexate (P=0.084) than patients without neurotoxicity.

About three-quarters (74.4%) of patients experiencing methotrexate neurotoxicity received leucovorin rescue, according to the investigators, who noted that leucovorin may interact with methotrexate and reduce its efficacy.

Relapse occurred in 15.4% (6/39) of patients with neurotoxicity and 2.1% (13/241) of patients with no neurotoxicity (P=0.0038).

The investigators said these findings add to the growing body of evidence that Hispanics and other minority pediatric patients with ALL experience “significant disparities” in treatment outcomes.

It remains unclear why Hispanic patients would have a higher risk of methotrexate neurotoxicity, and that must be explored in future studies, the investigators said.

The team is currently investigating whether biomarkers could be used to identify patients at risk of methotrexate neurotoxicity.

“Biomarkers may someday allow us to identify patients upfront, before even beginning therapy, who might be at risk for such outcomes,” Dr. Scheurer said. “If we can identify these at-risk patients, we can potentially employ strategies to either fully prevent or mitigate these toxicities.”

This research was supported by the National Institutes of Health and Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium, a St. Baldrick’s Foundation Consortium Research Grant. The researchers said they had no potential conflicts of interest.

Photo courtesy of Abbvie

The U.S. Food and Drug Administration (FDA) has expanded the label for venetoclax tablets (Venclexta^®) to include data on minimal residual disease (MRD).

The drug’s prescribing information now includes details on MRD negativity in previously treated patients with chronic lymphocytic leukemia (CLL) who received venetoclax in combination with rituximab in the phase 3 MURANO trial.

The combination of venetoclax and rituximab was FDA approved in June for the treatment of patients with CLL or small lymphocytic lymphoma, with or without 17p deletion, who received at least one prior therapy.

The MURANO trial (NCT02005471), which supported the FDA approval, included 389 patients with relapsed or refractory CLL.

The patients were randomized to receive:

• Venetoclax at 400 mg daily for 24 months (after a 5-week ramp-up period) plus rituximab at 375 mg/m² on day 1 for the first cycle and at 500 mg/m²  on day 1 for cycles 2 to 6 (n=194)
• Bendamustine at 70 mg/m² on days 1 and 2 for 6 cycles plus rituximab at the same schedule as the venetoclax arm (n=195).

Researchers evaluated MRD in patients who achieved a partial response or better. MRD was assessed using allele-specific oligonucleotide polymerase chain reaction, and the definition of MRD negativity was less than one CLL cell per 10,000 lymphocytes.

The researchers assessed MRD in the peripheral blood 3 months after the last dose of rituximab. At that time, 53% (103/194) of patients in the venetoclax-rituximab arm were MRD negative, as were 12% (23/195) of patients in the bendamustine-rituximab arm.

The researchers also assessed MRD in the peripheral blood of patients with a complete response (CR) or CR with incomplete marrow recovery (CRi). MRD negativity was achieved by 3% (6/194) of these patients in the venetoclax-rituximab arm and 2% (3/195) in the bendamustine-rituximab arm.

Three percent (3/106) of patients in the venetoclax arm who achieved CR/CRi were MRD negative in both the peripheral blood and the bone marrow.

“The rates of MRD negativity seen with Venclexta plus rituximab are very encouraging,” said MURANO investigator John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.

Additional results from the MURANO trial were published in The New England Journal of Medicine in March and are included in the prescribing information for venetoclax.

Venetoclax is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside the U.S.

Photo courtesy of Abbvie

The U.S. Food and Drug Administration (FDA) has expanded the label for venetoclax tablets (Venclexta^®) to include data on minimal residual disease (MRD).

The drug’s prescribing information now includes details on MRD negativity in previously treated patients with chronic lymphocytic leukemia (CLL) who received venetoclax in combination with rituximab in the phase 3 MURANO trial.

The combination of venetoclax and rituximab was FDA approved in June for the treatment of patients with CLL or small lymphocytic lymphoma, with or without 17p deletion, who received at least one prior therapy.

The MURANO trial (NCT02005471), which supported the FDA approval, included 389 patients with relapsed or refractory CLL.

The patients were randomized to receive:

• Venetoclax at 400 mg daily for 24 months (after a 5-week ramp-up period) plus rituximab at 375 mg/m² on day 1 for the first cycle and at 500 mg/m²  on day 1 for cycles 2 to 6 (n=194)
• Bendamustine at 70 mg/m² on days 1 and 2 for 6 cycles plus rituximab at the same schedule as the venetoclax arm (n=195).

Researchers evaluated MRD in patients who achieved a partial response or better. MRD was assessed using allele-specific oligonucleotide polymerase chain reaction, and the definition of MRD negativity was less than one CLL cell per 10,000 lymphocytes.

The researchers assessed MRD in the peripheral blood 3 months after the last dose of rituximab. At that time, 53% (103/194) of patients in the venetoclax-rituximab arm were MRD negative, as were 12% (23/195) of patients in the bendamustine-rituximab arm.

The researchers also assessed MRD in the peripheral blood of patients with a complete response (CR) or CR with incomplete marrow recovery (CRi). MRD negativity was achieved by 3% (6/194) of these patients in the venetoclax-rituximab arm and 2% (3/195) in the bendamustine-rituximab arm.

Three percent (3/106) of patients in the venetoclax arm who achieved CR/CRi were MRD negative in both the peripheral blood and the bone marrow.

“The rates of MRD negativity seen with Venclexta plus rituximab are very encouraging,” said MURANO investigator John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.

Additional results from the MURANO trial were published in The New England Journal of Medicine in March and are included in the prescribing information for venetoclax.

Venetoclax is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside the U.S.

Photo courtesy of Abbvie

The U.S. Food and Drug Administration (FDA) has expanded the label for venetoclax tablets (Venclexta^®) to include data on minimal residual disease (MRD).

The drug’s prescribing information now includes details on MRD negativity in previously treated patients with chronic lymphocytic leukemia (CLL) who received venetoclax in combination with rituximab in the phase 3 MURANO trial.

The combination of venetoclax and rituximab was FDA approved in June for the treatment of patients with CLL or small lymphocytic lymphoma, with or without 17p deletion, who received at least one prior therapy.

The MURANO trial (NCT02005471), which supported the FDA approval, included 389 patients with relapsed or refractory CLL.

The patients were randomized to receive:

• Venetoclax at 400 mg daily for 24 months (after a 5-week ramp-up period) plus rituximab at 375 mg/m² on day 1 for the first cycle and at 500 mg/m²  on day 1 for cycles 2 to 6 (n=194)
• Bendamustine at 70 mg/m² on days 1 and 2 for 6 cycles plus rituximab at the same schedule as the venetoclax arm (n=195).

Researchers evaluated MRD in patients who achieved a partial response or better. MRD was assessed using allele-specific oligonucleotide polymerase chain reaction, and the definition of MRD negativity was less than one CLL cell per 10,000 lymphocytes.

The researchers assessed MRD in the peripheral blood 3 months after the last dose of rituximab. At that time, 53% (103/194) of patients in the venetoclax-rituximab arm were MRD negative, as were 12% (23/195) of patients in the bendamustine-rituximab arm.

The researchers also assessed MRD in the peripheral blood of patients with a complete response (CR) or CR with incomplete marrow recovery (CRi). MRD negativity was achieved by 3% (6/194) of these patients in the venetoclax-rituximab arm and 2% (3/195) in the bendamustine-rituximab arm.

Three percent (3/106) of patients in the venetoclax arm who achieved CR/CRi were MRD negative in both the peripheral blood and the bone marrow.

“The rates of MRD negativity seen with Venclexta plus rituximab are very encouraging,” said MURANO investigator John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.

Additional results from the MURANO trial were published in The New England Journal of Medicine in March and are included in the prescribing information for venetoclax.

Venetoclax is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside the U.S.

Levofloxacin prophylaxis significantly reduced bacteremia in children with acute leukemias receiving intensive chemotherapy, according to results of a multicenter, randomized phase 3 trial.

Risk of bacteremia was not significantly reduced with levofloxacin in another cohort of children undergoing hematopoietic stem cell transplantation (HSCT), although a post hoc analysis accounting for time at risk did show a significant difference, according to results of this Children’s Oncology Group (COG) trial.

The reduction in risk for children with acute leukemias was similar to findings of adult studies showing the benefit of prophylactic antibiotics in patients with cancer-related neutropenia, said Sarah Alexander, MD, of the division of hematology/oncology, the Hospital for Sick Children, Toronto, and her coinvestigators.

Before this COG study, data on prophylactic antibiotics in children with cancer were limited to several small, single-group observational studies, Dr. Alexander and her coauthors wrote in JAMA.

Bacteremia was the primary outcome of the COG study, according to the investigators, because of its link to sepsis, increased health care utilization, and infection-related mortality. “Consequently, this outcome is meaningful to both clinicians and patients,” the investigators noted.

The multicenter, randomized, open-label phase 3 trial (ACCL0934) enrolled patients aged 6 months to 21 years, including 200 with acute leukemias (acute myeloid leukemia or relapsed acute lymphoblastic leukemia) who were to receive at least two intensive chemotherapy cycles, and 424 who were to receive a myeloablative autologous or allogeneic HSCT.

In the final analysis of the acute leukemias group, which included 195 patients, likelihood of bacteremia was 21.9% for those randomized to levofloxacin prophylaxis, versus 43.4% for no prophylaxis (P = 0.001).

In the final analysis of the HSCT group, which included 418 patients, likelihood of bacteremia was not significantly different, at 11.0% for levofloxacin prophylaxis, versus 17.3% for no prophylaxis (P = 0.06).

“Levofloxacin prophylaxis was effective at reducing the risk of bacteremia among patients with acute leukemia, but not among patients undergoing HSCT,” Dr. Armstrong and her coauthors said.

A post hoc analysis accounting for time at risk, however, showed a significant difference in favor of prophylaxis in both groups and a similar effect size between groups, according to investigators.

For the acute leukemias group, the rate of bacteremic episodes in that post hoc analysis was 4.9 versus 9.4 per 1,000 patient-days in the prophylaxis and no prophylaxis arms, respectively (P = 0.008). In the HSCT group, the rate was 5.3 versus 10.0 bacteremias per 1,000 patient-days in the prophylaxis and no prophylaxis arms (P = .02).

The similar effect size suggests that in the primary analysis, there was reduced power to detect a significant difference in the HSCT group because of fewer events, driven partly by a shorter duration of neutropenia in that group, Dr. Armstrong and her associates said.

“However, it is also plausible that the leukemia and HSCT groups had different supportive care measures or were infected with pathogens that had differential sensitivity to levofloxacin resulting in different efficacy of levofloxacin in the 2 groups,” they added.

Levofloxacin-resistant pathogens, such as viridans group streptococcal isolates and several Gram-negative isolates, often were detected in patients who had bacteremia events despite prophylaxis. This suggests that other interventions in combination with levofloxacin prophylaxis are probably needed to further decrease risk, the investigators said.

Further randomized studies are needed to better understand the risks of levofloxacin in relation to its benefits, according to the investigators, who reported 23 serious adverse events in 8 patients, 11 of which were considered unrelated or unlikely to be related to levofloxacin.

“The adoption of antibacterial prophylaxis is tempered by potential negative consequences including Clostridium difficile-associated diarrhea, bacterial resistance, and musculoskeletal toxicities,” Dr. Armstrong and her colleagues noted.

The research was supported by grants from the Community Clinical Oncology Program and National Cancer Institute. Dr. Alexander reported no disclosures. Coauthors reported disclosures related to Bristol-Myers Squibb, Chimerix, Jazz Pharmaceuticals, and the Children’s Oncology Group.

SOURCE: Alexander S, et al . JAMA. 2018;320(10):995-1004.

Levofloxacin prophylaxis significantly reduced bacteremia in children with acute leukemias receiving intensive chemotherapy, according to results of a multicenter, randomized phase 3 trial.

Risk of bacteremia was not significantly reduced with levofloxacin in another cohort of children undergoing hematopoietic stem cell transplantation (HSCT), although a post hoc analysis accounting for time at risk did show a significant difference, according to results of this Children’s Oncology Group (COG) trial.

The reduction in risk for children with acute leukemias was similar to findings of adult studies showing the benefit of prophylactic antibiotics in patients with cancer-related neutropenia, said Sarah Alexander, MD, of the division of hematology/oncology, the Hospital for Sick Children, Toronto, and her coinvestigators.

Before this COG study, data on prophylactic antibiotics in children with cancer were limited to several small, single-group observational studies, Dr. Alexander and her coauthors wrote in JAMA.

Bacteremia was the primary outcome of the COG study, according to the investigators, because of its link to sepsis, increased health care utilization, and infection-related mortality. “Consequently, this outcome is meaningful to both clinicians and patients,” the investigators noted.

The multicenter, randomized, open-label phase 3 trial (ACCL0934) enrolled patients aged 6 months to 21 years, including 200 with acute leukemias (acute myeloid leukemia or relapsed acute lymphoblastic leukemia) who were to receive at least two intensive chemotherapy cycles, and 424 who were to receive a myeloablative autologous or allogeneic HSCT.

In the final analysis of the acute leukemias group, which included 195 patients, likelihood of bacteremia was 21.9% for those randomized to levofloxacin prophylaxis, versus 43.4% for no prophylaxis (P = 0.001).

In the final analysis of the HSCT group, which included 418 patients, likelihood of bacteremia was not significantly different, at 11.0% for levofloxacin prophylaxis, versus 17.3% for no prophylaxis (P = 0.06).

“Levofloxacin prophylaxis was effective at reducing the risk of bacteremia among patients with acute leukemia, but not among patients undergoing HSCT,” Dr. Armstrong and her coauthors said.

A post hoc analysis accounting for time at risk, however, showed a significant difference in favor of prophylaxis in both groups and a similar effect size between groups, according to investigators.

For the acute leukemias group, the rate of bacteremic episodes in that post hoc analysis was 4.9 versus 9.4 per 1,000 patient-days in the prophylaxis and no prophylaxis arms, respectively (P = 0.008). In the HSCT group, the rate was 5.3 versus 10.0 bacteremias per 1,000 patient-days in the prophylaxis and no prophylaxis arms (P = .02).

The similar effect size suggests that in the primary analysis, there was reduced power to detect a significant difference in the HSCT group because of fewer events, driven partly by a shorter duration of neutropenia in that group, Dr. Armstrong and her associates said.

“However, it is also plausible that the leukemia and HSCT groups had different supportive care measures or were infected with pathogens that had differential sensitivity to levofloxacin resulting in different efficacy of levofloxacin in the 2 groups,” they added.

Levofloxacin-resistant pathogens, such as viridans group streptococcal isolates and several Gram-negative isolates, often were detected in patients who had bacteremia events despite prophylaxis. This suggests that other interventions in combination with levofloxacin prophylaxis are probably needed to further decrease risk, the investigators said.

Further randomized studies are needed to better understand the risks of levofloxacin in relation to its benefits, according to the investigators, who reported 23 serious adverse events in 8 patients, 11 of which were considered unrelated or unlikely to be related to levofloxacin.

“The adoption of antibacterial prophylaxis is tempered by potential negative consequences including Clostridium difficile-associated diarrhea, bacterial resistance, and musculoskeletal toxicities,” Dr. Armstrong and her colleagues noted.

The research was supported by grants from the Community Clinical Oncology Program and National Cancer Institute. Dr. Alexander reported no disclosures. Coauthors reported disclosures related to Bristol-Myers Squibb, Chimerix, Jazz Pharmaceuticals, and the Children’s Oncology Group.

SOURCE: Alexander S, et al . JAMA. 2018;320(10):995-1004.

Levofloxacin prophylaxis significantly reduced bacteremia in children with acute leukemias receiving intensive chemotherapy, according to results of a multicenter, randomized phase 3 trial.

Risk of bacteremia was not significantly reduced with levofloxacin in another cohort of children undergoing hematopoietic stem cell transplantation (HSCT), although a post hoc analysis accounting for time at risk did show a significant difference, according to results of this Children’s Oncology Group (COG) trial.

The reduction in risk for children with acute leukemias was similar to findings of adult studies showing the benefit of prophylactic antibiotics in patients with cancer-related neutropenia, said Sarah Alexander, MD, of the division of hematology/oncology, the Hospital for Sick Children, Toronto, and her coinvestigators.

Before this COG study, data on prophylactic antibiotics in children with cancer were limited to several small, single-group observational studies, Dr. Alexander and her coauthors wrote in JAMA.

Bacteremia was the primary outcome of the COG study, according to the investigators, because of its link to sepsis, increased health care utilization, and infection-related mortality. “Consequently, this outcome is meaningful to both clinicians and patients,” the investigators noted.

The multicenter, randomized, open-label phase 3 trial (ACCL0934) enrolled patients aged 6 months to 21 years, including 200 with acute leukemias (acute myeloid leukemia or relapsed acute lymphoblastic leukemia) who were to receive at least two intensive chemotherapy cycles, and 424 who were to receive a myeloablative autologous or allogeneic HSCT.

In the final analysis of the acute leukemias group, which included 195 patients, likelihood of bacteremia was 21.9% for those randomized to levofloxacin prophylaxis, versus 43.4% for no prophylaxis (P = 0.001).

In the final analysis of the HSCT group, which included 418 patients, likelihood of bacteremia was not significantly different, at 11.0% for levofloxacin prophylaxis, versus 17.3% for no prophylaxis (P = 0.06).

“Levofloxacin prophylaxis was effective at reducing the risk of bacteremia among patients with acute leukemia, but not among patients undergoing HSCT,” Dr. Armstrong and her coauthors said.

A post hoc analysis accounting for time at risk, however, showed a significant difference in favor of prophylaxis in both groups and a similar effect size between groups, according to investigators.

For the acute leukemias group, the rate of bacteremic episodes in that post hoc analysis was 4.9 versus 9.4 per 1,000 patient-days in the prophylaxis and no prophylaxis arms, respectively (P = 0.008). In the HSCT group, the rate was 5.3 versus 10.0 bacteremias per 1,000 patient-days in the prophylaxis and no prophylaxis arms (P = .02).

The similar effect size suggests that in the primary analysis, there was reduced power to detect a significant difference in the HSCT group because of fewer events, driven partly by a shorter duration of neutropenia in that group, Dr. Armstrong and her associates said.

“However, it is also plausible that the leukemia and HSCT groups had different supportive care measures or were infected with pathogens that had differential sensitivity to levofloxacin resulting in different efficacy of levofloxacin in the 2 groups,” they added.

Levofloxacin-resistant pathogens, such as viridans group streptococcal isolates and several Gram-negative isolates, often were detected in patients who had bacteremia events despite prophylaxis. This suggests that other interventions in combination with levofloxacin prophylaxis are probably needed to further decrease risk, the investigators said.

Further randomized studies are needed to better understand the risks of levofloxacin in relation to its benefits, according to the investigators, who reported 23 serious adverse events in 8 patients, 11 of which were considered unrelated or unlikely to be related to levofloxacin.

“The adoption of antibacterial prophylaxis is tempered by potential negative consequences including Clostridium difficile-associated diarrhea, bacterial resistance, and musculoskeletal toxicities,” Dr. Armstrong and her colleagues noted.

The research was supported by grants from the Community Clinical Oncology Program and National Cancer Institute. Dr. Alexander reported no disclosures. Coauthors reported disclosures related to Bristol-Myers Squibb, Chimerix, Jazz Pharmaceuticals, and the Children’s Oncology Group.

SOURCE: Alexander S, et al . JAMA. 2018;320(10):995-1004.

A nationwide cohort study found an association between a woman’s use of hormonal contraceptives and a small increased risk of nonlymphoid leukemia in her offspring.

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Maternal use of hormonal contraception either during pregnancy or in the 3 months beforehand was associated with a 46% higher risk of any leukemia in the children (P = .011), compared with no use, Marie Hargreave, PhD, of the Danish Cancer Society Research Center and her coauthors reported in Lancet Oncology.

The study of 1,185,157 children born between 1996 and 2014 included data from the Danish Cancer Registry and Danish National Prescription Registry and followed children for a median of 9.3 years.

Use during pregnancy was associated with a 78% higher risk of any leukemia in the offspring (P = .070), and contraception use that stopped more than 3 months before pregnancy was associated with a 25% higher risk of any leukemia (P = .039).

The researchers estimated that maternal use of hormonal contraceptives up to and including during pregnancy would have resulted in about one additional case of leukemia per 47,170 children; in other words, 25 additional cases of leukemia in Denmark from contraceptive use from 1996 to 2014.

The increased risk appeared to be limited to nonlymphoid leukemia only. The risk with recent use was more than twofold higher (HR, 2.17), compared with nonuse, and use during pregnancy was associated with a nearly fourfold increase in the risk of leukemia (HR, 3.87).

“Sex hormones are considered to be potent carcinogens, and the causal association between in-utero exposure to the oestrogen analogue diethylstilbestrol and subsequent risk for adenocarcinoma of the vagina is firmly established,” Dr. Hargreave and her colleagues wrote. “The mechanism by which maternal use of hormones increases cancer risk in children is, however, still not clear.”

Recent use of combined oral contraceptive products was associated with a more than twofold increased risk of nonlymphoid leukemia in offspring, compared with no use. However progestin-only oral contraceptives and emergency contraception did not appear to increase in the risk of lymphoid or nonlymphoid leukemia.

The association was strongest in children aged 6-10 years, which the authors suggested was likely because the incidence of nonlymphoid leukemia increases after the age of 6 years.

While acknowledging that the small increase in leukemia risk was not a major safety concern for hormonal contraceptives, the authors commented that the results suggested the intrauterine hormonal environment could be a direction for research into the causes of leukemia.

The study was supported by the Danish Cancer Research Foundation and other foundations. One author reported grants from the sponsoring foundations and another author reported speaking fees from Jazz Pharmaceuticals and Shire Pharmaceuticals.

SOURCE: Hargreave M et al. Lancet Oncol. 2018 Sep 6. doi: 10.1016/S1470-2045(18)30479-0.
 

A nationwide cohort study found an association between a woman’s use of hormonal contraceptives and a small increased risk of nonlymphoid leukemia in her offspring.

copyright Thinkstock

Maternal use of hormonal contraception either during pregnancy or in the 3 months beforehand was associated with a 46% higher risk of any leukemia in the children (P = .011), compared with no use, Marie Hargreave, PhD, of the Danish Cancer Society Research Center and her coauthors reported in Lancet Oncology.

The study of 1,185,157 children born between 1996 and 2014 included data from the Danish Cancer Registry and Danish National Prescription Registry and followed children for a median of 9.3 years.

Use during pregnancy was associated with a 78% higher risk of any leukemia in the offspring (P = .070), and contraception use that stopped more than 3 months before pregnancy was associated with a 25% higher risk of any leukemia (P = .039).

The researchers estimated that maternal use of hormonal contraceptives up to and including during pregnancy would have resulted in about one additional case of leukemia per 47,170 children; in other words, 25 additional cases of leukemia in Denmark from contraceptive use from 1996 to 2014.

The increased risk appeared to be limited to nonlymphoid leukemia only. The risk with recent use was more than twofold higher (HR, 2.17), compared with nonuse, and use during pregnancy was associated with a nearly fourfold increase in the risk of leukemia (HR, 3.87).

“Sex hormones are considered to be potent carcinogens, and the causal association between in-utero exposure to the oestrogen analogue diethylstilbestrol and subsequent risk for adenocarcinoma of the vagina is firmly established,” Dr. Hargreave and her colleagues wrote. “The mechanism by which maternal use of hormones increases cancer risk in children is, however, still not clear.”

Recent use of combined oral contraceptive products was associated with a more than twofold increased risk of nonlymphoid leukemia in offspring, compared with no use. However progestin-only oral contraceptives and emergency contraception did not appear to increase in the risk of lymphoid or nonlymphoid leukemia.

The association was strongest in children aged 6-10 years, which the authors suggested was likely because the incidence of nonlymphoid leukemia increases after the age of 6 years.

While acknowledging that the small increase in leukemia risk was not a major safety concern for hormonal contraceptives, the authors commented that the results suggested the intrauterine hormonal environment could be a direction for research into the causes of leukemia.

The study was supported by the Danish Cancer Research Foundation and other foundations. One author reported grants from the sponsoring foundations and another author reported speaking fees from Jazz Pharmaceuticals and Shire Pharmaceuticals.

SOURCE: Hargreave M et al. Lancet Oncol. 2018 Sep 6. doi: 10.1016/S1470-2045(18)30479-0.
 

A nationwide cohort study found an association between a woman’s use of hormonal contraceptives and a small increased risk of nonlymphoid leukemia in her offspring.

copyright Thinkstock

Maternal use of hormonal contraception either during pregnancy or in the 3 months beforehand was associated with a 46% higher risk of any leukemia in the children (P = .011), compared with no use, Marie Hargreave, PhD, of the Danish Cancer Society Research Center and her coauthors reported in Lancet Oncology.

The study of 1,185,157 children born between 1996 and 2014 included data from the Danish Cancer Registry and Danish National Prescription Registry and followed children for a median of 9.3 years.

Use during pregnancy was associated with a 78% higher risk of any leukemia in the offspring (P = .070), and contraception use that stopped more than 3 months before pregnancy was associated with a 25% higher risk of any leukemia (P = .039).

The researchers estimated that maternal use of hormonal contraceptives up to and including during pregnancy would have resulted in about one additional case of leukemia per 47,170 children; in other words, 25 additional cases of leukemia in Denmark from contraceptive use from 1996 to 2014.

The increased risk appeared to be limited to nonlymphoid leukemia only. The risk with recent use was more than twofold higher (HR, 2.17), compared with nonuse, and use during pregnancy was associated with a nearly fourfold increase in the risk of leukemia (HR, 3.87).

“Sex hormones are considered to be potent carcinogens, and the causal association between in-utero exposure to the oestrogen analogue diethylstilbestrol and subsequent risk for adenocarcinoma of the vagina is firmly established,” Dr. Hargreave and her colleagues wrote. “The mechanism by which maternal use of hormones increases cancer risk in children is, however, still not clear.”

Recent use of combined oral contraceptive products was associated with a more than twofold increased risk of nonlymphoid leukemia in offspring, compared with no use. However progestin-only oral contraceptives and emergency contraception did not appear to increase in the risk of lymphoid or nonlymphoid leukemia.

The association was strongest in children aged 6-10 years, which the authors suggested was likely because the incidence of nonlymphoid leukemia increases after the age of 6 years.

While acknowledging that the small increase in leukemia risk was not a major safety concern for hormonal contraceptives, the authors commented that the results suggested the intrauterine hormonal environment could be a direction for research into the causes of leukemia.

The study was supported by the Danish Cancer Research Foundation and other foundations. One author reported grants from the sponsoring foundations and another author reported speaking fees from Jazz Pharmaceuticals and Shire Pharmaceuticals.

SOURCE: Hargreave M et al. Lancet Oncol. 2018 Sep 6. doi: 10.1016/S1470-2045(18)30479-0.
 

Hispanic pediatric patients undergoing treatment for acute lymphoblastic leukemia (ALL) had a risk of methotrexate toxicity that was more than twice that of non-Hispanic whites, according to results of a prospective multicenter study.

Methotrexate toxicity often led to treatment modification or delays, which may have increased relapse risk in the Hispanic patients, according to investigator Michael E. Scheurer, PhD, MPH, of Baylor College of Medicine, Houston, and his colleagues.

“We had observed that our Hispanic patients tended to experience neurotoxicity more often than other groups, but we were surprised to see the magnitude of the difference,” Dr. Scheurer said in statement.

The study, described in Clinical Cancer Research, involved 280 patients with newly diagnosed ALL enrolled at one of three major U.S. pediatric cancer treatment centers. Nearly half of the patients (48.2%) were Hispanic, and approximately 86% had a diagnosis of pre B-cell leukemia.

The patients, who had a mean age of 8.4 years at diagnosis, were treated with modern ALL protocols and were followed from diagnosis to the start of maintenance/continuation therapy.

Methotrexate toxicity was seen in 39 patients at the time of the analysis. Of those patients, 29 (74.4%) were Hispanic, Dr. Scheurer and his coauthors reported.

Compared with non-Hispanic whites, Hispanics had a high risk of methotrexate neurotoxicity, even after the researchers accounted for age, sex, ALL risk stratification, and other factors (adjusted hazard ratio, 2.43; 95% confidence interval, 1.06-5.58).

Among nine patients who experienced a second neurotoxic event, all were Hispanic.

Patients who had neurotoxicity received an average of 2.25 fewer doses of intrathecal methotrexate, and slightly lower intravenous methotrexate doses. About three-quarters of the patients experiencing methotrexate toxicity received leucovorin after intrathecal methotrexate, according to the investigators, who noted that leucovorin may interact with methotrexate and reduce efficacy.

“These findings may help us better understand what factors contribute to poorer survival among Hispanic patients with ALL,” wrote Dr. Scheurer and his coauthors.

Relapse occurred in 15.4% of patients with neurotoxicity (6 of 39 patients), and in 2.1% of patients with no neurotoxicity (13 of 241 patients).

Taken together, the findings add to the growing body of evidence that Hispanics and other minority pediatric patients with ALL experience “significant disparities” in treatment outcomes, according to the investigators.

That body of evidence includes several recent cases series that suggest Hispanic patients with ALL have a high prevalence of methotrexate neurotoxicity.

It remains unclear why Hispanic patients would have a higher risk of methotrexate toxicity, and that must be explored in future studies, the investigators said.

The research team is currently investigating biomarkers that may help identify patients at risk of methotrexate toxicity up front. “If we can identify these at-risk patients, we can potentially employ strategies to either fully prevent or mitigate these toxicities,” Dr. Scheurer said in a statement.

The research was supported by the National Institutes of Health and Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium, a St. Baldrick’s Foundation Consortium Research Grant. The researchers reported having no potential conflicts of interest.

SOURCE: Taylor OA et al. Clin Cancer Res. 2018 Sep 11. doi: 10.1158/1078-0432.CCR-18-0939.

Hispanic pediatric patients undergoing treatment for acute lymphoblastic leukemia (ALL) had a risk of methotrexate toxicity that was more than twice that of non-Hispanic whites, according to results of a prospective multicenter study.

Methotrexate toxicity often led to treatment modification or delays, which may have increased relapse risk in the Hispanic patients, according to investigator Michael E. Scheurer, PhD, MPH, of Baylor College of Medicine, Houston, and his colleagues.

“We had observed that our Hispanic patients tended to experience neurotoxicity more often than other groups, but we were surprised to see the magnitude of the difference,” Dr. Scheurer said in statement.

The study, described in Clinical Cancer Research, involved 280 patients with newly diagnosed ALL enrolled at one of three major U.S. pediatric cancer treatment centers. Nearly half of the patients (48.2%) were Hispanic, and approximately 86% had a diagnosis of pre B-cell leukemia.

The patients, who had a mean age of 8.4 years at diagnosis, were treated with modern ALL protocols and were followed from diagnosis to the start of maintenance/continuation therapy.

Methotrexate toxicity was seen in 39 patients at the time of the analysis. Of those patients, 29 (74.4%) were Hispanic, Dr. Scheurer and his coauthors reported.

Compared with non-Hispanic whites, Hispanics had a high risk of methotrexate neurotoxicity, even after the researchers accounted for age, sex, ALL risk stratification, and other factors (adjusted hazard ratio, 2.43; 95% confidence interval, 1.06-5.58).

Among nine patients who experienced a second neurotoxic event, all were Hispanic.

Patients who had neurotoxicity received an average of 2.25 fewer doses of intrathecal methotrexate, and slightly lower intravenous methotrexate doses. About three-quarters of the patients experiencing methotrexate toxicity received leucovorin after intrathecal methotrexate, according to the investigators, who noted that leucovorin may interact with methotrexate and reduce efficacy.

“These findings may help us better understand what factors contribute to poorer survival among Hispanic patients with ALL,” wrote Dr. Scheurer and his coauthors.

Relapse occurred in 15.4% of patients with neurotoxicity (6 of 39 patients), and in 2.1% of patients with no neurotoxicity (13 of 241 patients).

Taken together, the findings add to the growing body of evidence that Hispanics and other minority pediatric patients with ALL experience “significant disparities” in treatment outcomes, according to the investigators.

That body of evidence includes several recent cases series that suggest Hispanic patients with ALL have a high prevalence of methotrexate neurotoxicity.

It remains unclear why Hispanic patients would have a higher risk of methotrexate toxicity, and that must be explored in future studies, the investigators said.

The research team is currently investigating biomarkers that may help identify patients at risk of methotrexate toxicity up front. “If we can identify these at-risk patients, we can potentially employ strategies to either fully prevent or mitigate these toxicities,” Dr. Scheurer said in a statement.

The research was supported by the National Institutes of Health and Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium, a St. Baldrick’s Foundation Consortium Research Grant. The researchers reported having no potential conflicts of interest.

SOURCE: Taylor OA et al. Clin Cancer Res. 2018 Sep 11. doi: 10.1158/1078-0432.CCR-18-0939.

Hispanic pediatric patients undergoing treatment for acute lymphoblastic leukemia (ALL) had a risk of methotrexate toxicity that was more than twice that of non-Hispanic whites, according to results of a prospective multicenter study.

Methotrexate toxicity often led to treatment modification or delays, which may have increased relapse risk in the Hispanic patients, according to investigator Michael E. Scheurer, PhD, MPH, of Baylor College of Medicine, Houston, and his colleagues.

“We had observed that our Hispanic patients tended to experience neurotoxicity more often than other groups, but we were surprised to see the magnitude of the difference,” Dr. Scheurer said in statement.

The study, described in Clinical Cancer Research, involved 280 patients with newly diagnosed ALL enrolled at one of three major U.S. pediatric cancer treatment centers. Nearly half of the patients (48.2%) were Hispanic, and approximately 86% had a diagnosis of pre B-cell leukemia.

The patients, who had a mean age of 8.4 years at diagnosis, were treated with modern ALL protocols and were followed from diagnosis to the start of maintenance/continuation therapy.

Methotrexate toxicity was seen in 39 patients at the time of the analysis. Of those patients, 29 (74.4%) were Hispanic, Dr. Scheurer and his coauthors reported.

Compared with non-Hispanic whites, Hispanics had a high risk of methotrexate neurotoxicity, even after the researchers accounted for age, sex, ALL risk stratification, and other factors (adjusted hazard ratio, 2.43; 95% confidence interval, 1.06-5.58).

Among nine patients who experienced a second neurotoxic event, all were Hispanic.

Patients who had neurotoxicity received an average of 2.25 fewer doses of intrathecal methotrexate, and slightly lower intravenous methotrexate doses. About three-quarters of the patients experiencing methotrexate toxicity received leucovorin after intrathecal methotrexate, according to the investigators, who noted that leucovorin may interact with methotrexate and reduce efficacy.

“These findings may help us better understand what factors contribute to poorer survival among Hispanic patients with ALL,” wrote Dr. Scheurer and his coauthors.

Relapse occurred in 15.4% of patients with neurotoxicity (6 of 39 patients), and in 2.1% of patients with no neurotoxicity (13 of 241 patients).

Taken together, the findings add to the growing body of evidence that Hispanics and other minority pediatric patients with ALL experience “significant disparities” in treatment outcomes, according to the investigators.

That body of evidence includes several recent cases series that suggest Hispanic patients with ALL have a high prevalence of methotrexate neurotoxicity.

It remains unclear why Hispanic patients would have a higher risk of methotrexate toxicity, and that must be explored in future studies, the investigators said.

The research team is currently investigating biomarkers that may help identify patients at risk of methotrexate toxicity up front. “If we can identify these at-risk patients, we can potentially employ strategies to either fully prevent or mitigate these toxicities,” Dr. Scheurer said in a statement.

The research was supported by the National Institutes of Health and Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium, a St. Baldrick’s Foundation Consortium Research Grant. The researchers reported having no potential conflicts of interest.

SOURCE: Taylor OA et al. Clin Cancer Res. 2018 Sep 11. doi: 10.1158/1078-0432.CCR-18-0939.

Photo by Kevin Patrick Robbins/McMaster University

Researchers believe they have identified cells that are responsible for relapse of acute myeloid leukemia (AML).

These “leukemic-regenerating cells” (LRCs), which are distinct from leukemic stem cells (LSCs), seem to arise in response to chemotherapy.

Experiments in mouse models of AML suggested that targeting LRCs could reduce the risk of relapse, and analyses of AML patient samples suggested LRCs might be used to predict relapse.

Allison Boyd, PhD, of McMaster University in Hamilton, Ontario, Canada, and her colleagues reported these findings in Cancer Cell.

The researchers evaluated the leukemic populations that persist after chemotherapy by analyzing AML patient samples and xenograft AML models. The team found that LSCs were depleted by chemotherapy, and a different cell population, LRCs, appeared to arise in response to treatment.

LRCs are “molecularly distinct from therapy-naïve LSCs,” the researchers said. In fact, the team identified 19 genes that are preferentially expressed by LRCs and could be druggable.

One of these genes is DRD2, and the researchers found they could target LRCs using a small-molecule antagonist of DRD2.

Targeting LRCs

Dr. Boyd and her colleagues compared the effects of treatment with a DRD2 antagonist in AML xenografts populated with therapy-naive LSCs and AML xenografts that harbored LRCs following exposure to cytarabine.

The researchers said DRD2 antagonist therapy “moderately” affected AML progenitors in the LSC model but “had profound effects on regenerating LRCs.”

Treatment with the DRD2 antagonist also improved the efficacy of chemotherapy.

In xenografts derived from one AML patient, treatment with cytarabine alone left 50% of mice with residual disease. However, the addition of the DRD2 antagonist enabled 100% of the mice to achieve disease-free status.

In xenografts derived from a patient with more aggressive AML, all recipient mice had residual disease after receiving cytarabine. Treatment with the DRD2 antagonist slowed leukemic re-growth and nearly doubled the time to relapse.

Targeting LRCs also reduced disease regeneration potential in samples from other AML patients.

“This is a major clinical opportunity because this type of leukemia is very diverse and responds differently across patients,” Dr. Boyd said. “It has been a challenge in a clinical setting to find a commonality for therapeutic targeting across the wide array of patients, and these regenerative cells provide that similarity.”

Predicting relapse

Dr. Boyd and her colleagues also analyzed bone marrow samples collected from AML patients approximately 3 weeks after they completed standard induction chemotherapy.

The team found that progenitor activity was enriched among residual leukemic cells. However, patient cells lacked gene expression signatures related to therapy-naive LSCs.

“Instead, these highly regenerative AML cells preferentially expressed our LRC signature,” the researchers said.

The team also found evidence to suggest that LRC molecular profiles arise temporarily after chemotherapy. The LRC signature was not observed at diagnosis or once AML was re-established at relapse.

“We think there are opportunities here because now we have a window where we can kick the cancer while it’s down,” Dr. Boyd said.

She and her colleagues also found the LRC signature might be useful for predicting relapse in AML patients.

The team assessed expression of SLC2A2, an LRC marker that has overlapping expression with DRD2, in 7 patients who were in clinical remission after induction.

The researchers found that chemotherapy increased expression of SLC2A2 only in the four patients who had residual disease—not in the three patients who remained in disease-free remission for at least 5 years.

“These results suggest that LRC populations represent reservoirs of residual disease, and LRC marker expression levels can be linked to clinical outcomes of AML relapse,” the researchers said.

This study was supported by the Canadian Cancer Society, the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research, and other organizations.

Photo by Kevin Patrick Robbins/McMaster University

Researchers believe they have identified cells that are responsible for relapse of acute myeloid leukemia (AML).

These “leukemic-regenerating cells” (LRCs), which are distinct from leukemic stem cells (LSCs), seem to arise in response to chemotherapy.

Experiments in mouse models of AML suggested that targeting LRCs could reduce the risk of relapse, and analyses of AML patient samples suggested LRCs might be used to predict relapse.

Allison Boyd, PhD, of McMaster University in Hamilton, Ontario, Canada, and her colleagues reported these findings in Cancer Cell.

The researchers evaluated the leukemic populations that persist after chemotherapy by analyzing AML patient samples and xenograft AML models. The team found that LSCs were depleted by chemotherapy, and a different cell population, LRCs, appeared to arise in response to treatment.

LRCs are “molecularly distinct from therapy-naïve LSCs,” the researchers said. In fact, the team identified 19 genes that are preferentially expressed by LRCs and could be druggable.

One of these genes is DRD2, and the researchers found they could target LRCs using a small-molecule antagonist of DRD2.

Targeting LRCs

Dr. Boyd and her colleagues compared the effects of treatment with a DRD2 antagonist in AML xenografts populated with therapy-naive LSCs and AML xenografts that harbored LRCs following exposure to cytarabine.

The researchers said DRD2 antagonist therapy “moderately” affected AML progenitors in the LSC model but “had profound effects on regenerating LRCs.”

Treatment with the DRD2 antagonist also improved the efficacy of chemotherapy.

In xenografts derived from one AML patient, treatment with cytarabine alone left 50% of mice with residual disease. However, the addition of the DRD2 antagonist enabled 100% of the mice to achieve disease-free status.

In xenografts derived from a patient with more aggressive AML, all recipient mice had residual disease after receiving cytarabine. Treatment with the DRD2 antagonist slowed leukemic re-growth and nearly doubled the time to relapse.

Targeting LRCs also reduced disease regeneration potential in samples from other AML patients.

“This is a major clinical opportunity because this type of leukemia is very diverse and responds differently across patients,” Dr. Boyd said. “It has been a challenge in a clinical setting to find a commonality for therapeutic targeting across the wide array of patients, and these regenerative cells provide that similarity.”

Predicting relapse

Dr. Boyd and her colleagues also analyzed bone marrow samples collected from AML patients approximately 3 weeks after they completed standard induction chemotherapy.

The team found that progenitor activity was enriched among residual leukemic cells. However, patient cells lacked gene expression signatures related to therapy-naive LSCs.

“Instead, these highly regenerative AML cells preferentially expressed our LRC signature,” the researchers said.

The team also found evidence to suggest that LRC molecular profiles arise temporarily after chemotherapy. The LRC signature was not observed at diagnosis or once AML was re-established at relapse.

“We think there are opportunities here because now we have a window where we can kick the cancer while it’s down,” Dr. Boyd said.

She and her colleagues also found the LRC signature might be useful for predicting relapse in AML patients.

The team assessed expression of SLC2A2, an LRC marker that has overlapping expression with DRD2, in 7 patients who were in clinical remission after induction.

The researchers found that chemotherapy increased expression of SLC2A2 only in the four patients who had residual disease—not in the three patients who remained in disease-free remission for at least 5 years.

“These results suggest that LRC populations represent reservoirs of residual disease, and LRC marker expression levels can be linked to clinical outcomes of AML relapse,” the researchers said.

This study was supported by the Canadian Cancer Society, the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research, and other organizations.

Photo by Kevin Patrick Robbins/McMaster University

Researchers believe they have identified cells that are responsible for relapse of acute myeloid leukemia (AML).

These “leukemic-regenerating cells” (LRCs), which are distinct from leukemic stem cells (LSCs), seem to arise in response to chemotherapy.

Experiments in mouse models of AML suggested that targeting LRCs could reduce the risk of relapse, and analyses of AML patient samples suggested LRCs might be used to predict relapse.

Allison Boyd, PhD, of McMaster University in Hamilton, Ontario, Canada, and her colleagues reported these findings in Cancer Cell.

The researchers evaluated the leukemic populations that persist after chemotherapy by analyzing AML patient samples and xenograft AML models. The team found that LSCs were depleted by chemotherapy, and a different cell population, LRCs, appeared to arise in response to treatment.

LRCs are “molecularly distinct from therapy-naïve LSCs,” the researchers said. In fact, the team identified 19 genes that are preferentially expressed by LRCs and could be druggable.

One of these genes is DRD2, and the researchers found they could target LRCs using a small-molecule antagonist of DRD2.

Targeting LRCs

Dr. Boyd and her colleagues compared the effects of treatment with a DRD2 antagonist in AML xenografts populated with therapy-naive LSCs and AML xenografts that harbored LRCs following exposure to cytarabine.

The researchers said DRD2 antagonist therapy “moderately” affected AML progenitors in the LSC model but “had profound effects on regenerating LRCs.”

Treatment with the DRD2 antagonist also improved the efficacy of chemotherapy.

In xenografts derived from one AML patient, treatment with cytarabine alone left 50% of mice with residual disease. However, the addition of the DRD2 antagonist enabled 100% of the mice to achieve disease-free status.

In xenografts derived from a patient with more aggressive AML, all recipient mice had residual disease after receiving cytarabine. Treatment with the DRD2 antagonist slowed leukemic re-growth and nearly doubled the time to relapse.

Targeting LRCs also reduced disease regeneration potential in samples from other AML patients.

“This is a major clinical opportunity because this type of leukemia is very diverse and responds differently across patients,” Dr. Boyd said. “It has been a challenge in a clinical setting to find a commonality for therapeutic targeting across the wide array of patients, and these regenerative cells provide that similarity.”

Predicting relapse

Dr. Boyd and her colleagues also analyzed bone marrow samples collected from AML patients approximately 3 weeks after they completed standard induction chemotherapy.

The team found that progenitor activity was enriched among residual leukemic cells. However, patient cells lacked gene expression signatures related to therapy-naive LSCs.

“Instead, these highly regenerative AML cells preferentially expressed our LRC signature,” the researchers said.

The team also found evidence to suggest that LRC molecular profiles arise temporarily after chemotherapy. The LRC signature was not observed at diagnosis or once AML was re-established at relapse.

“We think there are opportunities here because now we have a window where we can kick the cancer while it’s down,” Dr. Boyd said.

She and her colleagues also found the LRC signature might be useful for predicting relapse in AML patients.

The team assessed expression of SLC2A2, an LRC marker that has overlapping expression with DRD2, in 7 patients who were in clinical remission after induction.

The researchers found that chemotherapy increased expression of SLC2A2 only in the four patients who had residual disease—not in the three patients who remained in disease-free remission for at least 5 years.

“These results suggest that LRC populations represent reservoirs of residual disease, and LRC marker expression levels can be linked to clinical outcomes of AML relapse,” the researchers said.

This study was supported by the Canadian Cancer Society, the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research, and other organizations.