The mode and risk of disease progression significantly differs for patients with IgM monoclonal gammopathy of undetermined significance (MGUS) and those with non-IgM MGUS, Robert A. Kyle, MD, and his colleagues reported in the New England Journal of Medicine.

The risk for progression among IgM MGUS patients was 1.1 events/100 person-years, compared with 0.8 events among those with non-IgM MGUS – a significant difference. The researchers also found that risk is related to monoclonal (M) protein level and abnormal serum-free, light-chain assay results for both forms of MGUS.

Further, risk of progression varied with duration of follow-up in IgM MGUS, unlike non-IgM MGUS. However, for MGUS in general, “the risk of progression to myeloma or a related disorder is much less than the competing risk of death due to other causes,” Dr. Kyle, of the Mayo Clinic, Rochester, Minn., and his associates wrote.

The findings should help to determine the appropriate type of monitoring for MGUS patients, the researchers concluded.

The researchers reported results of the longest-yet follow-up study of MGUS patients. The team described median 34-year follow-up data on 1,384 patients with MGUS –70% with IgG type, 12% with IgA type, 15% with IgM type, and 3% with a biclonal gammopathy. (The patients formed the basis of an initial 2002 report.) They were diagnosed during 1960-1994, at a mean age of 72 years. Of these patients, 1,300 (94%) have died.

Among the 210 patients with IgM MGUS, the risk of progression was 2%/year in the first 10 years after diagnosis and 1%/year thereafter. Risk of progression did not vary during the follow-up of patients with non-IgM MGUS.

“The initial concentration of the serum M protein and the serum-free, light-chain ratio were the most important univariate risk factors for progression to a plasma cell disorder among patients with IgM or non-IgM MGUS. Combined, these two variables provided prognostic value in both IgM MGUS and non-IgM types of MGUS,” the authors wrote.

They explained that the difference may lie in the origins of MGUS. “IgM MGUS typically arises from a CD20+ lymphoplasmacytic cell that has not undergone switch recombination. … In contrast, non-IgM MGUS typically arises from mature plasma cells that have undergone switch recombination.”

During follow-up, 11% of the group (147) developed an MGUS-related disorder, including multiple myeloma, lymphoma with an IgM serum M protein, AL amyloidosis, macroglobulinemia, chronic lymphocytic leukemia, or plasmacytoma. This represents a 6.5-fold increased risk compared to the age- and sex-matched background population. Patients with IgM MGUS had a higher risk of progression than did those with non-IgM MGUS (relative risk, 10.8 vs. 5.7).

The overall risk of progression to a plasma cell–related disorder was 10% at 10 years; 18% at 20 years; 28% at 30 years; 36% at 35 years, and 36% at 40 years.

Among patients with IgM MGUS, the presence of high serum M protein (at least 1.5 g/dL) and an abnormal serum-free, light-chain ratio increased the risk of progression to 55% at 20 years, compared with a 41% risk among those patients with one risk factor and 19% among those with neither factor.

Among patients with non-IgM MGUS, the presence of both factors conferred a 30% risk of progression by 20 years. The risk was 20% among those with one factor and 7% among those with neither.

Compared with a control population, patients experienced about a 4-year shorter median survival time (8.1 vs. 12 years). Patients with IgM MGUS had worse 30-year overall survival than those with non-IgM MGUS (4% vs. 7%).

“There were 474 excess deaths in the cohort and 142 persons who had progression to multiple myeloma or a related disorder – findings that indicate that many additional deaths cannot be attributed to disease progression,” the authors noted.

The majority of deceased patients had died from non-plasma cell disorders (87%), including cardiovascular and cerebrovascular events, and nonplasma cell cancers. “In addition to the risk of malignant progression, this finding may be related to potentially serious disorders that led to the initial unexpected diagnosis of MGUS.”

The study was funded in part by the National Cancer Institute.

Dr. Kyle disclosed financial relationships with Celgene, Bristol-Myers Squibb, Amgen, Pharmacyclics, and Pfizer.

[email protected]

SOURCE: Kyle RA et al. N Engl J Med. 2018;378:241-9.

The mode and risk of disease progression significantly differs for patients with IgM monoclonal gammopathy of undetermined significance (MGUS) and those with non-IgM MGUS, Robert A. Kyle, MD, and his colleagues reported in the New England Journal of Medicine.

The risk for progression among IgM MGUS patients was 1.1 events/100 person-years, compared with 0.8 events among those with non-IgM MGUS – a significant difference. The researchers also found that risk is related to monoclonal (M) protein level and abnormal serum-free, light-chain assay results for both forms of MGUS.

Further, risk of progression varied with duration of follow-up in IgM MGUS, unlike non-IgM MGUS. However, for MGUS in general, “the risk of progression to myeloma or a related disorder is much less than the competing risk of death due to other causes,” Dr. Kyle, of the Mayo Clinic, Rochester, Minn., and his associates wrote.

The findings should help to determine the appropriate type of monitoring for MGUS patients, the researchers concluded.

The researchers reported results of the longest-yet follow-up study of MGUS patients. The team described median 34-year follow-up data on 1,384 patients with MGUS –70% with IgG type, 12% with IgA type, 15% with IgM type, and 3% with a biclonal gammopathy. (The patients formed the basis of an initial 2002 report.) They were diagnosed during 1960-1994, at a mean age of 72 years. Of these patients, 1,300 (94%) have died.

Among the 210 patients with IgM MGUS, the risk of progression was 2%/year in the first 10 years after diagnosis and 1%/year thereafter. Risk of progression did not vary during the follow-up of patients with non-IgM MGUS.

“The initial concentration of the serum M protein and the serum-free, light-chain ratio were the most important univariate risk factors for progression to a plasma cell disorder among patients with IgM or non-IgM MGUS. Combined, these two variables provided prognostic value in both IgM MGUS and non-IgM types of MGUS,” the authors wrote.

They explained that the difference may lie in the origins of MGUS. “IgM MGUS typically arises from a CD20+ lymphoplasmacytic cell that has not undergone switch recombination. … In contrast, non-IgM MGUS typically arises from mature plasma cells that have undergone switch recombination.”

During follow-up, 11% of the group (147) developed an MGUS-related disorder, including multiple myeloma, lymphoma with an IgM serum M protein, AL amyloidosis, macroglobulinemia, chronic lymphocytic leukemia, or plasmacytoma. This represents a 6.5-fold increased risk compared to the age- and sex-matched background population. Patients with IgM MGUS had a higher risk of progression than did those with non-IgM MGUS (relative risk, 10.8 vs. 5.7).

The overall risk of progression to a plasma cell–related disorder was 10% at 10 years; 18% at 20 years; 28% at 30 years; 36% at 35 years, and 36% at 40 years.

Among patients with IgM MGUS, the presence of high serum M protein (at least 1.5 g/dL) and an abnormal serum-free, light-chain ratio increased the risk of progression to 55% at 20 years, compared with a 41% risk among those patients with one risk factor and 19% among those with neither factor.

Among patients with non-IgM MGUS, the presence of both factors conferred a 30% risk of progression by 20 years. The risk was 20% among those with one factor and 7% among those with neither.

Compared with a control population, patients experienced about a 4-year shorter median survival time (8.1 vs. 12 years). Patients with IgM MGUS had worse 30-year overall survival than those with non-IgM MGUS (4% vs. 7%).

“There were 474 excess deaths in the cohort and 142 persons who had progression to multiple myeloma or a related disorder – findings that indicate that many additional deaths cannot be attributed to disease progression,” the authors noted.

The majority of deceased patients had died from non-plasma cell disorders (87%), including cardiovascular and cerebrovascular events, and nonplasma cell cancers. “In addition to the risk of malignant progression, this finding may be related to potentially serious disorders that led to the initial unexpected diagnosis of MGUS.”

The study was funded in part by the National Cancer Institute.

Dr. Kyle disclosed financial relationships with Celgene, Bristol-Myers Squibb, Amgen, Pharmacyclics, and Pfizer.

[email protected]

SOURCE: Kyle RA et al. N Engl J Med. 2018;378:241-9.

The mode and risk of disease progression significantly differs for patients with IgM monoclonal gammopathy of undetermined significance (MGUS) and those with non-IgM MGUS, Robert A. Kyle, MD, and his colleagues reported in the New England Journal of Medicine.

The risk for progression among IgM MGUS patients was 1.1 events/100 person-years, compared with 0.8 events among those with non-IgM MGUS – a significant difference. The researchers also found that risk is related to monoclonal (M) protein level and abnormal serum-free, light-chain assay results for both forms of MGUS.

Further, risk of progression varied with duration of follow-up in IgM MGUS, unlike non-IgM MGUS. However, for MGUS in general, “the risk of progression to myeloma or a related disorder is much less than the competing risk of death due to other causes,” Dr. Kyle, of the Mayo Clinic, Rochester, Minn., and his associates wrote.

The findings should help to determine the appropriate type of monitoring for MGUS patients, the researchers concluded.

The researchers reported results of the longest-yet follow-up study of MGUS patients. The team described median 34-year follow-up data on 1,384 patients with MGUS –70% with IgG type, 12% with IgA type, 15% with IgM type, and 3% with a biclonal gammopathy. (The patients formed the basis of an initial 2002 report.) They were diagnosed during 1960-1994, at a mean age of 72 years. Of these patients, 1,300 (94%) have died.

Among the 210 patients with IgM MGUS, the risk of progression was 2%/year in the first 10 years after diagnosis and 1%/year thereafter. Risk of progression did not vary during the follow-up of patients with non-IgM MGUS.

“The initial concentration of the serum M protein and the serum-free, light-chain ratio were the most important univariate risk factors for progression to a plasma cell disorder among patients with IgM or non-IgM MGUS. Combined, these two variables provided prognostic value in both IgM MGUS and non-IgM types of MGUS,” the authors wrote.

They explained that the difference may lie in the origins of MGUS. “IgM MGUS typically arises from a CD20+ lymphoplasmacytic cell that has not undergone switch recombination. … In contrast, non-IgM MGUS typically arises from mature plasma cells that have undergone switch recombination.”

During follow-up, 11% of the group (147) developed an MGUS-related disorder, including multiple myeloma, lymphoma with an IgM serum M protein, AL amyloidosis, macroglobulinemia, chronic lymphocytic leukemia, or plasmacytoma. This represents a 6.5-fold increased risk compared to the age- and sex-matched background population. Patients with IgM MGUS had a higher risk of progression than did those with non-IgM MGUS (relative risk, 10.8 vs. 5.7).

The overall risk of progression to a plasma cell–related disorder was 10% at 10 years; 18% at 20 years; 28% at 30 years; 36% at 35 years, and 36% at 40 years.

Among patients with IgM MGUS, the presence of high serum M protein (at least 1.5 g/dL) and an abnormal serum-free, light-chain ratio increased the risk of progression to 55% at 20 years, compared with a 41% risk among those patients with one risk factor and 19% among those with neither factor.

Among patients with non-IgM MGUS, the presence of both factors conferred a 30% risk of progression by 20 years. The risk was 20% among those with one factor and 7% among those with neither.

Compared with a control population, patients experienced about a 4-year shorter median survival time (8.1 vs. 12 years). Patients with IgM MGUS had worse 30-year overall survival than those with non-IgM MGUS (4% vs. 7%).

“There were 474 excess deaths in the cohort and 142 persons who had progression to multiple myeloma or a related disorder – findings that indicate that many additional deaths cannot be attributed to disease progression,” the authors noted.

The majority of deceased patients had died from non-plasma cell disorders (87%), including cardiovascular and cerebrovascular events, and nonplasma cell cancers. “In addition to the risk of malignant progression, this finding may be related to potentially serious disorders that led to the initial unexpected diagnosis of MGUS.”

The study was funded in part by the National Cancer Institute.

Dr. Kyle disclosed financial relationships with Celgene, Bristol-Myers Squibb, Amgen, Pharmacyclics, and Pfizer.

[email protected]

SOURCE: Kyle RA et al. N Engl J Med. 2018;378:241-9.

No shocker here: > 90% of American homes have ≥ 3 detectable allergens, and 73% have at least 1 allergen at elevated levels, acceding to the largest U.S. indoor allergen study to date.

Using data from National Institute of Environmental Health Sciences  (NHANES) 2005-2006, researchers studied levels of 8 common allergens (cat, dog, cockroach, mouse, rat, mold, and 2 types of dust mite allergens) in nearly 7,000 homes.

Mobile homes, older homes, rental homes, and rural homes were more likely to have higher amounts of indoor allergens, as were homes with pets and pests.

Elevated levels of dust mites were more common in the South and Northeast and humid regions. Cat and dust mite allergens were more common in rural settings compared with urban.

The NHANES 2005-2006 data allowed national comparisons for the first time of exposure and sensitization. Men and non-Hispanic blacks were less likely to be exposed to multiple allergens, and sensitization was more common in those groups compared with women and other racial groups, respectively. Exposure to several elevated allergens was most prevalent in rural areas. Sensitization rates were higher in urban areas.

The researchers emphasize that the relationships between allergen exposures, allergic sensitization, and disease are complex. They also note that studies are still investigating how allergen exposures interact with other environmental and genetic factors in asthma and allergies. However, among the tips they offer: vacuum every week, wash sheets and blankets in hot water every week, and lower indoor humidity levels below 50%.

No shocker here: > 90% of American homes have ≥ 3 detectable allergens, and 73% have at least 1 allergen at elevated levels, acceding to the largest U.S. indoor allergen study to date.

Using data from National Institute of Environmental Health Sciences  (NHANES) 2005-2006, researchers studied levels of 8 common allergens (cat, dog, cockroach, mouse, rat, mold, and 2 types of dust mite allergens) in nearly 7,000 homes.

Mobile homes, older homes, rental homes, and rural homes were more likely to have higher amounts of indoor allergens, as were homes with pets and pests.

Elevated levels of dust mites were more common in the South and Northeast and humid regions. Cat and dust mite allergens were more common in rural settings compared with urban.

The NHANES 2005-2006 data allowed national comparisons for the first time of exposure and sensitization. Men and non-Hispanic blacks were less likely to be exposed to multiple allergens, and sensitization was more common in those groups compared with women and other racial groups, respectively. Exposure to several elevated allergens was most prevalent in rural areas. Sensitization rates were higher in urban areas.

The researchers emphasize that the relationships between allergen exposures, allergic sensitization, and disease are complex. They also note that studies are still investigating how allergen exposures interact with other environmental and genetic factors in asthma and allergies. However, among the tips they offer: vacuum every week, wash sheets and blankets in hot water every week, and lower indoor humidity levels below 50%.

No shocker here: > 90% of American homes have ≥ 3 detectable allergens, and 73% have at least 1 allergen at elevated levels, acceding to the largest U.S. indoor allergen study to date.

Using data from National Institute of Environmental Health Sciences  (NHANES) 2005-2006, researchers studied levels of 8 common allergens (cat, dog, cockroach, mouse, rat, mold, and 2 types of dust mite allergens) in nearly 7,000 homes.

Mobile homes, older homes, rental homes, and rural homes were more likely to have higher amounts of indoor allergens, as were homes with pets and pests.

Elevated levels of dust mites were more common in the South and Northeast and humid regions. Cat and dust mite allergens were more common in rural settings compared with urban.

The NHANES 2005-2006 data allowed national comparisons for the first time of exposure and sensitization. Men and non-Hispanic blacks were less likely to be exposed to multiple allergens, and sensitization was more common in those groups compared with women and other racial groups, respectively. Exposure to several elevated allergens was most prevalent in rural areas. Sensitization rates were higher in urban areas.

The researchers emphasize that the relationships between allergen exposures, allergic sensitization, and disease are complex. They also note that studies are still investigating how allergen exposures interact with other environmental and genetic factors in asthma and allergies. However, among the tips they offer: vacuum every week, wash sheets and blankets in hot water every week, and lower indoor humidity levels below 50%.

Photo courtesy of Janssen

The US Food and Drug Administration (FDA) has granted priority review to a supplemental biologics license application (sBLA) for daratumumab (Darzalex®).

This sBLA is for daratumumab (D) to be used in combination with bortezomib, melphalan, and prednisone (VMP) for the treatment of patients with newly diagnosed multiple myeloma (MM) who are ineligible for autologous stem cell transplant.

The FDA expects to make a decision on the sBLA by May 21, 2018.

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

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

The priority review for this sBLA is based on data from the phase 3 ALCYONE study, which were presented at the 2017 ASH Annual Meeting and simultaneously published in NEJM.

In this study, researchers compared VMP to D-VMP in 706 patients with newly diagnosed MM who were not eligible for high-dose chemotherapy with autologous stem cell transplant.

D-VMP produced deeper responses than VMP. The overall response rate was 74% in the VMP arm and 91% in the D-VMP arm (P<0.0001). The rate of complete response was 24% and 43%, respectively (P<0.0001).

D-VMP also prolonged progression-free survival (PFS) compared to VMP.

The median PFS was 18.1 months in the VMP arm and was not reached in the D-VMP arm. The 12-month PFS was 76% and 87%, respectively. And the 18-month PFS was 50% and 72%, respectively.

The median overall survival was not reached in either treatment arm.

The most common grade 3/4 treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (40% and 39%), thrombocytopenia (34% and 38%), and anemia (16% and 20%).

The rate of grade 3/4 infections was higher in the D-VMP arm than the VMP arm—23% and 15%, respectively. The most common of these was pneumonia, with rates of 11% and 4%, respectively.

There were 6 deaths due to treatment-emergent adverse events in the D-VMP arm and 5 in the VMP arm.

About daratumumab

Daratumumab is a CD38-directed cytolytic antibody that is FDA approved for the following indications:

• In combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of MM patients who have received at least 1 prior therapy
• In combination with pomalidomide and dexamethasone for the treatment of MM patients who have received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor (PI)
• As monotherapy for MM patients who have received at least 3 prior lines of therapy, including a PI and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.
  

Photo courtesy of Janssen

The US Food and Drug Administration (FDA) has granted priority review to a supplemental biologics license application (sBLA) for daratumumab (Darzalex®).

This sBLA is for daratumumab (D) to be used in combination with bortezomib, melphalan, and prednisone (VMP) for the treatment of patients with newly diagnosed multiple myeloma (MM) who are ineligible for autologous stem cell transplant.

The FDA expects to make a decision on the sBLA by May 21, 2018.

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

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

The priority review for this sBLA is based on data from the phase 3 ALCYONE study, which were presented at the 2017 ASH Annual Meeting and simultaneously published in NEJM.

In this study, researchers compared VMP to D-VMP in 706 patients with newly diagnosed MM who were not eligible for high-dose chemotherapy with autologous stem cell transplant.

D-VMP produced deeper responses than VMP. The overall response rate was 74% in the VMP arm and 91% in the D-VMP arm (P<0.0001). The rate of complete response was 24% and 43%, respectively (P<0.0001).

D-VMP also prolonged progression-free survival (PFS) compared to VMP.

The median PFS was 18.1 months in the VMP arm and was not reached in the D-VMP arm. The 12-month PFS was 76% and 87%, respectively. And the 18-month PFS was 50% and 72%, respectively.

The median overall survival was not reached in either treatment arm.

The most common grade 3/4 treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (40% and 39%), thrombocytopenia (34% and 38%), and anemia (16% and 20%).

The rate of grade 3/4 infections was higher in the D-VMP arm than the VMP arm—23% and 15%, respectively. The most common of these was pneumonia, with rates of 11% and 4%, respectively.

There were 6 deaths due to treatment-emergent adverse events in the D-VMP arm and 5 in the VMP arm.

About daratumumab

Daratumumab is a CD38-directed cytolytic antibody that is FDA approved for the following indications:

• In combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of MM patients who have received at least 1 prior therapy
• In combination with pomalidomide and dexamethasone for the treatment of MM patients who have received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor (PI)
• As monotherapy for MM patients who have received at least 3 prior lines of therapy, including a PI and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.
  

Photo courtesy of Janssen

The US Food and Drug Administration (FDA) has granted priority review to a supplemental biologics license application (sBLA) for daratumumab (Darzalex®).

This sBLA is for daratumumab (D) to be used in combination with bortezomib, melphalan, and prednisone (VMP) for the treatment of patients with newly diagnosed multiple myeloma (MM) who are ineligible for autologous stem cell transplant.

The FDA expects to make a decision on the sBLA by May 21, 2018.

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

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

The priority review for this sBLA is based on data from the phase 3 ALCYONE study, which were presented at the 2017 ASH Annual Meeting and simultaneously published in NEJM.

In this study, researchers compared VMP to D-VMP in 706 patients with newly diagnosed MM who were not eligible for high-dose chemotherapy with autologous stem cell transplant.

D-VMP produced deeper responses than VMP. The overall response rate was 74% in the VMP arm and 91% in the D-VMP arm (P<0.0001). The rate of complete response was 24% and 43%, respectively (P<0.0001).

D-VMP also prolonged progression-free survival (PFS) compared to VMP.

The median PFS was 18.1 months in the VMP arm and was not reached in the D-VMP arm. The 12-month PFS was 76% and 87%, respectively. And the 18-month PFS was 50% and 72%, respectively.

The median overall survival was not reached in either treatment arm.

The most common grade 3/4 treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (40% and 39%), thrombocytopenia (34% and 38%), and anemia (16% and 20%).

The rate of grade 3/4 infections was higher in the D-VMP arm than the VMP arm—23% and 15%, respectively. The most common of these was pneumonia, with rates of 11% and 4%, respectively.

There were 6 deaths due to treatment-emergent adverse events in the D-VMP arm and 5 in the VMP arm.

About daratumumab

Daratumumab is a CD38-directed cytolytic antibody that is FDA approved for the following indications:

• In combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of MM patients who have received at least 1 prior therapy
• In combination with pomalidomide and dexamethasone for the treatment of MM patients who have received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor (PI)
• As monotherapy for MM patients who have received at least 3 prior lines of therapy, including a PI and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.
  

Clinical question: Does cost messaging at the time of ordering reduce prescriber use of high-cost medications?

Background: Overprescribing expensive medications contributes to inpatient health care expenditures and may be avoidable when low-cost alternatives are available.

Dr. Lublin is a hospitalist at the University of Colorado School of Medicine.

Clinical question: Does cost messaging at the time of ordering reduce prescriber use of high-cost medications?

Background: Overprescribing expensive medications contributes to inpatient health care expenditures and may be avoidable when low-cost alternatives are available.

Dr. Lublin is a hospitalist at the University of Colorado School of Medicine.

Clinical question: Does cost messaging at the time of ordering reduce prescriber use of high-cost medications?

Background: Overprescribing expensive medications contributes to inpatient health care expenditures and may be avoidable when low-cost alternatives are available.

Dr. Lublin is a hospitalist at the University of Colorado School of Medicine.

This video was filmed at Metabolic & Endocrine Disease Summit (MEDS). Click here to learn more.

This video was filmed at Metabolic & Endocrine Disease Summit (MEDS). Click here to learn more.

This video was filmed at Metabolic & Endocrine Disease Summit (MEDS). Click here to learn more.

Recurrent serious infections are relatively common among individuals with rheumatoid arthritis, particularly in the first year after an infection, according to findings from a study of the British Society for Rheumatology Biologics Register–Rheumatoid Arthritis.

Sujith Subesinghe, MBBS, from the academic department of rheumatology at King’s College London and his coauthors identified 5,289 individuals from the registry who had experienced at least one episode of serious infection. All patients were also on either conventional synthetic disease-modifying antirheumatic drugs (DMARDs) or biologic DMARDs at the time of their index infection.

TongRo Images/Thinkstock

“It has been shown previously that a history of SI [serious infection] is a strong predictor of subsequent SI, but what has not been shown before is that the organ class of the index event has a large impact on the likelihood of recurrent SI,” the authors wrote.

Each decade of increased age was associated with a 34% increase in risk of recurrent infection. Noting that multiple drug use was a surrogate measure of comorbidity at baseline, researchers found that individuals taking 6-10 drugs at baseline had a 26% increased risk for recurrent infection, while those treated with 11 or more drugs had a 74% increased risk.

The authors observed that baseline steroid use was higher among patients suffering sepsis, compared with other types of serious infection.

They observed that, although a strong association between serious infection and steroid use has been reported, no firm conclusions have been reached by systematic reviews or meta-analyses “Steroids are more likely to be prescribed to patients with more aggressive, recalcitrant disease; this group has a higher baseline infection risk, and therefore, there is potential for confounding by indication.”

However, baseline disease activity score, disease duration, seropositivity, and smoking did not significantly predict the likelihood of infection recurrence, despite the fact that these are traditional predictors of infection. The authors suggested this may be the result of a form of selection bias.

“Patients readmitted with SI were from an already at-risk group and therefore lack of association between traditional predictors of infection and recurrent SI may be spurious.”

Commenting on their findings, the authors observed that individuals with rheumatoid arthritis and a history of infection were a complex group to manage, and even small differences in relative infection risk with different biologics may become significant.

“Further research needs to be undertaken to understand the patterns of recurrent infection and to appreciate the nuances in differential infection profiles of immunosuppressive drugs, to promote safe therapeutic decisions and promote personalization of care.”

The study was supported by the British Society for Rheumatology. Two authors declared speaking fees or honoraria from the pharmaceutical industry.

[email protected]

SOURCE: Subesinghe S et al. Rheumatology [Oxford]. 2018 Jan 10. doi: 10.1093/rheumatology/kex469.

Recurrent serious infections are relatively common among individuals with rheumatoid arthritis, particularly in the first year after an infection, according to findings from a study of the British Society for Rheumatology Biologics Register–Rheumatoid Arthritis.

Sujith Subesinghe, MBBS, from the academic department of rheumatology at King’s College London and his coauthors identified 5,289 individuals from the registry who had experienced at least one episode of serious infection. All patients were also on either conventional synthetic disease-modifying antirheumatic drugs (DMARDs) or biologic DMARDs at the time of their index infection.

TongRo Images/Thinkstock

“It has been shown previously that a history of SI [serious infection] is a strong predictor of subsequent SI, but what has not been shown before is that the organ class of the index event has a large impact on the likelihood of recurrent SI,” the authors wrote.

Each decade of increased age was associated with a 34% increase in risk of recurrent infection. Noting that multiple drug use was a surrogate measure of comorbidity at baseline, researchers found that individuals taking 6-10 drugs at baseline had a 26% increased risk for recurrent infection, while those treated with 11 or more drugs had a 74% increased risk.

The authors observed that baseline steroid use was higher among patients suffering sepsis, compared with other types of serious infection.

They observed that, although a strong association between serious infection and steroid use has been reported, no firm conclusions have been reached by systematic reviews or meta-analyses “Steroids are more likely to be prescribed to patients with more aggressive, recalcitrant disease; this group has a higher baseline infection risk, and therefore, there is potential for confounding by indication.”

However, baseline disease activity score, disease duration, seropositivity, and smoking did not significantly predict the likelihood of infection recurrence, despite the fact that these are traditional predictors of infection. The authors suggested this may be the result of a form of selection bias.

“Patients readmitted with SI were from an already at-risk group and therefore lack of association between traditional predictors of infection and recurrent SI may be spurious.”

Commenting on their findings, the authors observed that individuals with rheumatoid arthritis and a history of infection were a complex group to manage, and even small differences in relative infection risk with different biologics may become significant.

“Further research needs to be undertaken to understand the patterns of recurrent infection and to appreciate the nuances in differential infection profiles of immunosuppressive drugs, to promote safe therapeutic decisions and promote personalization of care.”

The study was supported by the British Society for Rheumatology. Two authors declared speaking fees or honoraria from the pharmaceutical industry.

[email protected]

SOURCE: Subesinghe S et al. Rheumatology [Oxford]. 2018 Jan 10. doi: 10.1093/rheumatology/kex469.

Recurrent serious infections are relatively common among individuals with rheumatoid arthritis, particularly in the first year after an infection, according to findings from a study of the British Society for Rheumatology Biologics Register–Rheumatoid Arthritis.

Sujith Subesinghe, MBBS, from the academic department of rheumatology at King’s College London and his coauthors identified 5,289 individuals from the registry who had experienced at least one episode of serious infection. All patients were also on either conventional synthetic disease-modifying antirheumatic drugs (DMARDs) or biologic DMARDs at the time of their index infection.

TongRo Images/Thinkstock

“It has been shown previously that a history of SI [serious infection] is a strong predictor of subsequent SI, but what has not been shown before is that the organ class of the index event has a large impact on the likelihood of recurrent SI,” the authors wrote.

Each decade of increased age was associated with a 34% increase in risk of recurrent infection. Noting that multiple drug use was a surrogate measure of comorbidity at baseline, researchers found that individuals taking 6-10 drugs at baseline had a 26% increased risk for recurrent infection, while those treated with 11 or more drugs had a 74% increased risk.

The authors observed that baseline steroid use was higher among patients suffering sepsis, compared with other types of serious infection.

They observed that, although a strong association between serious infection and steroid use has been reported, no firm conclusions have been reached by systematic reviews or meta-analyses “Steroids are more likely to be prescribed to patients with more aggressive, recalcitrant disease; this group has a higher baseline infection risk, and therefore, there is potential for confounding by indication.”

However, baseline disease activity score, disease duration, seropositivity, and smoking did not significantly predict the likelihood of infection recurrence, despite the fact that these are traditional predictors of infection. The authors suggested this may be the result of a form of selection bias.

“Patients readmitted with SI were from an already at-risk group and therefore lack of association between traditional predictors of infection and recurrent SI may be spurious.”

Commenting on their findings, the authors observed that individuals with rheumatoid arthritis and a history of infection were a complex group to manage, and even small differences in relative infection risk with different biologics may become significant.

“Further research needs to be undertaken to understand the patterns of recurrent infection and to appreciate the nuances in differential infection profiles of immunosuppressive drugs, to promote safe therapeutic decisions and promote personalization of care.”

The study was supported by the British Society for Rheumatology. Two authors declared speaking fees or honoraria from the pharmaceutical industry.

[email protected]

SOURCE: Subesinghe S et al. Rheumatology [Oxford]. 2018 Jan 10. doi: 10.1093/rheumatology/kex469.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

ATLANTA – Minimal residual disease-guided treatment with azacitidine is an effective strategy for preventing or delaying hematological relapse in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) who are at high risk for relapse, according to findings from the open-label, interventional RELAZA2 trial.

Of 205 patients screened between 2011 and 2015 at 11 centers in Germany, 53 became minimal residual disease (MRD) positive while remaining in hematological remission. All 53 started azacitidine-based preemptive treatment, and 6 months after the initiation of the MRD-guided therapy, 31 (58%) were still in complete remission, while 22 (42%) relapsed after a median of three treatment cycles, Uwe Platzbecker, MD, reported at the annual meeting of the American Society of Hematology.

Of those still in complete remission, 21 patients responded with a decline of MRD below a predefined threshold, and 10 achieved stabilization in the absence of relapse, said Dr. Platzbecker of the University Hospital Carl Gustav Carus Dresden, Germany.

The overall response rate was greater in those who underwent allogeneic hematopoietic stem cell transplantation (71% vs. 48%), he noted.

“After 6 months, 24 patients continued to receive a median of nine subsequent azacitidine cycles. Seven patients completed 24 months of treatment according to protocol. Eventually, hematologic relapse occurred in eight of those patients (33%) but was delayed until a median of 397 days after initial MRD detection,” he said in an interview, adding that, overall, 26 of the 53 patients in the study (49%) experienced hematologic relapse, which was delayed until a median of 422 days after initial MRD detection.

Study subjects were adults with a median age of 59 years with measurable MRD suggestive of imminent relapse but who were still in CR. Most (48) had AML, and 5 had MDS. They were treated preemptively with six cycles of 75 mg/m² of azacitidine given subcutaneously on days 1-7 of each 1-month cycle. Those who continued treatment beyond the initial 6 months were treated with risk-adapted azacitidine-based therapy for up to 18 additional months.

Treatment was well tolerated. Grade 3 or 4 thrombocytopenia occurred in three patients, and grade 3 or 4 neutropenia occurred in 45 patients. Infections and pneumonia, which occurred in four and three patients, respectively, were the main serious side effects during the first 6 cycles.

“With a median follow-up of 13 months after the start of MRD-guided preemptive treatment, the actual overall and progression free survival rate was 76% and 42%, respectively,” Dr. Platzbecker said.

Chemotherapy frequently results in complete remission in patients with MDS or AML, but a substantial proportion of patients relapse even after allogeneic stem cell transplantation, he said, noting that treatment options in these patients are limited.

In the prospective RELAZA 1 trial, short-term preemptive azacitidine therapy was associated with sustained responses. RELAZA2 was designed to assess the ability of early nonintensive azacitidine treatment, directed by MRD monitoring after allogeneic stem cell transplantation and chemotherapy, prior to avert relapse.

The findings suggest that this approach is effective in patients at higher risk of relapse, but the success of treatment seems to be context dependent, Dr. Platzbecker said, explaining that this finding emphasizes the potential immunomodulatory role of hypomethylating agents.

“The study supports the prognostic importance of MRD in AML and may serve as a platform for future studies in combining hypomethylating agents and novel targeted therapies,” he concluded.

The RELAZA2 trial is sponsored by Technische Universität Dresden. Dr. Platzbecker reported serving as a consultant for, and receiving honoraria and research funding from Celgene, Janssen, Novartis, and Acceleron.

[email protected]

SOURCE: Platzbecker U et al. ASH 2017 Abstract #565.

ATLANTA – Minimal residual disease-guided treatment with azacitidine is an effective strategy for preventing or delaying hematological relapse in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) who are at high risk for relapse, according to findings from the open-label, interventional RELAZA2 trial.

Of 205 patients screened between 2011 and 2015 at 11 centers in Germany, 53 became minimal residual disease (MRD) positive while remaining in hematological remission. All 53 started azacitidine-based preemptive treatment, and 6 months after the initiation of the MRD-guided therapy, 31 (58%) were still in complete remission, while 22 (42%) relapsed after a median of three treatment cycles, Uwe Platzbecker, MD, reported at the annual meeting of the American Society of Hematology.

Of those still in complete remission, 21 patients responded with a decline of MRD below a predefined threshold, and 10 achieved stabilization in the absence of relapse, said Dr. Platzbecker of the University Hospital Carl Gustav Carus Dresden, Germany.

The overall response rate was greater in those who underwent allogeneic hematopoietic stem cell transplantation (71% vs. 48%), he noted.

“After 6 months, 24 patients continued to receive a median of nine subsequent azacitidine cycles. Seven patients completed 24 months of treatment according to protocol. Eventually, hematologic relapse occurred in eight of those patients (33%) but was delayed until a median of 397 days after initial MRD detection,” he said in an interview, adding that, overall, 26 of the 53 patients in the study (49%) experienced hematologic relapse, which was delayed until a median of 422 days after initial MRD detection.

Study subjects were adults with a median age of 59 years with measurable MRD suggestive of imminent relapse but who were still in CR. Most (48) had AML, and 5 had MDS. They were treated preemptively with six cycles of 75 mg/m² of azacitidine given subcutaneously on days 1-7 of each 1-month cycle. Those who continued treatment beyond the initial 6 months were treated with risk-adapted azacitidine-based therapy for up to 18 additional months.

Treatment was well tolerated. Grade 3 or 4 thrombocytopenia occurred in three patients, and grade 3 or 4 neutropenia occurred in 45 patients. Infections and pneumonia, which occurred in four and three patients, respectively, were the main serious side effects during the first 6 cycles.

“With a median follow-up of 13 months after the start of MRD-guided preemptive treatment, the actual overall and progression free survival rate was 76% and 42%, respectively,” Dr. Platzbecker said.

Chemotherapy frequently results in complete remission in patients with MDS or AML, but a substantial proportion of patients relapse even after allogeneic stem cell transplantation, he said, noting that treatment options in these patients are limited.

In the prospective RELAZA 1 trial, short-term preemptive azacitidine therapy was associated with sustained responses. RELAZA2 was designed to assess the ability of early nonintensive azacitidine treatment, directed by MRD monitoring after allogeneic stem cell transplantation and chemotherapy, prior to avert relapse.

The findings suggest that this approach is effective in patients at higher risk of relapse, but the success of treatment seems to be context dependent, Dr. Platzbecker said, explaining that this finding emphasizes the potential immunomodulatory role of hypomethylating agents.

“The study supports the prognostic importance of MRD in AML and may serve as a platform for future studies in combining hypomethylating agents and novel targeted therapies,” he concluded.

The RELAZA2 trial is sponsored by Technische Universität Dresden. Dr. Platzbecker reported serving as a consultant for, and receiving honoraria and research funding from Celgene, Janssen, Novartis, and Acceleron.

[email protected]

SOURCE: Platzbecker U et al. ASH 2017 Abstract #565.

ATLANTA – Minimal residual disease-guided treatment with azacitidine is an effective strategy for preventing or delaying hematological relapse in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) who are at high risk for relapse, according to findings from the open-label, interventional RELAZA2 trial.

Of 205 patients screened between 2011 and 2015 at 11 centers in Germany, 53 became minimal residual disease (MRD) positive while remaining in hematological remission. All 53 started azacitidine-based preemptive treatment, and 6 months after the initiation of the MRD-guided therapy, 31 (58%) were still in complete remission, while 22 (42%) relapsed after a median of three treatment cycles, Uwe Platzbecker, MD, reported at the annual meeting of the American Society of Hematology.

Of those still in complete remission, 21 patients responded with a decline of MRD below a predefined threshold, and 10 achieved stabilization in the absence of relapse, said Dr. Platzbecker of the University Hospital Carl Gustav Carus Dresden, Germany.

The overall response rate was greater in those who underwent allogeneic hematopoietic stem cell transplantation (71% vs. 48%), he noted.

“After 6 months, 24 patients continued to receive a median of nine subsequent azacitidine cycles. Seven patients completed 24 months of treatment according to protocol. Eventually, hematologic relapse occurred in eight of those patients (33%) but was delayed until a median of 397 days after initial MRD detection,” he said in an interview, adding that, overall, 26 of the 53 patients in the study (49%) experienced hematologic relapse, which was delayed until a median of 422 days after initial MRD detection.

Study subjects were adults with a median age of 59 years with measurable MRD suggestive of imminent relapse but who were still in CR. Most (48) had AML, and 5 had MDS. They were treated preemptively with six cycles of 75 mg/m² of azacitidine given subcutaneously on days 1-7 of each 1-month cycle. Those who continued treatment beyond the initial 6 months were treated with risk-adapted azacitidine-based therapy for up to 18 additional months.

Treatment was well tolerated. Grade 3 or 4 thrombocytopenia occurred in three patients, and grade 3 or 4 neutropenia occurred in 45 patients. Infections and pneumonia, which occurred in four and three patients, respectively, were the main serious side effects during the first 6 cycles.

“With a median follow-up of 13 months after the start of MRD-guided preemptive treatment, the actual overall and progression free survival rate was 76% and 42%, respectively,” Dr. Platzbecker said.

Chemotherapy frequently results in complete remission in patients with MDS or AML, but a substantial proportion of patients relapse even after allogeneic stem cell transplantation, he said, noting that treatment options in these patients are limited.

In the prospective RELAZA 1 trial, short-term preemptive azacitidine therapy was associated with sustained responses. RELAZA2 was designed to assess the ability of early nonintensive azacitidine treatment, directed by MRD monitoring after allogeneic stem cell transplantation and chemotherapy, prior to avert relapse.

The findings suggest that this approach is effective in patients at higher risk of relapse, but the success of treatment seems to be context dependent, Dr. Platzbecker said, explaining that this finding emphasizes the potential immunomodulatory role of hypomethylating agents.

“The study supports the prognostic importance of MRD in AML and may serve as a platform for future studies in combining hypomethylating agents and novel targeted therapies,” he concluded.

The RELAZA2 trial is sponsored by Technische Universität Dresden. Dr. Platzbecker reported serving as a consultant for, and receiving honoraria and research funding from Celgene, Janssen, Novartis, and Acceleron.

[email protected]

SOURCE: Platzbecker U et al. ASH 2017 Abstract #565.

Micrograph showing MDS

Researchers have developed a technique that may help predict whether patients with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) will respond to treatment with azacytidine (AZA).

“The new method, called AZA-MS, utilizes a cutting-edge technique known as mass spectrometry to measure the different forms of AZA inside blood cells of patients—such as the AZA molecules that are incorporated into the DNA or RNA,” said Ashwin Unnikrishnan, PhD, of the University of New South Wales in Sydney, Australia.

With this method, Dr Unnikrishnan and his colleagues found that patients who do not respond to AZA may incorporate fewer AZA molecules in their DNA and have lower DNA demethylation than responders. However, this is not always the case.

The researchers reported these findings in Leukemia.

The team initially tested AZA-MS in AZA-treated RKO cells and found that AZA-MS could quantify the ribonucleoside (5-AZA-cR) and deoxyribonucleoside (5-AZA-CdR) forms of AZA in RNA, DNA, and the cytoplasm—all in the same sample.

The researchers also found that AZA induced dose-dependent DNA demethylation but did not have an effect on RNA methylation.

The team then used AZA-MS to analyze bone marrow samples from patients with MDS (n=4) or CMML (n=4) who were undergoing treatment with AZA. All of the patients had received at least 6 cycles of the drug.

Each patient had 3 bone marrow samples collected—one immediately before starting treatment; one on day 8 of cycle 1 (C1d8); and one on day 28 of cycle 1 (C1d28), when they had spent 20 days off the drug.

Four of the patients were complete responders, and 4 were nonresponders. In each group, 2 patients had MDS, and 2 had CMML.

At C1d8, DNA-5-AZA-CdR was significantly greater in responders than nonresponders. And, overall, responders had increased DNA demethylation compared to nonresponders.

However, the researchers also observed differences among the nonresponders. Two nonresponders had very low levels of DNA-5-AZA-CdR at C1d8 and no demethylation. The other 2 nonresponders had much higher DNA-5-AZA-CdR and DNA demethylation levels, which were comparable to levels in responders.

The researchers said they could detect AZA and DNA-5-AZA-CdR intracellularly, as well as RNA-AZA, in the nonresponders with minimal DNA-5-AZA-CdR and DNA demethylation.

The team said this suggests that neither cellular uptake nor intracellular metabolism explain the low DNA-5-AZA-CdR in these patients. Instead, the researchers believe these patients may have a greater proportion of bone marrow cells that are quiescent and not undergoing DNA replication.

The researchers also believe the nonresponders with higher DNA-5-AZA-CdR may be explained by a failure to induce an interferon response, which is necessary for a clinical response.

On the other hand, these nonresponders could have defective immune cell-mediated clearance of dysplastic cells or increased tolerance to this clearance, the researchers said.

The team also noted that, at C1d28, DNA-5-AZA-CdR levels dropped (but were still detectable) in all 8 patients, and DNA methylation had nearly returned to pretreatment levels in all patients.

Micrograph showing MDS

Researchers have developed a technique that may help predict whether patients with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) will respond to treatment with azacytidine (AZA).

“The new method, called AZA-MS, utilizes a cutting-edge technique known as mass spectrometry to measure the different forms of AZA inside blood cells of patients—such as the AZA molecules that are incorporated into the DNA or RNA,” said Ashwin Unnikrishnan, PhD, of the University of New South Wales in Sydney, Australia.

With this method, Dr Unnikrishnan and his colleagues found that patients who do not respond to AZA may incorporate fewer AZA molecules in their DNA and have lower DNA demethylation than responders. However, this is not always the case.

The researchers reported these findings in Leukemia.

The team initially tested AZA-MS in AZA-treated RKO cells and found that AZA-MS could quantify the ribonucleoside (5-AZA-cR) and deoxyribonucleoside (5-AZA-CdR) forms of AZA in RNA, DNA, and the cytoplasm—all in the same sample.

The researchers also found that AZA induced dose-dependent DNA demethylation but did not have an effect on RNA methylation.

The team then used AZA-MS to analyze bone marrow samples from patients with MDS (n=4) or CMML (n=4) who were undergoing treatment with AZA. All of the patients had received at least 6 cycles of the drug.

Each patient had 3 bone marrow samples collected—one immediately before starting treatment; one on day 8 of cycle 1 (C1d8); and one on day 28 of cycle 1 (C1d28), when they had spent 20 days off the drug.

Four of the patients were complete responders, and 4 were nonresponders. In each group, 2 patients had MDS, and 2 had CMML.

At C1d8, DNA-5-AZA-CdR was significantly greater in responders than nonresponders. And, overall, responders had increased DNA demethylation compared to nonresponders.

However, the researchers also observed differences among the nonresponders. Two nonresponders had very low levels of DNA-5-AZA-CdR at C1d8 and no demethylation. The other 2 nonresponders had much higher DNA-5-AZA-CdR and DNA demethylation levels, which were comparable to levels in responders.

The researchers said they could detect AZA and DNA-5-AZA-CdR intracellularly, as well as RNA-AZA, in the nonresponders with minimal DNA-5-AZA-CdR and DNA demethylation.

The team said this suggests that neither cellular uptake nor intracellular metabolism explain the low DNA-5-AZA-CdR in these patients. Instead, the researchers believe these patients may have a greater proportion of bone marrow cells that are quiescent and not undergoing DNA replication.

The researchers also believe the nonresponders with higher DNA-5-AZA-CdR may be explained by a failure to induce an interferon response, which is necessary for a clinical response.

On the other hand, these nonresponders could have defective immune cell-mediated clearance of dysplastic cells or increased tolerance to this clearance, the researchers said.

The team also noted that, at C1d28, DNA-5-AZA-CdR levels dropped (but were still detectable) in all 8 patients, and DNA methylation had nearly returned to pretreatment levels in all patients.

Micrograph showing MDS

Researchers have developed a technique that may help predict whether patients with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) will respond to treatment with azacytidine (AZA).

“The new method, called AZA-MS, utilizes a cutting-edge technique known as mass spectrometry to measure the different forms of AZA inside blood cells of patients—such as the AZA molecules that are incorporated into the DNA or RNA,” said Ashwin Unnikrishnan, PhD, of the University of New South Wales in Sydney, Australia.

With this method, Dr Unnikrishnan and his colleagues found that patients who do not respond to AZA may incorporate fewer AZA molecules in their DNA and have lower DNA demethylation than responders. However, this is not always the case.

The researchers reported these findings in Leukemia.

The team initially tested AZA-MS in AZA-treated RKO cells and found that AZA-MS could quantify the ribonucleoside (5-AZA-cR) and deoxyribonucleoside (5-AZA-CdR) forms of AZA in RNA, DNA, and the cytoplasm—all in the same sample.

The researchers also found that AZA induced dose-dependent DNA demethylation but did not have an effect on RNA methylation.

The team then used AZA-MS to analyze bone marrow samples from patients with MDS (n=4) or CMML (n=4) who were undergoing treatment with AZA. All of the patients had received at least 6 cycles of the drug.

Each patient had 3 bone marrow samples collected—one immediately before starting treatment; one on day 8 of cycle 1 (C1d8); and one on day 28 of cycle 1 (C1d28), when they had spent 20 days off the drug.

Four of the patients were complete responders, and 4 were nonresponders. In each group, 2 patients had MDS, and 2 had CMML.

At C1d8, DNA-5-AZA-CdR was significantly greater in responders than nonresponders. And, overall, responders had increased DNA demethylation compared to nonresponders.

However, the researchers also observed differences among the nonresponders. Two nonresponders had very low levels of DNA-5-AZA-CdR at C1d8 and no demethylation. The other 2 nonresponders had much higher DNA-5-AZA-CdR and DNA demethylation levels, which were comparable to levels in responders.

The researchers said they could detect AZA and DNA-5-AZA-CdR intracellularly, as well as RNA-AZA, in the nonresponders with minimal DNA-5-AZA-CdR and DNA demethylation.

The team said this suggests that neither cellular uptake nor intracellular metabolism explain the low DNA-5-AZA-CdR in these patients. Instead, the researchers believe these patients may have a greater proportion of bone marrow cells that are quiescent and not undergoing DNA replication.

The researchers also believe the nonresponders with higher DNA-5-AZA-CdR may be explained by a failure to induce an interferon response, which is necessary for a clinical response.

On the other hand, these nonresponders could have defective immune cell-mediated clearance of dysplastic cells or increased tolerance to this clearance, the researchers said.

The team also noted that, at C1d28, DNA-5-AZA-CdR levels dropped (but were still detectable) in all 8 patients, and DNA methylation had nearly returned to pretreatment levels in all patients.

SAN FRANCISCO – Colorectal cancer originating on the right side carries a higher risk of recurrence or death after adjuvant oxaliplatin-based chemotherapy, suggests a new analysis of data from the SCOT (Short Course Oncology Therapy) trial. But patients with right-sided disease fare about the same whether given the usual 6 months of chemotherapy or half that.

“It’s becoming clear that right-sided tumors are different from left-sided tumors,” commented first author Mark P. Saunders, MD, PhD, a consultant oncologist at the Christie NHS Foundation Trust, Manchester, England. A large meta-analysis showed that early right-sided tumors were associated with poorer overall survival (JAMA Oncol. 2016 Oct 27. doi: 10.1001/jamaoncol.2016.4227), but it remains unclear at what point(s) in the course of disease and its treatment sidedness is exerting its influence.

Findings in context

“This study was interesting, but I feel that we still need more data coming from the main study,” session chair Michael J. Hall, MD, MS, a medical oncologist at the Fox Chase Cancer Center, Philadelphia, said in an interview. “It’s important to let us know that adjuvant chemotherapy appears to be beneficial, regardless of side, but there are still some other important questions.”

More detail on the difference by side according to chemotherapy duration and according to regimen (because recent data suggest CAPOX may have an edge over FOLFOX) could help tailor treatment, he proposed. For example, it is possible that patients with right-sided tumors will fare better if given 6 months of the CAPOX regimen.

Study details

The majority of the 3,219 patients studied, 63%, had tumors originating on the left side (splenic flexure or distally), according to data reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Compared with patients who had left-sided tumors, those with right-sided tumors (including any in the transverse colon) were older (median, 66 vs. 64 years; P less than .001), less often male (53% vs. 66%; P less than .001), more often had T4 stage (41% vs. 24%; P less than .001), and less often had stage II disease (17% vs. 21%; P =.001).

Patients with right-sided tumors had poorer 3-year disease-free survival (73% vs. 80%; hazard ratio, 1.401; P less than .0001), reported Dr. Saunders. This association weakened slightly after adjustment for T stage and N stage (HR, 1.215; P = .009).

However, benefit of 3 months versus 6 months of chemotherapy was similar whether patients had right-sided tumors (HR, 1.049) or left-sided tumors (HR, 0.910), with no statistically significant heterogeneity between these groups (P =.327).

A large translational substudy, Trans SCOT, is looking at various biomarkers such as microsatellite instability and mutations, and may shed more light on the mechanisms driving the different outcomes for right- and left-sided colorectal cancer, according to Dr. Saunders.

However, even when starting with more than 3,000 patients, drilling down by tumor sidedness and then further by characteristics such as molecular features (or regimen, overall stage, or T and N components) may result in underpowered analyses, he cautioned.

Dr. Saunders disclosed that he received honoraria from and has a consulting or advisory role with Amgen, Merck, Roche, and Servier.

[email protected]

SOURCE: Saunders MP et al. 2018 Gastrointestinal Cancers Symposium, Abstract 558.

SAN FRANCISCO – Colorectal cancer originating on the right side carries a higher risk of recurrence or death after adjuvant oxaliplatin-based chemotherapy, suggests a new analysis of data from the SCOT (Short Course Oncology Therapy) trial. But patients with right-sided disease fare about the same whether given the usual 6 months of chemotherapy or half that.

“It’s becoming clear that right-sided tumors are different from left-sided tumors,” commented first author Mark P. Saunders, MD, PhD, a consultant oncologist at the Christie NHS Foundation Trust, Manchester, England. A large meta-analysis showed that early right-sided tumors were associated with poorer overall survival (JAMA Oncol. 2016 Oct 27. doi: 10.1001/jamaoncol.2016.4227), but it remains unclear at what point(s) in the course of disease and its treatment sidedness is exerting its influence.

Findings in context

“This study was interesting, but I feel that we still need more data coming from the main study,” session chair Michael J. Hall, MD, MS, a medical oncologist at the Fox Chase Cancer Center, Philadelphia, said in an interview. “It’s important to let us know that adjuvant chemotherapy appears to be beneficial, regardless of side, but there are still some other important questions.”

More detail on the difference by side according to chemotherapy duration and according to regimen (because recent data suggest CAPOX may have an edge over FOLFOX) could help tailor treatment, he proposed. For example, it is possible that patients with right-sided tumors will fare better if given 6 months of the CAPOX regimen.

Study details

The majority of the 3,219 patients studied, 63%, had tumors originating on the left side (splenic flexure or distally), according to data reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Compared with patients who had left-sided tumors, those with right-sided tumors (including any in the transverse colon) were older (median, 66 vs. 64 years; P less than .001), less often male (53% vs. 66%; P less than .001), more often had T4 stage (41% vs. 24%; P less than .001), and less often had stage II disease (17% vs. 21%; P =.001).

Patients with right-sided tumors had poorer 3-year disease-free survival (73% vs. 80%; hazard ratio, 1.401; P less than .0001), reported Dr. Saunders. This association weakened slightly after adjustment for T stage and N stage (HR, 1.215; P = .009).

However, benefit of 3 months versus 6 months of chemotherapy was similar whether patients had right-sided tumors (HR, 1.049) or left-sided tumors (HR, 0.910), with no statistically significant heterogeneity between these groups (P =.327).

A large translational substudy, Trans SCOT, is looking at various biomarkers such as microsatellite instability and mutations, and may shed more light on the mechanisms driving the different outcomes for right- and left-sided colorectal cancer, according to Dr. Saunders.

However, even when starting with more than 3,000 patients, drilling down by tumor sidedness and then further by characteristics such as molecular features (or regimen, overall stage, or T and N components) may result in underpowered analyses, he cautioned.

Dr. Saunders disclosed that he received honoraria from and has a consulting or advisory role with Amgen, Merck, Roche, and Servier.

[email protected]

SOURCE: Saunders MP et al. 2018 Gastrointestinal Cancers Symposium, Abstract 558.

SAN FRANCISCO – Colorectal cancer originating on the right side carries a higher risk of recurrence or death after adjuvant oxaliplatin-based chemotherapy, suggests a new analysis of data from the SCOT (Short Course Oncology Therapy) trial. But patients with right-sided disease fare about the same whether given the usual 6 months of chemotherapy or half that.

“It’s becoming clear that right-sided tumors are different from left-sided tumors,” commented first author Mark P. Saunders, MD, PhD, a consultant oncologist at the Christie NHS Foundation Trust, Manchester, England. A large meta-analysis showed that early right-sided tumors were associated with poorer overall survival (JAMA Oncol. 2016 Oct 27. doi: 10.1001/jamaoncol.2016.4227), but it remains unclear at what point(s) in the course of disease and its treatment sidedness is exerting its influence.

Findings in context

“This study was interesting, but I feel that we still need more data coming from the main study,” session chair Michael J. Hall, MD, MS, a medical oncologist at the Fox Chase Cancer Center, Philadelphia, said in an interview. “It’s important to let us know that adjuvant chemotherapy appears to be beneficial, regardless of side, but there are still some other important questions.”

More detail on the difference by side according to chemotherapy duration and according to regimen (because recent data suggest CAPOX may have an edge over FOLFOX) could help tailor treatment, he proposed. For example, it is possible that patients with right-sided tumors will fare better if given 6 months of the CAPOX regimen.

Study details

The majority of the 3,219 patients studied, 63%, had tumors originating on the left side (splenic flexure or distally), according to data reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Compared with patients who had left-sided tumors, those with right-sided tumors (including any in the transverse colon) were older (median, 66 vs. 64 years; P less than .001), less often male (53% vs. 66%; P less than .001), more often had T4 stage (41% vs. 24%; P less than .001), and less often had stage II disease (17% vs. 21%; P =.001).

Patients with right-sided tumors had poorer 3-year disease-free survival (73% vs. 80%; hazard ratio, 1.401; P less than .0001), reported Dr. Saunders. This association weakened slightly after adjustment for T stage and N stage (HR, 1.215; P = .009).

However, benefit of 3 months versus 6 months of chemotherapy was similar whether patients had right-sided tumors (HR, 1.049) or left-sided tumors (HR, 0.910), with no statistically significant heterogeneity between these groups (P =.327).

A large translational substudy, Trans SCOT, is looking at various biomarkers such as microsatellite instability and mutations, and may shed more light on the mechanisms driving the different outcomes for right- and left-sided colorectal cancer, according to Dr. Saunders.

However, even when starting with more than 3,000 patients, drilling down by tumor sidedness and then further by characteristics such as molecular features (or regimen, overall stage, or T and N components) may result in underpowered analyses, he cautioned.

Dr. Saunders disclosed that he received honoraria from and has a consulting or advisory role with Amgen, Merck, Roche, and Servier.

[email protected]

SOURCE: Saunders MP et al. 2018 Gastrointestinal Cancers Symposium, Abstract 558.